Essentials of Internal Medicine

ESSENTIALS OF
INTERNAL MEDICINE
Nicholas J Talley, Brad Frankum
& David Currow
ELSEVIER
ESSENTIALS OF
INTERNAL MEDICINE
Third Edition
ESSENTIALS OF
INTERNAL MEDICINE
Third Edition
Nicholas J. Talley
MD, PhD, FRACP, FAFPHM, FRCP (Lond.), FRCP (Edin.), FACP, FAHMS
Professor of Medicine, Faculty of Health and Medicine, University of Newcastle,
Australia; Adjunct Professor, Mayo Clinic, Rochester, MN, USA; Adjunct Professor,
University of North Carolina, Chapel Hill, NC, USA; Foreign Guest Professor,
Karolinska Institutet, Stockholm, Sweden
Brad Frankum
OAM, BMed (Hons), FRACP
Professor of Clinical Education, and Deputy Dean, University of Western Sydney
School of Medicine; Consultant Clinical Immunologist and Allergist, Campbelltown
and Camden Hospitals, NSW, Australia
David Currow
BMed, MPH, PhD, FRACP
Professor, Discipline of Palliative and Supportive Services, Flinders University;
Flinders Centre for Clinical Change, Flinders University, SA , Australia
Sydney Edinburgh London New York Philadelphia St Louis Toronto
Churchill Livingstone
is an imprint of Elsevier
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This edition 2015 Elsevier Australia

1st edition 1990; 2nd edition 2000
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National Library of Australia Cataloguing-in-Publication Data
Talley, Nicholas Joseph, author.
Essentials of internal medicine / Nick Talley, Brad
Frankum, David Currow.
9780729540810 (paperback)
Internal medicine--Australia--Textbooks.
Frankum, Brad, author.
Currow, David (David C.), author.
616
Content Strategist: Larissa Norrie
Senior Content Development Specialist: Neli Bryant
Project Managers: Devendran Kannan and Srividhya Shankar
Edited by Teresa McIntyre
Proofread by Kate Stone
Cover and internal design by Tania Gomes
Index by Robert Swanson
Typeset by Midland Typesetters, Australia
Printed by China Translation and Printer Services Limited
FOREWORD BY KENNETH DEVAULT
Internal medicine is the broadest of fields, and a textbook to

cover the breadth of the specialty is a daunting task. There
are many attempts and few successes. The fact that this effort
is now in its third edition speaks to its quality and popularity. This outstanding text has many highlights, including
unique opening chapters on evaluating the literature, ethics,
pharmacology, genetics and imaging. They are followed by
specific, subspecialty-oriented discussions of all of the major
aspects of internal medicine. There are well-written chapters on specialties outside of medicine but where patients
often present to internists, including musculoskeletal disease, neurology, psychiatry, dermatology, ophthalmology
and obstetrics. These chapters will be of great benefit not
only to trainees but also to practicing internists who need a
quick and approachable reference when faced with problems

outside their comfort zone. I am a practicing gastroenterologist who has to address general topics with my patients, and
will keep this volume handy for rapid reference. The judicial
use of tables and color figures make the reading particularly
attractive. The editors and their impressive cadre of expert
authors are to be congratulated on this outstanding edition
which will compete for a prominent place on the desks of
practicing health care providers, trainees and students, particularly those preparing for board examinations.
Kenneth R DeVault, MD, FACG, FACP
Professor and Chair, Department of Medicine, Mayo Clinic Florida
FOREWORD BY NICHOLAS SAUNDERS
Both physician trainees studying for their college and board

examinations and senior medical students will welcome this
new edition of Essentials of Internal Medicine. This third edition is enhanced by the inclusion of chapter authors who are
experts in their field while maintaining the features of the
book that have made earlier editions so popular among those
preparing for examinations: conciseness; consistency; graphics, tables and images that clearly capture essential information; and reinforcement of important points through the use
of clinical pearls and self-assessment tasks.
In the main, chapters are organized by body system but
there are very useful additional chapters at the beginning and
end of the book that cover important basic concepts (such as
clinical pharmacology and genetics), contexts (such as pregnancy and older age) and approaches (such as evidence-based
practice and medical imaging) that are relevant to internist
practice. Throughout the book the focus is on clinical features, pathogenesis and pathophysiology, investigation and
management of patients with common disorders.
The editors comprise a very talented group, each recognized internationally for his expertise in internal medicine
and, importantly, clinical education. At the time of publication of this edition, Talley, a gastroenterologist, is one of
the 40 most highly cited living biomedical scientists in the
world; Frankum, a clinical immunologist and allergist, is
celebrated for his expert contributions to undergraduate and
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postgraduate education; and Currow, a specialist in oncology and palliative care, is making important, novel contributions to the organization and delivery of cancer services
and research.
The editors are also recognized for their professional
leadership, with Talley currently President of the Royal
Australasian College of Physicians, Frankum currently Vice
President of the Australian Medical Association (New South
Wales), and Currow a former President of both the Clinical Oncological Society of Australia and Palliative Care
Australia.
It is fitting that each of the three editors is an alumnus
of the University of Newcastle, Australia, whose medical
school places clinical education at the centre of its mission
and which has long been recognized for its educational
innovation and excellence. The third edition of Essentials of
Internal Medicine upholds and extends this reputation.
This book fills an important niche in the vast array of
medical publications and will be a valuable addition to the
bookshelves of students, physician trainees and generalists
who are already established in practice. It is sure to be consulted frequently.
Nicholas Saunders AO, MD, Hon LLD
Emeritus Professor, School of Medicine and Public Health,
University of Newcastle, Australia
CONTENTS
Foreword by Kenneth DeVault

Foreword by Nicholas Saunders
Preface
Contributors
Reviewers
Chapter 1
INTERNAL MEDICINE IN THE 21st
CENTURYBEST PRACTICE, BEST
OUTCOMES
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Brad Frankum, David Currow and Nicholas J Talley
General versus sub-specialty medicine

The importance of diagnosis
The physicians role in public health
The physician as scholar
Chapter 2
EVIDENCE-BASED MEDICINE AND
CRITICAL APPRAISAL OF THE
LITERATURE
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Jane Young and David Currow
Chapter 4
CLINICAL PHARMACOLOGY AND
TOXICOLOGY
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Matt Doogue and Alison Jones
Chapter outline
Introduction
Assessing the evidence
Sources of error
Assessing potential biases in different study
designs
Critical appraisal of the literature
Interpreting a studys ndings
Interpreting statistical analysis
Interpreting test results
Screening
Conclusion
Acknowledgments
Self-assessment questions
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Chapter 3
ETHICS
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Ian Kerridge and Michael Lowe
Chapter outline
Ethics in internal medicine
Ethical theories
Ethics and the law
Ethics, evidence and decision-making
Clinical ethics: theory and frameworks for

decision-making
Teaching about ethics
Physicianpatient relationships and
professionalism
Truth-telling
Condentiality
Consent
Mental competence
Consent for non-competent people: best
interests and advance care planning
End-of-life and futility
Cardiopulmonary resuscitation (CPR)
Dignity and the care of the elderly
Conict of interest and the pharmaceutical
industry
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Chapter outline
1. PRINCIPLES OF CLINICAL PHARMACOLOGY
Introduction
Pharmacokinetics
Administration
Bioavailability (F)
Clearance (CL)
Distribution
Drug transport
Other pharmacokinetics
Altered pharmacokinetics
Patient size
Pharmacodynamics
Concentrationresponse relationships
Therapeutic index
Drug targets
Physiological effects
More about the patient
The innocent bystander
2. QUALITY USE OF MEDICINES
Getting it right
The circle of care
Patient prole and drug prole(s)
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Contents
Prescribing
The prescribing checklist
Deprescribing
Adverse drug reactions
Drug interactions
Types of drug interaction
Therapeutic drug monitoring (TDM)
Drug regulation
Drug research
3. TOXICOLOGY
Epidemiology of poisoning
Sources of poisons information and advice
Clinical assessment of poisoned patients
Investigations
Risk assessment
Principles of management of poisoned patients
Common poisons and their management
Acetaminophen (paracetamol)
Non-steroidal anti-inammatory drugs (NSAIDs)
Tricyclic antidepressants
Newer antidepressants
Newer antipsychotics
Benzodiazepines
Insulin and oral hypoglycemics
Drugs of abuse or misuse
Amphetamines
Cocaine and crack cocaine
Gammahydroxybutyrate (GHB)
Opioids, such as heroin or morphine
Prescription drug abuse
Synthetic cathinones, e.g. vanilla sky, ivory
wave
Synthetic cannabinoids, e.g. spice, K2
Drink spiking
Chemicals
Acids and alkalis
Chlorine
Pesticides
Lead poisoning
Spider bites
Snake bites
Marine envenomation
Terrorism, and use of medical countermeasures
Chemical agents
Biological agents
Chapter 5
GENETICS
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John Attia
Chapter outline
Overview
The ow of genetic information
Transcription
Translation
Regulation
Genetic variation
Mendelian diseases
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Calculating the risks of disease

Some examples
Genetic testing in medicine
Cytogenetic studies
Fluorescence in situ hybridization (FISH)
Sequencing
Polymerase chain reaction (PCR)
Common chromosomal genetic conditions
Down syndrome
Turner syndrome
Klinefelter syndrome
Acknowledgments
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Chapter 6
MEDICAL IMAGING FOR INTERNISTS
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Lindsay Rowe
Chapter outline
1. CHEST RADIOGRAPHY
Principles of interpretation in chest X-rays
Patient demographics
Technical assessment
Lines, tubes and implants
Anatomical review
Review areas (hard to see areas)
Summary
2. THORACIC COMPUTED TOMOGRAPHY
Techniques of examination
Principles of interpretation in chest CT
Technical review
Initial image review
Key image review
Systematic review
Review areas
Summary
3. ABDOMINAL COMPUTED TOMOGRAPHY
Techniques of examination
Non-contrast CT abdomen
Non-contrast CT KUB
Arterial phase CT abdomen (CT angiogram, CTA)
Portal venous CT abdomen
Triple-phase CT abdomen
Delayed CT abdomen
Principles of interpretation in abdominal CT
Technical review
Key image review
Systematic review
Review areas
Summary
4. ABDOMINAL ULTRASOUND
Backgroundultrasound principles
Principles of ultrasound interpretation
Lower limb duplex ultrasound
5. HEAD COMPUTED TOMOGRAPHY
CT brain protocols
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Contents
Non-contrast (NCCT)
Contrast-enhanced (CECT)
CT angiography (CTA)
Perfusion CT
Principles of interpretation in brain CT
Technical review
Key image review
Systematic review
Review areas
Summary
6. HEAD MAGNETIC RESONANCE
MRI protocols
T1
T2
Inversion recovery (IR)
Diffusion-weighted imaging (DWI)
Gradient echo (GRE)
Gadolinium-enhanced (GAD)
Magnetic resonance angiography/venography
(MRA, MRV)
MR spectroscopy (MRS)
Magnetic resonance gated intracranial
cerebrospinal dynamics (MR-GILD, CSF
ow study)
Principles of interpretation in brain MR
Technical review
Key image review
Systematic review
Review areas
Summary
7. POSITRON EMISSION TOMOGRAPHY (PET)
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Chapter 7
PULMONOLOGY
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Brad Frankum
Chapter outline
1. PULMONARY MEDICINE
Clinical presentations of respiratory disease
Important clinical clues
Dyspnea
Patterns of breathing
Chronic cough
Clubbing
Hemoptysis
Solitary pulmonary nodule (coin lesion)
Mediastinal masses
Wheeze
Chest pain
Stridor
Overview of the respiratory system and
pathophysiology
Functional anatomy and physiology
Hypoxemia
Hypercapnia
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Oxygenhemoglobin associationdissociation
curve
Acidbase disturbances from a pulmonary
perspective
Respiratory acidosis
Respiratory alkalosis
Measurement of lung function
Spirometry
Interpretation of lung volumes
Diffusing capacity for carbon monoxide
(DLCO test)
Flowvolume loops
Interpretation of pulmonary functiontests
Control of breathing
Respiratory tract defenses
Mechanical defenses
Immune system
Genetics of lung disease
Pulmonary disorders
Respiratory failure
Hypoventilation
Diseases of the airways
Asthma
Allergic bronchopulmonary aspergillosis
(ABPA)
Bronchiectasis
Cystic brosis (CF)
Bronchiolitis
Chronic obstructive pulmonary disease
(COPD)
Interstitial lung disease (ILD)
Occupational lung disease
Granulomatous ILD
Eosinophilic pulmonary disorders
Acute eosinophilic pneumonia
Chronic eosinophilic pneumonia
Pulmonary hemorrhage
Pulmonary infections
Bacterial
Viral
Fungal
Mycobacterial
Other aspects
Pleural disease
Pleural effusion
Pneumothorax
Indications for a chest drain
Pulmonary vascular disease
Pulmonary hypertension (PH)
Pulmonary embolism (PE)
Diagnosis
Lung transplantation
Complications of lung transplantation
Pharmacology
Bronchodilators
Anti-inammatory agents
Respiratory sleep medicine
Overview of sleep medicine
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Contents

Respiratory sleep disorders
2. CRITICAL CARE MEDICINE
Resuscitation
Cardiac arrest (CA)
Diagnosis and disease management
Shock
Acute respiratory distress syndrome (ARDS)
Mechanical ventilation of the lungs
Non-invasive positive-pressure ventilation
(NIV)
Invasive positive-pressure ventilation (IPPV)
Extracorporeal membrane oxygenation
(ECMO)
Chapter 8
CARDIOLOGY
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Chapter outline
Clinical evaluation of the patient
Taking the historypossible cardiac symptoms
Physical examination
Investigation of cardiac disease
Electrocardiography (EKG)
Chest X-ray (CXR)
Echocardiography
Radionuclide myocardial perfusion imaging
Coronary angiography and cardiac
catheterization
Coronary CT angiography (CTCA) and
calcium scoring
Magnetic resonance imaging (MRI)
Dyslipidemia
Cholesterol, lipoproteins, apoproteins
Dyslipidemia and cardiovascular disease (CVD)
Lipid-modifying treatments
Coronary artery disease (CAD)
Prevalence
Pathophysiology
Stable coronary artery disease
Investigation
Management to improve prognosis
Management of symptoms in the CHD patient
Management of refractory angina
Acute coronary syndromes
Terminology
Pathophysiology of acute coronary syndromes
Management of STEMI
Management of NSTEACS/NSTEMI
Pharmacological therapy in acute coronary
syndromes
Valvular heart disease
Mitral valve disease
Mitral stenosis (MS)
Mitral regurgitation (MR)
Mitral valve prolapse (MVP) syndrome
Aortic valve disease
Aortic stenosis (AS)
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Aortic regurgitation (AR)

Tricuspid valve disease
Tricuspid stenosis (TS)
Tricuspid regurgitation (TR)
Pulmonary valve disease
Assessing the severity of valvular heart disease
and deciding on surgery
Cardiomyopathies
Dilated cardiomyopathy (DCM)
Hypertrophic cardiomyopathy (HCM)
Restrictive cardiomyopathy
Other cardiomyopathies
Cardiac arrhythmias
Sinus node disturbances
Sick sinus syndrome
Supraventricular premature complexes
(ectopics)
Supraventricular tachycardia (SVT)
Atrial utter
Atrial brillation (AF)
Ventricular arrhythmias
Conduction defects
Bundle branch block (BBB)
Fascicular blocks (hemiblocks)
Atrioventricular (AV) blocks
Cardiac failure
Denition
Causes
Diagnosis of congestive heart failure
Treatment
Devices
Infective endocarditis
Microbiology
Diagnosis
Management
Prevention
Pericardial diseases
Acute pericarditis
Pericardial effusion and tamponade
Chronic pericardial disease
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Chapter 9
HYPERTENSION
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Annemarie Hennessy
Chapter outline
Mechanisms of hypertension
Epidemiological evidence for hypertension and
its effects
Denitions of hypertension
Clinical presentations and investigations
Target-organ effects of hypertension
Blood vessels
Cardiac effects
Retinopathy
Renal changes secondary to hypertension
Brain
Treatment and targets for hypertension control
Specic targets linked to comorbid conditions
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Contents
Treatment for chronic primary hypertension

Normal adult
High-normal
Stage 1 hypertension
Higher stages of hypertension
Treatment in an acute setting
Chapter 10
NEPHROLOGY
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Annemarie Hennessy
Chapter outline
Inherited cystic kidney disease
Autosomal dominant polycystic kidney
disease (ADPCKD)
Medullary sponge kidney (MSK)
Medullary cystic disease and autosomal
recessive polycystic disease
Acquired kidney cystic disease
Simple renal cysts
Renal stones/kidney stones
Kidney and urinary tract infection
Mechanisms of disease
Clinical presentation, investigation and
diagnosis
Treatment and targets for urinary tract
infection
Inherited renal basement membrane disease
Thin basement membrane disease
Alports disease
Glomerulonephritis (GN)
Classication
Primary glomerular inammatory disease
Secondary glomerular inammatory disease
Sclerosing glomerular disease
Diabetes mellitus
Focal sclerosing glomerular nephropathy
(FSGN)
Vascular renal disease
Renal artery stenosis
Treatment of renovascular disease
Thrombotic thrombocytopenic purpura (TTP)/
Hemolytic uremic syndrome (HUS)
Malignant hypertension
Mechanisms of renal injury in hypertension
diagnosis
Treatment and targets
Scleroderma kidney
Mechanisms of scleroderma kidney and
renal crisis
diagnosis
Treatment and targets for scleroderma
Reux nephropathy
Clinical presentation, investigation
anddiagnosis
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Chronic kidney disease (CKD)

Classication systems and denitions
Early stages of CKD
Clinical presentations of stage 3 CKD
Clinical presentations of stages 4 and 5 CKD
End-stage renal disease (ESRD) and renal
replacement therapy
Acute renal failureacute kidney injury (AKI)
Tubulo-interstitial diseases
Acute interstitial nephritis (AIN)
Chronic tubulo-interstitial disease
Electrolyte disorders
Hypernatremia
Hyponatremia
Hyperkalemia
Hypokalemia
Inherited channelopathies associated with
hypertension or hyperkalemia
Hypokalemic alkalosis (with and without
hypertension)
Renal tubular acidosis
The kidneys in pregnancy and pregnancy-related
diseases
Normal adaptations to pregnancy
Underlying renal disease
Chapter 11
ENDOCRINOLOGY
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Mark McLean and Sue Lynn Lau
Chapter outline
System overview
Hormones, their transport and action
Feedback control of hormonal systems
Evaluating the function of hormonal systems
Pathogenic mechanisms of hormonal
disorders
Disorders of the pituitary and hypothalamus
Anatomy and physiology
Pituitary mass lesions
Hypopituitarism
Syndromes of hypersecretion
Surgery and radiotherapy for pituitary tumors
Inammatory and inltrative disorders
Diabetes insipidus (DI)
Thyroid disorders
Physiology and assessment of thyroid
function
Thyroid imaging
Thyroid autoimmunity
Hyperthyroidism
Hypothyroidism
Goiter and thyroid nodules
Thyroid cancer
Thyroid disease in pregnancy
Disorders of bone and mineral metabolism
Mineral homeostasis
Hypercalcemia
Hypocalcemia
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Contents
Osteoporosis
Osteomalacia and rickets
Pagets disease (PD)
Adrenal disorders
Physiology and assessment of adrenal
function
Adrenal insufficiency
Cortisol excess (Cushings syndrome)
Primary hyperaldosteronism (Conns
syndrome)
Pheochromocytoma
Congenital adrenal hyperplasia (CAH)
Incidentally found adrenal masses
(incidentaloma)
Growth and puberty
Causes of short stature
Onset of pubertyphysiology
Male reproductive endocrinology
Testicular function
Male hypogonadism
Causes of erectile dysfunction
Gynecomastia
Androgen replacement therapy
Female reproductive endocrinology
Clinical and laboratory evaluation
Hirsutism and hyperandrogenism
Polycystic ovary syndrome (PCOS)
Female hypogonadism
Endocrinology of pregnancy
Neuroendocrine tumors (NETs)
Overview
Differential diagnosis of a hypoglycemic
disorder
Treatment of malignant NETS
Disorders of multiple endocrine systems
Multiple endocrine neoplasia (MEN)
Other multiple endocrine tumor syndromes
Polyglandular autoimmunity (PGA) syndromes
Diabetes and metabolism
Overview of energy metabolism
Carbohydrate metabolism and diabetes
Type 1 diabetes mellitus (T1DM)
Complications of diabetes
Hypoglycemia
Gestational diabetes (GDM)
Disorders of energy excessoverweight and
obesity
The metabolic syndrome
Chapter 12
GASTROENTEROLOGY
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Magnus Halland, Vimalan Ambikaipaker,

Kara De Felice and Nicholas J Talley
Chapter outline
Esophagus
Dysphagia
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Motor disorders
Esophagitis due to causes other than acid reux
Stomach
Physiology of acid secretion
Dyspepsia and its management
Gastritis and gastropathy
Peptic ulcer disease (PUD)
Tumors
Post-gastrectomy complications
Gastroparesis
Small bowel
Celiac disease
Diarrhea
Malabsorption
Microscopic colitis
Tropical sprue
Small intestinal bacterial overgrowth (SIBO)
Eosinophilic gastroenteritis (EGE)
Chronic idiopathic intestinal pseudoobstruction (CIIP)
Short bowel syndrome
Nutritional deciency
Clinical clues to malnutrition
Nutritional assessment in end-stage liver
disease
Enteral and parenteral nutrition
Large bowel
Irritable bowel syndrome (IBS)
Constipation
Diverticular disease
Inammatory bowel disease (IBD)
Colon polyps
Bowel cancer screening
Recommendations for screening and
surveillance
Fecal occult blood testing (FOBT)
Malignant potential and surveillance
Gastrointestinal bleeding
Upper
Lower
Obscure GI bleeding
Management of iron-deciency anemia
Pancreas
Acute pancreatitis
Chronic pancreatitis
Autoimmune pancreatitis (AIP)
Pancreatic cysts
Chapter 13
HEPATOLOGY
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Nicholas J Talley
Chapter outline
Liver function tests and their abnormalities
Serum enzymes
Tests of synthetic function
Approach to the patient with liver disease
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Contents
Bilirubin metabolism and jaundice

Viral hepatitis
Hepatitis A (RNA virus)
Hepatitis B (DNA virus)
Hepatitis C (RNA virus)
Hepatitis D, E and G
Other viruses causing hepatitis
Cirrhosis
Useful investigations
Prognosis
Management
Ascites
Management
Hepatorenal syndrome (HRS)
Management
Hyponatremia
Spontaneous bacterial peritonitis (SBP)
Treatment
Portal hypertensive bleeding
Management
Portosystemic encephalopathy (PSE)
Precipitant-induced PSE
Persistent PSE
Minimal encephalopathy
Portopulmonary hypertension (POPH)
Hepatopulmonary syndrome (HPS)
Cirrhotic cardiomyopathy
Acute liver failure (ALF)
Liver transplantation
Drugs and the liver
Acetaminophen (paracetamol) and acute liver
disease
Alcohol and the liver
Specic liver diseases
BuddChiari syndrome (BCS)
Non-alcoholic fatty liver disease (NAFLD) and
non-alcoholic steatohepatitis (NASH)
Wilsons disease (hepatolenticular
degeneration)
Alpha-1 anti-trypsin deciency
Hemochromatosis
Autoimmune liver diseases
Autoimmune hepatitis (AIH)
Primary biliary cirrhosis (PBC) and primary
sclerosing cholangitis (PSC)
Systemic disease and the liver
Pregnancy and liver disease
Gallbladder and biliary tree
Gallstones
Acalculous cholecysitis
Porphyrias
Acute intermittent porphyria (AIP)
Porphyria cutanea tarda (PCT)
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Chapter 14
HEMATOLOGY
407
Harshal Nandurkar
Chapter outline
Hemostasis
Essential concepts
Components of the hemostatic system
Venous thrombosis
Predisposition to venous thrombosis
Diagnosis of venous thrombosis
Treatment of venous thromboembolism (VTE)
Post-thrombotic syndrome (PTS)
Antiphospholipid syndrome (APS)
Treatment
Thrombosis at unusual sites
Cerebral vein thrombosis (CVT)
Portal vein thrombosis (PVT)
Cancer and thrombosis
Bleeding disorders
Von Willebrand disease (vWD)
Hemophilia A
Hemophilia B
Bleeding disorders due to deciencies of
other coagulation factors
Platelet disorders
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura and
hemolytic uremic syndrome
Disseminated intravascular coagulation (DIC)
Diagnosis
Treatment
Coagulopathy in intensive care patients
Myeloproliferative disorders
Polycythemia rubra vera (PV)
Essential thrombocytosis (ET)
Primary myelobrosis (PMF)
Leukemia
Acute myeloid leukemia (AML)
Acute promyelocytic leukemia (APML)
Acute lymphoblastic leukemia (ALL)
Myelodysplastic syndrome (MDS)
Chronic myeloid leukemia (CML)
Chronic lymphocytic leukemia and other
B-cell disorders
Non-Hodgkin lymphomas
Diagnosis
Staging
Diffuse large B-cell lymphoma (DLBCL)
Double hit (DH) lymphomas
Burkitts lymphoma
Follicular lymphoma (FL)
Mantle-cell lymphoma (MCL)
Cutaneous lymphomas
Hodgkin lymphoma (HL)
Histological subtypes and cell biology
Staging
Risk stratication
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Contents
Plasma cell disorders

438
Monoclonal gammopathy of uncertain
signicance (MGUS)
438
Asymptomatic myeloma
438
Symptomatic myeloma
438
Prognostic markers in myeloma
439
Treatment of myeloma
439
Differential diagnosis
439
Anemia
440
Mechanisms of anemia
440
Common laboratory tests used for diagnostic
work-up
440
Approach to iron-deciency anemia
440
Management of iron deciency
442
Anemia of chronic disease
442
Thalassemias
442
Sideroblastic anemias
443
Macrocytic anemias
443
Hemolytic anemias
445
Drug-induced hemolysis
450
Non-immune acquired hemolytic anemias
450
451
Chapter 15
ONCOLOGY
455
Christos S Karapetis
Chapter outline
What is cancer?
DNA and genes
Basic elements of cancer biology
Essential elements of cancer diagnosis and
treatment
Prevention
Diagnosis
Screening
Signs and symptoms
Diagnostic tests
Prognosis
Cancer factors
Patient factors
Prognostic vs predictive factors
Treatment principles
Dening treatment goals
Adjuvant therapy
Neoadjuvant therapy
Supportive management
Maintenance therapy
Principles of chemotherapy
Attitudes to chemotherapy
Toxicity of cytotoxic chemotherapy
Principles of radiotherapy
Fractionation
Radiation effects
Treatment responsiveness
Endocrine responsive
Potentially curable following chemotherapy
alone
Tumors very sensitive to chemotherapy
Potentially curable following radiotherapy
xiv
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462
Personalized medicine
Molecular targeted therapy
Monoclonal antibodies (the ABs)
Tyrosine kinase inhibitors (the IBs)
Other
Familial cancers and cancer genetics
Oncological emergencies
Spinal cord compression
Febrile neutropenia
Cardiac tamponade
Addisonian crisis
Hypercalcemia
Hyponatremia
Superior vena cava (SVC) obstruction
Raised intracranial pressure (ICP)
Tumor markers in serum
Paraneoplastic syndrome
Cancer with unknown primary (CUP)
Diagnosis
Potentially treatable subgroups of CUP
Recent research and future directions
Lung cancer
Clinical presentation
Risk factors
Epidemiology and pathology
Non-small-cell lung cancer (NSCLC)
Small cell lung cancer (SCLC)
Renal cancer
Background
Diagnosis and staging
Treatment
Prognosis
Tumors of the pelvis, ureter and bladder
Epidemiology
Risk factors
Investigation and diagnosis
Treatment
Prostate cancer
Epidemiology
Screening
Staging
Management
Testis cancer
Epidemiology and risk
Pathology
Diagnosis
Prognostic factors in stage I NSGCT
Treatment
Post-chemotherapy residual masses
Relapsed disease
High-dose chemotherapy (HDCT)
Head and neck cancer
Early-stage disease
Advanced-stage disease
Human papillomavirus (HPV) infection
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Contents
Esophageal cancer
Pathology and epidemiology
Diagnosis and screening
Management
Gastric cancer
Epidemiology
Diagnosis
Treatment
Gastric MALT lymphoma
Colorectal cancer
Management
Future directions
Pancreatic cancer
Key points
Epidemiology
Diagnosis
Management
Hepatocellular carcinoma (HCC)
Key points
Risk factors
Prognosis
Treatment
Brain tumors
Low-grade glioma (astrocytoma and
oligodendroglioma)
Glioblastoma multiforme (GBM)
Lymphomasee Chapter 13
Melanoma
Management
Future directions
Sarcoma
Diagnosis
Treatment
Breast cancer
Epidemiology
Risk factors
Pathology
Screening
Management
Ovarian cancer
Key points
Diagnosis
Management
Future directions
Endometrial cancer
Diagnosis
Management
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Chapter 16
PALLIATIVE MEDICINE
489
Meera Agar and Katherine Clark
Chapter outline
Pain
Denition
Impact of the problem
Pathophysiological basis
Interventions to palliate the problem
Mucositis
Denition
Interventions
Fatigue
Denition
Nausea and vomiting
Denition
Cachexia and anorexia
Denition
Impact of the problems
Underlying pathophysiological basis
Interventions
Dyspnea
Denition
Constipation
Denition
Delirium
Denition
Insomnia
Denition
Chapter 17
IMMUNOLOGY
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499
499
500
501
503
Brad Frankum
Chapter outline
Key concepts in immunobiology
Innate and adaptive immunity
Specicity and diversity
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505
xv
Contents
Immunological memory
Hypersensitivity, autoimmunity and
immunodeciency
Immunity, inammation and tissue repair
Understanding immunobiology
Manipulation of the immune system
Allergic disease
Anaphylaxis
Allergic rhinitis (AR) and allergic conjunctivitis
(AC)
Chronic rhinosinusitis
Atopic dermatitis (AD)
Food allergy
Urticaria and angioedema
Drug allergy
Insect venom allergy
Eosinophilia
Hypereosinophilic syndrome (HES)
Mast cell disorders
Cutaneous mastocytosis (CM)
Systemic mastocytosis (SM)
Systemic autoimmune disease
Systemic lupus erythematosus (SLE)
Sjgrens syndrome (SS)
Inammatory myopathies
Scleroderma and CREST syndrome
Mixed connective tissue disease (MCTD)
IgG4-related disease
Primary vasculitis
Large-vessel vasculitis
Medium-vessel vasculitis
Small-vessel vasculitis
Single-organ vasculitis
Variable-vessel vasculitis
Autoinammatory disorders
Familial Mediterranean fever (FMF)
TNF-receptor-associated periodic syndrome
(TRAPS)
Immunodeciency
Primary immunodeciency
Secondary (acquired) immunodeciency
HIV/AIDS
Epidemiology
Risk factors for HIV infection
Pathophysiology
Clinical features and diagnosis
Management
Prognosis
Chapter 18
MUSCULOSKELETAL MEDICINE
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512
513
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521
521
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545
545
545
546
547
549
551
557
Kevin Pile
Chapter outline
An approach to a patient with painful joints
History
xvi
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558
Examination
Investigations
Rheumatoid arthritis (RA)
Genetics and environmental contribution
to RA
Pathology
Diagnosis
Clinical features and complications
Investigations
Treatment
Conclusions
Spondyloarthropathies
Ankylosing spondylitis (AS)
Psoriatic arthritis (PsA)
Reactive arthritis (ReA)
IBD-associated spondyloarthropathy
Adult-onset Stills disease
Crystal arthropathies
Gout
Pseudogout
Relapsing polychondritis (RP)
Osteoarthritis (OA)
Types of osteoarthritis
Clinical features
Specic joint involvement
Investigations
Treatment
Genetic connective tissue disorders
Painful shoulders
Clinical assessment
Examination
Rotator cuff disease
Frozen shoulder/adhesive capsulitis
Tennis elbow and golfers elbow
Tennis elbow (lateral epicondylitis)
Golfers elbow (medial epicondylitis)
Plantar fasciitis
Fibromyalgia
Epidemiology and etiology
Investigations
Prognosis, differential diagnosis and
treatment
Septic arthritis
Investigations
Treatment
Acute low back pain
Specic pathology leading to acute low
back pain
Management
Outcome
Chronic low back pain
Clinical assessment
Conservative treatment
Invasive treatment
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Contents
Chapter 19
NEUROLOGY
593
Christopher Levi, Thomas Wellings and

Brad Frankum
Chapter outline
Disorders of consciousness
Denitions
Levels of consciousness
Causes of coma
Assessment of the patient with impaired
consciousness
Headache
Primary headache syndromes
Secondary headache
Stroke
Acute assessment and management
Thrombolysis
Neurosurgical intervention
General care measures
Early secondary prevention
Intracerebral hemorrhage
Medical treatment
Surgical management
Subarachnoid hemorrhage (SAH)
Natural history and outcome of an
aneurysmal SAH
Surgical versus endovascular management
of SAH
Transient ischemic attack (TIA)
Denition
Differential diagnosis of transient neurological
disturbances
Pathophysiology
Investigation
Recurrent event risk
Prevention of recurrent events
Dementia
Diagnosis
Major dementia syndromes
Diagnostic work-up of the dementia patient
Other dementia syndromes
Seizures and the epilepsies
Seizure types
Assessing a patient after a seizure
Investigation of a rst seizure
The epilepsies
Important epilepsy syndromes
Choice of anticonvulsant therapy
Status epilepticus
Non-epileptic seizures
Balance, dizziness and vertigo
Hemodynamic dizziness or lightheadedness
Vertigo
Central pathologies
Treatment of vertiginous patients
Other balance disorders
Movement disorders
Tremor
Parkinsons disease (PD)
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619
619
621
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623
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Dementia with Lewy bodies (DLB)

Multisystem atrophy (MSA)
Progressive supranuclear palsy (PSP)
Corticobasal syndrome
Dystonia
Hyperkinetic movement disorders
NMDA encephalitis
Multiple sclerosis and CNS inammation
Multiple sclerosis (MS)
Neuromyelitis optica (NMO; Devics disease)
Acute disseminated encephalomyelitis
(ADEM) and transverse myelitis (TM)
Neurological manifestations of sarcoidosis and
Behets disease
Sarcoidosis
Behets disease
Neuromuscular disease
Myopathy
Genetic disorders
Neuromuscular disorders
Myasthenia gravis (MG)
Disorders of peripheral nerves
Motor neuron disease (MND)/amyotrophic
lateral sclerosis
Demyelinating neuropathy and GuillainBarr
syndrome (GBS)
Peripheral neuropathy
Chapter 20
PSYCHIATRY FOR THE INTERNIST
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629
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630
634
634
635
635
635
635
636
638
639
639
641
641
643
644
646
651
Brian Kelly
Chapter outline
Depression
Anxiety disorders
Post-traumatic stress disorder (PTSD)
Somatization
Eating disorders
Anorexia and bulimia nervosa
Suicide and deliberate self-harm
Psychotropic agents
Lithium carbonate
Anticonvulsants
Antipsychotic agents
Antidepressants
Chapter 21
CLINICAL INFECTIOUS DISEASES
651
651
652
652
653
653
654
654
655
655
655
656
656
658
659
Iain Gosbell
Chapter outline
Clinical approach to infectious diseases
Overview
History
Examination
Diagnostics in infectious diseases
Pre-analytical considerations
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661
661
xvii
Contents
Analytical considerations
Post-analytical considerations
Selected common clinically important organisms
Selected bacteria
Selected viruses
Selected fungi
Selected parasites
Anti-infective treatment
Is infection likely?
What are the likely pathogen(s)?
Are anti-infective drugs required?
Choice of empirical and denitive antibiotics
What host factors need consideration?
What therapy other than antibiotics is
required?
Ongoing assessment and further results
What is the duration and endpoint of
treatment?
Anti-infective agents
Antibiotics
Antiviral agents
Antifungals
Specic syndromes
Acute fever
Pyrexia of unknown origin (PUO)
Skin and soft tissue infections
Drug fever
Infections in special hosts and populations
Infections in immunosuppressed patients
Sexually transmitted infections (STIs)
Systemic viral infections
HIV
Hepatitis viruses
Herpesviruses
Zoonoses
Infection prevention and control
Administrative support
Judicious use of antibiotics
MRO surveillance
Infection control precautions
Environmental measures
Decolonization
Chapter 22
IMMUNIZATION
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664
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671
671
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683
685
685
685
686
692
692
692
692
692
696
696
697
697
697
697
697
698
701
Rob Pickles
Chapter outline
General principles
Immunizing agents
Factors affecting immunogenicity
Chemical and physical properties of antigens
(vaccines)
Physiological attributes of individuals
Route of administration
Presence of adjuvants
Contraindications
False contraindications
Egg allergy
xviii
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701
702
703
703
704
704
704
704
704
704
Booster doses
Immunization in specic populations
Pregnancy
Preconception
Breastfeeding
Immunocompromised hosts
Oncology patients
Solid-organ transplant patients
Hemopoetic stem-cell transplant (HSCT)
recipients
HIV/AIDS
Asplenia
Occupational exposure
Travel vaccines
Post-exposure prophylaxis (PEP)
Intramuscular immune globulin
Specic intramuscular immune globulin
preparations (hyperimmune globulins)
Specic immune globulins for intravenous
use
Routine immunization of adults
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711
Chapter 23
DERMATOLOGY FOR THE PHYSICIAN 715
Brad Frankum
Chapter outline
Acne
Autoimmune diseases of the skin
Psoriasis
Erythema nodosum (EN)
Bullous lesions
Dermatitis herpetiformis
Livedo reticularis
Skin problems associated with underlying
systemic disease
Acanthosis nigricans
Neutrophilic dermatoses
Pruritus
Pigmentation
Photosensitivity
Rash on the palms and soles
Red person syndrome (erythroderma or
exfoliative dermatitis)
Excessive sweating (hyperhydrosis)
Facial ushing
Genetic or congenital skin diseases
The phakomatoses
Skin disease associated with malignancy
Primary or secondary malignancy
Underlying malignancy
Chapter 24
MEDICAL OPHTHALMOLOGY
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715
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718
719
719
719
719
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721
721
721
721
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722
722
722
723
723
723
725
727
Michael Hennessy and Brad Frankum
Chapter outline
Introduction
Ocular history
727
727
728
Contents
Ocular examination
General inspection ndings
Visual acuity
Intraocular pressure
Field of vision
Pupils
Color vision
Ocular motility
Ophthalmoscopy
Auscultation
Pathological conditions
Retinal vascular disease
Hypertension
Retinal arterial occlusion
Retinal venous occlusion
Diabetic retinopathy (DR)
Non-arteritic anterior ischemic optic
neuropathy
Arteritisarteritic acute anterior ischemic
optic neuropathy
Uveitis
Retinitis
Scleritis and sclero-uveitis
Thyroid-related orbitopathy
Dry eye
Neoplasia and the eye
Neuro-ophthalmology
Optic neuritis (ON)
Papilledema
Extraocular muscle paralysis
Phakomatoses
Ocular effects of systemic medication
Chapter 25
WOMENS HEALTH FOR THE
PHYSICIAN
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730
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731
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732
732
733
733
734
Chapter 26
OBSTETRIC MEDICINE
750
751
751
753
753
754
754
754
755
755
756
757
759
Annemarie Hennessy
734
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735
736
736
736
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737
738
738
738
739
739
739
741
743
Andrew Korda
Chapter outline
Infertility
Age and infertility
Anovulatory infertility
Hyperprolactinemia
Infertility due to anatomical abnormalities of
the reproductive tract
Male factor infertility
Unexplained infertility
Contraception
Steroidal contraception
Non-steroidal contraception
Emergency contraception
Menopausal symptoms
Premenstrual syndrome
Abnormal uterine bleeding
Diagnosis
Management
Dysmenorrhea
Vulvar conditions
Management
Conditions with abnormalities on
examination
Chlamydia
Gonorrhea
Pelvic inammatory disease (PID)
Clinical features
Treatment
Sexual problems
Treatment
743
743
744
744
745
745
745
745
745
746
748
748
748
749
749
749
750
750
Chapter outline
General principles of medical obstetric care
Diabetes in pregnancy
Gestational diabetes
Type 1 diabetes in pregnancy
Hypertension in pregnancy
diagnosis
Prevention strategies for preeclampsia
Respiratory disease in pregnancy
Pneumonia
Asthma
Venous thromboembolism (VTE) in pregnancy
Thyroid disorders in pregnancy
Hypothyroidism
Hyperthyroidism
Common gastroenterological and liver disorders
in pregnancy
Gastroesophageal reux disease (GERD)
Constipation and irritable bowel syndrome
(IBS)
Cholestasis of pregnancy
Acute fatty liver of pregnancy (AFLP)
BuddChiari syndrome in pregnancy
Viral infection in pregnancy
Viral hepatitis
Immunological and hematological disease in
pregnancy
Iron-deciency anemia (IDA)
Cardiac disease in pregnancy
Arrhythmias and palpitations
Cardiomyopathy, including postpartum
cardiomyopathy
Other vascular conditions
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762
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763
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764
764
764
765
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766
766
767
767
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767
768
768
769
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770
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772
772
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xix
Contents
Obesity in pregnancy
Neurological conditions in pregnancy
Chapter 27
GERIATRIC MEDICINE
773
773
774
777
Will Browne and Kichu Nair
Chapter outline
Introduction
Epidemiology of aging
Aging and disease
Degenerative disease
Theories of aging
Conditions associated with apparent
acceleration of aging
Physiology of aging
Cardiovascular changes
Cardiac changes
Renal changes
Musculoskeletal changes
Neurological changes
Skin changes
Metabolic and endocrine changes
Gastrointestinal changes
Atypical presentation of disease
xx
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777
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778
778
779
779
779
779
779
780
780
780
780
780
780
Pathology: disease in older people

The giants of geriatrics
The six Is
The 6 Ss
Elder abuse
Osteoporosis
Comprehensive geriatric assessment
Physical examination in the elderly
Functional assessment
Healthy aging
What is healthy aging?
Lifestyle issues in older people
Diet
Malnutrition in the elderly
Exercise
Alcohol use
Prescription drug use/misuse
Adapting to reduced function and
independence
Facing the inevitable with dignity
Palliative care in the older patient
Living wills and advance care planning
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780
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787
787
788
Index
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788
789
PREFACE
The definition of a specialist as one who knows more and

more about less and less is good and true. Its truth makes
essential that the specialist, to do efficient work, must
have some association with others who, taken altogether,
represent the whole of which the specialty is only a part.
Dr Charlie Mayo
The American Board of Internal Medicine describes an
internist as a personal physician who provides long-term,
comprehensive care in the office and in the hospital, managing both common and complex illnesses of adolescents,
adults and the elderly. Accurate diagnosis is the key to successful long-term management; the internist must be an
expert diagnostician who applies their skill and knowledge
like a detective to solve an often difficult problem, craft a
sensible plan and make a positive difference. In order to
practice safely and provide the best possible outcomes, the
specialist physician must master multiple competencies that
include a broad and deep knowledge of diseases in body systems and disease prevention.
The first edition of Internal medicine: the essential facts was
written by a single author (the senior editor) while a consultant at Mayo Clinic, as a guide to mastering the core knowledge and clinical facts in internal medicine. The popularity
of the first edition with those sitting the American Board
in Internal Medicine, Membership of the Royal College of
Physicians, Fellowship of the Royal Australasian College
of Physicians (Part One) and similar examinations led to a
successful second edition by the three of us. This new third
edition has been completely revised and updated. All chapters have been written by experts in the field, followed by
careful editing to ensure that the material is set at the correct
standard. Every chapter has then undergone detailed peer
review and been subsequently revised and edited for consistency and clarity.
The new edition retains the most successful elements of
previous editions, including an emphasis on the facts that all
specialist physicians should know (or need to remember for
their examinations). In particular, we have striven to ensure
that essential areas that may be overlooked when one is reading
a major textbook or a review are highlighted, and irrelevant
facts or waffle are avoided. Traditionally difficult-to-master
topics such as medical genetics, poisonings, acidbase disturbances, medical epidemiology, medical dermatology and
interpreting cross-sectional images are included. Color illustrations to enhance recognition and learning, clinical pearls,
and lists and tables that must be memorized are integrated
into the text. Multiple-choice questions with answers and
explanations are included for revision purposes.
This book aims to provide a framework of knowledge
and the core facts that those sitting postgraduate examinations in internal medicine must know. For those wishing to
further enhance their clinical skills, a complimentary textbook Talley and OConnors Clinical examination: a systematic
guide to physical diagnosis (seventh edition) should be consulted. Essentials of Internal Medicine should also prove useful for senior medical students and those studying for other
examinations where core knowledge in internal medicine
is a requirement. We sincerely hope that this concise guide
to internal medicine will serve those striving for excellence.
Nicholas J Talley
Brad Frankum
David Currow
August 2014
xxi
CONTRIBUTORS
The editors would like to thank Teresa McIntyre for

her hard work and dedication to this project. We would
also like to acknowledge the following contributors and
reviewers for their work on this edition.
Meera R Agar MBBS, MPC, FRACP, FAChPM, PhD
Director of Palliative Care, Braeside Hospital,
HammondCare, NSW, Australia; Conjoint Associate
Professor University of New South Wales, Australia;
Clinical Trial Director, Ingham Institute of Applied
Medical Research, NSW, Australia; Senior Lecturer,
Discipline of Palliative and Supportive Services, Flinders
University, SA, Australia
Vimalan Ambikaipaker FRACP
Consultant Gastroenterologist and General Physician,
NSW, Australia
Robert Gibson BMed, FRACP

AASLD (American Association for the Study of Liver
Disease) and EASL (European Association for Study
of Liver Disease); Lecturer in Medicine, University
of Newcastle, NSW, Australia; Staff Specialist in
Gastroenterology and Hepatology, Hunter New England
Health Service, NSW, Australia
Iain Bruce Gosbell MBBS, MD (Research, UNSW),
FRACP, FRCPA, FASM
Foundation Professor of Microbiology and Infectious
Diseases, School of Medicine, University of Western
Sydney, NSW, Australia; Co-director, Antibiotic
Resistance and Mobile Elements Group, Ingham Institute,
Liverpool, NSW, Australia; Clinical Academic, Sydney
South West Pathology Service, Liverpool, NSW, Australia
David Arnold BMed, FRACP, FCCP

Respiratory Physician, John Hunter Hospital, University of
Newcastle, NSW, Australia
Magnus Halland BMed, BMedSci (Hons), MPH

Conjoint Lecturer, School of Medicine and Public Health,
Faculty of Health and Medicine, University of Newcastle,
NSW, Australia
John Attia MD, PhD, FRCPC, FRACP

Professor of Medicine and Clinical Epidemiology, Faculty
of Health and Medicine, University of Newcastle, NSW,
Australia; Academic Director, Division of General
Medicine, John Hunter Hospital, Newcastle, NSW,
Australia; Director, Clinical Research Design, IT, and
Statistical Support Unit, Hunter Medical Research
Institute, Newcastle, NSW, Australia
Annemarie Hennessy MBBS, PhD, FRACP, MBA

Foundation Professor of Medicine, School of Medicine
University of Western Sydney, NSW, Australia; Clinical
Academic Professor, Campbelltown Hospital, Sydney;
Dean, School of Medicine, University of Western Sydney;
Honorary Professor, University of Sydney; Honorary
Professor, University of New South Wales, NSW, Australia
Will Browne MBCHB, FRACP, MMed Sci

Eastern Health, Melbourne, Victoria, Australia
Katherine Clark MBBS, MMed, FRACP, FAChPM
Director of Palliative Care, Calvary Mater Newcastle,
NSW, Australia; Adjunct Professor, Faculty of Health and
Medicine, University of Newcastle; Adjunct Professor,
University of Wollongong, Australia
Kara De Felice
Gastroenterologist, Mayo Clinic, Rochester, Minnesota,
USA
Matthew Doogue FRACP
Clinical Pharmacologist and Endocrinologist, Department of
Medicine, University of Otago, Christchurch, New Zealand
xxii
Michael P Hennessy BMedSc, MBBS, MBioMedE,

FRANZCO
Prince of Wales Hospital, Sydney, NSW, Australia;
Specialist in General and Surgical Ophthalmology, private
practice, Sydney, NSW, Australia
Michael J Hensley MBBS, PhD
Head, Department of Respiratory and Sleep Medicine,
John Hunter Hospital, NSW, Australia; Emeritus Professor
of Medicine, University of Newcastle, NSW, Australia;
Adjunct Professor of Medicine, University of New
England, NSW, Australia
Alison L Jones MD, FRCPE, FRCP, CBiolFSB,
FRACP, FACMT, FAACT
Executive Dean, Faculty of Science, Medicine and Health,
University of Wollongong, Australia
Contributors
Christos S Karapetis MBBS, FRACP, MMedSc

Associate Professor, Flinders University, Adelaide, SA,
Australia; Regional Clinical Director, Cancer Services,
Southern Adelaide Local Health Network; Head,
Department of Medical Oncology, Flinders Medical
Centre, Adelaide; Director of Cancer Clinical Research,
Flinders Centre for Innovation in Cancer, SA, Australia
Brian J Kelly BMed, PhD, FRANZCP, FAChPM
Professor of Psychiatry, School of Medicine and Public
Health, Faculty of Health and Medicine, University of
Newcastle, NSW, Australia
Ian Kerridge BA, BMed(Hons), MPhil (Cantab),
FRACP, FRCPA
Director and Associate Professor in Bioethics, Centre
for Values, Ethics and the Law in Medicine, Sydney
Medical School, University of Sydney, NSW, Australia;
Haematologist/BMT Physician, Haematology Department,
Royal North Shore Hospital, Sydney, Australia
Andrew R Korda AM MA, MHL, MBBS, FRCOG,
FRANZCOG, CU
Professor of Obstetrics and Gynaecology, School of
Medicine, University of Western Sydney, NSW, Australia;
Consultant Emeritus, Royal Prince Alfred Hospital,
Sydney, NSW, Australia
Sue Lynn Lau MBBS, FRACP, PhD
Staff Specialist Endocrinology, Westmead Hospital,
Sydney, NSW, Australia; Senior Lecturer Endocrinology,
University of Sydney; Senior Lecturer Endocrinology,
University of Western Sydney, NSW, Australia
Christopher R Levi BMedSci, MBBS, FRACP
Senior Staff Specialist Neurologist, John Hunter Hospital,
Newcastle, NSW, Australia; Director of Clinical Research
and Translation, Hunter New England Local Health
District, NSW; Conjoint Professor of Medicine, Faculty
of Health and Medicine, University of Newcastle, NSW;
Honorary Professor of Neurology, The Salgrenska
Academy, University of Gothenburg, Sweden; Honorary
Principal Research Fellow, Florey Neuroscience and
Mental Health Research Institute, Melbourne, SA,
Australia; Practitioner Fellow, National Health and Medical
Research Council, Australia
Michael Lowe FRACP, BMed
Community Geriatrician, NT Department of Health,
Darwin, New Territories, Australia
Mark McLean BMed, PhD, FRACP
Professor of Medicine, University of Western Sydney School
of Medicine, NSW, Australia; Endocrinologist, Blacktown
and Westmead Hospitals, Sydney, NSW, Australia
(Kichu) Balakrishnan R Nair AM MBBS, MD
(Newc), FRACP, FRCPE, FRCPG, FRCPI,
FANZSGM, GradDip Epid
Professor of Medicine, and Associate Dean, Continuing
Medical Professional Development, School of Medicine
and Public Health, Newcastle, NSW, Australia; Director,

Continuing Medical Education and Professional
Development, Hunter New England Health, NSW,
Australia
Harshal Nandurkar MBBS, PhD, FRACP, FRCPA
Professor of Medicine, University of Melbourne, Victoria,
Australia; Director of Haematology, St. Vincents Hospital,
Melbourne, Victoria, Australia
Robert Pickles BMed, FRACP
Senior Staff Specialist Infectious Diseases, John Hunter
Hospital, New Lambton Heights, NSW, Australia
Conjoint Senior Lecturer, Faculty of Health and Medicine,
University of Newcastle, Australia
Kevin Pile MBChB, MD, FRACP
Conjoint Professor of Medicine, University of Western
Sydney, NSW, Australia; Director of Medicine,
Campbelltown Hospital, NSW; Senior Rheumatologist,
Campbelltown Hospital, NSW, Australia
Lindsay J Rowe MAppSci, BMed, FRANZCR
Associate Professor, School of Medicine and Public Health,
University of Newcastle, NSW, Australia; Visiting Adjunct
Professor, Murdoch University, Perth, WA, Australia;
Visiting Adjunct Professor, North Western Health Sciences
University, Minneapolis, MN, USA; Senior Staff Specialist
Radiologist, John Hunter Hospital, Newcastle, NSW,
Australia
Peter L Thompson MD, FRACP, FACP, FACC,
FCSANZ, MBA
Cardiologist and Director of Department of Research, and
Director of Heart Research Institute, Sir Charles Gairdner
Hospital, Nedlands, WA, Australia; Clinical Professor of
Medicine and Population Health, University of Western
Australia; Deputy Director, Harry Perkins Institute for
Medical Research, Western Australia
Peter AB Wark BMed, PhD, FRACP
Conjoint Professor, University of Newcastle, NSW,
Australia; Senior Staff Specialist Department of Respiratory
and Sleep Medicine John Hunter Hospital, NSW, Australia
Thomas P Wellings BSc (Med) MBBS (Hons)
FRACP
Neurologist, John Hunter Hospital, Newcastle, NSW,
Australia; Conjoint Fellow, University of Newcastle,
NSW, Australia
Jane M Young MBBS, MPH, PhD, FAFPHM
Professor in Cancer Epidemiology, University of Sydney,
NSW, Australia; Cancer Institute NSW Academic Leader
in Cancer Epidemiology; Scientific Director, Cancer
Institute New South Wales; Executive Director, Surgical
Outcomes Research Centre (SOuRCe), Sydney Local
Health District and University of Sydney, NSW, Australia
xxiii
REVIEWERS
Kristine Barlow-Stewart BSc, PhD, FHGSA

(Genetic Counselling)
Associate Professor, Director, Master of Genetic
Counselling, Sydney Medical School - Northern
University of Sydney, NSW, Australia
Gerard J. Byrne BSc (Med), MBBS (Hons), PhD,
FRANZCP
Head, Discipline of Psychiatry, School of Medicine,
University of Queensland, Qld, Australia
Director, Older Persons Mental Health Service, Royal
Brisbane & Womens Hospital, Herston, Qld, Australia
John V. Conaglen MB ChB, MD, FRACP
Associate Professor of Medicine, Waikato Clinical School
Faculty of Medical & Health Sciences, University of
Auckland, New Zealand
Steven Coverdale MBChB, FRACP, FCSANZ
Associate Professor of Medicine, University of
Queensland, Head, Sunshine Coast Clinical School,
School of Medicine, UQ, Senior Staff Specialist, Sunshine
Coast Hospital and Health Service, Qld, Australia
Fergus Doubal, Bsc (Hons), MB ChB, MRCP, PhD
Consultant Physician, Royal Infirmary of Edinburgh
and Honorary Senior Lecturer, University of Edinburgh,
Edinburgh, Scotland
Jon Emery MBBCh, MA, FRACGP, MRCGP, DPhil
Herman Professor of Primary Care Cancer Research,
University of Melbourne, Clinical Professor of General
Practice, University of Western Australia, Visiting
Research Fellow, University of Cambridge, Cambridge,
United Kingdom
Constance H. Katelaris MBBS, PhD, FRACP
Professor of Immunology, University of Western
Sydney, School of Medicine Consultant Immunologist,
Campbelltown Hospital, NSW, Australia
Karuna Keat MBBS (Hons), FRACP, FRCPA
Clinical Dean, University of Western Sydney, School
of Medicine; Consultant Immunologist, Campbelltown
Hospital, NSW, Australia
Mark Lucey MBBChBAO, MRCPI, MMedEd,
FCARCSI, FCICM
Senior Staff Specialist, Intensive Care Services, Royal
Prince Alfred Hospital, NSW, Australia
xxiv
Rob MacGinley MBBS, BMedSci, MMedSci, MClin

Epi, FRACP
Senior Staff Nephrologist and General Physician, Eastern
Health, Adjunct Associate Professor Medicine, Eastern
Health Clinical School, Monash University Clinical
Associate Professor, Deakin University, VIC, Australia
Angela Makris, MBBS, FRACP, PhD
Associate Professor, Liverpool Hospital, Sydney; Australia;
Heart Research Institute, University of Sydney, Sydney,
Australia; Conjoint AcademicUniversity of Western
Sydney, University of New South Wales, Australia
Jennifer H. MartinMBChB, MA (Oxon.), FRACP,
PhD
Chair of Clinical Pharmacology, University of Newcastle
and Senior Staff Specialist Calvary Mater Hospital, NSW,
Australia
Claire McLintock MB ChB Edin, FRACP, FRCPA
Auckland DHB Womens Health - Gynaecology,
Auckland, New Zealand, Greenlane Clinical Centre,
Auckland, New Zealand
Renee Mineo BAppSci MPhil
Senior Lecturer, Program Co-ordinator (Bachelor of
Applied Science- Medical Radiations)Discipline Medical
Radiations, School of Medical Sciences, RMIT University,
VIC, Australia
Anne-Maude Morency, MD, FRCSC
Maternal-Fetal Medicine Fellow, University of Toronto,
Ontario, Canada
Nhi Nguyen B Med Sci, MBBS, FCICM
Staff Specialist, Department of Intensive Care Medicine,
Nepean Hospital and Sydney Medical School Nepean,
NSW, Australia
Carolyn F. Orr MBChB, FRACP, PhD
Consultant Neurologist, Macquarie Neurology, Macquarie
University, NSW, Australia
Thomas M. Polasek, BSc, BPharm(Hons), PhD
Lecturer in Clinical Pharmacology, Flinders University
School of Medicine, SA, Australia
Poornima Roche MBBS, FRCS(Ophthalmology)
Senior Lecturer, Clinical Skills Unit, School of Medicine ,
James Cook University, Townsville, Qld, Australia
Reviewers
E. Michael Shanahan BMBS MPH PhD FAFOEM

FRACP
Associate Professor of Musculoskeletal Medicine, Flinders
University, Senior Staff Specialist (Rheumatology)
Southern Adelaide Local Health Network, SA, Australia
Jonathan Watson MA BMBCh FRCP PhD FRACP

Head of School, School of Medicine, Faculty of
Health, Deakin University, VIC,Australia, VMO
Gastroenterologist and Physician, Barwon Health,
Geelong, VIC,Australia
Stephen Shumack OAM, MBBS, FACD

Clinical Associate Professor, Sydney Medical School
Northern, University of Sydney, NSW, Australia
Tim Wigmore, MB, BCh, FRCA, FCICM, FFICM

Consultant Intensivist, Royal Marsden Hospital, London,
United Kingdom
Winnie Tong B.Sc (Med) MBBS FRACP FRCPA

Immunologist, Centre for Applied Medical Research,
StVincents Hospital, Sydney, NSW, Australia
Ingrid Winship MB ChB MD Cape Town FRACP

Inaugural Chair Adult Clinical Genetics, Royal Melbourne
Hospital, University of Melbourne, Executive Director of
Research, Melbourne Health, VIC, Australia
Elizabeth Verghese BSc(Hons), PhD,

GradCertTertEd
Lecturer, Victoria University, VIC, Australia
Mirna Vucak-Dzumhur MBBS, FRACP
Renal Physician, Western Renal Services, Sydney,
Australia Conjoint Senior Lecturer in Medicine, University
of Western Sydney and University of Notre Dame,
Fremantle, WA, Australia
Kwang Chien Yee B Med Sci (Hons), MBBS (Hons),

FRACP
VMO Physician and Gastroenterologist, Calvary Health
Care, Tasmania, Australia, Senior Lecturer in Medicine,
University of Tasmania, Tasmania, Australia.
xxv
CHAPTER 1
INTERNAL MEDICINE IN THE

21st CENTURYBEST PRACTICE,
BEST OUTCOMES
Brad Frankum, David Currow and Nicholas J Talley
The technological tools available to the modern internist
allow us to understand and investigate disease in our patients
in great depth. In the 21st century, targeted therapy offers
enormous capacity to alleviate suffering, but challenges us
to be absolutely precise with diagnosis, and with the use of
evidence in decision-making. Deciding when and how to
employ resources that are limited and expensive raises questions of ethics, equity, and where the balance lies between the
science of human biology and the art of caring for sick people.
Computer
technology
(including
sophisticated
approaches to dredging big data to rapidly identify the likely
diagnosis), ready access to information (for physicians,
their patients and families), and increasing use of molecular
and genetic diagnostic techniques are rapidly changing the
practice of modern internal medicine. Physicians need to be
able to use these tools, and we need to be flexible in the
way we learn. Perhaps surprisingly in this internet-driven
world the textbook, with its synthesis of information and
perspective on what is clinically important, retains its relevance as a cornerstone of medical education. We must also,
however, recognize that the experience and expertise of our
colleagues remains absolutely crucial to guide our ongoing
learning and development.
GENERAL VERSUS
SUB-SPECIALTY MEDICINE
There is a dichotomy in the practice of internal medicine.
On the one hand is the lure of specialization, of becoming
expert and authoritative in very narrow fields. On the other

hand is the need to retain the ability to treat patients in a
holistic manner.
Many patients present with undifferentiated illness,
often accompanied by multiple comorbidities. These people require a physician with the skills to sort out multiple
problems in the context of their overall health, both physical
and psychological, while taking into account their social
and cultural background. Too often the sub-specialist has
lost the will or confidence to manage a patients problems
when they fall outside a particular organ system. Patients
with multiple medical problems can become the victims
of an unseemly conflict between medical teams as to who
should take responsibility for their overall care, while each
specialty is absolute about how their body system should
be treated. For best outcomes, care must be highly coordinated; fragmented care puts patients at risk. Physicians as
medical experts must take a leadership role here; it is not the
responsibility of someone else.
As life expectancy increases in populations globally, as a
result of both improved living conditions and longer survival
due to the course of much chronic disease being ameliorated,
physicians need to maintain the skills to manage the elderly.
There is no doubt that the elderly experience unique physiological and pathological changes, but too often physicians
fail to factor this into their decision-making. As an example,
there is good evidence that polypharmacy is detrimental to
the prognosis of elderly patients regardless of which drug
combinations are being prescribed, yet most physicians
are more comfortable adding medications to a patients
1
Essentials of internal medicine
treatment than removing them. Similarly, the care provided

must be appropriate for each individual, and toward the end
of life withholding potential treatment may be a much better
choice than attempting heroic but clinically futile measures.
Arguments are made that there should be a renaissance
of generalism, particularly in the hospital setting, to allow
for more holistic and rational treatment of patients. Perhaps
a better alternative would be for all of us in the field of
internal medicine to strive to practice as internist first and
sub-specialist second. We also help patients more effectively
when we work as part of a healthcare team, recognizing and
employing the unique skills of colleagues as well as nursing
and allied health staff.
Most importantly, the care of patients should be conducted
in a partnership with the patient, and often also with their
family. No amount of technical knowledge and procedural
expertise on the part of the physician can treat patients effectively in the absence of trust and empathy. Communication
skills need to be increasingly sophisticated as peoples health
literacy increases. Poor outcomes for patients occur much
more frequently through failures of communication than due
to a lack of scientific knowledge on the part of physicians.
THE IMPORTANCE OF
DIAGNOSIS
Rational treatment of patients can only occur after rational
diagnosis. When diagnosis proves elusive, a sensible differential diagnosis can allow for the formulation of an appropriate
plan of investigation and management. Non-cardiac chest
pain, dyspnea, or abdominal pain for investigation
are not diagnosesthey are symptoms. The internist needs
to do better than allocating broad symptomatic labels to
patients. Internal medicine is the branch of medicine for the
expert diagnostician, and the discipline of committing to a
refined provisional and differential diagnosis identifies the
path forward for both clinician and patient.
Too often in modern medicine, physicians make cursory
attempts to form a diagnosis based on limited history and
physical examination, and then rely on investigations to
refine the diagnosis. A defensive approach often results
in excessive numbers of tests and more mistakes; this trap
should be avoided. An investigation is only helpful diagnostically if there is a reasonable pre-test probability that it will
be positive.
As an example, an autoimmune screen is often performed for a patient with fatigue as a presenting problem but
no other features of a systemic autoimmune disease. What,
then, to do when the antinuclear antibody (ANA) comes
back detectable in a titer of 1:160? Is this within the range
of normal? How many asymptomatic patients will have a
detectable ANA in low titer? How many extra tests should
now be performed to ensure that the ANA is not of significance? How do we deal with the inevitable anxiety of our
patient who consults the internet to find that ANA is found
in systemic lupus erythematosus, as indeed is the symptom
of fatigue? How will we look in the eyes of the patient when
we say to them that the positive test was really negative
and unimportant? If so, why was it ordered in the first place?
2
Furthermore, the larger the number of investigations

performed, the higher the likelihood that a result will fall
outside the reference range as a matter of chance. This is
the statistical nature of a normal distribution curve. An
abnormal result may be of no clinical significance, but still
needs to be explained to a patient. As diagnostic techniques
become more sensitive, especially imaging modalities,
increasing numbers of incidental findings result. The
physician needs to be able to discern between when this
needs further investigation and when it can be dismissed.
Most investigations are not innocuous and run the risk of
potential harm. Physicians have a societal responsibility to
be cost-conscious and all investigations should be ordered
judiciously.
THE PHYSICIANS ROLE IN

PUBLIC HEALTH
In the era of personalized medicine, there remains a critical
role for the physician as an advocate for, and guardian of,
public health.
The greatest impact on health that we can make as physicians remains in the area of global preventative medicine.
The world populations health will only continue to improve
with concentrated, ongoing efforts to implement vital
measures such as large-scale vaccination against infection;
tobacco, alcohol, and recreational drug control; screening
for pre-cancerous lesions, and earlier-stage cancers that can
be cured; obesity and diabetes mellitus prevention; protection from war, violence, and road trauma; reduction in the
spread of HIV, malaria, and tuberculosis; and minimalization of climate change. Even at a local level, it is essential for
physicians to argue the case for these measures, especially
in the face of ever-pressured health budgets, anti-scientific
misinformation from vested interests, and governments
intent on spending vastly more money on military defenses
than on preventative health.
As physicians we generally treat patients on a one-onone basis. Most feel, quite appropriately, duty-bound to
facilitate the best possible care for each individual patient.
There is, however, an opportunity cost for every dollar spent
on healthcare. It is an obligation for each of us to spend
this money appropriately and not waste valuable resources.
Appropriate care is not necessarily the same as the most
expensive care. Sometimes, simplifying investigations and
treatments serves patients interests far better.
THE PHYSICIAN AS SCHOLAR

Scholarly activity continues to define the essence of internal
medicine. Scientific analysis of material, education of others,
and ongoing research into basic and clinical mechanisms of
health and disease are the cornerstones of practice for the
internist.
The sources of information available to the physician
continue to expand. The temptation to be influenced by
vested interests is ever-present, whether that be from pharmaceutical companies trying to market drugs, researchers
Chapter 1 Internal medicine in the 21st centurybest practice, best outcomes
trying to maintain grant funding, colleagues trying to boost

referrals, or even textbook authors trying to sell their books!
Critical analysis of information through understanding the
many factors influencing and biasing the production and
presentation of data is the only way to guard against poor
decision-making. All physicians need to exercise the intellectual discipline of critical appraisal in these settings.
Most medical graduates understand the importance of
teaching and role-modeling provided by their senior colleagues. There is no more powerful lesson than seeing an
expert in action in a clinical setting, or having a complex
concept explained in an insightful and succinct fashion.
As learning becomes increasingly blended between the
classroom, the internet, and the clinical setting, the physician remains the central reference point for students and
junior doctors to comprehend what is really important to
understand and master. Physicians must take this responsibility as educators seriously. They must strive for excellence
as teachers just as they do as clinicians.
To research is to improve. If we do not strive for new
knowledge and understanding, our patients will not be able
to look forward to better healthcare in the future. Research
may involve an audit of an individuals current practice, or
may involve participation in a multi-national trial of a new
therapy. Whatever form it takes, it underpins the practice
of internal medicine. Our participation in research such as a
clinical trial is likely to improve our practice, no matter what
the outcome of the clinical trial.
As physicians, we must remain curious, vigilant, and
sceptical. If we remain inspired by the scholarship of medicine, we can no doubt be an inspiration to our patients and
colleagues.
CHAPTER 2
EVIDENCE-BASED MEDICINE AND CRITICAL

APPRAISAL OF THE LITERATURE
Jane Young and David Currow
CHAPTER OUTLINE
CRITICAL APPRAISAL OF THE LITERATURE

INTERPRETING A STUDYS FINDINGS
INTRODUCTION
ASSESSING THE EVIDENCE
Sources of error
Assessing potential biases in different study
designs
INTRODUCTION
In order for patients to benefit from gains in knowledge
achieved by medical science, the findings of research must
be integrated into routine clinical practice. Evidence-based
medicine is an approach to clinical practice in which there
is an explicit undertaking to incorporate the best available
scientific evidence into the process of clinical decision-making. Achievement of this requires skills in the identification,
critical appraisal and interpretation of relevant research studies in order to assess the strengths, limitations and relevance
of the evidence for the care of an individual patient.
ASSESSING THE EVIDENCE

When assessing the findings of scientific research, one of
the first considerations is whether the results of a study
are accurate. The accuracy of a study is also referred to as
INTERPRETING STATISTICAL ANALYSIS

INTERPRETING TEST RESULTS
SCREENING
CONCLUSION
its internal validity. To assess internal validity, potential

sources of error or bias in the study must be considered.
Sources of error
There are two major sources of error that affect research
studies. Random error arises due to chance variations in
study samples and can be thought of as adding noise to the
data. It reduces the precision of the findings but can be minimized by increasing the sample size of the study.
In contrast, systematic error is due to the way in
which the study was designed or conducted and will always
deviate a research finding away from the truth in a particular direction, resulting in an under- or over-estimate of
the true value. Systematic error may arise from the way
in which study participants were selected into the study
(selection bias), the accuracy of study measures (information bias) or the concomitant effect of other factors
on the outcome in question (confounding) (Box 2-1,
overleaf). It should be recognized that different sources of
5
Box 2-1
Types of systematic error

Selection bias
Error in the studys ndings which arises from the methods
used to select and recruit study participants.
If the relationship between the study factor and the
outcome is different for participants and non-participants
(those excluded, omitted or who declined to participate),
the studys results will be inaccurate.
Recruitment of random, population-based samples with
high consent rates minimizes potential selection bias in
a study.
Be alert to potential selection bias in studies which:
recruit volunteers
recruit other non-representative groups
have low participation or consent rates
have high losses to follow-up.
Information bias
Errors in the studys ndings due to inaccurate collection
of information.
Accuracy is how well the measure represents the true
value.
Reliability is the ability of a measure to provide
consistent results when repeated.
Measures that rely on the judgment of an individual can
be inuenced subconsciously by knowledge of
the research question.
In clinical trials, blinding of outcome assessors, clinicians
and patients to treatment allocation reduces the
potential for awareness of group allocation to inuence
study measures.
systematic error within the same study may work in the

same or opposing directions. However, as the true value of
interest is generally not known, the size of any error cannot be measured directly. Unlike random error, systematic
error cannot be reduced by increasing the size of the study
but must be minimized by good study design. Assessment
of the potential for systematic error requires consideration
of the potential for selection bias, information bias and
confounding within each study.
Assessing potential biases in different

study designs
A number of different types of study are used in clinical
research and each is susceptible to varying sources of systematic bias. An understanding of the key features of each study
design, and the most important sources of bias, provides the
basis for critical appraisal of the scientific literature. Furthermore, once the design of the study has been identified,
there are design-specific critical appraisal checklists, such as
those developed by the Critical Appraisal Skills Programme
(CASP) in the United Kingdom, that are readily available
6
In case-control studies, cases may have heightened

awareness of possible causes of their disease and so
have different recall of exposure to factors of interest
than controls (recall bias).
Confounding
Error in the studys ndings owing to mixing up of effects
due to the study factor with those due to other factors.
Occurs when there is an uneven distribution of
prognostic factors between the groups being compared.
In clinical trials, randomization aims to produce groups
which are equally balanced for both known and
unknown prognostic factors.
Randomization will usually control for confounding
if the sample size of the trial is large enough for the
comparison groups to have similar distributions of
prognostic factors.
Potential confounding is a major issue in nonrandomized studies that can be minimized by:
restricting study participation to exclude potential
confounding factors
matching participants in different study groups for
prognostic factors
stratifying participants by the prognostic factor and
analyzing each stratum separately
statistical modeling to adjust for the effect of
confounding.
on-line to provide a step-by-step guide to the assessment of

the methodological quality of research studies.
Randomized controlled trials

In randomized trials, participants are randomly allocated to
treatment groups, for example to new treatment or placebo.
The randomization process should achieve treatment groups
in which patients are similar for both known and unknown
prognostic factors (confounders) so that any differences in
outcome can be attributed to differences in treatment.
Well-designed randomized trials use a method to allocate
patients to treatment groups that is truly random and that
ensures that the sequence cannot be known or guessed in
advance by patients or those recruiting them (allocation concealment). Random number tables or computer-generated
sequences are the best methods to obtain a truly random
sequence. Inappropriate methods of randomization are those
in which the group allocation is not truly random, such as
alternating patients between treatment groups or selecting the
treatment group based on a patient characteristic (such as date
of birth) or day of clinic attendance. In addition to generating
Chapter 2 Evidence-based medicine and critical appraisal of the literature
a truly random sequence, the trial methods need to ensure

allocation concealment so that a clinicians decision to recruit
a particular patient to a trial and the patients decision whether
or not to participate cannot be influenced by knowledge of
the treatment group to which they will be allocated. Trial
methods must ensure that the randomization schedule is not
freely available to those involved in the actual recruitment of
patients. This can be achieved by use of a central randomization service in which clinicians contact the service by phone,
fax or e-mail to register a patient who has already consented
to be in the study, and to find out which treatment the patient
has been randomly allocated to receive.
Intention-to-treat (ITT) analysis is a method used
to preserve the randomization of participants at the analysis stage of a clinical trial. In ITT analysis, patients are
analyzed in the groups to which they were originally allocated, regardless of what may have happened in practice.
So any patients who decline the treatment to which they
were randomized, those who cross over to another group
for any reason, and those who drop out are analyzed as part
of their original allocated group. As all patients who were
randomized must be accounted for at final follow-up, the
trial methods should attempt to minimize any drop-outs
or losses to follow-up. Furthermore, the statistical methods
should describe how any losses to follow-up were dealt with
in the statistical analysis.
The use of blinding is a method to guard against information bias in randomized trials that also can be used in
non-randomized studies. Blinding or concealment of a
study participants treatment group ensures that preconceived attitudes or expectations of the relative effectiveness
of the treatments being compared cannot influence the study
data. Blinding of patients can guard against a placebo effect,
in which patients report better outcomes due to the psychological effect of receiving a treatment that they perceive as
being more effective than a control treatment. Blinding of
clinicians reduces the potential for overt or subconscious
differences in patient management that could arise from
knowledge of the treatment that has been received. Blinding
of other study staff such as outcome assessors, data collectors
and biostatisticians can minimize the risk that measurement
or analysis decisions are influenced by awareness of treatment
group. As blinding addresses any information bias that results
from participants attitudes and expectations of the likely
benefits of the treatment being tested, blinding is particularly
important for study outcome measures that are subjective,
such as pain, quality of life or satisfaction. Blinding is less
important for objective measures such as mortality.
Key points to consider in the assessment of a randomized
trial are summarized in Box 2-2.
Pseudo-randomized or quasi-experimental
trials
In these trials, the method of developing the treatment allocation sequence is not truly random. For example, alternate
patients could be allocated to different treatment groups, or
treatments could be offered according to days of the week
or last digit of a medical record number. A major concern
is whether there is any relationship between the method of
allocation and specific types of patient. For example, it may
Box 2-2
Key points for appraisal of a

randomized controlled trial
How was the randomization schedule developed?
Was this a truly random process?
Could patients, or those recruiting them, have been
able to know or deduce the next treatment allocation?
Were patients concealed to their treatment
allocations?
Were clinicians concealed to the patients treatment
allocations?
Were those responsible for measurement of study
outcomes blinded to the patients treatment
allocations, or were objective measures used?
Were all patients who were randomized accounted for
in the nal analysis in the groups to which they were
allocated (regardless of whether they actually received
this treatment)?
Were there any other factors that could have
inuenced the results of the study (e.g. poor
compliance with allocated treatment, large numbers
of patients crossing over to a non-allocated treatment
group, contamination between treatment groups, cointerventions or changes in healthcare delivery during
the trial that may have inuenced outcomes)?
Adapted with permission from Macmillan Publishers Ltd.
YoungJM and Solomon MJ. How to critically appraise an article.
Nature Clinical Practice Gastroenterology 2009;6(2):8291.
be that older or sicker patients attend a clinic on a particular day for reasons relating to clinical, administrative, access
or transport issues. In addition to careful consideration of
potential pitfalls of the group allocation method, other points
to consider in the assessment of a pseudo-randomized study
are the same as for randomized trials.
Cohort studies
Cohort studies involve the longitudinal follow-up of groups
of individuals to identify those who develop the outcome of
interest.
In a prospective cohort study, the individuals are identified at the start of the study and data are collected about
the study factors or exposures of interest as well as all
potential confounding factors. The cohort is then followed, usually for several years, with regular assessment
of study outcomes over this period.
In a retrospective cohort study, individuals are usually
identified from existing databases or records, and information about study factors, potential confounders and
outcomes is also obtained from existing data sources.
Retrospective cohort studies are usually much quicker to
complete than prospective studies, but a major disadvantage is that information about potential confounders may
not have been collected at the time the original data were
obtained. Box 2-3 (overleaf) summarizes key points to
consider in the assessment of a cohort study.
7
Box 2-3
Box 2-4

cohort study
Ten questions to ask about a

research article
Is the study prospective or retrospective?

Is the cohort well-dened in terms of person, time and
place?
Is the cohort population-based?
Were data collected on all important confounding
factors?
Were study outcomes and potential confounders
measured in the same way for all members of the
cohort?
Was the length of follow-up sufficient to identify the
outcomes of interest?
Were there large losses to follow-up?
Were those lost to follow-up likely to have different
outcomes to those who continued in the study?
1 Is the study question relevant?

2 Does the study add anything new?
3 What type of research question is being asked?
4 Was the study design appropriate for the research
question?
5 Did the study methods address the most important
potential sources of bias?
6 Was the study performed according to the original
protocol?
7 Does the study test a stated hypothesis?
8 Were the statistical analyses performed correctly?
9 Are the conclusions justied from the data?
10 Are there any conicts of interest?
Case-control studies
In case-control studies, cases are selected because they have
already developed the outcome of interest, for example a disease, and their history of exposure, risk factors or treatment
are compared with similar people who have not developed
the outcome of interest (controls). Case-control studies are
particularly useful to investigate risk factors when the clinical condition of interest is rare, as it would take too long to
recruit and follow up a prospective cohort of patients. Selection of appropriate controls and the possibility of recall bias
are major concerns with case-control studies.
Cross-sectional studies
In cross-sectional studies, information about the study factors and outcomes of interest are collected at one point in
time. The purpose of this type of study is to investigate associations between these factors, but it is not possible to draw
conclusions about causation as a sequence of events cannot
be established. A survey is an example of a cross-sectional
study.
CRITICAL APPRAISAL OF THE

LITERATURE
While a focus of the critical appraisal of a research study is
an assessment of the potential for bias in the design and conduct of the research, there are a number of other important
factors that should be considered (Box 2-4).
Two important considerations are whether the specific
research question addressed in the study is relevant to the
clinical question of interest, and whether the appropriate study design was used to answer this question. While
it is widely recognized that well-designed randomized
8
controlled trials provide the best quality evidence about

the effectiveness of medical therapies, other study designs
are optimal for different types of research question. For
example, an evaluation of the accuracy of a new diagnostic test would be best investigated using a cross-sectional
study design in which a consecutive sample of patients
received both the new test and an existing gold standard
test simultaneously. The accuracy of the new test could
then be established by comparing the results with the gold
standard test. Questions about prognosis are best answered
using prospective cohort studies.
Many studies are conducted that are not the optimal
design for the research question being addressed. This can
be because the optimal design is not acceptable or is not feasible with the time and resources available. For example, it
can be very difficult to conduct randomized trials to test new
surgical procedures, particularly when there is a large difference in the extent of surgery between the experimental and
standard approaches. Patients are likely to refuse to have a
non-reversible treatment option decided essentially on the
basis of the toss of a coin. Another circumstance where randomized trials are difficult is when the condition of interest is very rare so that it would be impossible to achieve the
required sample size within a reasonable timeframe. Many
organizations, such as those involved in the development
of evidence-based clinical practice guidelines, have developed hierarchies of evidence that rank study designs from
strongest to weakest for questions relating to therapeutic
effectiveness, prognosis or diagnostic test accuracy. For therapeutic effectiveness, for example, one hierarchy from strongest to weakest would be: randomized trial; a comparative
study with concurrent controls (pseudo-randomized trial,
prospective cohort study, case-control study, controlled
time series); comparative study with historical controls;
uncontrolled (single-arm) studies such as uncontrolled time

series or uncontrolled case series.
Meta-analysis is a statistical technique in which the
findings of several studies can be pooled together to provide
a summary measure of effect. Meta-analysis should always
follow a comprehensive systematic review of the literature
to identify all relevant primary studies and to assess the quality and comparability of these studies. When conducted
according to strict protocols, such as those developed by
the Cochrane Collaboration to minimize bias, systematic
review and meta-analysis can provide the strongest evidence on a topic as it incorporates all the relevant scientific
evidence from individual studies. Hence, most evidence
hierarchies have meta-analysis as the highest-ranked study
design. In the case of questions of therapeutic effectiveness,
meta-analysis of individual randomized controlled trials
would be considered the strongest evidence on the topic.
Key points to consider when assessing a systematic review
or meta-analysis are summarized in Box 2-5.
Box 2-5

systematic review or meta-analysis
Was the literature review sufficiently comprehensive to
identify all the relevant literature?
Were specic inclusion and exclusion criteria used to
select articles to be included in the review?
Were important types of article excluded (e.g. those in
foreign languages, unpublished articles)?
Was the quality of the included articles assessed using
explicit criteria by two independent reviewers?
Were numerical results and key ndings extracted
from the included articles by two independent
reviewers?
Was sufficient detail about the included studies
provided to enable comparisons of patient
characteristics, treatments and outcomes between
studies?
If a meta-analysis was conducted, was an assessment
of heterogeneity and the appropriateness of
calculating a summary measure assessed?
INTERPRETING A STUDYS
FINDINGS
Clinical studies use a variety of measures to summarize their
findings.
A point estimate is the single value or result that is
obtained from the study sample. It is the best estimate
of the underlying true value that has been obtained
from the study data. Different studies that address the
same clinical question may yield slightly different point
estimates due to small differences between the study

methods and samples and the play of chance.
Incidence and prevalence are measures commonly
used to describe the burden of disease in the community.
A rate is the number of events occurring in a defined
population over a specific time period, such as one year.
Incidence and prevalence are often mixed up, but shouldnt
be! An incidence rate is the number of new cases per population in a given time period, and is a measure of the risk
of developing the condition of interest. For example, cancer
incidence rates are usually reported as the number of new
cases per 100,000 people per year. In contrast, prevalence
is the number of people in the population with the condition of interest during a specified time period and is a good
measure of the impact of the disease in the community.
Prevalence includes cases that were diagnosed prior to but
continue to exist during the time period, as well as the new
cases that occur for the first time during the time period.
Point prevalence is the number of people in the population with the disease at a single point in time.
Rates can be standardized to allow valid comparisons
to be made between two or more different populations. For
example, the risk of most cancers increases with advancing
age. A comparison of cancer incidence rates between two
regions with different age structures would be misleading
if age were not taken into account, as a higher cancer incidence rate would be expected in the region with the older
population. The incidence rates for the different regions can
be age-standardized by calculating what the rates would be
if each region had the age structure of a standard population (direct standardization). In this way, the effect of age
is removed as much as possible from the comparison of the
cancer incidence rates.
Many clinical studies investigate the relationship between
a study factor (e.g. risk factor or type of treatment) and an
outcome. The results can be presented in a 2 2 contingency table, from which various measures of association or
effect can be calculated (Figure 2-1, overleaf). These measures can be reported in absolute or relative terms.
The absolute effect is simply the difference in means,
medians, proportions or rates between groups. Imagine
that in a hypothetical trial, 200 patients are randomly
allocated to either a new treatment for cancer (intervention group) or standard treatment (control group) and
the proportion who are disease-free at 12 months is the
primary outcome measure (Figure 2-1). If 20 (10%)
patients in the intervention group and 10 (5%) patients
in the control group are disease-free at 12 months, the
absolute risk reduction is 10 5 = 5%. The number
needed to treat (NNT) is the number of people who
need to be treated based on the trial to prevent 1 additional event over a specified period of time. The NNT
is calculated by taking the inverse of the absolute risk
reduction. In this example, the NNT is 1/(5/100) = 20,
showing that 20 people would need to be treated to prevent 1 additional recurrence at 12 months.
These results can also be presented in terms of the outcome of the intervention group relative to the control
group. The relative risk (sometimes called the risk
9
Consider a hypothetical trial comparing a new treatment

for cancer (intervention group) with the standard treatment
(control group), with 200 patients in each group. The
primary outcome is the proportion of patients who are
disease-free at 12 months. Twenty patients are
disease-free at 12 months in the intervention group
compared with 10 in the control group. The results can be
presented in a 2 2 table:
Diseasefree
Not
diseasefree
Total
Treatment
20(a)
180(b)
200
Control
10(c)
190(d)
200
Total
30
370
400
Event rate (proportion disease-free) in treatment group

= a/(a+b) = 20/200 = 10%
Event rate (proportion disease free) in control group
= c/(c+d) = 10/200 = 5%
Absolute risk reduction (ARR) = difference in event rates
= (a/(a+b)) (c/(c+d ) = 10 5 = 5%
Number needed to treat (NNT) = 20 (1/ARR)
Relative risk = (a/(a+b))/(c/(c+d) = 10/5 = 2
Odds ratio = (ad )/(bc) = (20 190)/(180 10) = 2.11
Figure 2-1 Example of a 22 table for calculating

measures of association
Adapted from Young JM. Understanding statistical analysis in the
surgical literature: some key concepts. Australian and New Zealand
Journal of Surgery 2009;79:398403.
ratio) compares the probability, or risk, of the event

(being disease-free at 12 months) in the two groups. In
this example, the event rate in the intervention group is
10% compared with 5% in the control group, giving a
relative risk of 10/5 = 2. This means that patients in the
intervention group are twice as likely to be disease-free
at 12 months compared with those in the control group.
The odds of an outcome are the ratio of it occurring
(numerator) to it not occurring (denominator). In contrast
to a proportion, individuals who are counted in the numerator are not also counted in the denominator. For example,
if 5 out of 20 patients develop a complication, the odds of the
complication are 5:15 or 0.33 whereas the corresponding
proportion is 5:20 or 0.25 (or 25%). An odds ratio (OR) is
the ratio of the odds of the outcome occurring in one group
compared with the odds of it occurring in a second group.
The odds ratio will be very close to the relative risk when
the outcome of interest is rare. However, for common outcomes, the odds ratio will depart from the relative risk. See
Figure 2-1 for how to calculate a relative risk and an odds
ratio from a 22 table.
For both odds ratios and relative risks, the null value, or
value at which there is no difference between groups, is 1.
If the likelihood of the outcome is greater in the intervention or exposure group compared with the control
group, the odds ratio or relative risk will be greater than
1. The larger the value of the odds ratio or relative risk,
the stronger the association is between the study factor
10
(treatment or exposure) and the outcome. An OR of

5.0, for example, indicates that patients in the treatment
or exposed group were 5 times more likely to develop
the outcome than patients in the control group, and an
OR of 1.3 means that they were 30% more likely to
doso.
Conversely, if the outcome is less likely in the treatment
or exposed group than the control group, the odds ratio
or relative risk will be less than 1 (but cannot be below
0). A value of 0.8 means that patients in the study group
were 20% less likely to develop the outcome of interest
compared with controls, and a value of 0.5 means that
they were half as likely to do so.
INTERPRETING STATISTICAL
ANALYSIS
Part of the critical appraisal of a research study is assessment
of the logic and appropriateness of the statistical methods
used. In clinical research, the focus of much statistical analysis is hypothesis testing. Therefore, it is imperative that
the studys hypotheses are clearly stated. The purpose of
hypothesis testing is to make a judgment as to whether the
studys findings are likely to have occurred by chance alone.
The choice of appropriate statistical tests to achieve this is
unrelated to the design of the study but is determined by the
specific type of data that have been collected to measure the
study outcomes (endpoints).
Where individuals can be grouped into separate categories for a factor (for example, vital status can only be
dead or alive), the data are categorical. There are different types of categorical data. Binary data occur when
there are only two possible categories. Where there are
more than two possible categories, the data are nominal
when there is no particular order to the categories (e.g.
blue, green or brown eye color), and ordinal when a natural order is present (e.g. stage of cancer).
Continuous data occur when a measure can take any
value within a range (e.g. age). Within a group of individuals, the values of continuous data can follow a bellshaped curve that is symmetrical around the mean value
(a normal distribution), or follow an asymmetrical distribution with a larger proportion of people having high
or low values (a skewed distribution).
In addition to the type of outcome data, the number of
patient groups being compared dictates the most appropriate statistical test. A third consideration is whether the
comparison groups are made up of different individuals and
are therefore independent of each other (e.g. treatment and
control groups in a two-arm randomized trial), or are the
same individuals assessed at different time points (e.g. in a
randomized cross-over study). In the latter case, study data
relate to pairs of measurements on the same individual.
Slightly different statistical tests are used depending on
whether the data are independent or paired, and a biostatistician can advise about the best approaches. An example of an
algorithm to choose the most appropriate statistical test for
two independent groups is given in Figure 2-2.
What type of
outcome measure?
Categorical
Continuous
e.g. quality of life
(QOL) score
2 categories
e.g. dead/alive
Normally
distributed?
>2 categories
e.g. mild/mod/high
Time to event
e.g. time to death
Small
numbers?
Yes
No
Yes
No
Compare
means
Compare
medians
Compare
%
Compare
%
Students
t-test
Wilcoxon
rank sum test
Fishers
exact test
Chi square
(2) test
Compare
survival
experience
Various
approaches
Survival
analysis
Figure 2-2 Algorithm to select statistical tests for analyzing a surgical trial (two independent groups)
Reprinted by permission from John Wiley and Sons. Young JM. Understanding statistical analysis in the surgical literature: some key concepts.
Australian and New Zealand Journal of Surgery 2009;79:398403.
Correlation is used to assess the strength of association

between two continuous variables. The Pearson correlation
coefficient (r) ranges from 1 to +1. A value of +1 means
that there is a perfect positive linear relationship between
the two variables, so as one increases, the other increases. In
contrast, a value of 1 means that there is a perfect negative
linear relationship, with one variable decreasing as the other
increases. A value of 0 means that there is no linear relationship between the two variables.
Statistical tests of hypotheses generate a probability or
p value that indicates the likelihood of obtaining the result
seen in the study if the truth is that there is no effect or no
difference between groups. A conventional cut-off for p of
0.05 or less to indicate statistical significance means that
there is a 5% (or 1 in 20) chance or less of obtaining the
observed finding or one more extreme in the study if there
is truly no difference between groups.
Due to natural variability, the results from different
samples will vary and each study provides an estimate of the
true value. Confidence intervals provide a range of values
around the study finding where the true value is likely to lie.
A 95% confidence interval indicates that the true value will
lie within this range in 95% of samples.
INTERPRETING TEST RESULTS

An everyday task for clinicians is to order and interpret
tests in light of a patients history and clinical examination. Whenever a test is undertaken there are four possible
results:
1 the patient has the disease and the test is positivetrue

positive
2 the patient has the disease but the test is negativefalse
negative
3 the patient doesnt have the disease but the test is positivefalse positive
4 the patient doesnt have the disease and the test is negativetrue negative.
This can be illustrated using a 2 2 table (Figure 2-3,
overleaf).
Sensitivity and specificity are used to describe the accuracy of the test.
Sensitivity is the percentage of affected persons with
a positive test (true positive proportion). Sensitivity
therefore means positive in disease (PID).
Specificity is the percentage of unaffected persons with
a negative test (true negative proportion). Specificity
therefore means negative in health (NIH) (Figure 2-3).
Test sensitivity and specificity are not related to how common the disease is in the community (prevalence). The
prevalence of disease in a population, or pre-test probability
of the disease, will alter how useful the test is for an individual patient. The positive predictive value (PPV) of a
test is the probability of disease in a patient with a positive
test, whereas the negative predictive value (NPV) is the
probability of no disease in a patient with a negative test
result. Figure 2-3 demonstrates how to calculate these values from a 2 2 table and shows that both PPV and NPV
are dependent on the underlying prevalence of the disease.
11
DISEASE
TEST
Truly present
Truly not present
Positive
TRUE POSITIVE
a
FALSE POSITIVE
b
Negative
FALSE NEGATIVE
c
TRUE NEGATIVE
d
Sensitivity
Specificity
Positive predictive value (PPV)
Negative predictive value (NPV)
Likelihood ratio positive test result (LR+)
=
=
=
=
=
=
=
a/(a + c)
d/(b + d)
a/(a + b)
d/(c + d)
sensitivity / (1 specificity)
(a/(a + c)) / (1 d/(b + d ))
a/(a + c) / (b/(b + d ))
Likelihood ratio negative test result (LR)
= (1 sensitivity) / specificity
= 1 a /(a + c) / d/(b + d)
= (c/(a + c)) / d/(b + d )
Post-test odds = pre-test odds LR

Post-test probability = post-test odds / (post-test odds +1)
Positive LR
(rule in disease)
Increased probability of disease

(approximate)
15%
30%
10
45%
Figure 2-3 Interpretation of test results using a 22 table

This means that a patient who has a positive test result and
who is from a group with a low prevalence of the disease has
a lower probability of having the disease than a patient with
a positive test result who is from a group with a high prevalence of the disease in question.
The likelihood ratio (LR) is another measure of the
usefulness of a diagnostic test. It provides a way of combining the sensitivity and specificity of a test into a single
measure (see Figure 2-3). As sensitivity and specificity are
characteristics of the test itself and are not influenced by
prevalence, the LR is not influenced by the prevalence of
disease in the population.
Imagine that a diagnostic test has a sensitivity of 0.95
and a specificity of 0.85. The likelihood ratio for a
positive test (LR+) is calculated by dividing the sensitivity by (1 specificity). In this example, the LR+ is
0.95/(10.85) = 6.3. The best test to rule in a disease
is the one with a LR+ near to or exceeding a value of 10.
The hypothetical test in this example does not meet this
criterion and so is only of limited value in ruling in the
disease for a patient with a positive test result.
The likelihood ratio for a negative test (LR) is calculated by dividing (1 sensitivity) by the specificity,
which is (10.95)/0.85 = 0.058 in this example. The
best test to rule out a disease is the one with a small
12
LR (<0.1). The hypothetical test meets this criterion,

suggesting that the disease can be ruled out in a patient
with a negative test result.
Likelihood ratios around 1.0 indicate that the test results
provide no useful information to rule in or rule out the
disease.
Likelihood ratios can be used to calculate the probability
that a patient has the disease taking into account the test
result (post-test probability).
In the above example, imagine that the prevalence of the
disease (pre-test probability) in the community is 10%
or 0.1. The pre-test odds of the disease are calculated by
dividing the prevalence by (1prevalence), which in this
case is 0.1/(10.1) = 0.1/0.9 = 0.11 or 11%.
The post-test odds are then calculated by multiplying the pre-test odds by LR+. In our example, this is
0.11 6.3 = 0.693.
To convert this to a post-test probability, the post-test
odds are divided by (post-test odds 1). In our example,
this is 0.693/1.639 = 0.409 or 40.9%.
So for a patient with a positive test result, the probability of
disease has risen from 10% to 41% on the basis of the test
result.
SCREENING
CONCLUSION
A tests sensitivity and specificity are particularly important when evaluating a screening test. Screening is used
to detect disease in affected individuals before it becomes
symptomatic. For example, Papanicolaou (Pap) smears and
mammograms are used to detect cervical and breast cancer,
respectively, to facilitate early treatment and reduce morbidity and mortality from these cancers. Before screening is
introduced, it must fulfill the following criteria:
there must be a presymptomatic phase detectable by the
screening test
intervention at this time will change the natural history
of the disease to reduce morbidity or mortality
the screening test must be inexpensive, easy to administer and acceptable to patients
the screening test will ideally be highly sensitive and
specific (although this is not usually possible)
the screening program is feasible and effective.
Critical appraisal is a systematic process to identify the

strengths and limitations of research evidence that can assist
clinicians to base their clinical practice on the most relevant,
high-quality studies. Critical appraisal skills underpin the
practice of evidence-based medicine.
ACKNOWLEDGMENTS
This chapter is based on the papers Young JM and Solomon
MJ. How to critically appraise an article. Nature Clinical
Practice Gastroenterology 2009;6(2):8291, and Young JM.
Understanding statistical analysis in the surgical literature:
some key concepts. Australian and New Zealand Journal of
Surgery 2009;79:398403.
13
SELF-ASSESSMENT QUESTIONS
1
A randomized controlled trial demonstrates that a new drug for cystic brosis reduces age-adjusted 10-year mortality
by 50% but does not cure the disease. The new drug has few side-effects and is rapidly adopted into the clinical care of
patients with cystic brosis in the community. Which of the following statements is correct?
A The incidence of cystic brosis will increase but prevalence will be unaffected.
B Both incidence and prevalence of cystic brosis will increase.
C Prevalence will increase but incidence will be unaffected.
D Neither incidence nor prevalence will change.
A randomized controlled trial was conducted to investigate the effectiveness of a new chemotherapy drug to improve
1-year survival for people diagnosed with advanced lung cancer. Overall, 300 people were randomized, 150 to the new
drug and 150 to standard treatment. However, 10 people who were allocated to receive the new drug decided not to
take it as they were worried about potential side-effects. These 10 people were all alive at 1 year. At 1 year, 80 people in
the new treatment group had died, compared with 92 in the standard treatment group. How many patients need to be
treated with the new drug to prevent 1 additional death at 12 months?
A 280
B 12.5
C 12.23
D 0.125
Alzheimer disease is a common condition in the community, affecting 13% of North Americans aged over 65 years.
A new test for Alzheimer disease has a sensitivity of 65% and a specicity of 80%. What is the probability that a 70-yearold with a positive test result has Alzheimer disease?
A 0.084
B 0.104
C 0.206
D 0.326
4 Which of the following statements about randomized controlled trials (RCTs) is/are correct?
i RCTs are always the optimal study design in clinical research.
ii Randomization ensures that equal numbers of patients receive the intervention and control treatments.
iii Randomization reduces information bias.
iii Randomization reduces random error.
A
B
C
D
(i) only
(ii) only
(ii) and (iii)
None
ANSWERS
1
C
People who take the new drug are less likely to die, so the number of existing cases will increase, thereby increasing
prevalence (new plus existing cases in the community). However, the number of new cases is not affected, so the
incidence will remain unchanged.
B.
The results of the study are summarized in the following 22 contingency table.
VITAL STATUS AT
1 YEAR
NEW TREATMENT
STANDARD
TREATMENT
Dead
80
92
Alive
70
58
Total
150
150
Intention-to-treat (ITT) analysis should be used to preserve randomization. Using ITT analysis, it is irrelevant whether people
who were randomized to receive the new treatment actually took the drug, as all study participants are analyzed in their
original group. The proportion who died in the new treatment group is 80/150 = 0.533 = 53.3%. The proportion who died
in the standard treatment group is 92/150 = 0.613 = 61.3%. Therefore, the absolute risk reduction (ARR) is 0.6130.533 =
0.08 = 8%. The number needed to treat is 1/ARR = 1/0.08 = 12.5.
14
D.
This calculation requires four steps. First, calculate the likelihood ratio of a positive test (LR+) which is given by
sensitivity/(1specificity). For this test, LR+ =0.65/(10.80) = 0.65/0.20 = 3.25.
Next, calculate the pre-test odds of this patient having the disease, which is given by prevalence/(1prevalence). In this
situation this is 0.13/0.87 = 0.149.
Next, calculate the post-test odds by multiplying the pre-test odds by LR+. In this case, this is 3.25 0.149 = 0.484.
Last, convert this to a post-test probability which is post-test odds/(post-test odds + 1). Here, this is 0.484/1.484 = 0.326.
Therefore, this patient with a positive test has a 32.6% probability of having Alzheimer disease.
4 D
None are correct. The optimal study design depends on the research question. RCTs are the optimal study design to test
the effectiveness of new treatments, but other study designs are optimal for questions of prognosis or diagnostic test
accuracy. While trials in which equal numbers of participants are randomized to each treatment group are common,
different proportions of patients can be randomized to each arm of an RCT (e.g. 1:2 or 1:3). The purpose of randomization
is to achieve treatment groups that are equivalent, so as to reduce the potential for selection bias and confounding.
Information bias (e.g. recall bias or measurement error) would not be affected by the randomization process. Random
error is chance variation or noise, and this can only be addressed by increasing the size of the study.
15
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CHAPTER 3
ETHICS
Ian Kerridge and Michael Lowe
CHAPTER OUTLINE
ETHICS IN INTERNAL MEDICINE
ETHICAL THEORIES
ETHICS AND THE LAW
ETHICS, EVIDENCE AND DECISION-MAKING
TRUTH-TELLING
CONFIDENTIALITY
CONSENT
MENTAL COMPETENCE
Consent for non-competent people: best
interests and advance care planning
CLINICAL ETHICS: THEORY AND

FRAMEWORKS FOR DECISION-MAKING
END-OF-LIFE AND FUTILITY
TEACHING ABOUT ETHICS
DIGNITY AND THE CARE OF THE ELDERLY
PHYSICIANPATIENT RELATIONSHIPS AND

PROFESSIONALISM
CONFLICT OF INTEREST AND THE

PHARMACEUTICAL INDUSTRY
ETHICS IN INTERNAL MEDICINE
patients (particularly those who are most vulnerable), and to

maximize the quantity and quality of life. When seen in this
way, ethics is an inextricable part of medicine, although many
of the ethical issues that arise in clinical practice never become
the focus of attention because they are dealt with unconsciously and because, for the most part, a doctor or medical
student practicing good medicine will be acting morally and
within the law. This, however, cannot be assumed.
What is required is that doctors and students be sensitive
to the ethical dimensions of healthcare, be aware of their own
and their patients values and needs, be aware of their professional ethics and professional relationships, have the moral
imagination to recognize that different, and perhaps better,
actions and outcomes are possible, and be willing to critically
reflect upon their decisions and behavior.
Ethics is concerned with the wellbeing of individuals and communities, and with discerning what we ought to do. Ethics (or
moral philosophy) is not simply a collection of attitudes, biases
or beliefs, but is a prescriptive, systematic analysis of human
behavior, and is normativewhich means that it asserts how
things should be. Ethics makes evaluative statements and judges
some actions or decisions as better than others. Ethics rarely,
however, provides simple or absolute answers, instead emphasizing the reasons according to which one action is better than
another and the processes by which individuals and groups
should make decisions that affect others.
Medicine is ultimately concerned with the application
of knowledge and expertise to ensure the care and safety of
17
ETHICAL THEORIES
Ethics can be divided into meta-ethics, normative ethics and
practical (or applied) ethics.
Meta-ethics deals with foundational ethical questions,
including the meaning of concepts such as good, right,
virtue and justice.
Normative ethics provides principles, rules, guidelines
and frameworks for guiding and evaluating the morality
of actions.
Practical ethics, which includes bioethics, research ethics, clinical ethics and public health ethics, refers to the
consideration of ethical questions in particular contexts.
There is a great range of ethical theories and frameworks.
The main schools of ethical thought are deontology, consequentialism and virtue ethics.
Deontology refers to a type of ethics based upon
duties. Deontological justifications usually rely upon
rules, principles or commandments (Table 3-1).
Table 3-1 Examples of deontological statements
BASIS
EXAMPLES
Rules
Do not give a deadly drug to anyone

nor make a suggestion to this effect
(from the Hippocratic Oath)
Principles
Respect for autonomy

Benecence
Non-malecence
Justice
Commandments
Thou shalt not kill
Consequentialism refers to an approach to ethics that

evaluates the morality of actions according to their consequences (Box 3-1). Utilitarianism, which is a form of
consequentialism, defines the right action as that action
which achieves the greatest good for the greatest number, where good is variously defined as pleasure, happiness, preference, satisfaction or benefit.
Box 3-1
Examples of outcomes of
importance to consequentialism
Utility
Equality
Cost
Equity
Virtue ethics looks at the character of the actors

involved in an ethical decision (Box 3-2). For Aristotle, the principal theorist of virtue ethics, wisdom and
virtue could be learnt through practice, with the virtuous person acting in a way consistent with a golden
mean between two extremes of character: being brave
18
rather than cowardly or foolhardy, or thrifty rather than

miserly or extravagant.
Box 3-2
Examples of virtues in internal

medicine
Truthfulness
Equanimity
Attention to detail
Empathy
In the practice of internal medicine, physicians commonly justify their actions using a range of principles, rules and virtues.
This approach is known as pragmatism. For example, a physician may not offer intensive care to patients with end-stage
chronic obstructive pulmonary disease on the grounds that
they are likely to have a poor quality of lifea consequentialist
argument. Or, they may warn a patient of the rare side-effects
of a necessary treatment, even knowing that this might scare
the patient, because they feel that patients should always be
made aware of material risksthis is a deontological approach.
Or, they may decide that they have to inform a patient that a
mistake has been made because to do otherwise would be dishonestan argument that may arise from virtue ethics.
ETHICS AND THE LAW

The relationship between ethics and the law is extremely
complex, as ethics both forms the basis of law and is shaped
or enriched by it. Ethics and law share many characteristics, such as a commitment to critical reasoning, logical
argumentation, discretionary decision-making, and critical
reflection. However, they also differ in important respects.
The law is precise, specific, and compulsory, and incorporates punishment and legal sanction. Ethics, in contrast, is
flexible, dynamic, action-guiding in new and emergent situations, and open to disagreement.
Although the law is the final civil or political authority,
ethics is the higher moral authority; and so any law may be
judged to be invalid, inappropriate or unethical. It is not
correct that in order to act ethically one only need act in
accordance with the law. At the very least, physicians should
incorporate an understanding of both ethics and the law into
their clinical practice, recognize that clinical situations may
raise ethical and legal issues, and identify where they need
ethical, legal and/or professional guidance.
ETHICS, EVIDENCE AND

DECISION-MAKING
When we make an ethical decision it is important that we
can justify it. In internal medicine, justification of many
decisions is done by reference to the evidence base of
thedecision. This straightforward approach is not available
in ethics.
Chapter 3 Ethics
In the 18th century, the philosopher David Hume

pointed out that there is a major difficulty in moving from
statements of evidence (is) to statements of ethics (ought).
Hume suggested that there is no logical way to go from a
statement about how the world is to a statement about how
it ought to be, or what we ought to do to get it there. These
are important insights because they remind us that data or
evidence (which can be loosely defined as data to which
we attach value) do not tell us how we should actas such
decisions are inevitably issues of value and judgment.
CLINICAL ETHICS: THEORY

AND FRAMEWORKS FOR
DECISION-MAKING
When we are making or justifying an ethical decision, it is
often useful to look carefully at the facts of the case and the
literature around similar cases. This gives us the is of the decision. It is also useful to look at the ethical reasoning around the
decision. This helps us in looking at the ought of the case.
However, when it comes to actually making the decision
we may still be left with a whole range of personal beliefs,
personal values, religious values, cultural norms and feelings
that differ from person to person, and that somehow still
need to be negotiated. It is important to note that ethics in
medicine is not solely the domain of physicians but can be
understood in many different ways by different individuals,
and through different professional and personal perspectives.
A number of frameworks have been proposed to guide
clinical decision-making. These include case-based reasoning, narrative ethics (which emphasizes a patients story)
and, most influentially, principle-based ethics.
Principle-based ethics focuses on four central and two
derived principles for ethical conduct:
autonomy
beneficence (doing good)
non-maleficence (not doing harm)
justice
veracity (truth-telling)
confidentiality/privacy.
In any situation, each of these principles (which are important in themselves) must be specified and balanced by other
principles and by rules. For example, respect for autonomy
requires that a patients consent is sought before commencing
therapy, but it does not require that a patients choices must
always be complied with, irrespective of their impacts upon
others, their rationale or their cost. Rules must also be articulated to clarify who can consent, what capacities are required
before one can consent, and what should be done where a
person is unable, because of illness, to consent.
Principle-based ethics is deceptively simple and has been
criticized on the grounds that this simplicity may obscure
considered ethical reflection. However, reference to ethical
principles provides a useful language and structure for ethical
deliberation in clinical practice. In Box 3-3 (overleaf) we have
suggested a more detailed framework that takes account of
some of the criticisms that have been made of principle-based
approaches to clinical ethics.
TEACHING ABOUT ETHICS

Physicians often need to explain and teach others about the
decisions they make. Medical school teaching about ethics
tends to concentrate on three areas: ethical sensitivity (being
aware that there is an ethical issue), ethical knowledge (including knowledge of theories and the law), and ethical reasoning.
Good students, who are sensitive, knowledgeable and reasonable, can still come to different decisions because of differences in values. When teaching about ethics, physicians
must make space for others views and opinions.
PHYSICIANPATIENT
RELATIONSHIPS AND
PROFESSIONALISM
The relationship between physicians and patients is based
largely upon trust. Hall and colleagues1 have defined trust
in healthcare as the optimistic acceptance of a vulnerable
situation in which the truster believes the trustee will care
for the trusters interests. This definition seems to suggest
that the difference between trust in healthcare and trust in
other situations is that in healthcare, the truster (the patient)
is already vulnerable, and the trusting relationship arises not
from the truster making themselves vulnerable, but from
them optimistically accepting this situation.
It can be seen that trust occupies a morally difficult part
of the domain of healthcare. Because of this, it is of great
importance that any factors that may mitigate against trust
are minimized. This means that physicians must be careful to maintain appropriate interpersonal boundaries with
patients, and accept the oversight provided by bodies concerned with governance and accreditation. One of the goals
of professional codes is to allow patients to trust members of
the professions in the assurance that professional organizations regulate their members.
TRUTH-TELLING
It is generally expected that physicians have a duty to tell
the truth. Truth is a complex concept in medicine, as it
may involve probability judgments as well as expert understandings that can be difficult to convey fully. While the
moral duty to tell the truth applies to everyone in society,
truth-telling is seen to be particularly important in medicine
because patients can only make informed decisions if they
are in possession of sufficient information.
Truth-telling in medicine can be seen as one manifestation of respect for patients, as a way to improve health
outcomes by involving people in their own care; and as a
way to maintain trust between a physician and a patient.
While it is sometimes argued that there may be situations
in which it is appropriate to lie to a patient in order to avoid
distressing them (an act referred to as therapeutic privilege), or that cultural respect may require that patients are
not told about their diagnoses, or that there is a right not
to know, for the most part research supports the act of
19
Box 3-3
A framework for ethical decision-making

Clearly state the problem
Consider the problem within its context and attempt to distinguish between ethical problems and other medical, social,
cultural, linguistic, and legal issues.
Explore the meaning of value-laden terms, e.g. futility, quality of life.
Get the facts
Find out as much as you can about the problem through history, examination and relevant investigations.
Take the time to listen to the patients narrative and understand their personal and cultural biography.
Are there necessary facts that you do not have? If so, search for them.
Consider the relevant ethical principles and concepts
Autonomy: What is the patients approach to the problem?
Benecence: What benets can be obtained for the patient?
Non-malecence: What are the risks and how can they be avoided?
Justice: How are the interests of different parties to be balanced?
Condentiality/privacy: What information is private and does condentiality need to be limited or breached?
Veracity: Has the patient and their family been honestly informed and is there any reason why the patient cannot know
the truth?
Are there other ethical concepts or issues that are particularly relevant to this case, such as vulnerability or trust?
Consider how the problem would look from another perspective or using another theory
Who are the relevant stakeholders? What is their interest? What do they have to lose? How salient are their interests?
How powerful are they? How legitimate are they? How urgent are they?
How would the problem look from an alternative ethical position? For example, consequentialist, rights-based, virtuebased, feminist, communitarian, care-based.
Identify ethical conicts
Explain why the conicts occur and how they may be resolved.
Consider the law
Identify relevant legal concepts and laws and how they might guide management.
Examine the relationship between the clinicalethical decision and the law.
Make the ethical decision
Clearly state the clinicalethical decision, justify it, enact it and evaluate it:
Identify ethically viable options.
Make the decision and justify it, for example by detailing how relevant ethical principles were specied and balanced
and by clarifying what issues or processes were considered most signicant, and why.
Take responsibility for the decision.
Communicate the decision and assist relevant stakeholders to determine an action plan.
Document the decision.
Assist/mediate resolution of any conict.
Evaluate the decision.
Kerridge I, Lowe M and Stewart C. Ethics and law for the health professions, 3rd ed. Sydney: Federation Press, 2009.
truth-telling, showing that it enhances coping, compliance

and the physicianpatient relationship. As a consequence,
concealing the truth from patients is now generally felt to
be unjustifiably paternalistic and in most clinical encounters the issue is not so much whether to tell the truth but
rather when and how to do so (e.g. with compassion, tact,
timeliness, and sensitivity).
20
CONFIDENTIALITY
Patients often reveal private information to their physicians because they believe that doing so will benefit them
and because they trust that this information will not be disclosed to others without their consent. There are, however,
a number of limits to clinical confidentiality that have been
Chapter 3 Ethics
established by law. In some jurisdictions or situations, physicians may be required by law to report blood alcohol levels, actual or potential acts of violence, and the presence of
infectious diseases.
The information age has brought up many new questions about the limits of confidentiality now that new technologies that allow greater sharing of information have been
developed. As a society we are still learning to deal with
what is allowable in e-mail, blog posts, social media pages,
cloud storage and shared information systems. Healthcare
workers will need to address some of these issues from first
principles rather than from widely recognized guidelines.
It is often difficult to maintain confidentiality where care
is delivered by teams rather than individuals, where patients
move between different healthcare contexts, and where
medical information is stored electronically. Nevertheless,
physicians need to continue to respect their duties regarding
confidentiality if they are to expect patients to reveal private
and potentially stigmatizing or embarrassing information
about themselves.
CONSENT
Consent is the primary means by which respect for autonomy is realized, and one of the key ways in which the
healthcare system ensures that patients are actively involved
in decisions about their healthcare. Key legal justifications
for consent include as a defense against a charge of assault,
and as part of a defense against some charges of negligence.
Internal medicine is often non-procedural, so the question
of assault may not arise. However, patients still need to consent to investigations, medications, and communication
with others because of the second justification.
For consent to be ethically and legally valid, it must occur
without coercion, the patient must be informed of material
risks, and they must have the capacity to understand and give
consent. In a negligence case, the litigants must prove (among
other things) that a physician has breached their duty of care.
If it can be shown that there was a problem with the consent processe.g. the patient was not informed of material
risksthen this might be used to demonstrate such a breach.
There is often disagreement about what information
should be provided to patients in any given situation, particularly about what risks should be discussed, or how it is
determined what risks are material. However, it is generally
accepted that adequate disclosure would include information about:
diagnosis (including degree of uncertainty about this)
prognosis (including degree of uncertainty about this)
options for investigations and treatments.
likely burdens and benefits of investigations and treatments (including possible adverse effects, time involved,
and likely cost)
whether the proposed treatment is established or
experimental
who would carry out the intervention
the consequences of choosing or not choosing the
intervention.
While this list provides a guide to what should be discussed

with patients in order to ensure that they can provide consent to treatment, the nature of the information given might
be modified by the seriousness of the patients condition, the
nature of the intervention, the riskiness of the intervention,
and the patients understanding and need for information.
MENTAL COMPETENCE
It is broadly accepted that patients should be allowed to make
decisions about their own medical care. Unfortunately, not
everyone is able to doso.
There are two different terminologies used for describing the inability to decide for ones self: impaired competence, and impaired decision-making capacity. Some
authors make a distinction between these two terms, referring to competency as a legal decision made by a judge that
a patient is able to make medical decisions for themselves;
and decision-making capacity as a physicians determination based on clinical examination that a patient is able to
make medical decisions for themselves. In the clinical setting, these terms are often used interchangeably.
Competence is usually assessed in terms of a particular
decision that a patient has to make. When assessing competence, it is important to carefully talk through the decision
with the patient, and judge whether their decision appears
to be rational. However, it is also important to attempt
to get a more general view of a persons decision-making
skillsthis is usually done by a cognitive assessment such as
a mini-mental state examination (MMSE). More complex
decisions require greater mental competence to work
through. Where there are serious consequences to decisions,
clinicians must try to be as certain as possible about whether
the patient is competent or not.
Cognitive assessment is not the same as competence assessment. A person can be cognitively intact but have impaired
decision-making capacity for some decisions, or a person may
be cognitively challenged but have decision-making capacity.
In a young person, the most common causes of impaired decision-making capacity are probably psychiatric conditions. In
an elderly person, the most common cause of impaired decision-making capacity is dementia. This means that impaired
cognition is a better indicator of impaired decision-making
capacity in the elderly than in the young.
Consent for non-competent people:

best interests and advance care
planning
In healthcare settings it is common for patients to be unable
to give valid consent themselves, so other ways of involving
the patient in decisions about their healthcare often need to
be found. In some cases a patient has previously expressed
their wishes, either in a written document (an advance directive) or through a legally recognized process (advance care
planning). While advance directives are often not available,
it is important to establish whether the patient has already
made decisions about their own care.
If evidence of advance planning is not available, decisionmaking for patients who cannot decide for themselves is
21
usually done through the use of a surrogate decision-maker.

The law typically provides for various mechanisms of substitute decision-making, including:
guardianship or orders from a court or guardianship
authority (a guardian is a person who is appointed by
a court or guardianship authority to make decisions on
behalf of an incompetent adult)
enduring powers of attorney over health matters
persons responsible (many jurisdictions now grant
rights to relatives and close friends to consent to treatment and have a hierarchy of possible decision-makers,
including a court/tribunal-appointed guardian; an
enduring guardian; a spouse in a close and enduring
relationship with the patient; an unpaid primary carer;
or a close friend or relative)
statutory health attorneys.
Surrogate decision-makers may decide for patients either by
considering a patients best interests or by attempting to
understand what decision the patient themselves might have
made had they been competent to do so. The latter process
is called substituted judgment.
Courts, guardianship authorities and guardians are generally required to make decisions in the best interests of the
patient. It is often difficult to define (medically, ethically and
legally) what is actually in the patients best interests, but this
generally includes both medical and social factors and their
impact on the patients life. Although it remains controversial (in law, but not in ethics or medicine), it is now largely
accepted that there may be situations in which withdrawal
of treatment may be in a persons best interestseven where
this may hasten their death.
Increasingly, surrogate decision-makers are urged to
make decisions based on a substituted judgment rather than
a decision from best interests criteria. While the evidence
suggests that in the absence of a clear advance directive it is
often very difficult for substitute decision-makers to make an
accurate substituted judgment, from an ethical perspective it
is certainly worthwhile encouraging them to try to do so.
In the absence of either an advance directive or a substitute
decision-maker, a physician may provide treatment without
explicit consent as long as the treatment is, in their opinion,
an emergency treatment that cannot be postponed until an
appropriate decision-maker is found. Hospitals will generally
have their own administrative procedures for when such circumstances arise, such as notifying medical directors or seeking second opinions.
END-OF-LIFE AND FUTILITY

Internal medicine is intimately concerned with matters of
life and death; and end-of-life situations are probably more
common in internal medical specialties than in any other.
This means that physicians working in internal medicine
need to be well prepared and comfortable in dealing with
patients at the end of their lives.
One of the more important aspects of end-of-life care
is that clinicians are aware that the patient is near the end
of their life, and that they develop a way of discussing this
with the patient and their family. In many cultures, such
22
discussions are expected to be oblique rather than direct,

and physicians will need to tread a careful path between
being sensitive to cultural norms and giving the wrong message. For example, overuse of euphemisms (e.g. passing on)
might mean that the patient or their family do not understand what is happening.
There is sometimes potential for disagreement in end-oflife decision-making. Two areas of disagreement are where
the physician believes that aggressive treatment is warranted
but the patient or family does not, and where the patient or
family believe that aggressive therapy is warranted but the
physician does not. There is also often disagreement among
family members about these points.
In the first situation, the patients rights are protected by
the need for valid consent, and the physician must take
care to present treatment options appropriately and not
coerce the patient and their family.
The second situationwhere the patient or family wants to have aggressive therapy that the physician
believes is inappropriateis often discussed by reference to the concept of futility.
Futility has been defined both by attempting to quantify it
numerically, and by attempting to define it qualitatively as a
situation in which patients cannot reach their desired goals
or outcomes. Both of these definitions run into difficulties.
Another approach to the question of futility is to define it
as a disagreement in goals between patients, families, and
treating staff. Defining it in this way does produce some
approaches that may allow the situation to be resolvedby
resolving the disagreement. This might involve both greater
attempts at communication and also the development of
institutional guidelines for when such situations occur.

End-of-life decision-making often includes decisions
about instituting CPR. Most hospitals will have clear policies about CPR which will include guidelines as to when
no CPR, DNR (do not resuscitate) or NFR (not for
resuscitation) orders may be written and how this should
be done.
Hospital policies often overlook the fact that the major
aim of CPR directives is to institute communication
between physicians, patients, patients relatives and other
health professionals about the goals of care and medical
management at the end of life. In some situations, this will
take the form of preparing a patient to make a decision about
whether they wish to have CPR undertaken in the event of
a cardiac arrest. In other situations, the aim will be to ensure
that the patient and their family know that CPR will not
be offered or performed. In all situations, CPR discussions
need to be approached sensitively and seen as just one small
part of a more comprehensive management plan.
DIGNITY AND THE CARE OF

THE ELDERLY
An increasing number of physicians patients are elderly
people with chronic disease. A key goal in management of
Chapter 3 Ethics
such patients is to maintain their dignity and sense of self. It

is important to realize that much of who we are as persons is
tied up in our social selves, so that we can appreciate elderly
peoples dignity best within their social settings.
Hughes2 has suggested a number of ethical principles
for the medical care of patients with dementia. He suggests
that while it is possible to have a good life with dementia in
appropriate circumstances, the tragedy of this disease should
not be overlooked. He also makes the important point that
we should continue to regard each person with dementia as
someone whose personhood is somehow maintainedeven
if it is increasingly difficult for onlookers to access.
This last point is often misunderstood and needs to be
emphasized. If an elderly patient with severe dementia is
admitted to hospital, and a decision is made to not proceed
with life-saving care, it is important that this be done from
a sense of maintaining the best interests of a valued person,
rather than dismissing the claims of a person without value.
CONFLICT OF INTEREST
AND THE PHARMACEUTICAL
INDUSTRY
All doctors have competing interests, and each professional
or personal role that we have is associated with a different set
of competing moral, social, and professional imperatives. In
ethical terms, what is necessary is to establish whether any of
these divergent interests constitute a genuine conflict of interest, such that ones commitment to patient care, research
or teaching is distorted or subverted. This is a matter both
for considered personal reflection and for the judgment of
peers and the community. Role conflicts can occur between
doctors roles as carers and advocates for patients, as agents
for spending, as educators, as researchers, and in numerous
other roles.
Relationships between medical professionals and
health-related industries (particularly the pharmaceutical
industry) have long been a source of intense debateboth
because physicians act as gatekeepers for the provision of

expensive services and because of public and professional
concerns that such relationships may become corrupted.
There is concern that relationships between physicians and
the pharmaceutical industry may increase the costs of healthcare, create gift relationships of reciprocity and mutual obligation, encourage prescribing of medicines that are either not
needed or are more expensive than existing alternatives, and
ultimately subvert the (proper) goals of medicine.
Unfortunately, it is not always easy to define or recognize conflicts of interest and their management is often
not straightforward. While all would agree that competing
interests should be declared, this is not in itself sufficient to
prevent their abuse, and it is important for individual physicians and students to consider whether any new relationship
or activity represents a real, potential, or perceived conflict
of interest. The profession as a whole also needs to develop
rigorous, transparent, and acceptable processes for managing
competing interests and for clarifying the circumstances in
which they should be managed. Some ways in which competing interests can be managed include through declaration, but also through consultation with others, abstention
from situations where they occur, and through divestment
or separation of relationships with pharmaceutical companies and with those pertaining to patient care. This is often
not straightforward.
In general, physicians should avoid actual and perceived
conflicts by not accepting meals, gifts, ghost-authorship,
support for partners and family members, or industryproduced educational resources; and should accept research
and educational support only under very limited and controlled circumstances.
References
1
Hall M, Dugan E et al. Trust in physicians and medical institutions:

what is it, can it be measured and does it matter? Milbank Quarterly
2001;79(4):61339.
Hughes J. Ethical issues and decision-making in dementia care.
Alzheimers Australia. Canberra: National Press Club, 2010.
23
Choose the MOST correct answer for each of these questions.
1
A 46-year-old man presents to the Emergency Department with a life-threatening gastrointestinal hemorrhage (GIH).
He has a card with him that states that he is a Jehovahs Witness and will not accept a blood transfusion. Despite every
effort to control his GIH, he continues to bleed. As he becomes more shocked, he becomes agitated and panicky and
starts saying that maybe he will accept a blood transfusion. In this situation, the doctors initial responsibility is:
A To follow the patients advance directive.
B To discuss with the patients family to ascertain whether they would allow the medical staff to overrule his directive
and give a transfusion.
C To contact the Jehovahs Witness local liaison committee to provide the patient with support.
D To assess the patients mental capacity and see whether he is no longer competent to make a decision.
E To contact the hospital lawyer about whether the patients advance directive can be overridden.
As part of your specialist practice, you become aware that one of the local family physicians is making poor decisions
about patients. At times this has resulted in late diagnoses and inappropriate medication usefalling far short of a
reasonable standard of care. Which of the following statements is most correct?
A You should always discuss your concerns with the physician rstit is unfair to judge the physician without hearing
his/her side of the story.
B This should be discussed as part of the hospital morbidity and mortality meeting.
C You should notify the local family physician organizations.
D You should contact the medical registration authority to seek advice.
E You should encourage patients under the care of this physician to raise concerns about their management with
him/her.
A woman with advanced dementia is admitted to the hospital at the end stage of the disease. She is semiconscious,
andhas apparently been so for some time. The patients son says his mother is staunchly religious (Roman Catholic)
and has always been opposed to euthanasia and mercy-killing. He requests a percutaneous endoscopic gastrostomy
(PEG) tube, saying that he believes that it would make her more comfortable. He is the appointed guardian of his
mother. Which of the following is most true?
A PEG tubes do not increase the lifespan of people with dementia, so it should not be offered.
B Since he is the guardian, his request must legally be accepted.
C A PEG tube may be used because it fullls a clear therapeutic aim (making the patient more comfortable); however,
you are not bound to follow the instructions of a guardian if you believe it is against the patients best interests.
D Although he is the guardian, he has no real say in his mothers medical decisions.
E Because the Roman Catholic Church does not require tube feeding in this circumstance, it should not be offered.
4 An unconscious patient with a cerebral hemorrhage is a registered organ donor on the national register of organ donors.
The advice of the register is that he has consented to being an organ donor. The senior physician in the intensive care
unit believes that it may be appropriate to discuss organ donation with the family. When she raises the subject of organ
donation with the patients partner, he says that he could not bear to think about organ donation because he is too upset
and that he cannot bear the thought of his partner being cut up like that. Which of the following is most true?
A A person may express a wish to consent to organ donation during their lifetime, but health professionals are not
bound to take the persons organs.
B The consent of a possible donor can be overturned by a family member but not a de facto partner.
C The preferences of partners or family members cannot be taken into account in these circumstances.
D Advance directives may be overridden if a person is no longer competent.
E Advance directives have no basis in lawthey are merely expressions of a persons wishes.
5
A 23-year-old-woman with a past history of chronic fatigue syndrome presents with an acetaminophen (paracetamol)
overdose. She states that she refuses treatment since her life is hell and she wishes to die. Her mini-mental state
examination (MMSE) score is 30/30. Which of the following responses is most correct?
A An order for compulsory treatment while she is undergoing psychiatric assessment should be completed, and she
should be forcibly treated while awaiting full assessment.
B The patient should be referred to palliative care services as she is likely to die without treatment.
C Because she has a normal MMSE score, she must be presumed to be mentally competent.
D This person must be assumed to be mentally incompetent until proven otherwise.
E An act of attempted suicide is, by denition, evidence of depression.
6 A patient with severe alcoholic dementia and a mini-mental state examination (MMSE) score of 17/30 is found to
have a large basal cell carcinoma on the cheek. On discussion, he seems to understand that it needs to be resected
as otherwise it will eat into the surrounding tissues. He understands that he will need skin grafting and that he will
not have a perfect cosmetic appearance afterwards. His main concern is that the operation will not make him into a
vegetable, and he can be reassured about this. With regard to the decision to have the surgery:
24
Chapter 3 Ethics
A Because this patient has a low MMSE score, he cannot be allowed to make this decision.
B Because the cancer will eventually be life-threatening, he can be operated on without his consent using common
law criteria.
C The patient seems to be unable to understand that his facial nerve may be damaged in the operation. Because he
cannot understand this material risk, he cannot be allowed to make this decision.
D If some relatives for him can be found, they can be used as surrogate decision-makers.
E The patient can consent to the decision because he is presumed to be competent and he understands the
procedure and the risks that are material to him.
ANSWERS
1
D.
This follows from the discussion in the chapter about competence. If the patient is competent, he can accept a
transfusion even if this goes against his previously expressed wishes. If he is not competent, then his advance directive may
stand but legal advice will need to be urgently sought. Competence is presumed in adults and must be disproved before a
person can be found incompetent.
D.
This is a question of professional regulation and hence the medical authority is an appropriate rst step. There may be
condentiality issues with answers B and C. Answers A and E are unlikely to be effective if the doctor is truly impaired, but
may delay investigation by the medical authority.
C.
This is a question of ethical reasoning. Answers A, B, and E are examples of inappropriate reasoning from facts to values.
Answer D is simply incorrect.
4 B.
Registration on an organ donor register is a form of express consent which is widely recognized. However, there is no
obligation to take organs from a donor. In some states or countries, the consent of the donor can be overridden by family
members, including de facto partners; while in others, there is no legal requirement to confer with the family if the donor
has expressed consent during their lifetime. However, even where it is not necessary to confer with family members, it
is common for this to occur out of ethical and sociocultural concern for the impact of donation on family members.
Advance directives are concerned with treatment of living patients and are not relevant to donation, although it may be
possible to have expressed donation consent within one. If that has occurred, the express consent would be the only
legally relevant issue and the rest of the directive would become ineffective on the death of the patient.
5
A.
Mental health laws provide for compulsory treatment when a person is suffering from a mental illness or disorder and they
are a danger to themselves or to others. Answer A is the most correct at the time of writing.
6 E.
Adult patients are presumed to be competent. This assumption may be disproved by evidence that the person cannot
understand the nature and the effects of treatment being offered, or where a patient is unable to communicate a decision.
25
CHAPTER 4
CLINICAL PHARMACOLOGY
AND TOXICOLOGY
Matt Doogue and Alison Jones
CHAPTER OUTLINE
PRESCRIBING
1. PRINCIPLES OF CLINICAL
PHARMACOLOGY
DEPRESCRIBING
INTRODUCTION
PHARMACOKINETICS
Administration
Bioavailability (F)
Clearance (CL)
Distribution
Drug transport
Patient size
PHARMACODYNAMICS
Therapeutic index
Drug targets
THE INNOCENT BYSTANDER
2. QUALITY USE OF MEDICINES

GETTING IT RIGHT
The circle of care
ADVERSE DRUG REACTIONS

DRUG INTERACTIONS
THERAPEUTIC DRUG MONITORING (TDM)

DRUG REGULATION
DRUG RESEARCH
3. TOXICOLOGY
EPIDEMIOLOGY OF POISONING
SOURCES OF POISONS INFORMATION AND
ADVICE
CLINICAL ASSESSMENT OF POISONED
PATIENTS
Investigations
Risk assessment
PRINCIPLES OF MANAGEMENT OF
POISONED PATIENTS
COMMON POISONS AND THEIR
MANAGEMENT
27
Non-steroidal anti-inammatory drugs (NSAIDs)
Newest antidepressants
Benzodiazepines
DRUGS OF ABUSE OR MISUSE
Amphetamines
Opioids, e.g. heroin or morphine
Synthetic cathinones, e.g. vanilla sky, ivory
wave
Clinical pharmacology is the clinical and scientific discipline

that involves all aspects of the relationship between drugs
and humans. In considering this relationship, it is useful to
consider drugs both in individual patients (pharmacotherapy) and in populations (pharmacoepidemiology). This
chapter on clinical pharmacology has three sections.
1 Principles of clinical pharmacologythe steps from
drug ingestion to drug effects; what the body does to
the drug (pharmacokinetics) and what the drug does
to the body (pharmacodynamics).
2 Quality use of medicines (QUM)the tools of safe,
effective and rational use of drugs in individuals and in
populations.
3 Clinical toxicologyunderstanding and managing supratherapeutic (toxic) doses of drugs and other
substances.
1. PRINCIPLES OF CLINICAL
PHARMACOLOGY

Drink spiking
CHEMICALS
Acids and alkalis

Chlorine
Pesticides
Lead poisoning
SPIDER BITES
SNAKE BITES
MARINE ENVENOMATION
TERRORISM, AND USE OF MEDICAL
COUNTERMEASURES
Chemical agents
Biological agents
In clinical studies, groups of patients are studied:

to define therapeutic doses for a population
to consider whether there are sub-populations of
response (for future pharmacokinetic and dynamic
research)
to describe drug disposition, and
to describe and quantify drug effects.
Applying the information derived from clinical studies to clinical practice is based on a thorough understanding of pharmacokinetic and pharmacodynamic variability and therefore the
relevance of trial data to an individual patientthese usually
vary greatly from the average of the population studied.
Treatment of a patient with a drug can be described by
the interaction between drug and patient through multiple
steps (Figure 4-1).
Administration
adherence
route
Prescription
Pharmacokinetics
INTRODUCTION
Pharmacotherapy has two components, patient and drug(s);
and two processes, pharmacokinetics and pharmacodynamics. Pharmacokinetics (PK)what the body does to the drugis
about the factors affecting drug exposure. Pharmacodynamics (PD)what the drug does to the bodyis about the factors
affecting drug effects.
Drug effects differ between individuals. Understanding
and managing therapeutic variability requires consideration
of both drug and patient.
In clinical practice, patients are treated with therapeutic
intent using drugs at doses
to maximize potential benefit, and
to minimize potential harm.
28
Dose
Clearance
metabolism
excretion
Pharmacodynamics
Patient
health
Effect/s
Bioavailability
absorption
first-pass
metabolism
activation
Concentration
Distribution
diffusion
transport
concentration at target
affinity to target
molecular effect/s
physiological effect/s
Figure 4-1 Pharmacotherapy, from prescription to

health
Chapter 4 Clinical pharmacology and toxicology
PHARMACOKINETICS
Pharmacokinetics, what the body does to the drug, is mainly
about the relationship between drug dose and drug concentration at steady state (Css). This can be understood byconsidering the active drug from administration to excretion
and all points in between. Inactive drug metabolites are not
biologically important and can usually be ignored.
To understand and apply pharmacokinetics, some math
is necessary. For example, doubling a drug dose usually
results in doubling the drug concentration.
CLINICAL PEARLS
The ABCD of pharmacokinetics:
A Administrationdrug dose and route
B Bioavailabilitypercentage of the drug dose reaching the systemic circulation
C Clearanceremoval of drug from the systemic
circulation
D Distributiontransport of drug to the site(s) of action
and distribution within the body
Administration
Administration of a drug involves dose and route.
Dose is amount per time and is usually given by drug
mass (e.g. mg) and frequency (e.g. daily). Duration of
dose is important, as it takes time (45 lives) to reach
steady-state concentration, and can take longer to
achieve therapeutic effects.
Route of administration is important to drug disposition. The most common route is oral, but every conceivable route is used to administer drugs, depending
on the physico-chemical characteristics of the drug.
The route of administration affects both the rate and the
extent of the drug reaching the systemic circulation.
Bioavailability (F)
Bioavailability is the proportion of the drug dose that reaches
the systemic circulation. For orally administered drugs, bioavailability is made up of absorption and first-pass hepatic
extraction. For orally administered drugs, there are three
steps in reaching the systemic circulation:
1 Ingested drug must remain intact in the gastrointestinal (GI) tract to reach the apical membrane of the
enterocytes.
2 The drug must cross the gut wall into the portal circulationdrug absorption. The proportion absorbed
is determined by drug transport (discussed later) across
both the apical and the basolateral membranes of
theenterocyte and by any drug metabolism within the
enterocyte.
3 The drug must pass from the portal circulation through
the liver to the systemic circulation. First-pass hepatic
extraction is the proportion removed by the liver.
Bioavailability is expressed as a percentage. For a drug with
high bioavailability (>70%), variability between individuals
is not usually important. However, for a drug with low bioavailability, variability causes some patients to be exposed to
more drug and others to less drug. For example, for a drug
with 10% bioavailability, 90% of the drug is removed before
reaching the systemic circulation. If this is halved (i.e. only
45% is removed), then 55%, or about five times as much, of
the drug will reach the circulation. Conversely, if the proportion of drug removed is only marginally increased from
90%, all the drug may be removed and hence no drug will
reach the target. Fooddrug interactions (e.g. grapefruit
juice and simvastatin, or food and oral bisphosphonates)
can affect absorption, and drugdrug interactions can affect
absorption and/or first-pass metabolism. These are particularly an issue for drugs with low bioavailability. A particular case in hospitalized patients is enteral feeding with the
potential for interactions affecting drug absorption.
Clearance (CL)
At steady state, the rate the drug enters the circulation (bioavailability dose amount dose frequency) equals the rate
the drug leaves the circulation (elimination). Elimination is
dependent on both drug concentration and the capacity of
the body to remove the drug, which can vary greatly. The
capacity of the body to remove the drug from the circulation is drug clearance, or more accurately apparent drug
clearance.
Clearance (L/h) is defined experimentally as dose
amount (mg) divided by area under the concentration
time curve (AUC) (h.mg/L). Clinically this corresponds to
dose (mg/h) divided by average concentration (mg/L). If a
patient has reduced clearance of a drug, the maintenance
dose should usually be reduced proportionally, e.g. half the
normal clearance = half the usual dose. Likewise, if a patient
has high clearance of a drug, the maintenance dose should
usually be increased proportionally, e.g. twice the normal
clearance = twice the usual dose.
clearance =
volume/time =
dose bioavailability
average steady-state concentration
amount/time percent
amount/volume
Equation 1
Equation 1 illustrates that clearance and bioavailability

determine steady-state drug concentration for any given
dose. Hence changes in clearance and bioavailability need
to be considered when choosing a maintenance drug dose.
Drugs are cleared from the body in two ways:
1 by metabolism to inactive metabolites
2 by excretion of active drug.
The most important method of clearing active drug is by
metabolism, and most drug metabolism occurs in the liver.
Excretion of active drug is most commonly in urine but may
also be in feces, in breath or in other body fluids.
Drug metabolism
Drug metabolism usually involves converting a biologically active molecule to one or more biologically inactive
molecule(s). Some drugs have an active metabolite, and
29
occasionally drugs have several active metabolites. All active

drug moieties are eventually cleared by metabolism or excretion. In most cases there is one drug moiety responsible for
most of the activity and others can largely be disregarded.
Drug metabolism is mediated by enzymes that evolved
in the biological arms race between animals and plants.
These enzymes serve as the defense against toxic xenobiotics ingested when animals eat plants, and their importance
to drug treatment is that they inactivate drugs ingested by
patients.
The cytochrome P450 enzymes (CYPs) catalyze oxidation and reduction reactions (Figure 4-2). Other enzymes
catalyze conjugation reactions such as glucuronidation by
the uridine diphosphate (UDP)-glucuronosyltransferases
(UGTs). Oxidation/reduction and conjugation are the two
major methods of drug metabolism. Proteases are responsible for protein catabolism, and most biologicals (e.g.
monoclonal antibodies) are eliminated by a combination of
protein catabolism and target binding, which is followed by
catabolism of the complex.
Ribbon
model of
CYP2C9
isozyme
Pro-drugs
Some drugs are administered as inactive pro-drugs and are
metabolized to the active form, for example aspirin, the
angiotensin-converting enzyme (ACE) inhibitors, and azathioprine. It is the pharmacokinetics of the active drug moiety, whether this be the parent drug or a metabolite, that is
clinically important.
Drug excretion
Some active drug moieties are excreted from the body
unchanged, not metabolized. Renal excretion is the most
important route and is a combination of two processes:
1 glomerular filtration
2 renal tubular transport.
The liver also excretes drugs in the bile via bile transporters.
After biliary excretion, some of these drugs are resorbed
from the gut (enterohepatic recirculation), although eventually they are either excreted in the feces or metabolized.
Cytochrome P-450
CYP3A
50%
Other
5%
5%
CYP2C9
15%
CYP2D6
25%
CYP1A2
J. Perkins
MS, MFA
CYP
Substrate
1A2
Acetaminophen, antipyrine, caffeine, clomipramine, olanzapine, ondansetron, phenacetin, rilozole, ropinirole, tamoxifen, theophyline, warfarin
2A6
Coumarin
2B6
Artemisinin, buproprion, cyclophosphamide, S-mephobarbital, S-mephenytoin, (N-demethylation to nirvanol), propofol, selegiline, sertraline
2C8
Pioglitazone
2C9
Carvedilol, celecoxib, fluvastatin, glimepiride, hexobarbital, ibuprofen, losartan, mefenamic, meloxicam, montelukast, nateglinide, phenytoin, tolbutamide, trimethadone,
sulfaphenazole, warfarin, ticrynafen, zafirlukast
2C19
Citalopram, diazepam, escitalopram, esomeprazole (S-isomer of omeprazole), irbesartan, S-mephenytoin, naproxen,nirvanol, omeprazole, pantoprazole, proguanil,
propranolol
2D6
Almotriptan, bufuralol, bupranolol, carvedilol, clomipramine, clozapine, codeine, debrisoquin, dextromethorphan, dolasetron, fluoxetine (S-norfluoxetine), formoterol,
galantamine, guanoxan, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexiletine, olanzapine, oxycodone, paroxetine, phenformin, phenothiazines,
propoxyphene, risperidone, selegiline, (deprenyl), sparteine, thioridazine, timolol, tolterodine, tramadol, tricyclic antidepressants, type 1C antirhythmics (e.g. encainide,
flecainide, propafenone),venlafaxine
2E1
Acetaminophen, chlorzoxazone, enflurane, halothane, ethanol (minor pathway)
3A4
Acetaminophen, alfentanil, almotriptan, amiodarone, astemizole, beclomethasone, bexarotene, budesonide, S-bupivacaine, carbamazepine, citalopram, cocaine, cortisol,
cyclosporine, dapsone, delavirdine, diazepam, dihydroergotamine, dihydropyridines, dilitiazem, escitalopram, ethinyl estradiol, fentanyl, finasteride, fluticasone,
galantamine, gestodone, imatinab, indinavir, itraconazole, letrozole, lidocaine, loratidine, losartan, lovastatin, macrolides, methadone, miconazole, midazolam, mifepristone
(RU-486), montelukast, oxybutynin, paclitaxel, pimecrolimus, pimozide, pioglitazone, progesterone, quinidine, rabeprazole, rapamycin, repaglinide, ritonavir, saquinavir,
spironolactone, sulfamethoxazole, sufentanil, tracrolimus, tamoxifen, terfenadine, testosterone, tetrahydrocannibinol, tiagabine, triazolam, troleandomycin, verapamil, vinca
alkaloids, ziprasidone, zonisamide
27
Doxercalciferol (activated)
Abacavir, acyclovir, alendronate, amiloride, benazepril, cabergoline, digoxin, disoproxil, hydrochlorothiazide, linezolid, lisinopril, olmesartan, oxaliplatin, metformin,
No/
moxifloxacin, raloxifene, ribavirin, risedronate, telmisartan, tenofovir, tiludronic acid, valacyclovir, valsartan, zoledronic acid
minimal
involvement
Figure 4-2 Cytochrome P450 drug-metabolizing enzymes. The proportion of drugs metabolized by each CYP
isozyme is shown. Known polymorphisms in these enzymes require a drug dosage adjustment. If two drugs are
metabolised by the same CYP enzyme, the normal routes or rates of metabolism can be affected and plasma
drug concentrations may be altered
From Raffa RB, Rawls SM and Beyzarov EP. Netters Illustrated pharmcology, updated ed. Philadelphia: Elsevier, 2014.
30
There are also other routes of excretion, for example volatile anesthetics excreted via the lungs.
that have half-lives of a few hours but remain in bone for

months or even years.
Variation in drug clearance
Half-life (t)
Drug clearance varies considerably between patients. Most

clinicians are aware that renal drug clearance is proportional
to glomerular filtration rate (GFR) and that drug metabolism
can be increased or decreased by other drugs (see section on
drug interactions below). However, there is also large variability in the clearance of metabolized drugs and hence their
concentrations. This becomes apparent when drug concentration or drug effect is monitored. One example is tacrolimus in renal transplant patients, where inter-individual
variability in metabolism by CYP3A means that about a 10fold range in dose is required to achieve the same drug concentration in different patients. Another example is warfarin
and the wide range of doses used to achieve a target INR
(international normalized ratio). While variability between
individuals is obvious in these cases, variability in clearance
is present for all drugs and is clinically most important for the
outliers, those patients with very low or very high clearance.
The half-life is the time taken for the drug concentration to

fall by a half. Experimentally it is calculated from the slope
(k) of the elimination phase of the log (ln) concentration
time curve. Drug half-life is important to dose interval. The
ideal dose interval is once daily, but drugs with short halflives usually need to be dosed more frequently, for example
most antibiotics.
Distribution
half-life =
ln 2 volume of distribution
clearance
Equation 3
The relationships between the major pharmacokinetic

parameters are shown in Beggs pharmacokinetic triangle
(Figure 4-3).
CLINICAL PEARL
At steady state, amount in = amount out, i.e. drug dose
= drug elimination.
When drugs reach the systemic circulation, they are not

evenly distributed about the body. Hydrophilic drugs are
usually found predominantly in extracellular fluid, and lipophilic drugs predominantly in cells. Most drugs are present
at different concentrations at different sites within the body.
The apparent volume of distribution (Vd) of a drug is the
volume the drug would occupy given the amount of drug in
the body (AB) and the steady-state concentration. For example, a drug with a Vd of 0.2L/kg is likely to be contained
within the extracellular fluid, whereas a drug with a Vd of
10L/kg is likely to be at higher concentrations in cells than
in plasma.
Importantly, volume of distribution allows estimation
of a loading dosethe amount of drug needed to quickly
reach a target concentration.
The above discussion applies to first-order pharmacokinetics, which applies to most drugs most of the time. For
drugs with first-order pharmacokinetics, doubling the dose
doubles the concentration.
Pharmacokinetics are illustrated graphically by
concentrationtime curves (Figure 44, overleaf).
Zero-order pharmacokinetics occurs when there is constant elimination (rather than constant clearance). Ethanol
is an example, familiar to many, of a drug that exceeds (saturates) the bodys capacity for elimination at therapeutic
doses; phenytoin is another example. In drug overdose,
elimination capacity is often exceeded and first-order principles, such as half-life, do not apply.
volume of distribution
= drug amount in the body concentration
Drug transporters move drugs across cell membranes. Understanding drug transport helps explain drug distribution and
Equation 2
Drug transport
volume = amount amount/volume

Amount of drug
in the body
CLINICAL PEARLS
na
eli
mi
t 1/2
tio
Distribution is about drug concentration at the site of

action. However, this can be hard to measure, and the relationship between plasma drug concentration and concentration at the site of action is not captured by a single metric.
For example, metformin has a short half-life in the circulation and is thus sometimes dosed three times daily. However, the concentration in the hepatocyte mitochondria
changes slowly, allowing dosing twice daily or even daily.
Another. more extreme. example is the bisphosphonates
bu
tio
V d istri
d
of
k
ra
te
co
lum
ns
ta
vo
nt
A loading dose is useful when rapid onset of drug

effect is desirable, e.g. acute pain, some infections.
In treating a chronic illness, start with a low dose
and titrate to effectstart low, go slow.
RE
rate of elimination
CL
clearance
Cp
plasma concentration
Figure 4-3 Beggs pharmacokinetic triangle.

The sides of the triangle show how the major
pharmacokinetic variables are related
31

A
Serum drug
concentration
IV administration
Efflux
transporter
Oral administration
Ion
transporter 2
12
Time (hours)
Drug administered
at 0 hours
18
Ion
transporter 2
24
Portal
circulation
Cell
Gut lumen
Serum drug
concentration
Multiple doses
Single dose
0
12
Steady-state
concentrations
achieved
18
24
Time (hours)
30
36
Figure 4-4 Drug concentrationtime curves for (A)

administration of the same drug by oral and IV routes;
and (B) multiple doses of an oral drug administered
every 6 hours and with rst-order elimination. As the
drug accumulates in the body, excretion eventually
balances absorption and this results in steady-state
concentrations being achieved
Figure 4-5 Lipophilic drugs are excluded from the

cell by efflux transporters; some are metabolised in
the cell. These systems protect us from environmental
xenobiotics (mostly plant toxins). Polar drugs require
transporters to enter and leave cells. These systems
provide us with access to micronutrients (e.g. essential
amino acids) and the ability to move endogenous
molecules in and out of cells.
hence drug concentration at the site of action. Drug transport is also important to absorption and excretion.
Functionally, there are three main groups of drug
transporters:
1 Efflux transporters take drugs that have diffused across
cell membranes into cells out of cells.
2 Anion and cation transporters move polar drugs
acrosscell membranes bi-directionally.
3 Vesicular transporters move large drug molecules across
cell membranes by endocytosis and exocytosis.
Transporters that allow drugs to cross cell membranes
(groups 2 and 3) can be grouped as facilitative transporters.
Like drug-metabolizing enzymes, drug transporters are not
only there to transport drugs but have endogenous substrates. Figure 4-5 illustrates the role of drug transporters in
the gastrointestinal epithelium.
tissues. Our current understanding of the role of transporters in pharmacokinetics is not as well developed as our
understanding of drug-metabolizing enzymes. The clinical
questions related to drug transport are: What is the likely
drug concentration at the site of action? What is the bioavailability and clearance? Both of these can be affected by
drug transport.
CLINICAL PEARL
At steady-state conditions, the net effect of drug transport is to maintain a concentration gradient across one
or more cell membrane(s). For example, efflux transporters result in low cerebrospinal uid concentrations
of many drugs. Transporters are particularly important
to drugs that act on intracellular targets.
Protein binding is only important in the interpretation of drug
concentrations. At steady state, the free drug concentration in
the circulation is in equilibrium with concentrations in tissues; but free concentration is seldom measured directly. The
measured plasma concentration of a drug is usually the total
plasma concentration, i.e. free drug concentration + concentration of drug bound to plasma proteins. Hence, changes in
protein binding or the concentration of plasma proteins can
affect interpretation of the drug concentration.
The physico-chemical properties and structural characteristics of drugs are important to drug disposition and
metabolism. One example is acidity/basicity, usually
described by the pKa of the drug. One clinical application of
this is alkalinization of urine to increase the renal excretion
of weak acids in some drug overdoses.
There are many drug transporters, each expressed to different extents in different tissues. Similarly, drugs are often
substrates of multiple transporters. Hence, for any particular drug different transporters are important in different
32
Drug pharmacokinetics vary substantially between individuals and are further altered in disease.
In clinical practice the dosing of most drugs is crude,
e.g. going from 1 tablet a day to 2. To make most treatment
decisions, relatively crude estimates of drug pharmacokinetics in the patient are sufficient. However, for a small number of drugs, relatively minor changes in clearance can be
important (drugs with a narrow therapeutic index); these
drugs should be monitored.
CLINICAL PEARL
Drugs with a narrow therapeutic index should be monitored using biomarkers of drug effect or drug concentrations.
Renal impairment
In dosing renally cleared drugs, there are good methods for
estimating GFR and hence renal drug clearance. The relationship between GFR and drug dose is shown in Figure
4-6. Renal drug clearance is traditionally estimated using
the Cockcroft and Gault equation, and most drug prescribing information is based on this equation. However, estimated GFR (eGFR) determined using other equations (e.g.
CKD-epi) is routinely provided by most laboratories and
may suffice as a guide, particularly if the patient is of average
body size and composition.
Caution: laboratory estimates of GFR are standardized to a particular patient size (1.73 m2) and hence need
to be corrected for patient size. An uncorrected eGFR will
underestimate renal drug clearance in a larger patient and
overestimate renal clearance in a smaller patient. For drugs
with a narrow therapeutic index, estimates of GFR are not
sufficient to guide dosing. Clinical monitoring, validated
biomarkers of drug effect or drug concentrations should
always pre-empt estimates of clearance.
CLINICAL PEARL
To adjust the dose of a drug in renal impairment, you
need the glomerular ltration rate (GFR) of the patient
and the fraction of the drug excreted unchanged (fe);
see Table 4-1.
100
Dose % normal
Drugs 50% renally

cleared (fe = 0.5)
50
Drugs 100% renally
cleared (fe = 1)
GFR (mL/min)
100
Figure 4-6 For a drug that is 100% renally cleared

(fe = 1), clearance is proportional to GFR and the dose
should be reduced proportionally to GFR. For a drug
that is 50% renally cleared (fe = 0.5), clearance of the
renally cleared component only is affected by GFR
and the dose reduction is therefore smaller
Drug information often presents dosing in renal impairment in categories according to GFR. These arbitrary decision points can lead to arbitrary decisions. For example,
when a decrease in drug dose is recommended at GFRs of
60 and 30mL/min, is 31 mL/min different to 29 mL/min or
the same as 57 mL/min? Some patients above the threshold
may need a change in dose or a drug stopped, while other
patients can still be treated rationally even after the threshold is crossed. A clinical decision should be based on clinical
observations of effects (benefits and harms), available disease
biomarkers and drug concentrations. These vary between
diseases and drugs.
For a drug 100% renally cleared and a patient with a
GFR half that of normal, a reasonable dose is half a normal dose. For a drug 50% renally cleared and patient with a
GFR half that of normal, a reasonable dose is 75% of normal. Other factors such as patient health, drug response and
tablet strengths are important to dose selection.
Some drugs are partially metabolized by proteases in the
kidney, most notably insulin; metabolism by the kidney is
not directly proportional to GFR.
Liver impairment
In dosing drugs that rely predominantly on metabolism for
clearance, there is no equivalent to GFR to estimate changes
in clearance. Hypoalbuminemia and international normalized ratio (INR) are late and imprecise markers of impaired
metabolic capacity. Close attention to symptoms or signs
of altered drug effect is needed when organ dysfunction is
suspected.
Cardiac impairment
Cardiac impairment affects blood flow to the clearing organs
and may further impair hepatic metabolism by liver congestion. Right heart failure often causes clinically relevant
reductions in absorption of drugs across the gut wall.
Metabolic impairment
Any change in physiology may affect the pharmacokinetics of
a drug. For example, hypothyroidism decreases drug clearance and thyrotoxicosis increases drug clearance by altering
cardiac output and cell metabolism. Acidosis or alkalosis can
alter the bioavailability and clearance of acidic and basic drugs
and, if severe, may impair hepatic function and thus decrease
drug metabolism.
Patient size
Patient size is important, but in adults size is a minor contributor to variability in drug response, unless very big or
very small. Both clearance and volume of distribution are
proportional to body size. In most circumstances, lean body
weight is the most valid descriptor of size.
In children, size differences also reflect physiological
differences. In young children (neonates and infants), both
maturation (age post-conception) and size need to be considered in selecting drug doses.
Obesity is a particular type of increased size and is increasingly common. With increasing obesity, fat mass increases
a lot and lean mass a little. The main pharmacological
33
Table 4-1 Examples of renally cleared drugs grouped

by therapeutic index
DRUG
fe
Narrow
Aminoglycosides
Digoxin
0.7
Lithium
Dabigatran
0.9
Low-molecular-weight heparins
0.7
Intermediate
Acyclovir and related antivirals
0.8
Allopurinol (active metabolite oxypurinol)
Atenolol
0.9
Clonidine
0.6
Gabapentin and pregabalin
0.9
Glycopeptides (e.g. vancomycin)
0.9
Levetiracetam
0.6
Memantine
0.7
Morphine-6-glucuronide
Paliperidone
0.6
Pramipexole
0.9
Topiramate
0.7
Wide
ACEIs
Baclofen
0.7
Carbapenems
Cephalosporins
Metformin
Penicillins
Sitagliptin
Varenicline
0.9
* Within-class variabilitymost are predominantly renally cleared.

Most ACEIs are pro-drugs of a renally cleared active moiety (
prilat).
ACEIs, angiotensin-converting enzyme inhibitors; fe, fraction of
dose excreted unchanged.
difference is increased volume of distribution of fat-soluble

drugs. An important clinical difference is overdosing errors
due to weight-based prescribing. Clearance is determined
by lean body weight.
Drug clearance, along with most physiological parameters, can be compared across species ranging from ants to
whales by weight to the power of 0.75 (kg0.75).
34
PHARMACODYNAMICS
Pharmacodynamics, what the drug does to the body, is
about the relationship between drug concentration and drug
response. Broadly, pharmacodynamics can be considered at
three levels.
1 Health effects for the patient are the ultimate measures of drug response. It is important to consider
all drug effects, unwanted as well as wanted. These
include global effects such as mortality or quality of
life; disease-specific effects such as exercise tolerance or
range of movement; and symptoms such as pain.
2 Physiological effects are often used clinically to monitor drug response and guide dosing, such as measuring
blood pressure after antihypertensives have been commenced. Physiological effects can often be monitored
by history and clinical examination or measured simply
in the clinic. A change in physiological effect can be a
useful marker of change in organ function in response
to treatment.
3 Molecular effects are frequently studied in scientific
experiments, as they are often specific to a particular
drug and can be studied experimentally outside the
body e.g. in vitro, in cell models or in gene expression
arrays. Some molecular effects are also useful as biomarkers of drug response.
A drug response is caused by a drug molecule acting on a
molecule or a group of molecules in the body. Any molecule in the body may be a drug target. A drug may either
increase or decrease the molecular activity of the target(s).
A drug response may be anywhere from 0 to the maximum
possible response (Emax). The Emax defines maximum efficacy. The greater the potential response, the greater the
potential efficacy. The concentration of drug that has 50%
of the maximum response is the EC50. The EC50 defines
drug potencythe lower the concentration required to
achieve the response, the greater the potency. Note that the
terms potency and efficacy are different concepts. A drug may
have high potency (low EC50) but low efficacy (Emax). Pharmacodynamics are illustrated graphically by concentrationresponse curves; see Figure 4-7.
CLINICAL PEARLS
Potency is the drug concentration required to
achieve a response.
Efficacy is how much response there is to a drug.
All drugs have multiple effects, and hence multiple

concentrationresponse curves can be plotted. This is particularly useful for comparing beneficial and harmful drug
effects. This is shown in Figure 4-7B.
Therapeutic index
The therapeutic index of a drug is the ratio between the
concentrations causing toxicity and efficacy. For a drug with
Box 4-1
% dose response
Emax drugs 1 and 3
Examples of drug classes with a

narrow therapeutic index
Emax drug 2
Antiarrhythmics
Anticoagulants
Anticonvulsants
1
Cytotoxics
EC50
EC50
drugs 1 drug 3
and 2
% dose response
Immunosuppressants
Some hormones, e.g. insulin
log drug concentration
Therapeutic
effect
Toxic
effect
EC50
B
activity of intracellular signaling pathways, e.g. G-protein

coupled receptors. In contrast, nuclear receptors increase or
decrease gene expression.
An agonist acts on a receptor to increase the signal,
whereas an antagonist decreases the signal. Strictly speaking, agonists and antagonists are drugs acting on a receptor,
rather than on other drug targets. For example, beta-agonists
and beta-blockers act on the beta-adrenergic receptors.
Receptor signaling may also be modified by drugs changing
the shape of the molecule rather than occupying the active
site. This is called allosteric modulation.
TD50
log drug concentration
Figure 4-7 Sigmoidal concentrationresponse

curves typical of many drugs. (A) Drugs 1 and 3 have
the same maximum efficacy (Emax) but drug 1 has a
higher potency (lower EC50). Drug 2 has a similarly
high potency (low EC50) to drug 1 but a lower efficacy
(Emax). (B) The therapeutic index is TD50/EC50, i.e. the
ratio between the concentrations causing toxicity
and efficacy. Note that toxic effect curves often have
different slopes to therapeutic effect curves
a wide therapeutic index, doses can be found that are likely
to have the desired effect but are unlikely to have unwanted
effects. Drugs with a narrow therapeutic index are loosely
defined as drugs for which a halving or a doubling of the
dose (or concentration) is likely to cause a significant change
in effects. However, this definition is only a starting point
and there are differences between patients as well as between
drugs. For example, sulfonylureas have a wide therapeutic
index in most circumstances, but in a frail elderly person a
sulfonylurea may have a narrow therapeutic index due to the
greater risk of hypoglycemia because of decreased counterregulatory responses and decreased awareness of symptoms.
Drugs of narrow therapeutic index are hard to define but
easy to recognize (usually). Examples of drug classes with
narrow therapeutic indices are shown in Box 4-1.
Drug targets
Receptors of endogenous signaling molecules, such as
neurotransmitters and hormones, are common drug targets.
A receptor may be activated by an agonist or blocked by an
antagonist. Cell membrane receptors increase or decrease the
CLINICAL PEARL
Drugs acting on nuclear receptors are more likely to
have multiple effects than drugs acting on cell membrane receptors.
Enzymes catalyze reactions and are usually found inside

cells. They are common drug targets and may be induced or
inhibited (the latter is more common). Enzymes may catalyze reactions involved in signaling pathways directly or may
produce or metabolize molecules important to cell function.
For example, dihydrofolate reductase is inhibited by methotrexate in the treatment of some autoimmune diseases and
some cancers.
Channels and transporters transport molecules across
cell membranes. Blocking or increasing their function alters
the concentration gradient of a molecule(s) across the cell
membrane. For example, the gastric proton pump inhibited
by proton pump inhibitors, or the potassium ATPase channel inhibited by sulfonylureas.
Signaling molecules may be directly targeted by drugs.
For example, tumor necrosis factor alpha (TNF-alpha) is a
cytokine targeted by several large molecule biological drugs
in the treatment of inflammatory diseases.
Other drug targets include structural molecules.
Some drug targets are difficult to classify, for example
some inhaled anesthetics alter cell membrane function nonspecifically, with differing effects on a range of receptors,
channels and transporters.
Drug specicity
Specificity is how much more likely one response is than
other responses. Specificity is often defined by relative
35
affinity for different molecular targets. A highly specific

drug will preferentially interact with one target molecule.
However, no drug is completely specific and as concentration increases, other molecules will be affected.
Specificity differs from therapeutic index in that specificity generally refers to molecular response rather than the
effect on the patient. Affecting multiple molecules is not
necessarily bad, as the total affect may be beneficial. Conversely, an increase in one response may move from benefit
to harm, for example anticoagulation.
Distribution and drug targets

To act on cytoplasmic enzymes or nuclear receptors, drugs
have to get inside cells and their effect is therefore determined by intracellular concentration. In contrast, extracellular
concentration is usually relevant for drugs acting on cell
membrane receptors, channels and transporters, and signaling molecules. Cell membrane drug transport is thus
particularly relevant to drugs targeting enzymes or nuclear
receptors (see drug transport, below).
CLINICAL PEARLS
Drug concentrations at intracellular targets are
dependent on both circulating drug concentration
and cell membrane transport.
For drugs acting on extracellular targets, free plasma
concentrations determine the concentration at the
target.
While the terms agonist and antagonist apply to drugs acting
on receptors, the concept of stimulation or suppression is
important and can be applied to physiological effects. Physiological effects are often primary or secondary outcomes of
drug trials and are particularly useful in predicting the likely
effects for individual patients. The physiological effects of the
drug that are observed in the trials can be considered against
the physiological state of the patient. For example, in treating
diabetes, stimulating insulin production with a sulfonylurea is
effective for type 2 diabetes but not for type1 diabetes.

When choosing a drug therapy, the potential benefits and
potential harms for a patient can be predicted to some extent
from trial data. The probabilities of benefits and harms can
be adjusted by considering the characteristics of this patient
relative to the average patient. Are they older or younger,
male or female, fit or unfit? What are the states of their
organs: heart, lungs, liver, kidneys, blood, bones, endothelium, gut, and (particularly) their brain?
THE INNOCENT BYSTANDER

While primarily treating one patient, the potential harm to
others needs to be considered. The greatest risk of bystander
drug exposure is to a fetus, with drug transfer to the fetus from
36
the mother via the placenta. Other examples include drugs

in breast milk, transfer via skin-to-skin contact, or radiation
from a radiopharmaceutical. More indirect examples include
a drug being administered to the wrong patient or the development of antibiotic-resistant organisms. Managing these
risks is part of the quality use of medicines (part 2).
In evaluating the benefits and harms in a decision to
treat a pregnant or breast-feeding mother, we need to consider: (1)the likely drug exposure of the fetus or infant and
the potential consequent drug effects; (2) the effect of the
mothers disease on the fetus or infant as well, especially
if untreated (e.g. with epilepsy); and (3) any effect on the
mothers ability to care for an infant.
In pregnancy, the rule of thumb is that fetal blood concentration equals maternal blood concentration. The second
factor to consider is stage of fetal development, as the risks of
drug exposure vary by trimester:
1st trimesterorganogenesis
2nd trimestermaturation (especially neurological)
3rd trimestermaturation and the circulatory and
respiratory changes that occur peripartum.
The third factor to consider is the risk of untreated disease
to both fetus and mother. Consequently, pharmacotherapy
in pregnancy is a specialized area with pregnancy risk classifications providing a useful starting point.
In breastfeeding, the rule of thumb is that infant drug
exposure is usually much less than maternal drug exposure.
To estimate likely infant drug exposure, there are three
pharmacokinetic variables to consider.
1 The weight-adjusted maternal dose (WAMD), which
provides a useful estimate of the infants drug dose relative to that of the mother.
2 Oral bioavailability, given that many parenterally administered drugs have very low oral bioavailability with consequent negligible systemic exposure for the infant.
3 Drug clearance by the infant, which increases with
maturation (post-conceptual age).
Consequently, if drug treatment is needed while breastfeeding, an option that poses minimal risk to the infant can often
be found.
2. QUALITY USE OF
MEDICINES
Quality use of medicines (QUM) is about using medicines
safely, effectively and economically. There are multiple
QUM tools deployed by communities in caring for groups
of patients, and others deployed by healthcare professionals
in the care of individual patients. Communities in healthcare can be grouped in several ways: by geography from the
nation down to the local community; by disease types; and
by sectors of healthcare.
QUM tools used by communities to support care across
groups of patients include drug regulations, drug formularies,
treatment guidelines and costeffectiveness analyses. Those
used by healthcare professionals for individual patients include
drug profiles, prescriptions, drug interaction assessment tools,

adverse reaction alerts and working in teams.
GETTING IT RIGHT
Prefacing any element of therapeutics with right can help to
define QUM objectives and select QUM tools: right diagnosis, right drug, right route, right dose, right time, right
patient. Figure 4-8 shows the circle of care: making the
diagnosis; identifying treatment options; selecting treatment with the patient; and assessing the treatment response.
Figure 4-9 shows the elements of the patient profile and the
drug profile. Matching the patient profile with drug profiles
is a QUM tool for individual patient care that can be used
in any setting.
The circle of care

1 The diagnosis. Accurate characterization of patient
problems for diagnosis of one or more disease(s) in a
patient is necessary for scientific therapeutics. This
allows application of the research literature to the individual case. Being based on diagnosis and pathophysiology is a strength of orthodox medicine.
2 Disease managementidentifying treatment options. In assessing the evidence for treatment(s), there
are many decision-support tools to identify treatment
options, such as evidence-based treatment guidelines. All
good decision-support tools are traceable to the primary
research information including relevant clinical trials.
3 Patient managementselecting the treatment with
the patient. Sometimes this is more of an art than a science. It usually includes negotiation with the patient to
match the treatment to the patient. Applying the principles outlined above supports rational treatment selection. Prescribing a drug or drugs is typically the final
step in this process.
Review
and audit
Patient
problems
History
Examination
Investigations
Patient to physician
communication
Patient care
Physician to patient
Environmental
communication
modification
Surgery
Disease
Drugs
management
Negotiation
Diagnosis
Evidence
Figure 4-8 The four steps in the circle of care.

Obtaining information from a patient, the history,
is critical to diagnosis. Imparting information to a
patient is critical to management, particularly in
chronic care
PATIENT PROFILE
1. Age
2. Sex
3. Body size and
composition
4. Family history and
ethnicity (genetics)
5. Adverse drug
reactions/allergies
6. Disease/s:
a. PDsusceptibility
b. PKdose
7. Current drug(s)
8. Smoking/alcohol/drugs
9. Pregnancy/lactation
10. Behaviorsadherence
DRUG PROFILE
1. Class
2. Pharmacodynamics
a. Actions
b. Beneficial effect(s)
c. Harmful effect(s)
3. Pharmacokinetics
a. Biovailability
b. Clearance
c. Volume of distribution
4. Indications/
contraindications
5. Interaction potential
6. Dose and duration
7. Monitoring
8. Overdose
Figure 4-9 Patient prole and drug prole

4 Assessing the treatment response. Has the treatment addressed the presenting problems, and is the
response consistent with the diagnosis? The response
of each patient to treatment should be assessed in a
planned manner. For most diseases and drug treatments, there are useful biomarkers to assess response
to treatment. These range from changes in symptoms
or signs to changes in biochemical or radiological test
results. Many treatment guidelines include recommendations for monitoring and follow-up.
Drugs are the subject of this chapter, while diseases are the
subjects of other chapters. QUM is about drugs and people
(patients and prescribers), and about reducing errors.

The elements of the patient profile and the drug profile are
shown in Figure 4-9. Matching the patient profile with the
drug profile(s) can be used to increase the potential for benefit and reduce the potential for harm. Simply selecting the
best drug on the basis of diagnosis is not sufficient.
Aligning the characteristics of the patient and the drug
using headings allows assessment of the potential for benefit
and harm to the individual. For example:
Does the patient have any contraindications?
Is the route appropriate?
Are there potential drugdrug interactions?
What is the likely adherence to the treatment plan?
PRESCRIBING
Prescribing is the communication of a written plan for drug
treatment. Prescribing registered drugs is regulated in most
countries. There are regulations governing who can prescribe, what can be prescribed, and who can dispense a registered drug. Prescribing, dispensing and administration of
drugs are usually done by different people. Prescribers are
mostly doctors, dispensers mostly pharmacists, and drugs
37
are mostly administered by nurses (acute care) or patients

(chronic care). Having three or more people, each bringing
different skills to drug treatment, reduces treatment errors
and improves quality of care.
Most prescribing errors are errors of communication,
resulting in wrong drug, wrong dose, wrong route, wrong
patient or wrong time. There are many other factors contributing to error, but with clear communication most can
be avoided.

Pharmacotherapy is complicated, and there are many patient
and drug variables to consider before prescribing (or not
prescribing) a medicine for a patient. In healthcare, therapeutic processes are complex and prone to error. Checklists
are increasingly used to support therapeutic processes in surgery and there is good behavioral research to suggest that
they can support good processes in other aspects of healthcare. Box 4-2 provides one example of a checklist to support
the prescribing process.
DEPRESCRIBING
When to start drug treatments is covered in detail in almost
every major guideline. However, when to stop drugs is not
and, partly because of this, polypharmacy accumulates with
multi-morbidity. Stopping drugs is hard and it is easy to justify the status quo, but a decision to continue is just as much a
decision as a decision to stop.
We recommend that every drug treatment be formally
reviewed at least annually. For every drug, ask yourself:
1 What are the potential benefits and potential harms for
this person?
2 Are the potential benefits greater than the potential
harms? If the answer is no, or uncertain, consider stopping the drug. One approach is the traffic light system
for review shown in Figure 4-10.
Deprescribing requires all the same steps as prescribing.
Sudden cessation can be dangerous and the results of deprescribing should be monitored and reviewed in the same way
as the results of prescribing.
ADVERSE DRUG REACTIONS

An adverse drug reaction (ADR) is a harmful effect of a drug,
or more precisely any response to a drug which is noxious,
unintended, and which occurs at doses used in man for
prophylaxis, diagnosis and therapy. An adverse drug event
(ADE) has a broader definition, including potential harm
as well as actual harm. Drug safety has similarities to road
safety: by reducing errors, we can reduce harm. For example, while wrong dose errors dont usually cause measurable
harm, reducing dosing errors is likely to increase benefit and
reduce harm across the community.
All drugs can cause adverse reactions, and some patients
are at greater risk of these than others. A patients ADR history and other characteristics, such as gender, age, ethnicity
and physiological state, help to quantify the likely risk of a
38
Box 4-2

Before prescribing, consider:
1 Goal/s of treatment and denitions of success and
failure:
a Symptom relief
b Disease modication
2 Drug selection:
a Drug for the problem?
b Drug for this patient:
past adverse drug reactions?
prognosis?
frailty and vulnerabilities?
3 Potential effects: is net benet likely for this patient?
a Potential benets for this patient?
b Potential harms to this patient?
4 Dose regimen:
a Loading dose or start low, go slow?
b Maintenance dose for this patient?
5 Potential drug interactions:
a Pharmacodynamic?
b Pharmacokinetic?
After prescribing, agree with the patient:
6 Monitoring for efficacy and toxicitywhat, when,
how and who?
a By patient
b By clinician
7 Risk management:
a Potential harms
b Treatment failures
c Action if treatment failure or harm occurs
8 Patient and carer/s understanding:
a Diagnosis/problem
b Management
9 Reviewwhen, where and who?
Finally, consider:
10 Problems not treated:
a Are there untreated problems?
b Should additional/alternative treatments be
offered?
I used the prescribing checklist in prescribing for this
patient
F
given adverse reaction. Considering the potential for ADRs

is part of prescribing assessment, and making plans with the
patient (and any carers) to identify and manage potential
ADRs is standard practice; for example, warning someone
of the potential gastrointestinal effects of a drug and what to
do if they occur.
CLINICAL PEARL
Anything that can do good can also do harm, and all
drugs have harmful effects. Monitor treatment by monitoring patients for both benets and harms to evaluate
the net clinical effect.
ADRs have driven much of the current regulatory

environment. The USAs 1938 Food, Drug and Cosmetic
Mary Jonesage 79
Problems
Ischaemic heart disease
Congestive heart failure
Type 2 DM
Hypertension
Mild cognitive impairment
Alcohol abuse
Steatohepatitis
Key
Medications
aspirin 100 mg mane
simvastatin 40 mg nocte
metoprolol CR 95 mg mane
cilazapril 2.5 mg mane
metformin 850 mg bd
quetiapine 25 mg nocte
diltiazem CR 180 mg mane
likely beneficial
likely harmful
Box 4-3
Rx Review
Describing ADRs using DoTS1

and EIDOS2
possibly futile
Figure 4-10 Mary Jones is a hypothetical patient.

Her current problems and current medications are
shown side by side in one view. For each medication
you, the prescriber, evaluate the likely net benet for
Mary. The selections in this case are not the point,
and we have insufficient information to critique these.
Each drug that is assessed as likely harmful should
be deprescribed, and deprescribing those assessed as
possibly futile should be discussed. We suggest that
aiming to deprescribe half of the possibly futile drugs
is a good starting point
Act was a response to the deaths of many children from

ingesting ethylene glycol used as the solvent for the elixir
form of the antibiotic sulfanilamide. The 1962 Kefauver
Harris amendment was a response to birth defects from
thalidomide.
A type A (augmented) reaction is one that is predictable from the pharmacological effect of the drug and
may respond to dose adjustment.
A type B (bizarre) reaction is usually due to a host
reaction to a drug, e.g. anaphylaxis.
This simple classification is long-established, and is useful
when prescribing drugs but is not sufficient to diagnose and
manage ADRs.
Assessing an event in a patient as a potential ADR
involves two steps. First, describing the event in relation
to the drug and the patient. An ADR can be described
usingthe DoTS and EIDOS method of Aronson and Ferner
(Box 4-3). Second, as with any diagnosis, causality should
be assessed. The Naranjo score (Box 4-4, overleaf) is one
method of assessing causality. While assessment of ADRs
is often neglected, clinical assessment using these tools is
cheap and easy compared with radiological imaging and
biochemical testing. All potential ADRs should be clearly
documented in the patients clinical record and reported to
the relevant pharmacovigilance body.
Drug safety is not reliably assessed using the randomized
controlled trials required for drug registration. To investigate drug safety, observational studies (e.g. case-control
studies) usually provide more robust data. Pharmacovigilance is the science relating to the detection, assessment,
understanding and prevention of adverse drug effects, and
most countries have formal pharmacovigilance programs.
Spontaneous reporting of ADRs by prescribers is an essential component of pharmacovigilance.
DoTS
Do Dose-relatednessusual, very high or very low?
T Time-relatednessimmediately, or after hours, days,
weeks or longer?
All drug effects are dose- and time-related. At what dose
and after what duration did the reaction occur?
S
Susceptibilitydescribe the patient. For example,

disease states or family history of autoimmunity
EIDOS
E Extrinsic chemical specieswhat is the drug or
related molecule responsible for the effect?
I
Intrinsic chemical specieswhat is/are the
molecule(s) that the drug affects?
D Distributionwhere are those molecules in the body?
O Outcomewhat is the pathophysiological effect?
S Sequelaewhat are the consequences for the
patient? The adverse effect
1. Aronson JK and Ferner RE. Joining the DoTS: new approach to
classifying adverse drug reactions. BMJ 2003;327(7425):12225.
2. Ferner RE and Aronson JK. EIDOS: a mechanistic classication
of adverse drug effects. Drug Saf 2010;33(1):1523.
DRUG INTERACTIONS
A drug interaction occurs when a patients response to a
drug is modified by something else. The interaction may be
due to other drugs, food or other substances, environmental factors, or disease. Drugdrug interactions (DDIs) are
interactions between drugs. DDIs can either increase drug
effect, potentially causing toxicity; or decrease drug effect,
potentially leading to therapeutic failure. Elderly patients are
especially vulnerable, with a strong relationship between
increasing age, the number of drugs prescribed, and the frequency of potential DDIs.

1 Behavioral: altered compliance
2 Pharmaceutical: outside the body
3 Pharmacokinetic: altered concentration:
a bioavailability: absorption or first-pass metabolism
b clearance: metabolism or excretion of active drug
c distribution: cell membrane transport to the site
of action
4 Pharmacodynamic; additive or opposing effect:
a mechanism: molecular signal (e.g. receptor)
b mode: physiological effect
One of the most common causes of significant DDIs is
induction or inhibition of drug metabolism. In these interactions, there is a perpetrator (the drug causing the change in
39
Box 4-4
The Naranjo score for assessing

causality of adverse drug reactions
(ADRs)
1 Are there previous conclusive reports on this
reaction?
Yes (+1); No (0); Do not know or not done (0)
2 Did the adverse event appear after the suspected
drug was given?
3 Did the adverse reaction improve when the drug was
discontinued or a specic antagonist was given?
4 Did the adverse reaction appear when the drug was
re-administered?
5 Are there alternative causes that could have caused
the reaction?
Yes (1); No (+2); Do not know or not done (0)
6 Did the reaction reappear when a placebo was
given?
Yes (1); No (+1); Do not know or not done (0)
7 Was the drug detected in any body uid in toxic
concentrations?
8 Was the reaction more severe when the dose
was increased, or less severe when the dose was
decreased?
9 Did the patient have a similar reaction to the same or
similar drugs in any previous exposure?
10 Was the adverse event conrmed by any objective
evidence?
Score
>9 = denite ADR
58 = probable ADR
14 = possible ADR
0 = doubtful ADR
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating
the probability of adverse drug reactions. Clinical Pharmacology
and Therapeutics 1981; 30(2):239245.
metabolism) and an object (the drug whose concentration is

changed). There are a relatively small number of perpetrator
drugs that can cause large changes in the concentrations of
other drugs. Of the object drugs, those with a narrow therapeutic index are particularly vulnerable; as are pro-drugs,
given that pro-drugs are dependent on a single metabolic
pathway for activation.
Patient harm from drug interactions can be reduced by:
using a personal formularyusing few drugs and knowing them well
recognizing drugs that are major perpetrators of
interactions
40
recognizing drugs with a narrow therapeutic index as

vulnerable to interactions
applying clinical pharmacology principles.
THERAPEUTIC DRUG
MONITORING (TDM)
Therapeutic drug monitoring is the use of measured drug
concentrations to inform drug treatment. TDM can be used
in diagnosis:
1 In therapeutic failure there are three main differential
diagnoses: low adherence, under-dosing and insufficient effect. TDM is a good discriminator of these
three possible diagnoses.
2 In suspected drug toxicity or drug overdose, TDM can
support or refute that symptoms are due to a drug or
that a drug overdose has been taken.
3 When a patient is well, a drug may continue to be prescribed but not taken. TDM can identify that continued prescribing is unnecessary.
The other use of TDM is as a therapeutic tool to adjust a
drug dose prospectively. Targeting a drug concentration
can reduce potential harm and increase potential benefit by
reducing pharmacokinetic variability.
CLINICAL PEARL
A target concentration is more precise than a target
dose.
TDM is less useful if there is an accurate measure of

drug effect(s), such as blood glucose and HbA1c in the treatment of diabetes. However, there are relatively few drugs for
which we have accurate measures of drug effect, and TDM
is therefore a very cheap and an under-utilized tool.
Measuring drug concentrations is generally cheap and
technically straightforward. To interpret a TDM result,
other information is needed in addition to the drug concentration. This includes:
drug dose (amount and frequency)
duration of the current dose (to assess steady state)
time after the last dose (concentration changes with
time).
Knowing whether your patient has a drug concentration
similar to, higher than, or lower than other patients treated
with the same drug is valuable.
The greatest use of TDM is in transplant medicine, and
to a lesser extent in neurology (epilepsy), infectious diseases,
and psychiatry. Given the difficulties of adherence and interpatient pharmacokinetic variability, TDM is one of the most
under-used tools in 21st century medicine.
DRUG REGULATION
Drug regulation is a fundamental component of health
systems aiming toward the societal goals of achieving safe,
effective and economic use of drugs. Drug regulation has

three main components in evaluating and regulating:
1 safety and efficacyconsidered by drug registration
bodies
2 cost-effective use of drugsconsidered by funding,
purchasing or advisory bodies
3 drug researchconsidered by registration bodies, ethics committees and public research funding bodies.
Drug registration bodies such as the Food and Drug
Administration (FDA; USA), European Medicines Evaluation Agency (EMEA; Europe), Pharmaceutical and Medical Devices Agency (PMDA; Japan) and the Therapeutic
Goods Administration (TGA; Australia) manage safety and
efficacy in multiple ways. For example:
regulating manufacture and distributionis the right
substance in the right place at the right time?
evaluating new drugs by comprehensive review of their
safety and efficacy for the treatment of particular diseases
in particular patients
evaluating the bioequivalence or biosimilarity of drugs
co-ordinating pharmacovigilance.
Bodies that fund, or advise on funding, drugs operate at
several levels. Some operate nationally, such at the United
Kingdoms National Institute for Health and Care Excellence (NICE) or Australias Pharmaceutical Benefits Advisory Committee (PBAC). Others consider spending for
particular parts of the community, such as insurers for their
policy-holders, or hospitals for their patients.
Pharmacoeconomics is the science of assessing costs
and benefits to inform decisions about resource use and
expenditure on drugs. To prioritize health spending, it is
necessary to compare the costs, potential benefits and potential harms of treatment options. Benefits and harms may be
compared subjectively; but for comparison across drugs, diseases and patients, objective or quasi-objective measures are
needed.
One of the most widely used is the quality-adjusted lifeyear (QALY). While particular QALYs might be contentious, a strength is their transparency. This allows evaluation
of uncertainty, open discussion and helps with the alignment of spending with societal values.
In making funding decisions about new drug treatments,
a commonly used metric is the incremental costeffectiveness ratio (ICER). The ICER is the difference in cost divided
by the difference in net effectiveness (benefits minus harms)
between the new drug treatment and existing care. While
most clinicians do not undertake such analyses formally, these
are implicit in every treatment decision. Cost minimization is
more easily understood; when treatments do not significantly
differ, costs can be compared. For example, a new generic
drug that has demonstrated bioequivalence would be evaluated primarily on its relative costs.
Pharmacoepidemiology is the study of the use and
effects of drugs on groups of people. The language of pharmacoepidemiology is statistics and to translate the information from clinical trials and other research, it is necessary to
understand statistics!
DRUG RESEARCH
Medicine is research-based. A few words that mean a lot! Science requires the challenge and testing of ideas, whereas belief
requires acceptance of ideas. The scientific consensus on the
treatment of disease usually (although not always) reflects the
existing evidence, and for a new treatment to be accepted it
should be tested against the existing treatment. For an experiment to be valid, it should be relevant (what is measured matters) and reliable (the method is reproducible). Many research
methods are used to gather the information needed to determine whether a drug is safe, effective and cost-effective.
In assessing drug efficacy, the final step is usually the
randomized controlled trial (RCT). In a RCT the new
treatment is compared with the existing treatment in a representative group of patients under conditions that minimize potential bias (e.g. randomization and blinding). Large
RCTs are based on data from smaller clinical studies that
establish estimates of doseeffect relationships (see the sections on pharmacokinetics and pharmacodynamics, above).
Before drugs are studied in people, multiple types of
pre-clinical experiments are carried out. These include animal experiments (in vivo), laboratory experiments (in vitro)
and computational experiments (in silico). Many different
experiments are needed to describe a drug. For example,
to predict the metabolism in humans of a new drug, multiple in vitro studies are conducted to develop data for use
in in silico models before testing in selected in vivo models.
Simultaneously, multiple other experiments are conducted
to describe other variables, such as the potential effects of
the drug on different tissues or its potential carcinogenicity.
Knowing which research methods can answer a particular question and understanding their limitations helps clinicians to interpret research. For example, RCTs are the gold
standard method for comparing the efficacy of two treatments. However, RCTs are poor at assessing drug safety, as
they are usually not powered to quantify events occurring
less commonly and vulnerable patients are often excluded.
Assessing drug safety has two components. First, toxicity can be studied in pre-clinical studies and in early human
dose-finding studies. Second, adverse eventswhich may
be rare or occur a long time after commencing treatment
should be systematically evaluated. Some observational
study designs, such as case-control studies, are well suited to
identifying and quantifying adverse events.
Costefficacy studies use efficacy and safety data from
RCTs and observational studies, together with costs relevant
to the study question(s), to inform policy-makers and clinicians. To assess costefficacy, it may be necessary to consider
a number of efficacy and safety outcomes. Some outcomes
can be quantified, e.g. time off work, resources required for
independent living, but many are inherently subjective. To
assign values (utilities) to different health states, it is necessary to ask people and there are a number of standardized
methodologies used to assign utilities.
Drug research is conducted by people and organizations
which, in addition to answering research questions, have
other objectives such as career advancement or increasing
shareholder value. Robust scientific research methods are
required to be transparent (published) and reproducible so that
41
others can repeat the experiment. In the long term, this provides protection from falsehood.
3. TOXICOLOGY
EPIDEMIOLOGY OF POISONING
Poisoned patients represent:
510% of an emergency departments workload
510% of medical admissions.
CLINICAL PEARLS
In more developed countries, approximately 1%
of people with poisoning are at serious risk and
require intensive support.
Distinguishing this 1% among all presentations with
poisoning is difficult.
Mortality rates from poisoning remain relatively static in

many countries. Severe poisoning in more developed countries occurs with a relatively small group of drugs which
includes tricyclic antidepressants, anticonvulsants, opioids,
amphetamines and cocaine.
Many patients co-ingest their drugs in overdose with alcohol, and the effects of both alcohol and the drug(s) in question are seen. Co-ingestions of multiple drugs may occur, and
present a particular challenge. The frequently encountered
substances in more developed countries are covered below.
SOURCES OF POISONS
INFORMATION AND ADVICE
Toxicology information and advice is available from many
sources, including poisoning information centers and websites for management (e.g. www.TOXINZ.com; WikiTox;
www.atsdr.cdc.gov). Clinical reasoning and judgment can
be augmented with expert advice, particularly for management in the more complex cases.
Most data are based on case series, given the extreme difficulty in conducting prospective trials. Even a single case
report can be of value in such a setting.
CLINICAL ASSESSMENT OF
POISONED PATIENTS
Taking a history from a poisoned patient is critically
important in determining:
what substance?
how much?
the exact timing?
by what route the person has been exposed, e.g.
ingestion, inhalation?
Corroborative evidence (empty packets of drugs,
containers of chemicals, family/observer history) is
42
important. Finding out the source of the drug or toxin

may help to prevent subsequent self-poisoning.
Ask why the overdose was taken. A sympathetic nonjudgmental approach works best with the majority of
patients.
Simple assessments of mental health are also required,
with expert guidance from psychiatry. Serious suicidal
intent is more likely with younger males, the elderly,
where planning has taken place, where a note has been
left and where the patient has taken trouble not to be
discovered.
The past medical history, especially asthma, jaundice,
drug misuse (including alcohol), head injury, cardiovascular or renal problems, and past psychiatric illness and
harm, are helpful to guide future clinical management.
Ask about allergies.
On clinical examination, first check airway, breathing,
circulation (ABC) and institute necessary life-support
measures.
Complete a full physical examination, paying particular
attention to the items listed in Table 4-2.
Investigations
Check urea and electrolytes (UECs), arterial blood
gases (ABGs), and perform baseline electrocardiography
(EKG). In the EKG, the heart rate rhythm and any QTc
prolongation should be particularly noted.
Most patients have a metabolic acidosis, but if respiratory alkalosis is seen then salicylate (aspirin) poisoning
should be suspected.
Blood glucose and acetaminophen (paracetamol) concentrations must be checked in any patient who is
unconscious. Rarely (e.g. in acetaminophen poisoning),
drug blood concentrations are required to guide clinical
management.
CLINICAL PEARLS
If respiratory alkalosis is seen, then salicylate (aspirin) poisoning should be suspected.
A blood sugar level estimation and acetaminophen (paracetamol) level must be carried out in any
patient who is unconscious.
Interpreting drug concentrations is complexseek

advice early. As a general rule of thumb, it takes 5
half-lives to fully eliminate a drug, and 4 half-lives
to return to the therapeutic efficacy level. However,
when toxic quantities of drugs have been ingested, the
half-life of that drug may be extended due to saturation of enzymes involved in its metabolism, e.g. with
carbamazepine.
Currently, individual patient pharmacogenomic data
are not routinely used in the management of overdose,
but will be expected be in future. For example, mutations in CYP2CP and VKORC1 predict increased sensitivity to warfarin.
Table 4-2 Physical examination of a suspected poisoned patient
BODY PART/SYSTEM
EXAMINE
Central nervous system
Check Glasgow Coma Scale (GCS), tone, power, reexes and coordination (look for ataxic
gait which can occur in toxic alcohol/anticonvulsant poisoning)
Eyes
Check pupil size (e.g. small with opioids or organophosphorus insecticide poisoning; large
in tricyclic antidepressant overdose)
Check presence (e.g. anticonvulsants) or absence of horizontal nystagmus
Cardiovascular system
Heart rateelevated (e.g. tricyclic antidepressants, theophylline) or reduced (e.g. digoxin,

beta-blockers)
Blood pressure (e.g. reduced in tricyclic antidepressants, elevated after cocaine)
Respiratory system
Respiratory rate may be increased (salicylate poisoning) or decreased (e.g. opioid or

benzodiazepine poisoning)
Skin
Look for needle marks, bruises, razor marks

Check state of hydration
Cyanosis (e.g. CNS-depressant drugs)
Gastrointestinal system
Check for bowel sounds before giving activated charcoal

Feel for palpable liver to indicate possible liver disease and altered metabolism of drugs
Right upper quadrant tenderness may indicate liver toxicity from acetaminophen
(paracetamol)
Epigastric tenderness may indicate gastrointestinal toxicity to NSAIDs
Weight
Helps determine whether toxicity is likely, given the dose ingested
Body temperature
Increased (e.g. ecstasy, SSRIs) or reduced (e.g. CNS depressants)
CNS, central nervous system; NSAIDs, non-steroidal anti-inammatory drugs; SSRIs, selective serotonin reuptake inhibitors.
Drugs of abuse are frequently detected in urine using

detection strips that can identify opioids, cannabis,
amphetamines and benzodiazepines, but may miss some
of the newer drugs of abuse (see below). Rhabdomyolysis may be present with myoglobinuria in amphetamine
or caffeine intoxication.
A cranial computed tomography (CT) examination
will be required to investigate coincident head injury or
intracerebral events, if a patient presents unconscious or
with focal neurological signs.
Risk assessment
All of the above clinical and investigation information
(including the use of information and advice sources) is then
integrated to formulate a risk assessment, i.e. a prediction
of the most likely clinical course for the patient and any
potential complications, and this informs the tailor-made
management plan for that patient. This is the critical clinical
judgment process in clinical toxicology.
PRINCIPLES OF MANAGEMENT
OF POISONED PATIENTS
Meticulous supportive care is critical to good outcome
in poisoned patients. Doing simple things well, such as
administering intravenous fluids and giving oral activated
charcoal (if the patient presents within an hour of the
overdose), are sufficient to support most patients while

they eliminate the drug(s). Only patients who have taken
significant overdoses need further measures to prevent
absorption or increase elimination of the drug.
The American Academy of Clinical Toxicology
recommends:
oral activated charcoal 50g (orally or by nasogastric
tube) if ingestion of a substantial amount of drug has
taken place within the past 1hour
multiple doses of activated charcoal to be given to
adsorb the drug and enhance its elimination if drugs
such as digoxin, phenytoin or carbamazepine have
been ingested.
Oral activated charcoal is not of value if:
more than 1 hour has elapsed
treating ingestion of acids, alkalis, alcohols or metals.
CLINICAL PEARL
Give oral activated charcoal 50 g (orally or by nasogastric tube) if ingestion of a substantial amount of
drug has taken place within the past 1hour.
A nasogastric tube will be used very rarely to aspirate

stomach contents if there has been recent ingestion of
a toxic liquid. Gastric lavage with a large-bore tube to
remove tablets is no longer recommended.
43
Whole-bowel irrigation with polyethylene glycol can

achieve bowel clearance of tablets if iron or slow-release
preparations such as theophylline have been ingested
in a potentially toxic dose. The dose is 500 mL/h in
preschool children and 1 L/h if the person is above preschool age; its administration would usually be on the
advice of a clinical toxicologist.
Hemodialysis is occasionally used for serious poisoning
with aspirin, carbamazepine, ethylene glycol or theophylline, again after specific specialist advice.
CLINICAL PEARL
Hemodialysis is occasionally used for serious poisoning with aspirin, carbamazepine, ethylene glycol or
theophylline.
Intralipid 20% given as a bolus of 1.5 mL/kg followed by

0.25mL/kg/min for 3060 minutes has been used in the
management of serious poisoning with lipophilic drugs
such as tricyclic antidepressants, beta-blockers or local
anesthetics. Its use is still considered experimental but is
potentially life-saving.
In young patients poisoned with cardiotoxic agents,
maintain effective cardiopulmonary resuscitation (CPR)
throughout because good neurological outcomes can be
achieved even with hours of CPR. In serious poisoning,
management of seizures, coma and cardiovascular complications and intubation, where required, are also critical
to good outcome.
In contrast to the commonly held views, antidotes for

poisoning are rare, with the exception of those listed in
Table 4-3.
Patients are usually discharged from medical care once
the toxic effects of their overdose have worn off. This is
a clinical judgment based on response to questions, lack
of tachycardia or bradycardia, a demonstrated ability to
walk safely, and no visual problems.
Patients with sedative drug overdoses have residual
cognitive deficits, even when the above parameters
are normal, and should avoid driving for 3 days.
COMMON POISONS AND

THEIR MANAGEMENT
Acetaminophen (paracetamol) remains one of the most
common drugs taken in overdose. Ingestion of more than
200mg acetaminophen/kg bodyweight or 10g (whichever
is the less) in any one 24-hour period is associated with the
risk of developing hepatotoxicity (and more rarely renal toxicity), unless the antidote N-acetylcysteine is given within
810 hours of the overdose being taken.
If a patient presents more than 4 hours after an
overdose, a plasma acetaminophen level should be
requested regardless of the stated dose. If the plasma
acetaminophen concentration is close to or above the
treatment line on the acetaminophen nomogram currently in use (see Figure 4-11 for an example), then
Table 4-3 Poison antidotes
POISON
ANTIDOTE
Beta-blockers
IV glucagon, high-dose insulin euglycemic therapy
Calcium-channel blockers
10% calcium gluconate, 10% calcium chloride, glucagon, high-dose

insulin euglycemic therapy
Cyanide
Oxygen, high-dose hydroxycobalamin
Digoxin
Digoxin-specic antibodies
Ethylene glycol/ methanol
Ethanol, 4-methylpyrazole
Lead
DMSA, DMPS, disodium calcium edetate
Iron salts
Desferrioxamine/deferrioxamine
Opioids
Naloxone, naltrexone
Organophosphorus insecticides, nerve agents
Atropine, for nerve agents oximes (pralidoxime, obidoxime, H1-6):

note that oximes are no longer recommended for routine use in
organophosphorus insecticide poisoning
N-acetylcysteine (preferred) or methionine
Thallium
Prussian blue
DMPS, 2,3-dimercapto-1-propanesulfonic acid; DMSA, dimercaptosuccinic acid; IV, intravenous.

Adapted from Jones AL, in JA Innes (ed), Davidsons Essentials of medicine. Edinburgh: Elsevier, 2009.
44
160
150
140
900
130
800
120
110
700
100
600
90
80
500
70
400
60
50
300
40
30
200
20
100
0
Blood paracetamol concentration (mg/L)
Blood paracetamol concentration (micromol/L)
1000
10
0
0
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Figure 4-11 The Australian paracetamol (acetaminophen) treatment nomogram. Note that in some units the
protocol for intravenous N-acetylcysteine has been altered, in particular to try to reduce the incidence of early
anaphylactoid reactionsthe approved protocol should be checked or a clinical toxicologist consulted if there
is any doubt
Reproduced with permission from the Medical Journal of Australia. www.mja.com.au/journal/2008/188/5/guidelines-managementparacetamol-poisoning-australia-and-new-zealand-explanation
N-acetylcysteine should be administered intravenously

(IV) over approximately 20 hours. If the concentration
is below the line, this level is often rechecked at 4hours
to see if it subsequently crosses the line, indicating
the need for N-acetylcysteine. The acetaminophen
nomogram cannot be applied for repeat or staggered
overdoses, or if the timing of ingestion cannot be
determined with confidence.
If the patient presents less than 4 hours after an overdose, then an acetaminophen level should be taken
at 4 hoursif taken earlier than this, it cannot be
interpreted.
If the presentation is within 1 hour, give activated
charcoal.
If the timing of ingestion is unknown or the history
is not clear, it is wise to err on the side of caution and
treat with N-acetylcysteine according to the standard
protocol (Table 4-4, overleaf).
In approximately 12% of cases of administration of Nacetylcysteine an anaphylactoid reaction occurs within
the first 2 hours of the infusion, characterized by skin
flushing, rash, wheeze and, extremely rarely, by cardiac
arrest.
Management is supportive: administration of antihistamines and epinephrine if needed, and stopping the
infusion for at least 30 minutes; then the infusion can be
restarted at the rate of 50 mg/kg/h, with monitoring.
Tracking of repeat acetaminophen levels to ensure they

dont cross the nomogram line and to ensure complete
metabolism of acetaminophen has been recommended
and has been adopted in some centers.
The most important risk factor for liver damage after acetaminophen ingestion is the extent of delay, beyond 8 hours,
until treatment with N-acetylcysteine commences.
Clinical or biochemical evidence of hepatic injury may
not be apparent for up to 24 hours after an acute acetaminophen overdose. Developing an alanine aminotransferase (ALT) level >1000IU/L within 12 hours of
starting N-acetylcysteine is correlated with highest prothrombin time ratios (international normalized ratios)
and poor prognosis.
Hepatic failure, encephalopathy and death remain
uncommon outcomes, although acetaminophen
remains the most important single cause of acute liver
failure in Western countries.
Bernals modification of the Kings College London
OGrady criteria (pH <7.25 more than 24 hours after
the overdose, prothrombin time in seconds, degree of
acidosis and renal dysfunction) is used to determine the
need for transplantation, and additionally uses a lactate
level of >3.0 mmol/L after resuscitation as an indicator.
Persistent elevation of serum lactate is a bad sign. Markers of liver regeneration such as microRNA offer future
promise as prognostic markers.
45
Table 4-4 Standard protocol for administration of N-acetylcysteine in acetaminophen (paracetamol) overdose,
according to the patients weight
PATIENTS LEAN
BODYWEIGHT
(KG)
INITIAL INFUSION
BAG; mL
VOLUME OF NACETYLCYSTEINE
TO BE ADDED TO
200mL OF 5%
GLUCOSE: INFUSED
OVER 1560
MINUTES
SECOND
INFUSION BAG;
mL VOLUME OF NACETYLCYSTEINE
TO BE ADDED TO
500mL OF 5%
GLUCOSE: INFUSED
OVER 4 HOURS
THIRD INFUSION BAG;

mL VOLUME OF NACETYLCYSTEINE TO BE
ADDED TO 1000ML OF 5%
GLUCOSE: INFUSED OVER
16 HOURS
50
37.5
12.5
25
60
45.0
15.0
30
70
52.5
17.5
35
80
60.0
20.0
40
90
67.5
22.5
45
0.75x
0.25x
0.5x
Adapted from product information (Mayne Pharma Ltd, Melbourne,Vic) and Daly FFS et al. Guidelines for the management of paracetamol
poisoning in Australia and New Zealandexplanation and elaboration. Med J Aus 2008;188(5)296302.
Non-steroidal anti-inammatory drugs

(NSAIDs)
Overdose with NSAIDs such as ibuprofen and naproxen
are common. Mild abdominal pain, vomiting and occasional diarrhea are the common manifestations. Both are
frequently self-limiting.
Urea, electrolytes and creatinine, and full blood count
should be checked on every patient presenting with NSAID
overdose. Ensure adequate hydration. Consider H2 blockade
(e.g. ranitidine) for symptomatic relief of gastric pain.
Tricyclic antidepressants such as amitriptyline remain commonly prescribed.
Symptoms after overdose include dry mouth, blurred
vision and impaired cognition (including anticholinergic delirium).
Signs include reduced Glasgow Coma Scale (GCS)
scores, tachycardia and seizures.
An EKG should be taken, and monitoring continued.
Look for tachycardia and QRS prolongation >120 ms,
which predicts risk of seizures and arrhythmias; more so
if the QRS >160 ms. If the QRS >160 ms or arrhythmias
occur, administer 1 mmol/kg of IV sodium bicarbonate.
Oral activated charcoal should be given only if the
patient is seen within 1hour of ingestion.
Seizures should be treated with sodium bicarbonate
(to reduce the central nervous system [CNS] penetration of the drug) and a benzodiazepine such as diazepam
10mg IV or lorazepam.
46
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs such as fluoxetine, sertraline and citalopram are less
toxic than tricyclic antidepressants in overdose. However,
arrhythmias and seizures can occur. Rarely, but especially
if a combination of serotonergic agents has been taken, then
serotonin toxicity may occur (Figure 4-12).
Serotonin toxicity is a spectrum disorder, not a discrete syndrome as such. It is potentially life-threatening and
can be caused by a mixture of serotonergic drugs (acting on
5-hydroxytryptamine [5-HT] receptors) in normal or overdose quantities.
It is managed by stopping any further doses of 5-HT
drugs, meticulous supportive care and, where significant
features occur, cyproheptadine (which blocks 5-HT2 receptors in the CNS) is administered orally 12 mg stat then
48 mg every 46 hours.
Other antidepressants
SNRIs (serotonin norepinephrine reuptake inhibitors)
such as venlafaxine have drowsiness as the most common clinical feature in overdose. Other effects include
seizures, tachycardia, hypotension or hypertension, and
rarely arrhythmias. Venlafaxine overdoses are not associated with prolonged QTc or QRS. EKG monitoring
and supportive care is all that is required in most cases.
NaSSAs (noradrenergic and specific serotonergic antidepressants) such as mirtazapine are remarkably safe in
overdose. EKG monitoring and supportive care is all
that is required in most cases.
Has a serotonergic agent been taken with

the past 6 weeks?
If yes, move to the right
If no, then it is not serotonin toxicity
Are ANY of the following sign or symptoms

present:
tremor and hyperrefexia;
spontaneous clonus; muscular rigidity;
temp >38C and ocular clonus or
inducible clonus: ocular clonus and either
agitation or diaphoresis; inducible clonus
and either agitation of diephoresis?
SEROTONIN TOXICITY
If yes, move to the right

If no, then it is not serotonin toxicity
Figure 4-12 Diagnosis of serotonin toxicity.

Adapted from Dunkley EJ et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
QJM 2003;96(9):635-42.
NRIs (norepinephrine reuptake inhibitors) such as

roboxetine also seem safer in overdose. No serious
sequelae have been reported in two cases of taking up to
52 mg of roboxetine. EKG monitoring and supportive
care is all that is required in most cases.
of the drug(s) or insulin have worn off. 50 ml IV of 50%

dextrose is frequently followed by an infusion of 1020%
dextrose titrated to the patients blood glucose level. Insulin
is non-toxic if ingested.
Octreotide has been used as an antidote in severe sulfonylurea (gliclazide, glibenclamide) toxicity.
These include drugs such as clozapine, risperidone, quetiapine and olanzapine. All antipsychotic drugs block dopamine receptors (D2) and serotonin (5-HT blocking). Some,
such as clozapine, olanzapine and quetiapine, also block H1
histamine and alpha-adrenergic receptors.
In overdose they can cause hypotension, tachycardia
and drowsiness. Potentially life-threatening consequences
include QT prolongation and respiratory depression. Death
has been reported after an estimated overdose of 10,800 mg
of quetiapine.
CLINICAL PEARLS
In approximately 12% cases of administration of
N-acetylcysteine, an anaphylactoid reaction occurs
within the rst 2 hours of the infusion.
Up to 20% of patients who overdose on NSAIDs may
experience seizures or renal dysfunction.
In patients with a history of convulsions or toxininduced cardiotoxicity, or those who have ingested
tricyclic antidepressants, umazenil may precipitate
seizures or ventricular arrhythmias.
Benzodiazepines
Benzodiazepines taken alone in overdose are rarely fatal
and present with drowsiness, cerebellar signs and confusion. However, the patients GCS score may be reduced for
24 hours. Some clinicians administer the antidote flumazenil, but it is seldom needed in clinical practice and is contraindicated in multiple drug overdose.
Meticulous supportive care, including maintenance of
the airway, is required in those with an impaired GCS score.

Overdose with these agents by diabetic patients is common.
The key principles are to work out what dose of what has
been taken, with what anticipated length of action, and to
provide additional IV blood glucose support until the effect
DRUGS OF ABUSE OR MISUSE

Amphetamines
Amphetamine-related presentations account for >1% of
hospital admissions and often represent high-acuity patients
with aggressive behavior. Inadequate or inappropriate sedation is a major clinical issue. All symptomatic patients should
have EKG, blood pressure and temperature monitoring
for >6 hours. Methamphetamine, or ice, may be injected
intravenously, swallowed or smoked.
Ecstasy (MDMA; 3,4-methylenedioxy-N-methylam
phetamine) produces feelings of euphoria and intimacy.
Patients presenting to hospital are commonly intravascularly
47
deplete and hot. The heat occurs due to local muscular

production of heat and a central CNS (5-HT) source. The
amount of time the patients core spends at above 39C is
critical to poor clinical outcome. Management consists of
sedation with benzodiazepines if required, cool IV fluids
(often patients need 35 L) and management of complications (see Table 4-5).

Cocaine is usually sniffed or snorted into the nose, or
injected. Crack cocaine is heated and sniffed.
Mild to moderate intoxication causes euphoria, agitation, cerebellar signs, dilated pupils, headache, tachycardia and hallucinations.
Features of severe intoxication include convulsions,
coma, severe hypertension and stroke.
Complications include the entire list above with amphetamines (Table 4-5). In addition, central chest pain due to
coronary artery vasospasm and myocardial infarction (MI)
can occur. All patients should be observed with EKG monitoring for >2 hours. It is important to consider the cocaine
as a precipitant, as the investigation and management differs
significantly from that of ischemic heart disease.
Diagnosis of cocaine-related MI is difficult, as 84% of
patients with cocaine-related chest pain have abnormal
EKGs even in the absence of MI, and half of all cocaine
users have elevated creatine kinase concentrations in
the absence of MI; serum troponin is the most useful
test to date.
The cornerstones of therapy for chest pain are generous
doses of benzodiazepines to decrease central adrenergic
stimulation, high-flow oxygen, nitrates (sublingual and
intravenously) and aspirin. Patients with ongoing ischemia

can be treated with low doses of calcium-channel blockers
(verapamil) or alpha-blockers (phentolamine). Avoid betablockers because of the risk of enhancing coronary vasoconstriction and and the theoretical risk of unopposed alpha
stimulation which would cause uncontrolled hypertension.
Patients with continuing chest pain and/or EKG findings despite these measures should proceed to coronary
angiography.
GHB is liquid Ecstasy and has a mild seaweed flavor. It is
taken in small amounts to achieve a high, but dosing is difficult and newer users in particular may experience sedation
problems. Patients present with a diminished GCS score
with small or midpoint pupils. They often recover spontaneously within a few hours, with airway and sometimes
respiratory support.
CLINICAL PEARL
Patients with gammahydroxybutyrate toxicity present
with a diminished GCS score with small or midpoint
pupils. The differential diagnosis is opioid poisoning.
Opioids, such as heroin or morphine

Patients poisoned with opioids present with reduced GCS
score, reduced respiratory rate and volume, and small pupils.
Provision of an adequate airway and ventilation is critical to
good outcome in most cases.
Reversal of the poisoning is achieved by administration
of 0.82 mg IV naloxone (IV is better than IMtitrate
Table 4-5 Complications of amphetamine intoxication (including Ecstasy)
COMPLICATION
HOW COMMON?
MANAGEMENT
Hyponatremia due to syndrome of

inappropriate ADH secretion (SIADH)
Very rare
Water restriction
Intracerebral hemorrhage
Uncommon
CT/MRI required if any focal neurological signs are

present or GCS score is reduced
Serotonin toxicity
Uncommon
Cyproheptadine (as above under SSRIs)
Hypertension
Uncommon
GTN infusion, benzodiazepines, labetalol (mixed

alpha- and beta-antagonist)
Avoid beta-blockers
Hyperthermia
Common
Cooling measures, diazepam, specic 5-HT agonists

such as cyproheptadine
Rhabdomyolysis
Uncommon
IV uids, cooling measures
Supraventricular and ventricular

tachycardia
Uncommon
Short-acting antiarrhythmic drugs, e.g. esmolol for

SVT
Seizures
Uncommon
IV diazepam
5-HT, 5-hydroxytryptamine; ADH, antidiuretic hormone; CT, computed tomography; GCS, Glasgow Coma Scale; GTN, glyceryl trinitrate;
IV, intravenous; MRI, magnetic resonance imaging; SSRIs, selective serotonin reuptake inhibitors; SVT, supraventricular tachycardia.
48
against GCS score, respiratory rate and oxygen saturations).

A common pitfall is giving inadequate doses as an infusion
after the initial bolus. As a rule of thumb, this should be 23of
the dose required to initially rouse the patient, per hour.
CLINICAL PEARLS
Reverse opioid poisoning by administering 0.82mg
IV naloxone boluses (IV is better than IMtitrate
against GCS score, respiratory rate and oxygen saturations).
A common pitfall is giving inadequate doses as an
infusion after the initial bolus. As a rule of thumb, this
should be 23 of the dose required to initially rouse
the patient, per hour.

Prescription drug abuse in some countries is now overtaking
illicit drugs as a cause of poisoning. There is high abuse and
poisoning potential for oxycodone, methadone and other
opioids, and for benzodiazepines such as alprazolam and
oxazepam. In terms of risk of death per 100,000 singlesubstance exposures, methadone and morphine rank among
the highest in the world.
Synthetic cathinones, e.g. vanilla sky,

ivory wave
Synthetic
cathinones
include
mephedrone,
3,4methylenedioxypyrovalerone and 3,4-methylenedioxy-Nmethylcathinone (MDMC; also known as methylone).
They are beta-ketone analogues of amphetamines. Sold as
bath salts or gas stations on the internet, the packs usually say not for human consumption. They are abused for
stimulant effect and smoked or ingested orally. Case reports
demonstrate dependency and deaths, nose bleeds, high suicidality, CNS stimulation, and cardiac toxicity withpossible QTc prolongation. They may not cross-react with urine
assays for amphetamines.

Synthetic cannabinoids are cyclohexylphenolaminoalkylindoles and include many different products with a high affinity for CB1 and CB2 receptors with active metabolites. They
are more potent than tetrahydrocannabinol (THC) from
cannabis. They are sold as herbal incense products on the
internet or in shops. These are abused by smoking and there
are case reports of tolerance, dependence and withdrawal,
with attendant driving issues. Recently a case was reported
in New York with seizures, sinus tachycardia and a creatine
kinase level of 2700 IU/L.
Drink spiking
Most poisoning from drink spiking is due to alcohol. On rare
occasions, drinks are spiked with additional drugs such as
GHB or short-acting benzodiazepines. If samples of urine and
blood are obtained from patients, they should be taken as soon
as possible for toxicology screening, using legal precautions.
CHEMICALS
Many toxic chemicals exist in household environments,
such as bleaches, acids, alkalis, toxic alcohols and pesticides.
Acids and alkalis

These are corrosive, with oral cavity and pyloric injury more
likely with acids and esophageal injury with alkalis. Endoscopy may be required to assess the degree of injury, and surgery may be necessary in a minority of cases. Do not empty
the stomach, as this carries the risk of lung aspiration. Water
should be given.
Chlorine
This is commonly available for swimming pools, and may
also be released when acid cleaners are combined with
bleaches. Respiratory irritation, coughing and bronchospasm may occur, which are managed with nebulized bronchodilators such as salbutamol. Rarely, a delayed pulmonary
edema may occur.
Pesticides
These are taken in overdose, especially in rural settings.
They include organophosphorus (OP) insecticides, glyphosate and permethrins. Occasionally paraquat is taken, which
is of particular concern because of the lack of effective treatment options.
Most pesticide poisoning is treated with meticulous
supportive care, including ventilatory support as required.
Atropine is the most commonly used antidote in organophosphorus insecticide poisoning. Oximes were once used
to reactivate phosphorylated acetylcholinesterase at nerve
endings. How effective oximes are is very much in question,
resulting in their diminishing use globally.
The fatality rate following deliberate ingestion of OPs in
developing countries may be as high as 70%. Three sequential phases are seen after ingestion; see Table 4-6 (overleaf).
Lead poisoning
Exposure to lead is common from mining and smelting
sources. High lead levels are associated with neurological
(e.g. motor neuropathy), hematological (e.g. anemia, basophilic stippling) and gastrointestinal effects (e.g. abdominal
pain). The World Health Organizations current blood lead
action intervention level is 10 microg/dL. Evidence is building of neurocognitive deficits with chronic low lead levels
(<10 microg/dL).
The primary management for lead intoxication is to
reduce or prevent exposure, although in cases where lead
concentration in the blood exceeds 45 microg/dL, chelation
therapy with dimercaptosuccinic acid (DMSA) or 2,4-dim
ercapto-1-propanesulfonic acid (DMPS) is indicated. Specialist advice is needed for this.
SPIDER BITES
The majority of spider bites cause only minor effects (local
swelling, pan, redness and itch). Most bites require no
49
Table 4-6 Phases in organophosphorus poisoning
PHASE
TIME AFTER
EXPOSURE
Acute cholinergic
syndrome
Within 1 hour
Intermediate
syndrome (IMS)
Organophosphateinduced delayed
polyneuropathy
(OPIDN)
LASTS
4872 hours
CLINICAL FEATURES
MANAGEMENT
Miosis, muscle fasciculation,

followed by limb, respiratory
and sometimes extraocular
muscle paralysis
Plasma cholinesterase
conrms exposure
Remove contaminated
clothes, give oral
activated charcoal,
IV atropine reverses
bronchorrhea,
bradycardia and
hypotension
Role of oximes is
contentious
More than
48 hours
Progressive muscle
weakness due to
neuromuscular junction
failure
Complete recovery is
possible with ventilatory
care
13 weeks or with
chronic exposure
Degeneration of long
myelinated nerve bers
lead to paresthesiae and
progressive limb weakness
Supportive care
Recovery often
incomplete
Modied from Karalliedes L, Chapter 4, in JA Innes (ed), Davidsons Essentials of medicine. Edinburgh: Elsevier, 2009.
specific measures beyond analgesia, but a few species can

cause severe and systemic features, in which case the appropriate antivenom is used.
SNAKE BITES
Snake bite is a common life-threatening condition in many
countries; farmers, soldiers, rice-pickers and hunters are at
particular risk, as are leisure travelers whose alcohol-fueled
curiosity leads to unwanted encounters with snakes. Not all
bites lead to envenomation, i.e. dry bites.
First aid for snake bite is immobilization and appropriate
pressure immobilization bandaging, although guidelines
specific to country and species vary on this. Identification
of the type of snake is made from direct visual identification of the snake, which is unreliable, and where available using venom detection kits from the wounds bite
site (best) or urine (less good). This aids the choice of
antivenom to be administered intravenously. In general,
it is better practice to give specific snake antivenom than
polyvalent antivenom, because of the higher risk of adverse
reactions with the polyvalent antivenom. Additional tests
such as coagulation and platelet counts are required in
some cases, e.g. brown snake envenomation, and guidance
on the management of snake bite from an experienced
toxinologist is recommended.
Cardiovascular, respiratory and renal support may be
needed, as may treatment for coagulopathies. Most patients
who receive medical attention in developed countries survive their envenomation.
50
MARINE ENVENOMATION
Bluebottle (Physalia spp.) stings are common and can be
treated with warm water.
Toxic jellyfish such as the box jellyfish (Chironex fleckerii)
can cause death from acute respiratory failure or acute cardiac arrest. Acetic acid (vinegar) is used on the tentacles of
adherent box jellyfish to inactivate nematocysts, but if not
available then tentacles should be removed without delay,
taking precautions to protect your skin as you do so. An
antivenom is available for the box jellyfish.
Carukia barnesi and other jellyfish can cause Irukandji
syndromeheadache, hypertension, severe muscular
and abdominal pain, elevated troponin I levels, cardiac
dysfunction (with MI in about a third of patients). Systemic magnesium, in slow boluses of 1020 mmol, may
attenuate pain and hypotension in Irukandji syndrome.
The blue-ringed octopus (Hapalochaena maculosa) yields
a potent neurotoxin which may first manifest itself with
paresthesiae, tightness in the chest, cranial nerve palsies,
e.g. bulbar palsy, followed by respiratory arrest. The best
management is intubation if required and supportive
care.
TERRORISM, AND USE OF

MEDICAL COUNTERMEASURES
Chemical agents
As a hopefully never-in-a-lifetime event, physicians may
be required to manage patients who have been exposed to
terrorist activity. Mass sickness or fatalities occurring over
a short period, all exhibiting the same types of symptoms
and signs, or patients reporting unusual smells or tastes
might alert clinicians to the possibility of an attack having
occurred. Management of such situations requires resolve,
calmness and specific knowledge, much of which is readily
available and frequently updated on government preparatory and emergency websites, e.g. those of the Centers for
Disease Control and Prevention (CDC), Agency for Toxic
Substances and Disease Registry (ATSDR) and health
departments. Diagnostic features and broad principles of
care are discussed here.
If people have been exposed to toxic chemicals it is vital
that thorough decontamination takes place before medical
care can continue beyond the principles of airway, breathing
and circulation support, and perhaps even antidote administration where early administration is critical to outcome
(i.e. ABCD). Decontamination after a chemical terrorism
event usually occurs near the incident site and is undertaken
by the fire services (e.g. Hazmat teams) in most countries.
In addition, minor decontamination facilities are available in
key emergency departments for patients presenting directly
to such facilities. After decontamination, it is important to
look for signs of toxidromes (Table 4-7), while protecting
staff with personal protective equipment (PPE) of the appropriate level (see local emergency department policy on PPE).
Biological agents
Unlike chemical attacks, where the features often develop
within minutes, incubation times of biological agents often
allow victims to spread far away and then present to their
local healthcare providers. Diagnostic skills, attention to
hygiene to avoid spread by respiratory or direct skin contact,
and antimicrobials appropriate to the underlying diagnosis
together with excellence in communication underpin effective clinical care (Table 4-8, overleaf).
Table 4-7 Possible toxidromes after chemical attack
SIGNS AND SYMPTOMS
LIKELY EXPOSURE
RELEVANT MANAGEMENT
Difficulty in seeing and breathing,

miosis, bronchorrhea, reduced
consciousness, weakness and
fasciculation, i.e. acute cholinergic
syndrome
Nerve agent*
Airway, breathing, circulation

Atropine and antidote, e.g. DuoDote
(contains atropine and oxime) to be given
quickly after exposure. Note that not all
nerve agents, e.g. sarin, respond to oximes
Diazepam improves survival
Intubation and ventilation as required
Decreased plasma or red blood cell
cholinesterase suggests a diagnosis of
poisoning
Skin burns (mustards sometimes

smell like garlic, onions or mustard)
Acids, alkalis, mustard agents
Decontaminate appropriately and treat as

for burns
Bronchospasm, coughing, painful

eyes, i.e. irritant syndrome
Chlorine
Skin decontamination, bronchodilators

Beware the potential for late-onset
pulmonary edema
Respiratory distress, fever, cough,

nausea, chest tightness, pulmonary
edema (if inhalational exposure),
vomiting and diarrhea (if ingestion),
low blood pressure, respiratory
failure. Death within 72 hours
Ricin* (derived from castor beans)
Supportive medical care, e.g. intravenous

uids, ventilatory support
No known antidote
Activated charcoal if suspected recent
ingestion
Very rapid symptoms after exposure,

that include lightheadedness, rapid
breathing, emesis, respiratory
depression, opisthotonus, seizures
and cardiac arrest
Hydrogen cyanide*
Supportive care, e.g. cardiopulmonary

resuscitationcare is needed to avoid direct
oral to oral contact
The antidote of choice is
hydroxycobalamin, and must be given as
quickly as possible after exposure
* Management information sourced from the Emergency Preparedness and Response section of the website of the Centers for Disease
Control and Prevention www.bt.cdc.gov.
51
Table 4-8 Clinical features and management of biological agents
CLINICAL SIGNS AND SYMPTOMS
LIKELY AGENT
MANAGEMENT
Bacillus anthracis infection occurs in three forms:

1. Cutaneousitchy lump which develops into a
vesicle, then a painless ulcer 13 cm in diameter
with a typical black (necrotic) area in the center
2. Inhalationcommon cold symptoms (EXCEPT
rhinorrhea), followed by severe breathing
difficulty and cardiovascular system shock.
Usually fatal
3. Gastrointestinalnausea, vomiting, fever
followed by abdominal pain, hematemesis and
severe diarrhea. Death occurs in 2560% of
cases
Anthrax
(B.anthracis)
Meticulous supportive care, ciprooxacin

500mg twice daily or doxycycline pending
sensitivity results.*
Acute generalized vesicular or pustular rash,

deep-seated, hard and well-dened lesions in
the same stage of development, with the greatest
concentrations on the face and distal extremities,
oral mucosa and soles
Patient looks toxic
Note that a smallpox diagnostic risk calculator is
available at www.bt.cdc.gov/agent/smallpox
Smallpox
(Variola major)
Isolate all cases and face-to-face or

household contacts after the onset of fever,
and give supportive care
No currently effective antibiotic or immune
therapy
Vaccination for contacts, including up to the
rst few days after exposure*
Bubonic plague is the most common manifestation

with a painful bubo occurring in the groin, axillae
or cervical lymph nodes
If untreated, septicemia and a pneumonic process
results. Pneumonic plague is characterized by high
fever, chills and breathing difficulty
Plague
(Yersinia pestis)
Take laboratory samples (lymph node

aspirate, blood cultures, sputum). Gramnegative organisms with a safety pin
appearance provide a rapid presumptive
diagnosis
Begin antibiotic immediatelystreptomycin
1g twice daily or gentamicin 5mg/kg/day
With foodborne botulism, symptoms begin within

6 hours to 10 days after eating the toxin-containing
food
Symptoms include blurred vision, double vision,
drooping eyelids, slurred speech, difficulty
swallowing, and muscle weakness that moves
down the bodyrst shoulders, then arms, then
breathing
Note that there is no person-to-person spread
Botulism
(Clostridium
botulinium toxin)
Meticulous supportive care, including

ventilator support where necessary
Antitoxin is available*
Severe hemorrhagic fever
Filoviruses (Ebola,
Marburg)
Isolation to disrupt further transmission

No known effective treatment#
Severe hemorrhagic fever
Arenaviruses
(Lassa fever,
JuninArgentine
haemorrhagic fever)
Supportive care
* Information sourced from the Emergency Preparedness and Response section of the website of the Centers for Disease Control and
Prevention (CDC) www.bt.cdc.gov.
# Information sourced from the CDC website: http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/vhf.htm (lovirus and arenavirus
fact sheets).
52
For the following questions, one or more responses may be correct.
1 The bioavailability of an oral preparation of a new drug is assessed in a cross-over study. The summary results of the
cross-over study are shown below.
Route
IV
Oral
Dose
20 mg
50 mg
Cmax
2 mg/L
0.5 mg/L
AUC
60 mg.h/L
30 mg.h/L
AUC, area under the curve; Cmax, maximum concentration; IV, intravenous.
What is the oral bioavailability of this drug?

A 80%
B 60%
C 40%
D 20%
E 10%
2 A drug is 70% renally eliminated and 30% metabolized by cytochrome P450 3A4. The usual dose is 100mg twice a day.
Your patient has a stable creatinine clearance of 30 mL/min (normal is approximately 100 mL/min). What dose would
achieve usual drug concentrations? This drug is available in 30 mg and 100 mg scored tablets.
A 100 mg twice a day
B 100 mg daily
C 60 mg daily
D 30 mg twice a day
E 30 mg daily
3 A patient treated for hypertension comes for review. 24-hour blood pressure monitoring shows she is under-treated.
You double the dose of her medication but there is minimal change in her blood pressure. What is the most likely
explanation for the minimal response to the doubling of the drug dose?
A The patient is not taking the drug.
B The patient has secondary hypertension.
C The patient has very high drug clearance.
D There is a drugdrug interaction.
E The patient is already at the top of the doseresponse curve.
4 Drug toxicity due to unintended drugdrug interactions is most commonly caused by what mechanism?
A Displacement from protein binding.
B Inhibition of p-glycoprotein efflux transporters.
C Inhibition of drug-metabolizing enzymes.
D Inhibition of renal drug transporters.
E Induction of drug absorption.
5 A 40-year-old tells you he had a rash when given penicillin as a child. He has not had penicillin since. What should you
advise him?
A He is at high risk of anaphylaxis if exposed to penicillin antibiotics and should wear a Medic Alert bracelet.
B He should undergo desensitization to penicillin.
C He should undergo further assessment for penicillin allergy.
D He could be treated with penicillin if necessary but should also receive a corticosteroid and an antihistamine.
E He is at low risk of future adverse reactions and can have penicillin antibiotics if needed in the future.
6 Costefficacy analyses are frequently undertaken to assess whether a new drug should be funded by the government
or an insurer. In a costefficacy analysis, what is the best description of efficacy?
A Improvement in primary outcome for patients treated with the new drug compared with placebo.
B Benet harm of the new drug compared with placebo.
C Benet harm of the new drug compared with usual care.
D Change in mortality of the new drug compared with placebo.
E Change in mortality of the new drug compared with usual care.
53
7 Which of the following is the best antidote for hydrogen cyanide poisoning?
A Oxygen
B Hydroxycobalamin
C Sodium thiosulfate
D Dicobalt edetate
E Amyl nitrite
8 Which of the following is not a feature of late acetaminophen (paracetamol) poisoning in humans?
A Right upper quadrant abdominal pain
B Renal-angle tenderness on palpation
C Prolonged prothrombin time
D Methemoglobinemia
E Nausea
9 Poisoning with which of the following does not cause mydriasis (dilated pupils)?
A Benzodiazepines
B Organophosphorus insecticides
C Tricyclic antidepressants
D Antihistamines
E Ice (methamphetamine)
10 Which of the following is not true of snake bites?
A The populations most at risk are rural farming ones.
B Antivenins are almost always needed to treat victims.
C Bite-site testing for venom detection is the preferred diagnostic tool.
D Compression bandaging is recommended as a rst aid measure.
E Administration of antivenin may be associated with an anaphylactic reaction.
11 Which of the following is not true of ricin?
A It is an extract from the castor bean.
B It can cause pulmonary edema.
C It has an antidote.
D It can cause systemic hypotension.
E It can cause vomiting and diarrhea.
ANSWERS
1 D
Bioavailability is the proportion of the dose reaching the systemic circulation. As all of an IV dose enters the systemic
circulation, oral bioavailability can be calculated by comparing the drug exposure (AUC) of the oral dose vs the IV dose.
The oral AUC is half the IV AUC, but only 40% of the oral dose was given IV. Half of 40% is 20%. Thus, 80% of the oral dose
is either not absorbed or is metabolized before it reaches the circulation (rst-pass metabolism).
2 B.
Metabolism is likely to be unchanged, and it is only the renally cleared portion that will be affected by the renal
impairment. With 30% metabolic clearance and about 20% renal clearance (i.e. one-third of 70%), this patient will have
about half normal clearance and the half-life will be doubled. Either the dose could be halved or the dose interval could be
doubled. A single tablet once a day is simple, as well as being about the right dose. This will give this patient a starting dose
that gives a similar drug exposure to other patients. The dose of every patient still needs to be adjusted based on patient
response.
3 A or E.
Poor adherence to drug treatment is the most common cause of treatment failure in chronic care, particularly for
asymptomatic conditions. Secondary hypertension occurs in a signicant minority of patients with hypertension and
should always be considered, but is not a good explanation for lack of dose response. Many drugs of wide therapeutic
index are given in doses at the top of their doseresponse curves, and therefore increasing the dose often has only a small
effect on response. Variability in drug clearance and drug interactions always need to be considered, but are less likely
explanations of the lack of response on increasing the dose.
4 C.
Drug interactions cause drug toxicity either by an additive effect or by increasing a drug concentration, as in this
case. Inhibition of drug-metabolizing enzymes is the most common cause of drug toxicity due to a pharmacokinetic
interaction. Displacement from protein binding only causes a minor transient increase in drug concentration. Increased
drug absorption by inhibition of efflux transporters or decreased renal excretion can both cause clinically important drug
toxicity.
54
5 C.
Anaphylaxis to penicillin is potentially fatal and is one of the most common drug causes of anaphylaxis. However, rashes
at the time of febrile illnesses are common, especially in children. Many people are incorrectly labeled as being allergic to
penicillin, and not having access to a major group of antibiotics can compromise the treatment of some conditions. It is
not usually possible to make a diagnosis one way or the other on the basis of a distant history of rash. Investigation of drug
allergy is a specialized area and suspected cases should be referred to an immunologist.
6 C.
In considering whether to fund a new drug, a comparison with current practice should always be made. If the drug were
better than placebo but not as good as current care, it would not offer a clinical advantage. The correct comparator is thus
usual care. In assessing the clinical value of the drug, we are interested in net efficacy, the sum of the benets minus the
sum of the harms. If the drug is more effective than current treatments, we may be prepared to pay more for it.
7 B.
While oxygen, sodium thiosulfate, dicobalt edetate and amyl nitrite have all been used in cyanide poisoning,
hydroxycobalamin has the best benet with the fewest side-effects and is the current antidote of choice.
8 D.
Methemoglobinemia occurs in cats but not humans after acetaminophen overdose. Right upper quadrant tenderness
and nausea often reect hepatic injury and the need to check liver function tests including clotting (prothrombin time or
international normalized ratio). Renal-angle tenderness, while rarer, can indicate kidney injury and prompts the need to
check renal function tests.
9 B.
Opioids, organophophorus insecticide exposures and nerve agents can cause miosis (pin-point pupils).
10 B.
Bites from snakes may be dry and antivenin is not usually administered unless signs of envenomation occur. Antivenin is
potentially antigenic and reactions do occur. Where venom detection kits are available, e.g. in Australia, bite-site testing of
venom for venom detection is preferred, together with positive identication of the snake if possible.
11 C.
There is no known antidote to ricin poisoning.
55
CHAPTER 5
GENETICS
John Attia
CHAPTER OUTLINE
OVERVIEW
THE FLOW OF GENETIC INFORMATION
Transcription
Translation
Regulation
GENETIC VARIATION
MENDELIAN DISEASES
GENETIC TESTING IN MEDICINE
Cytogenetic studies
Fluorescence in situ hybridization (FISH)
Sequencing
COMMON CHROMOSOMAL GENETIC

CONDITIONS
Down syndrome
Turner syndrome
CALCULATING THE RISKS OF DISEASE

Some examples
OVERVIEW
There are 23 pairs of chromosomes in the human
genome: 22 pair of autosomes and 1 pair of sex chromosomes (Figure 5-1). One copy of each pair is inherited at
fertilization, one from the father through the sperm and
one from the mother through the egg.
Chromosomes are made of deoxyribonucleic acid
(DNA) complexed with various proteins (histones and
non-histones); see Figure 5-2. Each chromosome has a
centromere, where the DNA is tightly packed, and telomeres, which is the name given to the ends of the chromosome. The centromere is not quite in the center
of the chromosome, creating a short arm (called p for
petit, meaning small in French) and a long arm (called

q for queue, meaning tail in French).
DNA is a double-stranded helix (Figure 5-3) made up
of nucleotides; each nucleotide is made up of a sugar and
a phosphate group linked to one of four different bases:
adenine or guanine (called purines), or cytosine or thymine (called pyrimidines).
Adenine (A) on one DNA strand of the helix pairs
with thymine (T), and guanine (G) pairs with cytosine (C).
RNA (ribonucleic acid) has a different base, uracil
(U), instead of thymine.
The total genome (the DNA across all chromosomes)
is 3.1 billion base pairs (bp).
57

3
5
GC
TA
AT
minor
groove
GC
pitch
3.6 nm
AT
GC
CG
13
14
15
10
11
16
17
12
AT
major
groove
TA
CG
18
TA
AT
19
20
22
21
TA
GC
Figure 5-1 Human karyotype (male)
From Strachan T and Read A. Human molecular genetics, 4th ed.

New York: Garland Science, 2011.
THE FLOW OF GENETIC

INFORMATION
The general flow of information was thought to be
from one gene on the DNA to one on the RNA to one
protein, although recent discoveries have substantially
expanded this paradigm, described in the sections on
transcription and translation, below.
Only 1.1% of the genome (total DNA) consists of
protein-coding genes; this represents around 20,000
genes in total. Another, smaller, portion of the genome
consists of RNA-coding genes, of which around 6000
exist (see section on regulation, below). The function of
the remaining vast majority of DNA is unclear.
Transcription
A protein-coding gene is converted to messenger RNA
(mRNA) by RNA polymerase II in a process called
transcription. During this process, the DNA helix is
unwound and a copy of the sense strand is created. The
process of transcription is upregulated by a number of
H1 histone
formation of
solenoid structure
10 nm
octameric
histone
core
1 nm
Figure 5-3 DNA helix. A, adenine; C, cytosine;

G, guanine; T, thymine
proteins that bind to specific sequences at the start

ofeach gene.
These specific sequences at the start of each gene are
called promoters and come in different flavors
(Figure5-4):
the TATA box, found about 25 bp from the start
of the gene (shown in orange)
the GC-rich box, found in place of TATA in some
genes (shown in blue)
the CAAT box, found 80bp from the start of the
gene (shown in purple).
Enhancers perform the same function as promoters
but are typically found much further away from the
gene and help to express genes in the right tissues. The
DNA loops out to bring the promoter and the enhancer
together to stimulate the transcription of a particular
gene.
nucleosome
2 nm
DNA
uncoiling to enable
high-level gene
expression
looped domain
30 nm
chromatin
fiber
scaffold of nonhistone proteins
Figure 5-2 Packaging of deoxyribonucleic acid (DNA)

From Strachan T and Read A. Human molecular genetics, 4th ed. New York: Garland Science, 2011.
58
Chapter 5 Genetics
(A)
100
90
80
70
60
50
40
30
20
10
+1
900
800
700
600
500
400
300
200
100
+1
(B)
1000
Figure 5-4 Location of promotors (A) and enhancers (B) relative to the start of a coding region (labeled +1)
Once the DNA has been transcribed into messenger

RNA (mRNA), the mRNA moves to the cytoplasm to
act as the blueprint for one or more protein(s).
The coding sequences of genes can overlap so that a
stretch of DNA can code for many different mRNAs; it
is the promoters and enhancers that are responsible for
deciding which gene is transcribed.
Translation
Not all of the mRNA molecule codes for protein. The
mRNA sequence consists of coding sections (called
exons) and intervening sections (called introns).
In a process of splicing, the introns are removed and
the coding exons are brought together (Figure 5-5).
This splicing is variable, such that different exons can
be brought together to code for different forms of the
same protein (called isozymes or isoforms) or to form
completely different proteins. For example, the proopiomelanocortin gene codes for one mRNA that can
be the blueprint for three different proteins and four

related proteins.
Splicing is carried out by a complex of proteins
and RNA (called small nuclear ribonucleoproteins
(snRNPs), the spliceosome (Figure 5-6).
Introns are usually recognized because they start
with GT and end with AG (the GT-AG rule),
although this is obviously not the only cue.
The mRNA transcript also undergoes other changes,
where the start of the transcript is capped by a special
guanine and a long tail of adenines is added to the end
(A)
Splice
donor site
E1
GU
Branch site
E2
A
exon 1
intron 1
gt
Splice
acceptor site
E2
A
AG
3
U2
(B)
exon 2
ag
GU
U1
intron 2 exon 3
gt
ag
Binding of U4/U5/U6
snRNP complex;
U5 snRNP binds to
donor and acceptor
sites
Transcription of gene
(B)
E1
E2
gu
(C)
E3
ag
gu
E2
E1
E2
U4 U6
U5
E1
5
3
U1
U2
E3
Splicing of exonic sequences 1, 2

and 3 to produce mature RNA
(D)
(C)
ag
Cleave primary RNA transcript

at and discard intronic
sequences 1 and 2
E1
U1 snRNP binds to
splice donor site and
U2 snRNP binds to
branch site
E1
Transcription unit
(A)
AG
Cleavage of splice
donor and acceptor
sites and splicing
of E1 to E2
Intronic
sequence
(D)
E3
E1
5
E2
3
Figure 5-5 Splicing of a mRNA transcript, with (B)

transcription, (C) cleaving and (D) splicing together
of a transcript
Figure 5-6 Mechanism for splicing a transcript, with

(B) recognition of splice sites, (C) snRNP complex
formation and (D) removal of intron


59
of the transcript (a poly-A tail). These modifications

influence the location, function and degradation of the
transcript.
The sequence of the mRNA is translated into a chain
of amino acids (a protein) via the ribosome, which is
a complex of proteins and various ribosomal RNAs
(rRNA, specified by RNA-coding genes); Figure 5-7.
The ribosome is composed of a large and a small
sub-unit. Starting at the beginning of the mRNA,
the ribosome looks for the start signal, the nucleotide sequence AUG. This is the start codon and
codes for methionine; every protein therefore begins
with this amino acid which is later cleaved off.
The ribosome then reads each group of three nucleotides (codon) on the mRNA and brings in the corresponding amino acid. This amino acid is bound
to a transfer RNA (tRNA), another in the family of
RNAs specified by RNA-coding genes. The ribosome catalyzes the bonding of each amino acid to
the previous one as it moves along the mRNA.
When the ribosome hits a stop codon, it stops adding amino acids and releases the protein; there are
three codons that signal a stop.
Multiple ribosomes can bind a single mRNA, meaning
that multiple protein molecules can be made from the
one mRNA template.
P site
(A)
Regulation
The greatest change in genetic dogma in the past 30 years has
been the discovery of the role of RNA in gene expression.
We have mentioned that RNA-coding genes are the
blueprint for RNA that will be part of the ribosome (rRNA)
or form transfer RNA (tRNA) or be part of the spliceosome
(snRNA). Another class of non-coding RNA is microRNA
(miRNA) or small interfering RNA (siRNA). Both are
short RNA molecules, about 20 nucleotides long, that
interfere with mRNA translation. miRNA binds a complementary sequence on an mRNA molecule and causes its
degradation, while siRNA binds and blocks the sequence,
leading to repression of translation. Because of imperfect
binding, one miRNA or siRNA can downregulate many
different mRNAs (Figure 5-8).
Another mechanism of regulation is through epigenetic
changes. Epigenetics refers to heritable changes that are
mediated through mechanisms other than a change in DNA
sequence. The two main epigenetic mechanisms are:
Histone modificationthe most common modification is acetylation of the histone protein (addition
of an acetyl group), but other mechanisms include
methylation (addition of a methyl group), ubiquitylation (addition of ubiquitin, a 76 amino acid protein that
tags proteins for destruction), phosphorylation (addition
of a phosphoryl group) and sumoylation (addition of a
A site
(B)
Met
Met
A
C
C
Gly
A
C
C
A
C
C
UAC
CCC
AUG
GGG
Large
ribosomal
unit
Initiator
tRNAMet
UAC
AUG
mRNA
GGG
UAC
UAC
Small ribosomal unit
(D)
(C)
Met
Gly
Met
A
C
C
A
C
C
UAC
CCC
AUG
GGG
UA
UAC
AUG
Gly
Tyr
A
C
C
A
C
C
CCC
AUG
AUG
GGG
UAC
Ribosome moves
along by one codon
Figure 5-7 Process of translation with (B) binding of an amino acid, (C) covalent addition to the nascent protein
and (D) progress along the mRNA transcript
60
Chapter 5 Genetics
Long ds RNA
Dicer
Ago + other
RISC proteins
Ago + other
RITS proteins
siRNA
Activated RISC
Activated RITS
Cap
Poly(A)
Cap
Poly(A)
Cap
Poly(A)
DNA
HMT
DNMT
Histone methylation
DNA methylation
Degraded RNA
Transcription repressed
Figure 5-8 Mechanisms of regulation by small RNAs. DNMT, DNA methyltransferase, HMT, histone
methyltransferase; RISC, RNA-induced silencing complex; RITS, RNA-induced transcriptional silencing
SUMO protein, a class of small proteins that direct proteins in cellular traffic). These histone modifications are
thought to affect the packing of the DNA and hence the
ability to transcribe and translate DNA.
Methylationthis consists of the addition of a methyl
group to the DNA (not to protein, as in histone modification). The methyl group is attached to a cytosine
that is next to a guanine, i.e. a CG sequence. Stretches
of CG sequences are called CpG islands (where the p
represents the phosphate group in the DNA backbone).
This methylation tends to silence the gene and prevent
transcription.
GENETIC VARIATION
The Human Genome Project has revealed that humans are,
on average, >99% identical in their DNA sequences, meaning that all the variation we see in appearance, color, height,
build, etc. is due to the 1% difference (plus environmental
differences). Although this sounds small, 1% of 3 billion bp
is still 30 million bp.
These differences, called polymorphisms, may take a
number of different forms (Figure 5-9, overleaf):
the presence or absence of an entire stretch of DNA
(insertion/deletion polymorphisms), a variation of
which involves DNA duplication, called copy number

variation (CNV)
repeating patterns of DNA that vary in the number
of repeats; each repeating unit may vary from 23 to
hundreds of base pairs long and may repeat a few times
to hundreds of times
a change in a single base pair, called a single-nucleotide
polymorphism (SNP; pronounced snip); this is by far the
most common kind of variant.
What constitutes the difference between a variant that is
normal (polymorphism) and a variant that is pathogenic
(mutation)? Ultimately, it is the functional impact of the
variant on the protein that provides the answer. However,
frequency of the variant is often a surrogate, presumably
because of selection against a poorly functioning or absent
protein; a variant that is found at a frequency of 1% or more
in the population is often judged to be a polymorphism,
whereas a variant found in less than 1% is judged to be a
mutation.
Some variants are present in parts of the gene that are
translated, i.e. that code for proteins. Because the genetic
code that governs the matching of codons to amino acids
is redundant, a change in the DNA may mean that the
same amino acid is coded for; this is called a synonymous
change. However, a number of other possibilities arise:
61

A Common (wild-type) allele
B Polymorphisms
Deletion
Dele
ted s
MENDELIAN DISEASES
egm
ent
Insertion
Inserted segment
Tandem repeat
Repeated segments
Single-nucleotide polymorphism (SNP)

Nucleotide variation
Figure 5-9 Common (wild type) allele (A) and the

four types of genetic polymorphism (B)
A missense mutation means that a single nucleotide

variant has changed a codon to specify a different amino
acid, i.e. a non-synonymous change. The effect of this
change will be smaller if the new amino acid is in the
same class as the old one, or larger if the new amino acid
is in a different class. This may lead to alteration, loss, or
a completely new function of the protein.
A nonsense mutation means that the single nucleotide
variant has created a premature stop codon, leading to
loss of function of that protein.
A frameshift mutation means that an insertion or a
deletion has shifted the coding frame and how codons
are read, usually creating a premature stop codon.
A variant may change the splice sites, either blocking
proper splicing or creating a new splice site.
A note about terminology and notation: the point along the
DNA at which a genetic variant is found is called a locus.
The normal sequence at that locus is denoted by a capital letter, and the variant or mutant sequence is denoted by
a small letter: for example, someone who has the normal
base at a SNP locus on the maternal chromosome and the
62
variant base on the paternal chromosome is denoted Aa

(heterozygote); someone with a normal sequence at both
chromosomes is denoted AA (homozygote normal); and
someone with a variant at both chromosomes is denoted aa
(homozygote variant).
Some characteristics or functions depend on only a single

gene; consequently, mutations in that gene are highly likely
to cause disease. These are the traditional genetic diseases,
e.g. cystic fibrosis or Huntington disease.
Other characteristics are governed by a few genes (oligogenic) or by many genes (polygenic); variants or mutations
in each of these genes will individually increase or decrease
the risk of disease by a little; examples of these complex
diseases are diabetes, obesity, inflammatory bowel disease,
and asthma.
It is important to understand the patterns by which
mutations can lead to disease.
A dominant mutation means that one copy of the
mutation at a locus is enough to cause the full disease,
e.g. people with Aa or AA both have the disease.
A recessive mutation means that two copies of the
mutation at a locus are needed to cause the full disease,
e.g. only people with aa have the disease. Those with Aa
do not show the disease but are carriers for it.
A co-dominant or additive mutation means that there
is a gene dosage effect. Those with one copy of the mutation, Aa, have some degree of the disease; and those with
two copies, aa, have the full disease. This is usually the
mode of action of genes involved in complex diseases.
The symbols used for a genetic pedigree are shown in
Figure 5-10. The dominant and recessive modes of action
lead to five different patterns of inheritance in families, and
it is important to recognize these when presented with a
pedigree.
1 Autosomal dominant: an affected person usually
has at least one parent with the mutation. The parent
may or may not express the condition (i.e. be affected
by it), depending on the penetrance (see below) of the
mutation. However, the condition may also be due to
a de novo (new or spontaneous) dominant mutation that
occurred during or shortly after conception. A child
with one affected and one unaffected parent has a
50% chance of having the disease.
2 Autosomal recessive: an affected person usually has
unaffected parents, but they are very likely to be mutation carriers. A child born of two carriers has a 25%
chance of having the disease.
3 X-linked dominant: an affected person usually has at
least one affected parent. The children of an affected
female have a 50% chance of having the disease,
whereas only the daughters of an affected male have the
disease (since the male only passes on his Y chromosome to a son and not his X chromosome). This is a
rare form of inheritance.
Chapter 5 Genetics
Male
Mating
Female
Consanguineous
mating (optional)
Sex unknown/
not stated
Brothers
Unaffected
Twin brothers
Affected
Miscarriage
Carrier (optional)
Dead
6 offspring,
sex unknown/
not stated
Figure 5-10 Symbols used in pedigree diagrams

4 X-linked recessive: affected persons are mainly male,

since they only have one X chromosome, but females
can be affected if they are born of an affected father and
a carrier mother. Females can also be affected, often
more mildly, depending on the rate of expression of
the X chromosome copy on which the mutated gene
is located. This is because in females one copy of the
X chromosome is randomly switched off (inactivated;
see below). Usually this inactivation is random, but if
it is skewed towards inactivation of the X chromosome
carrying the normal gene copy, the female can express
the condition. An affected male is usually born of a carrier mother. In other cases, the mutation is de novo.
5 Y-linked inheritance: only males are affected and
they usually have an affected father. There are only a
small number of genes on the Y chromosome.
There are a couple of issues that complicate the interpretation of pedigrees:
The mutation may have reduced penetrance, i.e. it may
not manifest itself all the time. For example, in a pedigree, all those who are Aa for a dominant mutation
would be expected to show disease but this may not be
the case, partly because in some the disease may manifest later in life or not at all.
X-inactivation: Although female embryos have two
copies of the X chromosome, very early in development
(at the blastula stage) one copy, either the maternal or
the paternal copy of the X, is randomly inactivated,
and this inactivation will be the same in all daughter
cells. This means that a different X may be inactivated
across different tissues, making the interpretation of an
X-linked pedigree difficult. Males, having only one X
chromosome, do not have this process.
CALCULATING THE RISKS

OFDISEASE
It is important to be able to calculate the risk of disease in
relatives or children, once a family member has been identified with a mutation. An important tool in doing these calculations is the Hardy-Weinberg distribution.
The Hardy-Weinberg distribution states that if the
normal sequence A has a frequency in the population of
p and the variant sequence a has a frequency of q, then the
proportion of people in the population who are AA is p p or
p2, and the proportion in the population who are aa is q q
or q2. The proportion who are Aa is pq and the proportion
who are aA is qp, and hence the proportion who are heterozygous is pq+qp or 2pq. The entire population is represented
by these people, so p2+2pq+q2=1.
Some examples
Example 1
A male with an autosomal recessive disease marries a woman
who is a carrier for the same disease. What is the risk of disease in their children?
The answer can be calculated using a Punnett square (a
2 2 table named after an early 20th-century geneticist).
The mother is Aa and the father is aa; assuming that the
fertilization of a sperm and egg are random, and each parent contributes one copy of each chromosome/gene to their
child, the risk to the children can be drawn as shown below:
A
Aa
aa
Aa
aa
i.e. 50% of the children will be carriers Aa (24) and 50% will
have disease aa (24).
Example 2
An autosomal recessive condition affects 1 person in 10,000.
What is the expected frequency of carriers in the population?
Given that for a recessive disease a person must be aa to
show disease, then 110,000 must be equal to q2, or q = 1100. Because
everyone is either p or q, the frequency of p must be 99100. Given
that carriers are the heterozygotes, their frequency is 2pq, or
2 1100 99100 = about 1 in 50.
Example 3
A man who knows he is a carrier for cystic fibrosis (CF) is
thinking of marrying a woman whose CF status is unknown.
Given that the carrier frequency is 1 in 25, what is the risk to
their children without any further testing?
If the woman is a carrier and we know the man is a carrier,
then the risk to their children is (using a Punnett square like
the one above). However, the risk that a woman is a carrier is

; therefore, the risk that the woman is a carrier and that they
pass CF on to their children is
= 1 in 100.
Example 4
Redgreen color blindness is an X-linked recessive disease.
The frequency of the recessive variant is . What proportion of the population might be expected to be carriers?
63
The variant frequency, q, is 112. There are no male carriers; since males only have one X chromosome, they either
have the disease or not. Only females can be carriers and the
Hardy-Weinberg distribution tells us that this group, 2pq, is
2 112 1112 = 22144, or 15% of women are carriers. Women
with the disease are q2 = 112 112 = 1144 or 0.7%.
(A) 2 breaks in same arm
GENETIC TESTING IN
MEDICINE
It is important to be familiar with the different types of
genetic tests and the answers they can provide, as well as
their limitations.
Cytogenetic studies
Given that the 23 pairs of chromosomes are tightly condensed in the nucleus of a cell, the best time to visualize
them is when they have been untangled during cell division. White blood cells are allowed to grow and divide in
culture in the presence of an agent (colcemid) that blocks
cells during mitosis, so that chromosomes have replicated
and are maximally unfolded. The chromosomes are then
stained with a dye that binds DNA (Giemsa) and differential
staining leads to bands of DNA where dye has been bound
(dark) and where it has not (light). Under the microscope,
each chromosome has a distinct pattern of dark and light
bands, called G-banding (Fig 5-11).
Analysis of chromosomes in this way can reveal different
abnormalities:
Deletion or duplication of an entire chromosome, e.g.
Turner syndrome is a single copy (monosomy) of the
X chromosome, while Down syndrome is three copies
(trisomy) of chromosome 21.
Formation of an abnormal chromosome, e.g. a ring
chromosome (Figure 5-12).
Deletion or duplication of a section of a chromosome.
Ifthe section is large enough, then this can be seen from
the G-banding pattern.
(A)
(B)
q21
q21.1
q21.21
q22
q21.23
q21.3
Figure 5-11 Karyotyping, with increasing resolution

from (A) to (C)
64
Deletion
Inversion
Interstitial
deletion
Paracentric
inversion
Inversion
Join broken
ends
c
d
e
f
Ring
chromosome
Pericentric
inversion
Figure 5-12 Mechanisms for forming abnormal

chromosomes
Re-arrangement of a section of a chromosome. A section of the chromosome can be removed, flipped and
re-inserted back on the same chromosome, called an
inversion; or can be re-inserted on a completely different
chromosome, called a translocation. If a section on this
second chromosome is also removed and exchanged
with the first chromosome, it is called a reciprocal translocation (Figure 5-13).
Fluorescence in situ hybridization

(FISH)
(C)
q21.1
q21
q21.1
(B) 2 breaks in different arms
This technique uses a DNA probe(s) labeled with a fluorescent marker, allowing a certain sequence or a certain section
of a chromosome to be visualized when the probe binds to
its target. All of the abnormalities described above can be
detected at higher resolutions with FISH. An example of
the use of FISH is to detect the BCR-ABL1 translocation
that is responsible for chronic myeloid leukemia (CML).
A reciprocal translocation between the BCR oncogene on
chromosome 22 and the ABL1 oncogene on chromosome
9 leads to a fusion ABL1BCR protein and a fusion BCR
ABL1 protein (Figure 5-14); the latter is a protein kinase
that is unregulated. The translocation leaves a longer than
usual chromosome 9 and a shorter than usual chromosome
22, which has been labeled the Philadelphia chromosome.
Chapter 5 Genetics
on ethnicity. Again, if a common mutant is not initially

seen, then sequencing may be required.
Reciprocal translocation

Acentric
fragments
exchanged
PCR is a method by which a small amount of DNA can be

amplified by repeatedly separating the strands of the DNA
helix and replicating the sequence in vitro. Using specific
primers to guide the replication allows the presence of a
specific point mutation/SNP to be checked for. For example, testing for factor V Leiden, a pro-coagulant variant that
predisposes to deep vein thrombosis and pulmonary embolism, is done using this method since the SNP that codes
for this is unique and similar across the world (although the
frequency of this SNP varies by ethnicity).
Centric and
acentric fragments
exchanged
Stable in
mitosis
Unstable in
mitosis
Figure 5-13 Mechanism for a reciprocal translocation
COMMON CHROMOSOMAL
GENETIC CONDITIONS

Down syndrome
22
der (9)
BCR
Ph
BCR
ABL1
ABL1
ABL1 gene
BCR gene
Ph1 fusion gene 5
3
fusion gene
8.5 kb BCR-ABL1 mRNA
p210 fusion protein
Figure 5-14 Formation of BCRABL1 fusion protein

Sequencing
Some variants/mutations may be too small to see with FISH.
An example is CF; although one point mutation is responsible for almost 70% of the mutations seen in this disease, the
other 30% is due to hundreds of other mutations, including
insertions and deletions. If the common point mutation is
not found initially (using PCR, see below), then sequencing
is the next step. For beta-thalassemia, hundreds of different
mutations have been described and their frequency depends
This is the most common chromosomal condition in liveborn infants and most often is the result of aneuploidy
where there is a trisomy (three copies) of chromosome 21.
Rarely, the additional copy of chromosome 21 is present as
an unbalanced translocation. Babies with Down syndrome
are born more frequently to women over the age of 35 years.
The characteristic facial features are prominent epicanthal
folds, flattened nose, small mouth and protruding tongue.
Associated features include:
congenital heart defects in about 45% of cases, including atrial septal defect (ASD) and ventricular septal
defect (VSD)
gastrointestinal abnormalities in approximately 5%,
including duodenal atresia or stenosis
obesity in approximately 50%
hearing loss in 4080%
endocrine abnormalities, particularly hypothyroidism, and to a lesser degree hyperthyroidism and type 1
diabetes
hematological disorders, especially polycythemia and
leukemia
sleep apnea
early risk of Alzheimer disease.
Turner syndrome
This syndrome presents in women who are short and stocky;
the karyotype is XO, i.e. one X chromosome. Associated
features include:
gonadal dysgenesis, presenting as reduced fertility,
hypogonadism, and premature ovarian failure
renal anomalies occurring in 3050% of patients,
particularly horseshoe kidney
cardiovascular disease, especially coarctation and aortic
valvular disease, along with hypertension
endocrine disease, with elevated risks of premature
osteoporosis, thyroid disease and diabetes.
65
This syndrome occurs in males who have at least one extra
X chromosome, typically XXY but potentially XXXY.
The associated conditions include:
hypogonadism and infertility
neuropsychiatric problems, including lack of insight,
poor judgment and mild cognitive impairment
pulmonary disease: chronic bronchitis and bronchiectasis
endocrine problems: higher risk of breast cancer and
diabetes.
66
ACKNOWLEDGMENTS
Figures 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8, 5-10, 5-11,
5-12, 5-13, 5-14 and the figures appearing in the Selfassessment questions are 2011 Garland Science from
Human Molecular Genetics, 4th edition, by T Strachan and
A Read. They are reproduced by permission of Garland
Science/Taylor & Francis LLC.
Chapter 5 Genetics
1 The most common gene defect for cystic brosis (CF) is the delta-F508 mutation in which three DNA bases coding for
amino acid 508 of the CFTR protein are missing. This is an example of what kind of mutation?
A Missense
B Nonsense
C Frameshift
D Deletion
E Splice site
2 In testing a patient for suspected cystic brosis (CF), you get back a report saying that they are negative for the
delta-F508 mutation. The correct interpretation is that:
A They probably do not have CF.
B They probably do have CF but the test is unreliable.
C They may have CF but have a different mutation in the CFTR gene.
D They need to have their parents and siblings tested in order to make a diagnosis.
3 How many genes are there in the human genome?
A 5,000
B 20,000
C 100,000
D 250,000
E 500,000
4 RNA-coding genes code for all of the following except:
A mRNA
B rRNA
C tRNA
D snRNA
E miRNA
5 The function of siRNA is to:
A degrade mRNA
B block transcription
C block translation
D inhibit tRNA
E inhibit rRNA
6 The most common kind of genetic variant in the human genome is:
A insertion polymorphism
B deletion polymorphism
C microsatellite
D copy number variant
E single-nucleotide polymorphism
7 What mode of inheritance is evident in these pedigrees? (All images from Strachan T and Read A, Human molecular
genetics, 4th ed. New York: Garland Science, 2011.)
A Autosomal recessive
B X-linked recessive
C Autosomal dominant
D X-linked dominant
a
I
1
II
1
10
11
12
III
?
1
10
11
12
13
67
I
1
II
1
III
1
IV
?
1
I
1
II
1
III
3
IV
?
1
I
1
II
1
III
1
IV
10
?
1
10
11
12
13
14
8 A patient has a typical appearance of Down syndrome but the karyotype shows only two copies of chromosome 21,
i.e. no trisomy. In this case the explanation is likely:
A A translocation between chromosome 21 and another chromosome in one of the parents
B A deletion on chromosome 21 inherited from one of the parents
C An inversion on chromosome 21 inherited from one of the parent
D A ring chromosome 21
E Monosomy in one of the parents
68
Chapter 5 Genetics
9 A genetics lab tests for the 10 most common CF mutations that together account for 80% of all mutations. What is the
risk of still being a CF carrier if the genetic test is negative?
A 20%
B 10%
C 4%
D 1%
E <0.1%
10 The effect of methylation of DNA is to:
A Reduce transcription
B Reduce translation
C Increase transcription
D Increase translation
E Increase DNA turnover
ANSWERS
1 D.
The deletion of three base pairs means that the encoded protein loses one amino acid but the rest of the reading frame is
not affected, i.e. it is not shifted so missense and nonsense mutations are not introduced.
2 C.
Delta-F508 is just the most common of thousands of different mutations that have been described in CF.
3 B.
Most estimates are between 20,000 and 30,000.
4 A.
RNA-coding genes code for RNA molecules that are catalytically or enzymatically active. mRNA is translated to protein.
5 C.
Most regulatory RNAs work at the post-transcriptional level to affect mRNA stability and function.
6 E.
7 a C.
An affected person usually has at least one affected parent, i.e. the disease does not skip generations. A child with one
affected and one unaffected parent has a 50% chance of having the disease, i.e. 50% of each generation has the disease.
b A.
An affected person usually has unaffected parents, but they are likely to be carriers, i.e. the disease skips generations.
Achild born of two carriers has a 25% chance of having disease, i.e. 25% of that generation is affected.
c B.
Affected persons are mainly males, since they only have one X chromosome. An affected male is usually born of a carrier
mother.
d D.
An affected person usually has at least one affected parent such as with an autosomal dominant disease, but all the
daughters of an affected male have disease (since the male only passes on his Y chromosome to a son and not his
X chromosome).
8 A.
Down syndrome is also a trisomy of some part of chromosome 21, if not the whole chromosome then some part of it;
since parts of chromosomes are not able to survive on their own (except for ring chromosomes), they must exist by being
attached to other chromosomes, e.g. translocation.
9 D.
Risk of being a CF carrier is 120 and risk of being a false negative on the test is 15, therefore risk of still being a carrier is
1
20 15 = 1100 (1%).
10 A.
Methylation is involved in gene regulation, usually in reducing expression.
69
CHAPTER 6
MEDICAL IMAGING FOR INTERNISTS

Lindsay Rowe
CHAPTER OUTLINE
PRINCIPLES OF INTERPRETATION IN
CHEST X-RAYS
Anatomical review
Summary
2. THORACIC COMPUTED TOMOGRAPHY

TECHNIQUES OF EXAMINATION
CHEST CT
Technical review
Key image review
Systematic review
Review areas
Summary
3. ABDOMINAL COMPUTED
TOMOGRAPHY
Non-contrast CT KUB
Arterial phase CT abdomen (CT angiogram, CTA)

Delayed CT abdomen
ABDOMINAL CT
Technical review
Key image review
Systematic review
Review areas
Summary
BACKGROUNDULTRASOUND PRINCIPLES
PRINCIPLES OF ULTRASOUND
INTERPRETATION
LOWER LIMB DUPLEX ULTRASOUND
5. HEAD COMPUTED TOMOGRAPHY

CT BRAIN PROTOCOLS
Non-contrast CT (NCCT)
Contrast-enhanced CT (CECT)
Perfusion CT
BRAIN CT
71
Technical review
Key image review
Systematic review
Review areas
Summary
cerebrospinal dynamics (MR-GILD, CSF ow
study)
BRAIN MR
6. HEAD MAGNETIC RESONANCE
MRI PROTOCOLS
T1
T2
Gradient echo (GRE)
Magnetic resonance angiography/venography
(MRA, MRV)
Technical review
Key image review
Systematic review
Review areas
Summary
7. POSITRON EMISSION TOMOGRAPHY

(PET)
Plain-film chest radiography is the single most common
imaging test obtained in clinical medicine, and has advantages and disadvantages (Box 6-1).
PRINCIPLES OF
INTERPRETATION IN CHEST
X-RAYS
The technique for systematic review of chest X-rays is akin
to a clinical short case examination. Initially steps are followed and practiced with a routine developed (Box 6-2).
Patient details, including name, age and sex, as well as
the date and time of exposure, are initially sought from
the image.
Four parameters of image technical adequacy need to be

routinely assessed prior to interpretation to avoid artifacts
being misconstrued as evidence of disease:
patient positionanteroposterior (AP) or posteroanterior (PA)?
exposureunder- or over-exposed?
inspiratory effortadequate or inadequate?
rotationneutral or rotated?
Patient position
Studies performed anterior-to-posterior (AP) or posteriorto-anterior (PA) appear very different, and diagnostic errors
will be made if they are not recognized (Table 6-1, overleaf).
Obvious clues to an AP study are identifying labels saying
supine, sitting or AP and the presence of appliances such
as endotracheal tubes and EKG leads. Reliable features for
an AP include noting the chin low over the upper chest,
the clavicles being steep and curved low in the chest, arms
Box 6-1
Clinical utility of plain-lm radiography of the chest

Advantages
Available
Cost-effective
Small radiation dose
Interpreter-friendly
Intermediate/high sensitivity for common conditions:
effusion, pneumothorax, pneumonia, mass >1 cm
Baseline study for monitoring of disease and treatment
Rapid clinical triage for acute disease
72
Disadvantages
False sense of security
Premature termination of imaging investigations
Over-utilization
Low sensitivity for common disorders:
pulmonary embolism, nodule <1 cm, interstitial disease
Intermediate specicity for many ndings
Radiographic lag time with clinical disease
Image ndings discordant with clinical ndings
Chapter 6 Medical imaging for internists
Box 6-2
Systematic interpretation of chest X-ray

Name and other details
Patient position (anteroposterior [AP], posteroanterior
[PA])
Exposure
Inspiratory effort
Rotation
Name
Function
Assess correct position
Assess structural integrity
Recognize complications
Anatomical review
Mediastinum
Divisions
Trachea
Position
Carina
Main stem bronchi
Diaphragm
Position
Shape
Sub-diaphragmatic
Stomach, bowel loops, liver/spleen enlargement
Skeletal
Spine
Ribs, sternum
Shoulder girdles
Chest wall
Breast contour
Skin and muscle
Review areas
The hard-to-see areas
Below the diaphragm
Through the heart
Chest wall
Shoulder girdles
Lung apices
Trachea
Overview
Gross perception
Systematic review
Lungs
Aeration
Vascularity
Hilum
Lobar anatomy
Pleura
Peripheral
Phrenic angles
Fissures
Heart
Size (cardiothoracic ratio)
Cardiac margin clarity
Specic heart chambers
Summary
Comparison with previous study
Correlation of ndings and probable diagnosis
Need for additional imaging
straight by the sides and the scapulae clearly over the lung
fields. Additional clues could include widening of the mediastinum, cardiomegaly with a raised cardiac apex, very concave elevated diaphragms and uniform upper-to-lower-lobe
vascular prominence.
decreased vascularity. An underexposed chest X-ray lightens the lung fields and enhances lung markings, simulating
conditions such as pneumonia, interstitial lung disease and
cardiac failure (Table 6-2, overleaf).
Inspiratory effort
Exposure
A broad rule for adequate radiographic exposure is that the
thoracic vertebrae should be discernable through the density
of the heart. Overexposure renders the vertebrae very easily
identified, while underexposure obliterates all detail. This
rule is important to assess, as an overexposed chest X-ray
mimics emphysema with dark lung fields and apparent
A guideline for adequate inspiration is having at least 10

posterior and 7 anterior ribs visible above the diaphragm.
The hallmarks of an expiratory study are elevation and exaggerated upward convexity of the diaphragms, cardiomegaly
(pancaking), mediastinal widening and opacity of the lung
bases commonly mimicking the appearance of congestive
cardiac failure.
http://internalmedicinebook.com
73
Rotation
Patient rotation induces apparent mediastinal shift, including
the cardiac silhouette and the trachea. Rotation is assessed by
comparing the distance of the medial ends of both clavicles
Table 6-1 Features useful to differentiate AP from PA
chest X-ray
FEATURE
AP (ANTEROPOSTERIOR)
PA
(POSTEROANTERIOR)
relative to the thoracic spinous processes, usually around T4

(claviclespinous interval, CSI).
In the presence of scoliosis, application of this method is
invalid.
When no rotation is present, the CSIs are equidistant;
when there is rotation they will be unequal.

These often provide clues on the underlying disease state
and should be assessed by:
1 identifying the line or tube
2 knowing its function
3 confirming the normal position
4 assessing structural integrity
5 observing for complications.
Labels
AP, supine, sitting,

mobile
Erect
Endotracheal
tube
Present
Absent
EKG leads
Present
Absent
Anatomical review
Arm position
Beside the thorax
Oblique to the
thorax
The sequence of anatomical review will vary with each case,

but all components should be assessed (Box 6-2).
Humeral
length
Long, with shaft
Short, only the

head
Overview
Scapula
Over lung elds
Off lung elds
Clavicle
Curved, steep, low
Straight, oblique
Chin
Visible
Absent
Gastric air
Gas in gastric body
Airuid level
fundus
Review from a distance provides a wider perspective and aids

perception of obvious findings such as disparity in lung size
and opacity, mass lesions, mediastinal shift, mastectomy and
shoulder girdle conditions such as fracture and malignancy.
Systematic review
A systems approach is used to simplify the search pattern
lungs, heart and mediastinum, skeletal and review areas.
Mediastinum
Widened
Normal
Heart
Enlarged, elevated
apex
Normal
Diaphragm
Elevated, more
convex
Lower, gentle
curve
Vascularity
Uniformly
prominent
No vascular
gradient
Narrow upper
lobes
Dilated lower
lobes (vascular
gradient)
Lungs
The lung contents are assessed globally, then specific details
are sought. A simple ABCDEF mnemonic may assist:
A Aeration
B Blood vessels
C Costophrenic and cardiophrenic angles
D Diaphragm
E Endotracheal and endobronchial structures
F Fissures.
Table 6-2 Chest exposure assessment guidelines
NORMAL
UNDEREXPOSURE
OVEREXPOSURE
Spine
Perceptible
Not visible
Clear detail
Lung elds
Black
Whiter
Very black
Vascularity
Clear
Prominent
Absent
Mediastinum
Clear detail
Widened
Absent
Trachea
Clear
Very clear
Almost absent
Mimics
Vascular markings
Pneumonia
Interstitial disease
Pulmonary edema
Emphysema
Asthma
Pulmonary hypertension
74
pulmonary trunkmarked by the left hilum pulmonary

artery
aorto-pulmonary windowabove the left pulmonary artery
and below the aortic arch
transverse aortic archmarked by the semicircular contour at the superior extent of the cardiac silhouette.
The right heart border has three divisions:
right atriumconvex shadow from the diaphragm to
the junction with the superior vena cava marked by the
transition from the convex right atrium to the vertically
straight superior vena cava
superior vena cavavertical, straight-edged opaque
density beginning at the atrial-caval constriction and
extending vertically over the right hilum and then curving laterally toward the lung apex
right paratracheal stripea distinct opaque margin on the
right side of the trachea which is a combination shadow
of the right tracheal wall and azygous vein.
Figure 6-1 Normal chest X-ray
Cover-up method
A useful practical method to assist in the detection of subtle
right-to-left changes in aeration, as well as subtle parenchymal disease, can be to cover the lung fields with a piece of
paper. The paper is then slowly lowered as the viewers eyes
focus on the structures revealed at the edge of the descending paper, comparing the left-to-right structures.
Heart and mediastinum
The combined structures of the heart, great vessels and
mediastinal contents are depicted as a composite radioopaque structure referred to as the cardiac silhouette. This
is assessed by its size, definition of the heart borders and
specific chamber analysis.
Size
The transverse dimension of the heart is expressed as a ratio
to the transverse dimension of the thoracic cage (cardiothoracic ratio), which should be less than 50%.
Heart border denition
The heart borders should be sharp and well defined at the
heartlung interfaces.
If they are not, this may be a sign of opacifying disease
such as pneumonia and atelectasis in the lung segments
abutting the affected chamber (silhouette sign).
Loss of the left ventricular border is seen in lingula disease and of the right atrium in middle lobe disease.
A common variant fat pad located at the cardiac apex
often blurs its definition and is not to be confused with
disease.
Heart chambers
The left heart border has five divisions:
left ventriclediaphragm to below the hilum
left atriumshort, 2cm segment above the left ventricle
Skeleton
The thoracic spine, posterior and anterior ribs, as well
as the shoulder girdles including clavicle, scapula and
humerus, are reviewed to identify abnormalities that could
be related to a chest abnormality. A destructive lesion in
a rib, for example, may be relevant to a lung mass due to
metastasis, symmetrical glenohumeral erosion as a sign of
rheumatoid arthritis, and resorption of the distal clavicles
in hyperparathyroidism.

Abnormalities away from the lung fields are readily overlooked but are often important.
Below the diaphragm pneumoperitoneum, bowel
obstruction, and a medially displaced gastric air bubble
as a sign of splenomegaly may be identified.
Through the cardiac silhouette, the air density of a
hiatus hernia or a spinal mass may be seen.
Evaluation of the chest wall for mastectomy, skin lesions
and subcutaneous emphysema provide occasional but
important clues to a chest disease process.
The shoulders may show signs of lung-related disease
such as rheumatoid arthritis or malignancy.
Scrutiny of the often-obscured lung apex may elucidate
a Pancoast tumor, tuberculosis or a pneumothorax.
Finally, tracheal shift may be a feature of goiter, lymphoma or upper lobe volume loss.
Summary
Following the systematic review, relevant positive and negative findings can be correlated and final statements made
(Table 6-3, overleaf). Named imaging signs of the chest
should only be used when they are clearly present, as they
often have specific meaning for a disease process or anatomical localization and, while useful, may be misleading when
incorrectly applied (Table 6-4, see below). Comparison
with a previous study, if not already viewed, should be made
for assessing disease activity.
75
FEATURES
PA
PA SPOT
PNEUMONIA
Opacity
Initially hazy or uffy
with acinar nodules
Rapidly conuent
Lobar
Air bronchogram
(arrow)
Silhouette sign
ATELECTASIS
Opacity (arrow)
Lobar or segmental
Bronchovascular
crowding
Air bronchogram
Shift
Fissures
Mediastinum
Diaphragm
Trachea
EMPHYSEMA
Increased lucency
Low vascularity (arrow)
Large hilar vessels
Lower lobe
compression
Flat, low diaphragm
Wide intercostal spaces
Bullae
Barrel chest
Small tear-drop heart
OTHER
CT
76
Table 6-3 Thumbnails of chest disease
FEATURES
PA
PA SPOT
OTHER
CT
PNEUMOTHORAX
Lucent hemithorax
Pleural surface visible
(arrow)
Absent vessels
Atelectasis
Deep sulcus
Larger on expiration
Signs of tension
Wide intercostal
spaces
Mediastinal shift
Depressed diaphragm
EFFUSION
Blunted costophrenic
angle
Meniscus sign (arrow)
Thickened ssures
Effusion
Effusion
PET
continues
77
CARCINOMA
Mass lesionsize
Irregular margins
Pleural attachment
Nodal involvement
Cavitation (SCC)
Peripheral collapse
PET-avid (arrow)
Table 6-3 Thumbnails of chest disease continued
PA
PA SPOT
METASTASES
Multiple nodules
(arrow)
Round
Variable size
Sharp margins
Lower lobe dominance
May cavitate
INTERSTITIAL
NODULAR
15mm nodules
Well dened (arrow)
May calcify
ACUTE INTERSTITIAL
GROUND-GLASS
OPACITY
Midlower zones
Hazy density (arrow)
Poorly dened
Vessels obscured
Septal thickening
Kerley lines
CHRONIC
INTERSTITIAL
RETICULAR
Thin lines
Honeycomb (arrow)
Pleural contact
Distortion
Traction bronchiectasis
Low lung volume
OTHER
CT
78
FEATURES
FEATURES
PA
PA SPOT
OTHER
CT
PULMONARY
EMBOLISM
Normal CXR
Atelectasis
Wedge-shaped opacity
Convex opacity
Lack of vessels
(arrowhead)
Filling defect on CT
(arrow)
Large pulmonary trunk
ACUTE PULMONARY
EDEMA
Bilateral (batwing)
Perihilar opacity
Lucent periphery
(arrow)
Lucent centrally
Air bronchogram
CT, computed tomography; CXR, chest x-ray; PA, posterior-to-anterior view; PET, positron emission tomography; SCC, squamous-cell carcinoma.
79
CONGESTIVE
CARDIAC FAILURE
Cardiomegaly
Ground-glass opacity
Kerley B lines (arrow)
Pleural effusions
Dilated upper lobe
veins
Table 6-4 Common named imaging signs of chest disease
SIGN
DEFINITION
SIGNIFICANCE
Air bronchogram
Air-lled bronchi surrounded by uid-lled

alveoli
Pus: pneumonia
Fluid: pulmonary edema
Blood: hemorrhage
Cells: bronchioalveolar carcinoma
Protein: proteinosis
Cardiothoracic ratio
The ratio of the transverse diameter of the

heart and the thorax
When greater than 50%, is due to cardiomegaly
Ground-glass opacity
Hazy lung density that does not obliterate

vascular markings
Interstitial edema
Alveolitis
Meniscus sign
Smooth, concave sweeping contour of the

costophrenic sulcus
Pleural effusion
Silhouette sign
Cardiac border loses clear denition due to

contact with opacied lung segment
Disease is in the lung segment abutting the heart

(pneumonia, tumor, collapse)
2. THORACIC COMPUTED
TOMOGRAPHY
Computed tomography (CT) of the chest is an integral
component of chest evaluation and has broad applications.
These include investigation of an abnormality found on
chest X-ray, investigation of clinical signs and symptoms,
tumor management from diagnosis to staging, biopsy planning and response to therapy. CT has unique application in
the assessment of thoracic trauma. While there are many
advantages, significant drawbacksespecially higher radiation dosedo exist (Box 6-3).
Box 6-3
Clinical utility of CT scans

of the chest
Disadvantages
Higher radiation dose
Higher cost
Intravenous contrast
reactions
Extended breath-holding
required
Supine position occasionally
not tolerated
Over-utilization
Large number of images
Requires adequate
computer systems for
image display
Competent technical staff
for image acquisition
False-positive diagnoses,
especially benign nodules
Rarely used in pregnancy
Nursing mothers withhold
breast feeds for 24 hours
after IVI contrast study
PRINCIPLES OF
INTERPRETATION IN CHEST CT
Advantages
Available
Fast
Excellent
anatomical detail
Rapid
reconstructions
multi-planar, 3D,
vascular
Wide areas of
coverage
Choice of vascular
phase
High sensitivity and
specicity for most
diseases
Detection of small
lesions
Compatible with
implanted devices
CT scans of the chest produce a large number of images to

review in different planes. A systematic routine is necessary
to avoid diagnostic error and maximize the derivation of
information (Box 6-4, overleaf).
CT, computed tomography; IVI, intravenous injection.
Different CT techniques are employed in specific clinical situations (Table 6-5). Knowledge of these techniques
is pivotal in deriving the maximal information in different
clinical scenarios.
80
Table 6-5 Common techniques in CT scans of the chest
EXAMINATION
ACRONYM
TECHNIQUE
INDICATION
Non-contrast CT
NCCT
No IV contrast
Helical mode
Supine
Suspended inspiration
Neck to renal hilum
Contrast contraindication
Poor venous access
Identify calcication:
coronary artery calcium score
tuberculous granuloma
calcied lymph nodes
hamartoma
Pneumothorax, pneumomediastinum
Pleural calcication
Bone disease
Foreign body detection
High-resolution CT
HRCT
No IV contrast
Non-helical, thin section
Supine inspiration and expiration
Supplemental prone inspiration
Apices to below diaphragm
Interstitial lung disease

Parenchymal scars
Emphysema
Bronchiectasis
Foreign body localization
Post IVI 20- to 30-second delay

Helical mode
Contrast in aorta and pulmonary
arteries
Neck to renal arteries
All chest disease
Routine contrast CT
CT angiogram
CTA
Helical mode
Maximum contrast in aorta
Neck to aortic bifurcation
Aortic disease:
aneurysm, dissection, coarctation
Neck vessel disease:
occlusion, dissection
Coronary artery disease
Arteriovenous malformation
Pulmonary sequestration
SVC obstruction
CT pulmonary angiogram
CTPA
Post IVI 20-second delay

Helical mode
Maximum contrast in pulmonary
trunk
Pulmonary artery disease

Pulmonary embolism
Post IVI at time intervals

Helical mode
Neck to aortic bifurcation
Arteriovenous malformations
Nodule characterization

Helical mode
Neck to cardiac apex
Coronary artery disease
CT perfusion
Cardiac CT
CCT
CT, computed tomography; IV, intravenous; IVI, intravenous injection; SVC, superior vena cava.
81
Box 6-4
Systematic interpretation of chest CT

Technical review
Clarify phase of contrast when scan performed:
CT angiogram, CT pulmonary angiogram, routine
Review the topogram (scanogram)
Identify and review mediastinal and lung windows:
axial followed by coronal
Identify the rst and last scans
Conduct fast survey of all images (mediastinal and lung
windows)
Key image review
Review key images:
thyroid
aortic arch
pulmonary arteries and carina
hila
four chambers of heart
diaphragm
Systematic review
Sequential assessment of all images:
lung apices to sub-diaphragm abdomen
trachea, mainstem and lobar bronchi
pulmonary trunk, right and left pulmonary arteries
aorta and branches
superior vena cava
Lung parenchyma
Pleural surfaces, lung ssures
Esophagus
Heart, pericardium
Diaphragm, retrocrural contents
Skeletal, including spine, ribs, sternum, scapula
Review areas
Thyroid gland
Supraclavicular fossae and axillae
Apices
Mediastinal lymph nodes
Sub-diaphragmatic organs and spaces
Summary
Comparison with previous studies
CT, computed tomography.
1. Review the topogram (scanogram)
Name, date of study and some scanning parameters can give

diagnostic clues and the clinical relevance of the study.
The image depicts the chest as a frontal chest X-ray, with

at least 10% of diagnoses such as pleural effusion, mass and
consolidation being visible.
Technical review
Identification of the vascular phase in which the images have
been acquired should be done early in the diagnostic process
by identifying the location and density of contrast within
the superior vena cava, heart chambers, pulmonary arteries
and aorta.
Maximum density in the right ventricle and pulmonary
arteries is expected in a CTPA, in the left ventricle and
aorta in a CTA, and in all cardiac chambers, aorta and
pulmonary vessels in a routine CT scan of the chest.
Absence of contrast in any structure may be due to a
NCCT, extravasation, or superior vena caval or thoracic
outlet obstruction.
2. Identify and review mediastinal and lung

windows
Images depicting the lung parenchyma (lung window) and
mediastinal contents (mediastinal window) are recognized
in axial and coronal planes.
Lung windows are photographically lighter and clearly
demonstrate the branching vessels, bronchi, fissures and
lung tissue.
Mediastinal windows have black, featureless lung
fields with clear definition of the mediastinal contents
including the thyroid, trachea, superior vena cava, aorta
and its branches, lymph nodes, esophagus, heart and
pericardium.
3. Identify the rst and last scans
An overview can quickly identify major abnormalities and

help focus the interpretation. This can be achieved with an
initial four-step analysis.
Defining the upper and lower limits of the scan gives an

overview of the anatomy to be reviewed and what has been
excluded.
82
4. Conduct fast survey of all images

(mediastinal and lung windows)
Key image review

Isolating key levels in the chest can initially simplify interpretation (Table 6-6).
Rapid sequential review of all images provides the opportunity to appreciate gross abnormalities and normal anatomy.
Table 6-6 Key landmarks in CT chest imaging
ANATOMY
MEDIASTINAL WINDOW
THYROID GLAND
1. Thyroid gland
2. Internal jugular vein
3. Common carotid
artery
4. Trachea
5. Thoracic vertebra, T2
AORTIC ARCH
1. Aortic arch
2. Superior vena cava
3. Trachea
4. Esophagus
5. Thymus
6. Sternum
7. Scapula
8. Pulmonary vessels
9. Oblique ssure
10. Anterior junction line
11. Upper lobe
PULMONARY ARTERIES
1. Pulmonary trunk
2. Right pulmonary artery
3. Left pulmonary artery
4. Carina
5. Right main bronchus
6. Left main bronchus
7. Ascending aorta
8. Superior vena cava
9. Descending aorta
10. Esophagus
11. Oblique ssure
12. Lower lobe
HEART
1. Right atrium
2. Right ventricle
3. Interventricular
septum
4. Left ventricle
5. Left atrium
6. Pulmonary vein
7. Lower lobe bronchus
8. Descending aorta
9. Esophagus
10. Oblique ssure
11. Right middle lobe
12. Lower lobe
LUNG WINDOW
10
5
2 1
3
4
11
8
9
2
10
5 46
11
12
2
1
11
3
4
5
9 8
10
7
6
12
continues
83
Table 6-6 Key landmarks in CT chest imaging continued
ANATOMY
MEDIASTINAL WINDOW
DIAPHRAGM
1. Right atrium
2. Right ventricle
3. Interventricular
septum
4. Left ventricle
5. Descending aorta
6. Esophagus
7. Oblique ssure
8. Lower lobe
9. Lingula
10. Right middle lobe
SUB-DIAPHRAM
1. Liver, right lobe
2. Liver, left lobe
3. Stomach
4. Spleen
5. Inferior vena cava
6. Descending aorta
7. Lower lobes of lungs
LUNG WINDOW
10
2 3
1
9
7
6
5
8
2
1
5
6
3
4
7
Thyroid gland
Beginning in the neck, the thyroid is marked by its high
density due to its iodine content surrounding the trachea.
A common routine is to then observe the trachea and its
adjacent structures on sequential scans through to the carina
and into the main stem bronchi.
Aortic arch
The transverse aorta dominates the image as an oblique
right-to-left tubular structure. Branches to the neck and
arms can be identified. A high concentration of contrast in
the superior vena cava is visible to the right of the arch.
Pulmonary arteries and carina

The distinct Y-shaped structure of the pulmonary trunk
originating out of the right ventricle and branching into the
left and right pulmonary arteries lies immediately inferior to
the aortic arch, separated by the aorto-pulmonary window.
The trachea dominates this level where it bifurcates at the
carina and the main stem bronchi diverge to the hilum.
Four chambers of the heart

The oblique long axis of the interventricular septum and
cardiac apex are identified. Situated posteriorly behind the
ventricles, the left atrium receives the pulmonary veins while
the right atrium receives the superior and inferior vena cava.
The normal pericardium is defined as a line 1 mm or less
separated from the myocardium by a layer of fat.
Diaphragm
The dome of the diaphragm initially appears in the anterior to
central hemithorax and then merges toward the lateral chest
margin. At the posterior inferior extent of the diaphragm
attachment, the crura become apparent near T12L1 and
84
the retrocrural space becomes identifiable where lymph

nodes, cisterna chyli and azygous veins are located.
Systematic review
All images and their contents are systematically reviewed in
both lung and mediastinal windows, initially on axial images
and then on coronal images.
Review areas
At the end of interpretation, a last review of some key but
often overlooked areas is undertaken.
The thyroid gland is frequently abnormal, such as goiter, and effects on the superior mediastinal contents and
trachea are common.
Review of the neck, supraclavicular, axillary and mediastinal regions for lymphadenopathy requires careful scrutiny.
The lung apices need to be re-inspected for pleural thickening, tuberculosis, lung bullae and Pancoast tumor.
Sub-diaphragmatic organs such as the liver, spleen, pancreas, adrenal glands and kidneys are important to assess.
Finally, select a bone window setting and review the
skeleton for abnormalities such as fractures and neoplastic lesions.
Summary
Following the systematic review, relevant positive and negative findings can be correlated and final statements made.
If contrast has not been administered appropriately for the
clinical question being investigated and is deemed suboptimal this should be noted. Correlation of any findings with
previous and additional imaging is also performed.
3. ABDOMINAL COMPUTED
TOMOGRAPHY
A CT scan of the abdomen has similar advantages and disadvantages to chest CT. The use of oral contrast is considered integral to most examinations other than in acute
emergencies, identification of renal system calculi and some

selected organ evaluations such as that of the adrenal gland.
Different CT techniques are employed in specific clinical
situations (Table 6-7).
Table 6-7 Common techniques in CT scans of the abdomen
EXAMINATION
ACRONYM
TECHNIQUE
INDICATION
Non-contrast CT
NCCT
No IV contrast
Helical mode
Supine
Suspended inspiration
Lung base to symphysis pubis
Contrast contraindication
Poor venous access
Identify calcication:
calculi
tuberculous granuloma
calcied lymph nodes
tumor calcication
Gas:
pneumoperitoneum
pneumatosis intestinalis
emphysematous cholecystitis
intrahepatic gas
pneumothorax
Fatlipoma, myelolipoma
Bone disease
Foreign body detection
Non-contrast CT KUB
CT KUB
No IV contrast
Non-helical, thin section
Supine inspiration
Supplemental prone scan if stone at
VUJ
Renal calculi
Same as for NCCT above
CT angiogram
CTA
Helical mode
No oral contrast
Aortic disease:
aneurysm, dissection, coarctation
Vessel disease:
occlusion, dissection
Arteriovenous malformation
IVC obstruction/stula
Portal venous CT
CTPV
Helical mode
Maximum contrast in portal vein
No oral contrast
Routine abdominal study

Solid organ disease
Obstruction of ducts
Portal vein disease
Triple-phase
abdominal CT
CTTP
Helical mode
Three sequential studies obtained:
non-contrast
arterial
portal venous
May add additional delayed study
Lesion characterizationliver,
adrenal, renal
Organ necrosispancreas
Gastrointestinal hemorrhage
Delayed phase CT
CTD
Helical mode
Delayed study 25 minutes or longer
Renal collecting system obstruction

Active bleeding sites
Liver lesions
CT, computed tomography; IV, intravenous; IVC, inferior vena cava; IVI, intravenous injection; KUB, kidneysuretersbladder;
VUJ, vesico-ureteric junction.
85
The study is performed from above the diaphragm to the
inferior aspect of the symphysis pubis. No contrast is found
in the aorta, inferior vena cava, portal vein or the kidneys,
rendering them isodense with the adjacent organs.
Box 6-5
Systematic interpretation of
abdominal CT
Non-contrast CT KUB
A variation of a non-contrast abdominal CT is performed for

the assessment of renal colic, focusing on the kidneys, ureters
and bladder (KUB). Image acquisition is performed from the
upper poles of the kidneys to the symphysis pubis, rather than
going as high as the lung bases. Intravenous and oral contrast
are not given as these can obscure opaque calculi.
Technical review
Clarify phase of contrast when scan performed:
NCCT, CT KUB, CTA, PVCT, DCT, TPCT
Arterial phase CT abdomen

(CT angiogram, CTA)
Image acquisition is performed 2030 seconds postinjection, capturing contrast in the arterial system. Aneurysms, stenoses, occlusions and bleeding sites can be
depicted.

Contrast perfuses the abdominal viscera and drains back to
the portal vein and liver. This produces prominent enhancement of the liver parenchyma.
Three successive scans are performednon-contrast, arterial and portal venoususually of the upper abdomen for
the pancreas and liver. These are most commonly employed
in the evaluation of liver, pancreatic and intestinal masses.
Delayed CT abdomen
A delayed study of 25 minutes allows contrast to accumulate in the collecting system of the kidneys, ureters and bladder, to assess lesions such as tumors and lacerations. Pooling
in the intestine may be identified as a sign of hemorrhage.
PRINCIPLES OF
INTERPRETATION IN
ABDOMINAL CT
CT scans of the abdomen produce a large number of images
to review in different planes. A systematic routine is necessary to avoid diagnostic error and maximize the derivation of
information (Box 6-5).

Identify axial and then coronal images
Identify the rst (lung bases) and last (lower pelvis)
images
Conduct fast survey of all images
Key image review
Lung bases
Liver, porta hepatis
Renal hilum
Iliac crest
Mid-pelvis
Symphysis pubis
Systematic review
Cephalo-caudad progression
Organ-by-organ assessment
Slice-by-slice assessment
Review areas
Para-aortic and pelvic lymph nodes
Inguinal canals
Abdominal wall and iliopsoas
Lung bases
Pneumoperitoneum search
Skeletal (spine, ribs, sternum, scapula, pelvis)
Summary
CT, computed tomography; CTA, CT angiogram; KUB, kidneys
uretersbladder; PVCT, portal venous CT; TPCT, triple-phase CT.
Technical review
The phase of vascular contrast can be identified by the location and density of contrast within the aorta, portal vein and
86
kidneys (Table 6-8). Knowledge of the various techniques

is pivotal in deriving the maximal information in different
clinical scenarios. Maximum density in the aorta and its
branches signifies an arterial phase acquisition (CTA), in the
portal vein the portal venous phase (PVCT), and contrast in
the renal pelvis a delayed study (DCT).
Table 6-8 General criteria for identifying contrast phase in CT scan of the abdomen
ARTERIAL
(20-SECOND
DELAY)
NON-CONTRAST
PORTAL VENOUS
(50- TO
70-SECOND
DELAY)
DELAYED (25
MINUTES DELAY)
Aorta
Neutral
Very dense
Slightly dense
Neutral
Vena cava
Neutral
Neutral
Slightly dense
Neutral
Portal vein
Neutral
Neutral
Dense
Neutral
Kidneys
Neutral
Cortex dense
Cortex and medulla

dense
Dense pelvis, ureters
Key image review
An overview can quickly identify major abnormalities and

help focus the interpretation. This can be achieved with an
initial four-step analysis.
It can be useful, especially for the inexperienced reader, to

be able to identify a few key images and be familiar with
their contents (Table 6-9, overleaf).
Lung bases
The image depicts the abdomen as a frontal abdominal

X-ray with at least 10% of diagnoses such as obstruction and
calculus being visible. Given its wide range of coverage, usually beyond that of the axial image acquisitions, incidental
abnormalities of the lung bases, such as pleural effusion and
masses, as well as those in the thighs can be seen.
With mediastinal window settings, the basal lung fields

are black with very little vascular structure visible. The
heart is typically evident, with the right and left ventricles separated by the interventricular septum. The aorta
and esophagus are visible.
On lung windows, the branching pulmonary vessels and
bronchi are displayed.
2. Identify axial and coronal images

Axial images are recognizable by the depiction of organs in
cross-section. There are fewer images in the coronal plane
and these demonstrate the abdominal contents as an abdominal X-ray; for an overview it is often useful to review these
first.

The upper limit of the scan is recognizable by the lowattenuating lung fields and their gradual reduction as the
diaphragm comes into the image plane. The lowest extent of
the scan, through to the pelvis, should be at least to the symphysis pubis to include the bladder and ano-rectal junction.
4. Conduct fast survey of all images

Rapid sequential review of all images, initially in the coronal plane, provides the opportunity to appreciate normal
anatomy and gross abnormalities such as bowel obstruction,
masses, aortic aneurysm and free fluid.
Liver, porta hepatis

The hallmark of the porta hepatis is contrast within the
portal vein arcing over the inferior vena cava.
The right and left lobes of the liver are usually identifiable, but the separating falciform ligament may not be
evident at this level.
The upper poles of both kidneys, the spleen, stomach
and body of the pancreas are typically present at this
level.
Renal hilum
Both kidneys at their hilum in the portal venous phase
show contrast in the draining renal veins entering into
the inferior vena cava.
The aorta is evident to the left side of the L3 vertebra.
The inferior aspect of the right lobe of the liver dominates the right side.
87
Table 6-9 CT of the abdomenkey images
KEY IMAGE LEVEL
NORMAL
LUNG BASELUNG
WINDOW
1. Right ventricle
2. Left ventricle
3. Right atrium
4. Descending aorta
5. Esophagus
ABNORMAL
1
3
2
5
4
6
Lung metastases (arrows)

LUNG BASEABDOMINAL
WINDOW
1. Right ventricle
2. Left ventricle
3. Right atrium
4. Descending aorta
1
2
3
4
Pleural effusion (arrow) and pericardial

effusion (arrowhead)
PORTA HEPATIS
1. Portal vein
3. Liver, left lobe
4. Liver, caudate lobe
5. Stomach
6. Pancreas, tail
7. Pancreas, body
8. Spleen
9. Kidney
10. Aorta
3
2
7
10
Liver cirrhosis (A), ascites (B) and

splenomegaly (C)
RENAL HILUM
1. Renal hilum
2. Renal vein
3. Kidney
5. Aorta
6. Superior mesenteric vein
7. Pancreas, head
9. Stomach
10. Descending colon
11. Jejunum
8
2
7 6
4
5
9
11
1
3 10
Transitional cell carcinoma, renal pelvis

(arrow)
88
KEY IMAGE LEVEL

ILIAC CREST
1. Iliac crest
2. Right kidney
3. Psoas muscle
4. Aorta
6. Cecum
8 Colon, hepatic exure
9. Jejunum
10. Descending colon
NORMAL
9
5
ABNORMAL
3
10
Aortic aneurysm (arrow) with rupture

(arrowhead)
MID-PELVIS
1. Bladder
2. Uterus
3. Rectum
4. Acetabulum
5. Coccyx
6. Gluteus maximus
7. Common femoral vein
8. Common femoral artery
2
6
3
5
Carcinoma of the bladder (arrow)

SYMPHYSIS PUBIS
1. Rectum, anus
2. Cervix
3. Retropubic space
4. Symphysis pubis
5. Ischio-rectal fossa
6. Obturator internus
7. Gluteal crease
8. Gluteus maximus
9. Ischium
10. Femur
11. Femoral vein
12. Femoral artery
4
3
11
12
2
10
9
5
7
Plasmacytoma, right pubis (arrows)
The upper origins of the psoas muscle abut the posterior

margin of both kidneys with an interposed layer of perinephric fat.
Iliac crest
The ascending and descending colon and variable loops
of the small bowel fill the majority of the anterior and
lateral aspects of the abdomen.
The inferior vena cava and the aorta lie anterior to the
spine, and on occasions the aortic bifurcation becomes
evident as two common iliac artery branches.
The psoas muscle is readily identified, flanking the L4
vertebral body.
Variably visible in many normal individuals, dependent
on body habitus and degree of inspiration, will be the
lower aspect of the right lobe of the liver and lower pole
of the right kidney.
Mid-pelvis
At the level of the hip joints, the thin-walled bladder lies
in the midline anteriorly.
In females the uterus is a solid structure sited anterior
to the rectum.
The external iliac artery and vein bilaterally lie lateral to
the bladder, as does the muscle of the obturator internus.
Symphysis pubis
The joint cavity of the symphysis pubis is a reliable indicator of an image low in the pelvis, with fat identifiable
in the retropubic space. The anus and rectum are readily
identifiable, and in males the prostate gland.
The distinctive fat-filled ischio-rectal fossa flanked by
the obturator internus, puborectalis and gluteus maximus is apparent.
89
Box 6-6
Clinical utility of ultrasound

Advantages
Allows point examination in region of interest
Performed in real time
Non-ionizing radiation
No contrast agents are employed
Little to no patient preparation
Disadvantages
Poor detail of air/gas structures (lung, bowel)
Limited bone and intra-articular detail
Not suitable for all patients
Interpretation unfriendly
Incomplete display of all anatomy/pathology
Operator-dependent
Can be time-consuming
Systematic review
Box 6-7
Begin at the lung bases and progressively move caudally.

Initially, an organ-by-organ assessment is done. Follow this
with a slice-by-slice analysis with all depicted structures in
the slice reviewed.
With vascular structures such as the aorta and inferior
vena cava, with their branches, selecting them for specific review by observing them over sequential slices is
the best method.
The colon is analyzed by beginning either at the cecum
or the rectum and following the colon over sequential
images. Due to its multiplicity of convolutions, the
small bowel is similarly assessed from the duodenum or
cecum.
Contraindications for ultrasound

Obesity
Muscular body habitus
Excessive abdominal gas
Uncooperative patient
Inability to follow breathing instructions
Inability to suspend respiration
Large open wounds
Topical surgical dressings and drains
Unskilled operator and diagnostician
Review areas
At the end of the interpretation, a last review of some key
and often overlooked areas is undertaken.
Lymph node evaluation is often neglected; specific
locations need to be sought for, including para-aortic,
aorto-caval, retrocrural, pelvic and inguinal regions.
Inspecting the lower pelvic scans to exclude inguinal
hernias can then be done.
Scrutinize the abdominal wall and iliopsoas muscles for
collections and abscess.
As a last procedure, changing the image display to lung
windows demonstrates the lung parenchyma to view
such abnormalities as pleural effusion, pneumothorax,
masses and collapse. By reviewing the entire abdomen
with this lung window, pneumoperitoneum can be
confirmed. Select a bone window setting to identify
abnormalities such as fractures and neoplastic lesions.
Summary
If contrast has not been administered appropriately for the
clinical question being investigated and is deemed suboptimal, this should be noted. Correlation of any findings
with previous and additional imaging is also performed.
90
Diagnostic ultrasound is a safe and rapid imaging technique.
It is non-invasive, usually painless, and requires no contrast
medium and limited or no patient preparation (Box 6-6).
Not all patients are able to undergo ultrasound (Box 6-7).
BACKGROUNDULTRASOUND
PRINCIPLES
Ultrasound waves from a transducer pass through the
underlying body tissues and are reflected back as returning
echoes. The time it takes for a generated wave to enter and
then return is converted to a depth below the probe, while
the number of returning echoes is converted to a displayed
density (echogenicity) which may be black, white or one
of many shades of gray.
Tissues which allow for through-transmission with little
echo are displayed black (hypo-echoic, anechoic).
High numbers of returning echoes are displayed white
(hyper-echoic, echogenic).
Each organ is examined in the longitudinal and transverse
planes (see Box 6-8 for an overview of the assessment
procedure).
Box 6-8
abdominal ultrasound
Name and other patient details
PRINCIPLES OF ULTRASOUND
INTERPRETATION
Interpretation of ultrasound images initially appears confusing and daunting to the uninitiated. Applying basic principles will simplify interpretation, and with practice provides a
framework for better understanding (Table 6-10).
Longitudinal and transverse images
Doppler examinations
Patient position (erect, decubitus)
Anatomical review
Overview
Gross perception
Systematic organ review
Pancreas, liver, biliary ducts, gall bladder
Right and left kidneys, bladder
Spleen
Flanks, lung bases, pelvic contents
Summary
Correlate organ ndings
Compare with previous study/other imaging
Table 6-10 Ultrasound anatomy and pathological correlations
ANATOMY
NORMAL
ABNORMAL
LIVER METASTASES
Homogeneous liver parenchyma

Smooth surface
Normal branching portal vein (arrow)
Multiple hypo-echoic round masses (arrows)

Mass effect on portal vessels
Homogeneous liver parenchyma

Smooth surface
Normal branching portal vein
Solitary round hyper-echoic mass (arrow)

Peripheral vascularity
LIVER HEMANGIOMA
continues
91
Table 6-10 Ultrasound anatomy and pathological correlations continued
ANATOMY
NORMAL
ABNORMAL
LIVER DILATED BILIARY

DUCTS
Bile ducts not visible

Normal portal vein branches visible
Dilated ducts (arrows)

Converge at the porta
LIVER CIRRHOSIS WITH

ASCITES
F
Smooth liver edge

Sharp echogenic perihepatic fat interface
Hypo-echoic perihepatic uid (F)

Nodular cirrhotic nodules (arrow)
PORTAL VEIN
THROMBOSIS
Doppler examination
Flow direction toward the liver (arrow)
Good wave above neutral ow line
(arrowhead)
Echogenic clot in portal vein (arrow)

Very little ow detected (arrowhead)
GALL BLADDER
CALCULI
GB
Thin-walled, hypo-echoic gall bladder (GB)

Posterior acoustic enhancement
92
Cholelithiasis with echogenic surfaces

(arrows)
Posterior acoustic shadowing (arrowheads)
Thick-walled gall bladder (W)
Pericholecystic uid
Table 6-10 Ultrasound anatomy and pathological correlations
ANATOMY
NORMAL
ABNORMAL
PANCREAS TUMOR
Carcinoma
hypo-echoic
SMV
SV
Splenic vein (SV) posterior to the pancreas

Merges with superior mesenteric vein (SMV)
Pancreas draped over SV and SMV (arrows)
Hypo-echoic shadowing mass in the head

(arrows)
SPLEEN METASTASIS
S
K
Homogeneous (S)
Smooth surface (arrows)
Abuts left kidney (K)
Intra-splenic heterogeneous mass (arrows)
KIDNEY
Hydronephrosis
Dilated renal pelvis and
calyces
RSF
Smooth outline
Hypo-echoic cortex
Echogenic renal sinus fat (RSF)
LOWER LIMB DUPLEX

ULTRASOUND
Ultrasound is the gold standard for identifying deep vein
thrombosis (DVT), with sensitivity and specificity of greater
than 95%. Patients with large calves, edematous calves, small
vessels, marked skin sensitivity and pain limit the sensitivity
of the study below the knee.
Duplex ultrasound is called duplex because the veins are
examined in two waysstructurally and flow (Doppler).
Dilated renal pelvis and calyces (arrows)
Each vein is imaged systematically in transverse and

longitudinal planes, with and without compression.
Doppler examination is then performed in quiet respiration and with calf compression (augmentation) to confirm lack of blood movement when thrombosis occludes
the vessel lumen. Both deep veins (external iliac, common and superficial femoral, popliteal, soleal and posterior tibial veins) and superficial veins (lesser and greater
saphenous) are imaged.
93
The hallmark ultrasound triad of venous thrombosis is a

vein that is incompressible, contains echogenic thrombus
and lacks Doppler flow. Identifying DVT mimics, such as
cellulitis, inguinal hernia, Bakers cyst and gastrocnemius
tear, is important (Box 6-9).
radiation dose, as well as other factors (Box 6-10). Prior

to any CT study, patient suitability should be assessed
(Table6-11).
CT BRAIN PROTOCOLS
Box 6-9
Non-contrast (NCCT)
Ultrasound criteria for deep vein

thrombosis (DVT)
A CT brain study without contrast is the most common

protocol to be used.
It has high sensitivity for acute blood, whether this
be extradural, subdural, subarachnoid, intracerebral
or intraventricular, depicted as increased density. The
increased density of acute blood is primarily due to clot
retraction.
Hydrocephalus, tumors, midline shift and features
of cerebral edema can quickly and accurately be
determined.
Structural
Incompressible vein
Intraluminal thrombus
Intraluminal echoes
Doppler
No ow at rest
No respiratory phasic ow uctuation
No augmented ow with calf compression
Contrast-enhanced (CECT)
Intravenous injection (IVI) of iodinated contrast increases
the sensitivity for demonstration of brain pathology from
10% to 50%. Any lesion which induces increased vascular
permeability and disrupts the bloodbrain barrier will show
enhancement (MAGIC DR; see Box 6-11).
5. HEAD COMPUTED
TOMOGRAPHY
CT scans of the brain are performed in a wide variety of
clinical scenarios and are frequently pivotal in determining
management. Selection of patients to undergo CT studies
of the brain needs to be based on clear clinical grounds and
an awareness of its deficiencies in diagnostic accuracy and
Image acquisition when contrast is maximal in the aorta
opacifies the neck and intracranial arteries for the purpose
of identifying stenoses, aneurysm, occlusions and other
vascular disorders.
Box 6-10
Clinical utility of CT scans of the brain

Advantages
Fast
Rapid diagnosis
Fewer motion artifacts
Broad patient compatibility
Body habitus, claustrophobia, metal implants
Readily available
Reader friendly
High sensitivity in acute intra-cerebral conditions
Trauma, hemorrhage, midline shift, seizure
CTA studies without complications of digital subtraction
angiography (DSA) catheter
Iatrogenic vascular and embolic disease
Accurate base study for comparison
Disease progression/complication/regression
Multiplanar reconstructions
Disadvantages
Radiation dose
Acute injury, accumulated dose, pregnancy, cancer
Complications of iodine contrast
Anaphylaxis, allergy, renal failure, vasovagal
False sense of security
Premature termination of search
Insensitive for infarction in rst 424 hours
Inconspicuous lesions not identied
Small size, <1cmneuroma, aneurysm
Isodense lesions to brainsubacute subdural/
subarachnoid hemorrhage
Leptomeningeal diseasemeningitis, metastatic
disease
Diffuse diseasewhite matter: leukoencephalopathy,
demyelination
Hidden locationsvertex: high convexity; oor
of middle cranial fossa; posterior fossa; foramen
magnum
CTA, CT angiogram.
94
Table 6-11 Patient preparation checklist prior to CT
ITEM
RATIONALE
PRINCIPLES OF
INTERPRETATION IN BRAIN CT
Denite CT scan
indications
Correct modality selection, ensure

coverage of correct area, correct
scan technique
Accurate interpretation of CT scans of the brain is based on

knowledge of brain anatomy, key landmarks and development of a systematic approach (Box 6-12).
Assess need for

contrast
Tumor, infection, CTA (aneurysm,

arteriovenous malformation,
occlusion)
Box 6-12
Claustrophobia
screening
Motion artifact, inability to complete

the scan
Pregnancy
screening
To avoid unnecessary radiation to

the developing fetus
Renal function
May prevent administration of

intravenous (IV) contrast to avoid
renal failure
Contrast allergy
May prevent administration of IV

contrast to avoid allergic reactions
Patient
compliance
Any motion during scanning creates

motion artifact image degradation
Patient safety
Vital sign assessment and in-scanner

monitoring supervised when needed
Review of
previous imaging
Assess cumulative radiation doses;

identify abnormalities to guide
present scan
Box 6-11
Differential diagnosis for contrastenhanced brain lesions

MAGIC DR
M Metastasis, meningioma
brain CT
Technical review
Identify the rst and last scans
Conduct fast assessment of all images
Identify normal calcications
Pineal, choroid plexus, falx
Key image review
Foramen magnum
Posterior fossa
Pituitary fossa
Suprasellar
Internal capsulebasal ganglia
Lateral ventricles
Vertex
Systematic review
Sequential assessment of all images
Base to vertex
A Abscess
G Glioma
I Infarct
C Contusion
D Demyelination
R Radiation
Perfusion CT
Rapid sequential brain scanning following IV contrast injection allows cerebral perfusion maps to be generated; these
depict cerebral blood flow (CBF), cerebral blood volume
(CBV) and mean transit time (MTT). From these maps,
cerebral ischemia and infarction can be quantified.
Review areas
Brain stem
Craniocervical junction
Foramen magnum
Mastoid sinuses
Middle ear complex
Orbits and contents
Nasopharynx
Bonecalvarium, skull base
Summary
95

Intubation tubes confirm the acute status of the patient.

Identify the atlanto-axial relationships to exclude unexpected dislocation or fracture.
Technical review
Identifying whether contrast has been given and what vascular phase is being demonstrated allows specific details to
be observed. Contrast in the circle of Willis may identify
an aneurysm or arteriovenous malformation. A delayed contrast scan can depict a ring-enhancing lesion.

Early in the interpretive process it is crucial to gain an overview and quickly identify major abnormalities. This can be
achieved with an initial four-step analysis.

The lateral view of the skull, at a minimum, is available
for review, and skull fractures, calcifications and bony
lesions can be identified.
This confirms the cephalad and caudad anatomy that has

been included in the study, to ensure adequate coverage.
3. Conduct fast assessment of all images

Especially with digital viewing, a sequential, rapid display of
each image is possible and will allow an appreciation of gradual changes in anatomy and the perception of gross pathology such as masses, bleeds, hydrocephalus and midline shift.
4. Identify normal calcications

Physiological calcifications in the brain are common, especially of the pineal gland, choroid plexus and falx cerebri,
and should be identified early so as to not be misconstrued
as abnormalities (Table 6-12).
Table 6-12 Normal variant intracranial calcications
LOCATION
AGE
(Y)
PINEAL GLAND
1090
<40 y: 60%
>40 y: 100%
Dense
Midline
<1 cm
Roof of aqueduct
Curvilinearcircular
aneurysm, cyst
Dense, >1cm
germinoma
CHOROID
PLEXUS
1090
>50 y: 100%
Bilateral
Dense
Arc-like
Midline divergence
Lateral ventricle
Trigone
Focal dense
calcication
papilloma
carcinoma
96
INCIDENCE
DESCRIPTION
CT
DIFFERENTIAL
DIAGNOSIS
Table 6-12 Normal variant intracranial calcications
LOCATION
AGE
(Y)
INCIDENCE
FALX CEREBRI
1090
>50 y: 100%
Midline
Thin
Peripherally denser
Often discontinuous
Focal thickening
meningioma
Generalized
thickening
subdural
hematoma
venous
thrombosis
TENTORIUM
CEREBELLI
>40
>40 y: 50%
Thin
Often discontinuous
Petrous apex to
posterior clinoid
(petro-clinoid
ligament)
Focal thickening
meningioma
Generalized
thickening
subdural
hematoma
BASAL
GANGLIA
>60
>60 y: 10%
Fine, granular sandlike calcications

Basal ganglia
lentiform nucleus
<60 y: metabolic
disease
Calcium:
hyperparathyroidism
Iron: Farrs disease
Manganese:
Hallervorden-Spatz
disease
DENTATE
NUCLEUS
>60
>60 y: 10%
Fine, granular sandlike calcications

Dentate nucleus
of the cerebellum,
usually bilaterally
<60 y: metabolic
disease
Hyperparathyroidism
DESCRIPTION
CT
DIFFERENTIAL
DIAGNOSIS
continues
97
Table 6-12 Normal variant intracranial calcications continued
LOCATION
HYPEROSTOSIS
FRONTALIS
AGE
(Y)
INCIDENCE
>40
>60 y: 100%
DESCRIPTION
CT
Dense ossication
Frontal bone
Inner table
Thickness 515mm
External cortex
Tide-line on inner
table
DIFFERENTIAL
DIAGNOSIS
Pagets disease
patchy sclerosis
in dipole
broad lucent
zone
cortical
thickening
Key image review

To simplify the many structures and landmarks depicted on
CT images, isolation of the following key image planes can
simplify interpretation (Table 6-13).
Table 6-13 CT brain anatomy and pathological correlations
CT LANDMARKS
NORMAL
TOPOGRAM
1. Frontal bone
2. Parietal bone
3. Occipital bone
4. Sella turcica
5. Sphenoid sinus
1
4
FORAMEN MAGNUM
1. Foramen magnum
2. Clivus
3. Medulla
4. Vertebral artery
5. Subarachnoid space
6. Ethmoid sinus
7. Nasal bones
8. Globe
98
ABNORMAL
7
8
6
2 4
3
1 5
COMMON
ABNORMALITIES
Bone:
fracture
metastasis
myeloma
hemangioma
Pagets disease
Brain:
calcifying tumor
meningioma (arrow)
oligodendroglioma
craniopharyngioma
pituitary mass
aneurysm
Tumor:
glioma
meningioma
Subarachnoid space:
coning (arrows)
hemorrhage
Skull base tumor:
chordoma
glomus tumor
Table 6-13 CT brain anatomy and pathological correlations
CT LANDMARKS
NORMAL
POSTERIOR FOSSA
1. Cerebellum
2. Pons
3. Fourth ventricle
4. Petrous temporal bone
5. Temporal lobe
6. Cavernous sinus
7. Sphenoid sinus
8. Cribriform plate
9. Greater wing of
sphenoid
10. Optic nerve
10 8
3
1
13
12
11
9
9
8
7
5
3
4
10
10
9
7
5
3
2
COMMON
ABNORMALITIES
Bone:
metastasis
chondrosarcoma
Cerebellum:
infarction
hemorrhage
glioma
Pons:
basilar artery aneurysm
glioma
hemorrhage (arrow)
Cerebello-pontine angle:
acoustic neuroma
Fourth ventricle:
intraventricular hemorrhage
ependymoma
7 6
PITUITARY FOSSA
1. Internal occipital
protuberance
2. Cerebellum
3. Pons
4. Fourth ventricle
5. Cerebello-pontine
cistern
6. Sigmoid venous sinus
7. Basilar artery
8. Posterior clinoid
process
9. Sella turcica (pituitary
fossa)
10. Temporal lobe
11. Gyrus rectus, frontal
lobe
12. Orbital plate
13. Frontal sinus
SUPRASELLAR
1. Venous conuence
2. Cerebellum,
hemisphere
3. Cerebellum, vermis
4. Transverse venous
sinus
5. Midbrain
6. Interpeduncular cistern
7. Basilar artery
8. Temporal lobe
9. Sylvian ssure
10. Frontal lobe
ABNORMAL
Pituitary:
tumor
hemorrhage (arrow)
Bone:
metastasis
chondrosarcoma
Cerebellum:
infarction
hemorrhage
glioma
Pons:
basilar artery aneurysm
glioma
hemorrhage
Cerebello-pontine angle:
acoustic neuroma
Fourth ventricle
intraventricular hemorrhage
ependymoma
Cerebellum:
infarction
hemorrhage
glioma
Midbrain:
tip of basilar aneurysm
glioma
(arrows)
Frontal lobe:
glioma
infarction
hemorrhage
Temporal lobe:
glioma
infarction
hemorrhage
continues
99
Table 6-13 CT brain anatomy and pathological correlations continued
CT LANDMARKS
BASAL GANGLIA
1. Occipital lobe
2. Posterior falx
3. Pineal gland
4. Third ventricle
5. Frontal horn, lateral
ventricle
6. Septum pellucidum
7. Corpus callosum
8. Anterior falx
9. Caudate nucleus, head
10. Lentiform nucleus
11. Internal capsule,
anterior limb
12. Internal capsule, genu
13. Internal capsule,
posterior limb
14. External capsule
15. Insula
16. Sylvan ssure
17. Frontal lobe
18. Temporal lobe
LATERAL VENTRICLES
1. Body of lateral ventricle
2. Choroid plexus
3. White matter, corona
radiata
4. Corpus callosum, genu
5. Corpus callosum,
splenium
6. Posterior falx
7. Anterior falx
8. Frontal lobe
9. Parietal lobe
NORMAL
8
5 7
10
4
18
17
9
6
3
11
12
14
16
15
13
Ventricles
hemorrhage
hydrocephalus
midline shift
Cerebral hemisphere:
infarction (arrows)
hemorrhage
tumor
edema
Ventricles:
hemorrhage (arrows)
hydrocephalus
infarction
hemorrhage (arrowheads)
tumor
edema
7
8
4
1
COMMON
ABNORMALITIES
25
6
VERTEX
1. Falx cerebri
2. Pre-central gyrus
3. Central sulcus
4. Post-central gyrus
5. Frontal lobe
6. Parietal lobe
5
1
3
6
100
ABNORMAL
2
4
infarction
hemorrhage (arrows)
tumor
edema (arrowhead)
Falx
hemorrhage
meningioma
shift
Foramen magnum
Vertex
At the skull base, the large foramen magnum is readily

identifiable.
The medulla is centrally placed, flanked by the two vertebral arteries and surrounded by the low-attenuating
cerebrospinal fluid (CSF).
Loss of the subarachnoid space can be a sign of brainstem coning (see Table 6-13).
The distinctive thin, linear high density of the falx

cerebri separates the two hemispheres.
The dominant features of the hemispheres are the sulci
and gyri as well as the gray and white matter. Each gyrus
is surrounded by lower-attenuating sulci containing
CSF.
Gyral edema can erase the sulci, subarachnoid blood
increases sulcal density, and sulcal widening is a sign of
gyral atrophy.
Subdural hemorrhage often is visible at this level.
Posterior fossa
The cerebellar hemispheres with the surface folia, superior cerebellar peduncle and fourth ventricle dominate
the images.
The transition from the smaller medulla to the larger
pons is apparent, and the inferior aspect of the fourth
ventricle comes into view.
The cerebello-pontine angle is identifiable as a concave
transition between the two structures and lies adjacent
to the internal auditory meatus.
Pituitary fossa
The simultaneous depiction of the anterior, middle and posterior fossae produces a distinctive X appearance, with the
intersection at or adjacent to the pituitary fossa. The normal
gland can be difficult to identify, although low-density CSF
surrounds the pituitary stalk.
Suprasellar
Within a few images above the sella, the CSF density of the
suprasellar cistern comes into view in which, even without
contrast, the circle of Willis and its major branches can be
defined. Subarachnoid hemorrhage often lies in this location
as a high density.

At this level, the distinctive periventricular bent band
of low attenuation marking the internal capsule is surrounded by the higher-attenuating thalamus, lentiform
and caudate nuclei.
The Sylvian fissure delineates the temporal lobe.
The lateral and third ventricles, cerebral aqueduct and
corpus callosum dominate the midline structures.
Lateral ventricles
The body of the lateral ventricle dominates this level.
Additionally, the deep white matter of the corona radiata and sulci of the hemispheres are clearly visible.
Both anterior and posterior edges of the falx, superior
sagittal sinus and corpus callosum lie in the midline.
Systematic review
Sequential assessment of all images from base to vertex can
then follow, with attention to the same and other details.
Review areas
Anatomical regions of the brain on CT require closer
scrutiny, especially the brainstem.
The transition from medulla to pons is marked by
its increasing size and the appearance of the fourth
ventricle.
The midbrain is recognizable by its hallmark Mickey
Mouse appearance, with the ears representing the
cerebral peduncles, the nose the cerebral aqueduct and
the indented chin the colliculi.
Other regions requiring specific review include the
craniocervical junction, foramen magnum, mastoid
sinuses, middle ear complex, orbits and contents, nasopharynx and, importantly, bone windows to evaluate
the calvarium and skull base.
Summary
Following the systematic review, relevant positive and negative findings can be correlated and final statements made. If
contrast has not been administered, its relevance for an additional study would be considered; as would an MRI study.
6. HEAD MAGNETIC
RESONANCE
Magnetic resonance imaging (MRI, MR) is widely applied
to many body systems and abnormalities including the
brain, spine, joints, muscles, liver and biliary tree. MRI is
the gold standard for brain imaging and has a number of
advantages over CT, especially regarding disease sensitivity
and specificity (Box 6-13, overleaf). Safety issues for MRI
are a major factor in many patients not able to undergo the
study (Box 6-14, overleaf).
101
Box 6-13
Clinical utility of brain MRI

Advantages
No ionizing radiation
No demonstrable short-term or long-term complications
Image in any plane (multiplanar)
High-resolution images for detail
IV contrast often not required
Vascular imaging without contrast (MRA, MRV)
High sensitivity to neuronal disease and inammation
(DWI, IR)
Characterizes chemical composition and metabolic
activity (MRS)
High sensitivity to hemosiderin as a marker of previous
hemorrhage
Differentiates acute from chronic disease (DWI)
Disadvantages
Time-consuming
Availability
Higher cost
Sequence selection specic
Claustrophobia
Many incompatible medical and bio-stimulation implants
Prosthetic/hardware artifacts
Limitationsbone, air, time, expertise
DWI, diffusion-weighted image; IR, inversion recovery; IV, intravenous; MRA, magnetic resonance angiography; MRS, magnetic resonance
spectroscopy; MRV, magnetic resonance venography.
MRI PROTOCOLS
Box 6-14
Safety considerations for MRI

Magnetic elds
Medical and bio-stimulation implants
Pacemakers
Neurostimulators
Cardiac debrillators
Insulin pumps
Cochlear implants
Capsule endoscopy
Some stents and clips
Foreign bodies
Explosive shell fragments
Jewelry
Some tattoos
Acupuncture needles
Orbit metal fragments
Phones, watches
Credit-card demagnetization
Physiological issues
Elevated body temperature
Vertigo
Peripheral nerve stimulation
Pregnancy
T1
Cryogenic liquids
Emergency quench causing room hypoxia
Noise
Acoustic noise levels (<120dB)
Claustrophobia
Motion artifact
102
The physics and jargon of MRI are complex. The fundamental basis for image production is the effects induced
in hydrogen protons within body tissues when placed in a
strong magnetic field and pulsed by radiofrequency (RF)
waves from different angles, wavelengths and time intervals (pulse sequences). By varying the parameters of the
RF pulse, the T1 and T2 properties of the tissue are elicited. By repeating the pulse numerous times, the emitted
tissue signal is progressively summated to produce a proton map recording its excitation and relaxation properties
(Tables 6-14 and 6-15).
Short pulse-sequence parameters (short TR [repetition

time], short TE [echo time]) highlight contrast between
tissues, providing excellent depiction of anatomical
detail.
It is a short sequence, with fat being the most conspicuous normal high-signal component.
High-signal abnormalities on T1 include lipoma,
melanin, subacute hemorrhage due to methemoglobin, highly proteinaceous material and some calcified
collections.
The normal posterior pituitary is of high signal due to
the presence of protein hormonal precursors.
T2
Longer pulse sequences (long TR, long TE) allow more
water to relax and contribute high signals to the image
(H2O=T2).
Both physiological water (e.g. CSF) and pathological
water (e.g. edema) are demonstrated, with excellent
anatomical detail.
Table 6-14 MRI sequences in the brain
SEQUENCE
PHYSICS
TISSUES
ENHANCED
INDICATIONS
ABNORMALITIES
T1
Short TR
Short TE
6090 seconds
Fat
Cystic vs solid
lesions
Baseline sequence
Excellent anatomical
detail
Pre-contrast comparison
Normal and fat lesions
Subacute hemorrhage
Fatlipoma
Melaninmelanoma
Methemoglobinsubacute
blood
Proteincolloid cyst
Calciummeningioma
T2
Long TR
Long TE
23 minutes
Water
Physiological waterCSF
Pathological water
edema
Hydrocephalus
Tumor, infection,
inammation
IR
Inversion pulse
fat suppression
Longer TR
Longer TE
35 minutes
Water
Edema
Fat suppression
STIRedema
FLAIRedema,
demyelination
Tumor, infection,
inammation
Myositis
DemyelinationMS, myelitis
DWI
20 seconds
Cytotoxic edema
Acute pathology
Acute infarction
GRE
Low-angled shot
Can weight T1
or T2
Hemosiderin
Chronic hemorrhage
Subtle previous
hemorrhage
Tumors, AVM
Diffuse axonal injury (DAI)
GAD
Short TR
Short TE (T1)
6090 seconds
Vessels
Inamed tissues
Subtle pathology
Bloodbrain barrier
integrity
Tumor, infection,
inammation
Surgery complications
MRA
35 minutes
Flowing arteries
Stroke, headache
Visual disturbance
Occlusion, aneurysm,
vasculitis
MRV
35 minutes
Cerebral veins
Headache
Intracranial hypertension
Venous sinus thrombosis
CSF ow
13 minutes
Cerebrospinal uid
Hydrocephalus
Obstructive hydrocephalus
Normal pressure
hydrocephalus
Venous outow obstruction
MRS
<60 seconds
Necrotic tissues
Tumor (high choline)
Tumor, abscess
AVM, arteriovenous malformation; CSF, cerebrospinal uid; DWI, diffusion-weighted image; FLAIR, uid-attenuated inversion recovery;
GAD, post-gadolinium; GRE, gradient echo; IR, inversion recovery; MRA, magnetic resonance angiography; MRS, magnetic resonance
spectroscopy; MRV, magnetic resonance venography; MS, multiple sclerosis; STIR, short T1 inversion recovery; TE, echo time; TR,
repetition time.
Both fat and water will be high signal on T2, which

can be confusing with edema but can be differentiated
by comparing T1where water will not be high signaland by selectively suppressing the fat signal with
inversion recovery (STIR) or fat saturation techniques
(fatsat).

IR sequences are used widely to show both physiological
water (e.g. CSF) and pathological water (e.g. edema). It is
more sensitive to water than routine T2-weighted studies and has the added advantage of being able to electively
suppress the signal of either fat (STIR) or water (FLAIR) to

highlight more subtle pathological edema. The disadvantage
is that anatomical detail is compromised.

DWI is a critical sequence to define, in particular, acute
cerebral infarction. Ischemia impairs the cellular membrane
transport mechanisms such that the cell swells due to osmosis (cytotoxic edema). Diffusion of water is then restricted
across the cell membrane, and this restriction is displayed as
an intense high signal.
103
Table 6-15 MRI basic sequences
MRI
SEQUENCE
NORMAL
ABNORMAL
T1 sagittal
Excellent depiction of anatomy

High signal in fat, methemoglobin, melanin
Normal high signal in posterior pituitary
Glioma of the corpus callosum (arrow)
Cerebrospinal uid (CSF): bright signal

Graywhite matter differentiation
Pathological edemafrom tumor (arrows)

Compression of lateral ventricle
Midline shift (arrowhead)
Fluid (CSF) attenuated

Graywhite matter differentiation
Accentuates pathological edemamultiple

sclerosis (arrows)
T2 axial
Inversion recovery
(IR) axial
104
Table 6-15 MRI basic sequences
MRI
SEQUENCE
NORMAL
ABNORMAL
Diffusion-weighted
image (DWI)
Assesses movement across cell

membranes
Acute restriction shows as high signal

Demonstrates acute infarction (arrow)
Demonstrates hemosiderin
Hemorrhagic lesions
Multiple arteriovenous malformations

Low signal margins due to recurrent
bleeding (arrows)
Contrast in vessels and choroid

No parenchymal enhancement
No meningeal enhancement
Multiple mass lesions (metastasis)

Homogeneous enhancement (arrows)
Gradient echo
(GRE)
Post-gadolinium
(GAD)
continues
105
Table 6-15 MRI basic sequences continued
MRI
SEQUENCE
NORMAL
ABNORMAL
Magnetic
resonance
angiography (MRA)
MCA
ICA
ACA
BA
PCA
VA
Flow-dependent, endoluminal ow
Internal carotid (ICA), vertebral (VA), basilar
(BA), anterior cerebral (ACA), middle
cerebral (MCA), posterior cerebral (PCA)
arteries
Magnetic
resonance
venography (MRV)
Occlusions, aneurysms, anomalies

Acute embolic occlusion of middle
cerebral artery (arrow) and internal carotid
artery (arrowhead)
SSS
SS
TS
IJ
SGS
Flow-dependent, endoluminal ow
Superior sagittal sinus (SSS), straight sinus
(SS), transverse sinus (TS), sigmoid sinus
(SGS), internal jugular (IJ)
An extension of DWI is to combine the sequence with

identifying the movement of molecules along the long axis
of a nerve fiber, which can then be graphically displayed in
three dimensions to develop brain maps (MR tractography)
to show connectivity, degeneration and demyelination.
Gradient echo (GRE)

The sequence has the advantage of being fast and using
less RF power. T2 contrast is compromised and artifacts
are more common.
It is useful to identify hemosiderin content in a lesion,
confirming the presence of previous hemorrhage;
106
Venous sinus thrombosis (arrows)
described as a blooming effect. Hemosiderin produces

signal loss, which is black and more prominent in size
than on other sequences.
It is especially useful in identifying vascular lesions,
including aneurysms and arteriovenous malformations,
diffuse axonal injury and bleeding tumors.
Gadolinium is the standard IV contrast agent used in MR
examinations. When placed in a magnetic field, especially with T1-weighted sequences, gadolinium exhibits
strong para-magnetic effects and will emit a high signal. Fat
suppression is usually applied to this T1 sequence (T1 fat sat

or T1-FS), as fat has a bright signal with T1 which can be
confused with enhancement.
The essential pathophysiology is that any cause for
increased vascular permeability (tumor, infection, inflammation, etc.) will allow gadolinium to migrate from the
intravascular compartment to the extravascular space across
the bloodbrain barrier.
Gadolinium-enhanced MRA (MRA-GAD) is also performed non-routinely to better show vascular anatomy,
especially of the smaller vessels, such as in vasculitis.

cerebrospinal dynamics (MR-GILD, CSF
ow study)
Quantitative measurements of CSF flow, arterial inflow and
venous outflow can be made, which document disturbances
in normal flow dynamics and can assist in the diagnosis particularly of normal-pressure hydrocephalus, benign intracranial hypertension and venous sinus stenoses.
PRINCIPLES OF
INTERPRETATION IN BRAIN MR
Magnetic resonance angiography/

venography (MRA, MRV)
Moving blood produces signal loss, as the blood components
leave the field before they relax and therefore do not emit a
signal (signal void, black blood imaging). Most commonly,
blood is imaged with a time-of-flight (TOF) method where
the incoming blood is excited with a short TR allowing the
emitting of a high signal (white blood method). Imaging of
veins (MRV) uses the same methods as MRA.
Accurate interpretation of MR scans of the brain is based on

knowledge of brain anatomy, key landmarks and development of a systematic approach (Box 6-15, overleaf).
Technical review
Metabolites of neuron chemistry can provide insights into

the diagnosis of tumors, infections, stroke, and metabolic
and neurodegenerative diseases. The four common clinically used metabolites are choline (Cho), N-acetyl aspartate
(NAA), creatine (Cr) and lactate. Water and fat signals are
initially suppressed and the metabolites are then measured in
very small concentrations (Table 6-16).
Ischemic stroke induces a large amount of anaerobic
glycolysis, characterized by high lactate levels.
Choline is a marker of cell membrane breakdown, cell
turnover and necrosis found in active tumors.
Tumors which have been treated with radiation
with complete ablation have high lactate, low NAA
and creatine, but no choline.
Tumor recurrence or residual tumor post-radiation
will have elevated choline.
NAA is a neuronal activity marker and decreases when
any disease process reduces neuronal activity, such as
Alzheimers disease.
Creatine provides a measure of energy stores, which are
depleted in tumors.
An abscess cavity will typically have high lactate centrally and the wall high in choline, but absent NAA.
Identify sequences and their anatomical planes displayed.

Contrast images marked by high signal in all vessels, if available, should be identified early as these frequently show an
abnormality.

The number of sequences and the resulting large number of
images to be viewed can be rationalized using a systematic
approach.
To gain an initial overview of the case, review axial T2,
then the IR and finally the axial DWIs, correlating any
abnormal findings with each sequence.
Identifying post-contrast images next can be helpful
to highlight an abnormality. MRA study, when performed, needs to be surveyed to identify that all vessels
are present and there is no large aneurysm or stenosis
apparent.
Any additional special MR sequence needs to be
recognized.
Interpreting axial MR images can utilize a similar technique
as in CT: rapid assessment, identifying the first and last
scans, fast assessment of all images, and identifying normal
and abnormal signal changes.
Table 6-16 MRS metabolitepathological correlations
NAA
CHOLINE
CREATINE
LACTATE
Stroke
Low
High
Low
High
Tumor
Low
High
Low
High
Abscess
Absent
High
Low
High
Radiation
Low
Low
Low
High
107
Box 6-15
brain MR
DWI:
high signal foci of acute restricted diffusion
Post-contrast (gadolinium)
Technical review
Identify sequences and anatomical planes
Review T2 axial rst, then IR, then DWI
Review contrast images
Review MRA studies for vascular disease
Conduct fast assessment of all images
Identify any gross abnormalities
Key image review
Axial T2, IR:
foramen magnum
posterior fossa
pituitary fossa
suprasellar
internal capsulebasal ganglia
lateral ventricles
vertex
Systematic review
Sequential assessment of all images
Correlate contrast abnormalities with non-contrast
Review areas
Brainstem
Cerebello-pontine angles
Internal auditory meatus
MRA: all vessels present
DWI
Summary
DWI, diffusion-weighted image; IR, inversion recovery; MRA, magnetic resonance angiography.
Key image review

In MR studies of the brain, the axial, sagittal and coronal
planes are usually displayed. To simplify the many structures and landmarks depicted on axial T2 MR images, isolation of seven key image planes can simplify interpretation
(Table6-17).
Foramen magnum
At the skull base, the large foramen magnum is readily
identifiable.
The medulla is centrally placed, flanked by the two
vertebral arteries and surrounded by high signal cerebrospinal fluid.
Posterior fossa
The cerebellar hemispheres with the surface folia, superior cerebellar peduncle and fourth ventricle dominate
the images.
The transition from the smaller medulla to the pons is
apparent.
Pituitary fossa
The simultaneous depiction of the anterior, middle and
posterior fossae produces a distinctive X appearance,
with the intersection at or adjacent to the pituitary fossa.
108
The pituitary gland is clearly seen on sagittal T1, where

the posterior lobe will be high signal due to the presence
of proteinaceous hormones.
Suprasellar
Within a few images above the sella, the high-signal
CSF density of the suprasellar cistern comes into view.
Flow voids within the circle of Willis and its major
branches can be defined.

At this level, the distinctive periventricular bent band
of lower-signal white matter marks the internal capsule,
surrounded by the higher-attenuating thalamus, lentiform and caudate nuclei.
The Sylvian fissure delineates the temporal lobe.
The lateral and third ventricles, cerebral aqueduct and
corpus callosum dominate the midline structures.
Lateral ventricles
The body of the lateral ventricle dominates this level.
Additionally, the deep white matter of the corona radiata and sulci of the hemispheres are clearly visible.
Both anterior and posterior edges of the falx, superior
sagittal sinus and corpus callosum lie in the midline.
Table 6-17 MRI brain anatomy and pathological correlations
KEY IMAGE LEVEL
NORMAL
FORAMEN MAGNUM
1. Foramen magnum
2. Clivus
3. Medulla
4. Vertebral artery
5. Subarachnoid space
6. Sphenoid sinus
7. Nasal septum
8. Maxillary sinus
ABNORMAL
7
8
6
2
4 5
3
5
1
Fluid-lled cyst lateral medulla

Cystic astrocytoma (arrow)
POSTERIOR FOSSA
1. Cerebellum
2. Pons
3. Cerebellar tonsils
4. Internal auditory meatus
5. Temporal lobe
6. Cochlea
7. Sphenoid sinus
8. Ethmoid air cells
9. Greater wing of sphenoid
8
5
7
4
2
3
High signal, wedge-shaped, cerebellar

hemisphere infarct (arrows)
PITUITARY FOSSA
1. Transverse sinus
2. Cerebellum
3. Pons
4. Fourth ventricle
5. Basilar artery
6. Pituitary fossa
7. Internal carotid artery
8. Temporal lobe
9. Greater wing, sphenoid
10. Optic nerve
11. Globe
12. Nasal septum
11
12
10
9
8
7 6
5
3
4
2
1
Pituitary macroadenoma (arrow)

continues
109
Table 6-17 MRI brain anatomy and pathological correlations continued
KEY IMAGE LEVEL

SUPRASELLAR
1. Venous conuence
2. Cerebellum, hemisphere
3. Pons
4. Middle cerebral artery
5. Optic chiasm
6. Temporal lobe
7. Temporal horn, lateral
ventricle
8. Optic nerve
9. Optic foramen
10. Gyrus rectus
11. Globe
NORMAL
ABNORMAL
11
8
9
10
5
7
3
2
Basilar artery aneurysm (arrow)

INTERNAL CAPSULEBASAL
GANGLIA
1. Occipital lobe
2. Posterior falx
3. Pineal gland
4. Posterior horn
5. Third ventricle
6. Septum pellucidum
7. Frontal horn, lateral ventricle
8. Corpus callosum
9. Frontal lobe
10. Head of caudate nucleus
11. Internal capsule, posterior
limb
12. Lentiform nucleus
13. Sylvan ssure
14. Temporal lobe
9
7
13 12
8
6 10
11
5
14
3
9
4
2
1
Colloid cyst, third ventricle (arrowhead)

Obstructive hydrocephalus (arrows)
LATERAL VENTRICLES
1. Body of lateral ventricle
2. White matter, corona radiata
3. Posterior falx
4. Anterior falx
5. Frontal lobe
6. Parietal lobe
4
5
Agenesis of the corpus callosum
110
Table 6-17 MRI brain anatomy and pathological correlations
KEY IMAGE LEVEL
NORMAL
VERTEX
1. Falx cerebri
2. Pre-central gyrus
3. Central sulcus
4. Post-central gyrus
5. Frontal lobe
6. Parietal lobe
ABNORMAL
5
1
2
3
Parafalcine mass, meningioma (arrow)
Vertex
High over the convexity of the hemispheres, the dominant
features are the high-signal sulci and lower-signal gyri as
well as the gray and white matter. Gyral edema can erase the
sulci, and sulcal widening is a sign of gyral atrophy.
Systematic review
Sequential assessment of all images from base to vertex can
then follow, with attention to the same and other details.
Review areas
Anatomical regions of the brain on MR require closer
scrutiny, especially the brainstem. As part of this, the
cerebello-pontine angles and internal auditory meatus
need to be located and reviewed for mass lesions.
MRA images are evaluated for stenoses, occlusions and
aneurysms.
Inspection of DWIs for high-signal changes is especially
relevant as a sign of acute ischemia when stroke syndromes are being investigated.
Once injected the isotope undergoes decay, emitting

a positron which quickly encounters an electron within
35mm, combines with the electron causing both to disappear (annihilation event) and produces two gamma rays
at 180 to each other. These two emitted gamma rays are
detected as almost simultaneous registrations by the scanner,
which allows calculation of their location in the body. The
greater the number of annihilation events from a location, the
brighter it will be displayed on the image. At the same time,
a CT scan is performed and the PET data are co-registered
into an anatomical location (PET-CT) (Figure6-2).
The major uses are in oncology, to confirm masses with
high metabolic activity as a sign of malignancy, lymphoma,
staging of malignancy (especially involvement of lymph
nodes), response to therapy and to document recurrence
ofdisease.
Summary
If contrast has not been administered, its relevance for an
additional study would be considered.
7. POSITRON EMISSION
TOMOGRAPHY (PET)
Positron emission tomography uses various isotopes which
enter into a specific biochemical pathway and accumulate where these sites are most active. One of the most
commonly used is fluorine tagged with glucose (fluorodeoxy-glucose, FDG).
Figure 6-2 Fused CT-PET image of the chest. It

shows carcinoma in the left lung (arrowhead) with
extensive mediastinal lymph node metastases (arrow).
111
CHAPTER 7
PULMONOLOGY
David Arnold, Peter Wark, Michael Hensley and Brad Frankum
MEASUREMENT OF LUNG FUNCTION
CHAPTER OUTLINE
CLINICAL PRESENTATIONS OF
RESPIRATORY DISEASE
IMPORTANT CLINICAL CLUES
Dyspnea
Chronic cough
Clubbing
Hemoptysis
Solitary pulmonary nodule (coin lesion)
Mediastinal masses
Wheeze
Chest pain
Stridor
OVERVIEW OF THE RESPIRATORY SYSTEM

AND PATHOPHYSIOLOGY

Hypoxemia
Hypercapnia
Oxygenhemoglobin associationdissociation
curve
ACIDBASE DISTURBANCES FROM A

PULMONARY PERSPECTIVE
Spirometry
Diffusing capacity for carbon monoxide
(DLCO test)
Flowvolume loops
Interpretation of pulmonary function tests
CONTROL OF BREATHING
RESPIRATORY TRACT DEFENSES
Mechanical defenses
Immune system
GENETICS OF LUNG DISEASE

PULMONARY DISORDERS
Respiratory failure
Hypoventilation
DISEASES OF THE AIRWAYS
Asthma
Allergic bronchopulmonary aspergillosis (ABPA)
Bronchiectasis
Cystic brosis (CF)
Bronchiolitis
Chronic obstructive pulmonary disease (COPD)
Granulomatous ILD
EOSINOPHILIC PULMONARY DISORDERS

113
PULMONARY HEMORRHAGE
PHARMACOLOGY
Bronchodilators
PULMONARY INFECTIONS
Bacterial
Viral
Fungal
Mycobacterial
Other aspects
RESPIRATORY SLEEP MEDICINE

PLEURAL DISEASE
RESUSCITATION
Pleural effusion
Cardiac arrest (CA)
PNEUMOTHORAX
DIAGNOSIS AND DISEASE MANAGEMENT
PULMONARY VASCULAR DISEASE

MECHANICAL VENTILATION OF THE LUNGS
LUNG TRANSPLANTATION
CLINICAL PRESENTATIONS OF
RESPIRATORY DISEASE
Disorders of the respiratory system present in relatively few
ways, all of which relate to its underlying structure and function. Ventilation, gas exchange, maintenance of acidbase
balance, and protection from infection are the key responsibilities of the lungs and its supporting structures.
Failure of ventilation can occur when there is pathology at any level of the airway. Mechanical obstruction of
the upper airway, damage or disease of the lower airway,
impairment of the structures responsible for moving the
chest wall and diaphragm, and failure of the central control
mechanisms of breathing can all result in ventilatory failure
(Box 7-1).
Gas exchange can fail as a result of reduced ventilation,
or due to problems of perfusion. Perfusion of the lung can
be impaired by:
pulmonary thromboembolism
pulmonary hypertension, either primary or secondary
to other lung disease
cardiac disease leading to pulmonary venous congestion, e.g. left ventricular failure
Cardiac disease leading to shunting, e.g. congenital
heart defects, ventricular septal defect
pericardial disease
hematological disorder, e.g. hyperviscosity.
Acidbase disorders can be due to primary pulmonary
problems, or to renal and metabolic disorders.
114
Shock
Acute respiratory distress syndrome (ARDS)
Non-invasive positive-pressure ventilation (NIV)
Invasive positive-pressure ventilation (IPPV)
Extracorporeal membrane oxygenation (ECMO)
The lungs control pH through exhalation of carbon

dioxide. Any fall in blood pH is a trigger for increased
ventilatory drive.
Impairment of ventilation will lead to respiratory
acidosis.
Chronic ventilatory impairment will result in renal
compensation; the kidneys retain bicarbonate to compensate for CO2 retention. Increased serum bicarbonate
thus may be a sign of chronic respiratory acidosis.
Infection of the airways and parenchyma is common.
The lung has an enormous surface area that interacts
with the environment.
Innate and adaptive immune mechanisms are under
constant microbiological challenge.
Mechanical (cough, cilia), chemical (mucus), humoral
(antibodies), cellular (macrophages, neutrophils, lymphocytes) and molecular (defensins, interleukins) mechanisms are all vital in preventing tissue invasion.
Repeated failure of these defense mechanisms should
raise the prospect of immunodeficiency.
IMPORTANT CLINICAL CLUES

Dyspnea
Breathlessness or dyspnea is the most common respiratory
symptom and the most important to the patient. The most
accepted definition is that of the Consensus Statement from
the American Thoracic Society in 1999:
Dyspnea is a term used to characterize a subjective
experience of breathing discomfort that consists of
qualitatively distinct sensations that vary in intensity.
Chapter 7 Pulmonology
The experience derives from interactions among multiple

physiological, psychological, social, and environmental
factors, and may induce secondary physiological and
behavioral responses.
treatment. There are a number of scales in use, such as that

shown in Box 7-2.
Box 7-2
Modied Medical Research Council

(MRC) dyspnea scale
CLINICAL PEARL
The most common causes of chronic dyspnea are
asthma, chronic obstructive pulmonary disease
(COPD), cardiac failure and lack of tness.
Both acute and chronic dyspnea can be due to the full range
of respiratory diseases, as well as cardiac, hematologic and
psychogenic causes.
The grading of dyspnea is essential for accurate initial
assessment, and for measuring progress with and without
Grade/description of breathlessness
I only get breathless with strenuous exercise.
I get short of breath when hurrying on the level or
walking up a slight hill.
I walk slower than people of the same age on the level
because of breathlessness, or have to stop for a breath
when walking at my own pace on the level.
I stop for a breath after walking about 100 meters or after
a few minutes on the level.
I am too breathless to leave the house, or I am breathless
when dressing.
Box 7-1
Disorders of ventilation
Upper airway pathology
Obstructive sleep apnea
Upper airway mechanical dysfunction, e.g. tracheal
stenosis, vocal cord dysfunction
Foreign body inhalation
Oropharyngeal disorders, e.g. tonsillar hypertrophy,
epiglottitis, malignancies
Lower airway obstructive pathology
Reversible airways disease: asthma
Chronic obstructive pulmonary disease: emphysema,
chronic bronchitis
Bronchiectasis
Cystic brosis
Neoplasm: primary and secondary
Lower airway parenchymal pathology
Infection: pneumonia
Interstitial inammatory disease: idiopathic,
pneumoconiosis, autoimmune, granulomatous,
drug-induced, hypersensitivity
Neoplasm
Chest wall and pleural abnormalities
Pleural effusion
Empyema
Skeletal deformity, e.g. kyphoscoliosis, fractured ribs
Malignancymesothelioma
Pneumothorax
Primary or secondary muscle disease, e.g.
polymyositis, muscular dystrophy, drug-induced
myopathy
Central control problems
Central sleep apnea
Sedation, e.g. due to drugs, primary cerebral disease
Tachypnea is a vital sign of respiratory illness, with respiratory rates above 30/min considered a danger sign in the
context of an acute respiratory illness.
Tachypnea in the absence of clinical signs of lung disease,
and with a normal chest X-ray, can be due to the following.
Psychiatric disease (panic disorder, anxiety disorder);
hyperventilation syndrome is often accompanied by
peripheral paresthesiae
Pulmonary vascular disease
pulmonary embolism
primary pulmonary hypertension
Early stages of parenchymal lung disease
pulmonary edema
interstitial lung disease
lymphangitis carcinomatosis
Neuromuscular causes
respiratory muscle weakness
brain disease, e.g. stroke, encephalitis, usually
affecting the brain stem
Miscellaneous
metabolic acidosis, e.g. salicylate poisoning
fever or pain
hyperthyroidism
CheyneStokes respiration is rhythmical variation in
ventilatory effort, which varies between hypopnea and
hyperpnea.
CLINICAL PEARL
CheyneStokes breathing occurs when there is dysfunction of the respiratory center in the medulla. This
may be due to chronic hypoxia, metabolic disorders, or
primary brain disease.
115
airway tumors
tuberculosis.
Chronic cough
Chronic cough is defined as 8 weeks or more of cough.
Clubbing
CLINICAL PEARL
Clubbing is an important physical sign. The pathophysiology is unknown, but theories include chronic vasodilatation
of digital vessels, and/or the production of growth factors
such as platelet-derived growth factor in the lungs, or elsewhere (Box 7-3).
There are warning clues about chronic cough:

smokerthink lung cancer
hemoptysisthink lung cancer or tuberculosis
dysphoniathink laryngeal cancer
abnormal chest X-rayevery patient with a chronic
cough must have a chest X-ray.
Hemoptysis
Causes of hemoptysis
Causes
The three most common causes of chronic cough are:
1 chronic rhinosinusitis
2 asthma
3 gastroesophageal reflux.
CLINICAL PEARLS
In the setting of chronic cough where the cause is
unclear, consider performing bronchial provocation
tests to diagnose an underlying airway hyper-reactivity.
Patients may have more than one cause of cough.
For example, patients with asthma will frequently be
atopic and also have allergic rhinitis. Asthma may
also be exacerbated by esophageal reux.
Other causes include:

vocal cord dysfunction (also called upper airway dysfunction syndrome, UADS)
chronic bronchitis (cough with sputum for 3 months a
year, 2 years in a row)
congestive heart failure
bronchiectasis (usually cough with sputum daily)
drugs, e.g. angiotensin-converting enzyme inhibitors
(ACEIs)
Respiratory:
Lung cancer
Chronic bronchitis, usually an acute exacerbation
Pulmonary infarction (from pulmonary embolism)
Infection:
bronchiectasis , especially cystic fibrosis
lung abscess
pneumonia
tuberculosis
fungal lung diseaseusually Aspergillus: mycetoma, invasive fungal infection
parasitic lung infection, e.g. fluke
Foreign body (aspirated)
Post-traumatic (lung contusion)
Vasculitic syndromes, e.g. Goodpastures syndrome, anti-neutrophil cytoplasmic autoantibody
(ANCA)-associated vasculitis
Idiopathic pulmonary hemosiderosis
Rupture of a mucosal vessel after vigorous coughing
Iatrogenic, e.g. post trans-bronchial lung biopsy
(TBLB), bronchial biopsy, computed tomography
(CT)-guided fine-needle aspiration biopsy (FNAB)
Cardiovascular:
Mitral stenosis
Pulmonary edema due to left heart failure
Bleeding diathesis
Box 7-3
Causes of clubbing
Common causes of clubbing
Cardiac:
Cyanotic congenital heart disease
Respiratory:
Lung carcinoma (usually not small cell)
Suppurative lung disease:
bronchiectasis (cystic brosis and non-CF)
lung abscess (rare)
empyema (rare)
Lung brosis:
idiopathic pulmonary brosis
other causes of interstitial brosis
116
Uncommon causes of clubbing

Familial
Respiratory:
Tuberculosis
Gastrointestinal:
Cirrhosis, especially biliary
Inammatory bowel disease
Celiac disease
Endocrine:
Thyrotoxicosis (thyroid acropachy)
Spurious:
Nasal bleeding
Hematemesis
Mouth bleeding, e.g. dental or gum disease
CLINICAL PEARLS
Presence or absence of the above features does not
prove or disprove malignancy; they are a guide only.
A lesion in a smoker (current or ex) is malignant until
proven otherwise.
Causes of massive hemoptysis

Common:
Lung cancer
Bronchiectasis, usually cystic fibrosis
Uncommon:
Tuberculosis
Fungus ball (mycetoma/aspergilloma)
Lung abscess
Mediastinal masses
Mediastinal masses may present with symptoms due to pressure effects on surrounding structures, e.g. with dyspnea or
dysphagia, or be found incidentally on thoracic imaging
(Box 7-4). They may also be found in conjunction with
symptoms of the underlying cause, e.g. in the setting of
malignancy.
CLINICAL PEARL
In massive hemoptysis (200600mL in 24 hours), the
cause of death is asphyxiation, not hypovolemia.
Wheeze
Wheeze is caused by airflow through a narrowed airway, or
by high-velocity airflow.
Expiratory wheeze is generally a sign of dynamic airway
compression, and suggests pathology such as asthma or
chronic obstructive pulmonary disease (COPD).
Inspiratory wheeze is more often a sign of a fixed
mechanical obstruction, such as a tumor or a foreign
body in a bronchus.
Solitary pulmonary nodule

(coin lesion)
Causes
1
2
3
4
5
6
Primary lung cancer

Metastatic tumor
Granuloma (from past infection)
Hamartoma
Fungus ball
Lung abscess
CLINICAL PEARL
Lack of wheeze in the setting of obstructive airway disease due to asthma or COPD can be a sign of severity,
suggesting low airow.
Factors favoring a solitary lesion

beingmalignant
Chest pain
Pleuritic chest pain is sharp, localized, and occurs on inspiration. It is a sign of disease of the parietal pleura.
Causes include infective pleurisy, pulmonary embolism
with infarction, pneumothorax, malignancy, and empyema.
Muscular and skeletal structures are a common cause of
chest pain.
Chest pain is not an infrequent symptom in patients with
asthma. It is thought to be musculoskeletal in origin in some
cases, perhaps due to hyperinflation of the chest cavity.
Smoker
Increasing age of patient
Previous lung malignancy
Lesion >1cm in diameter
Lesion not present on old X-rays
Non-calcification of the lesion
Irregular border of lesion on X-ray or CT scan
Box 7-4
Mediastinal masses on chest X-ray

Anterior (the 5 Ts)
Thyroid
Thymoma
Teratoma
Terrible lymphoma or carcinoma
Tortuous vessels
Middle
Bronchogenic cyst
Pleuropericardial cyst
Posterior
Aortic aneurysm
Paravertebral abscess
Neurogenic tumor, e.g. neurobroma
Hiatus hernia
117
Stridor
The respiratory system is a complex servo-control network

for homeostasis of arterial oxygen, carbon dioxide and acid
base status, linked to sophisticated voluntary processes for
speech, singing and other cortical functions.
The role of the lungs is to import oxygen, export carbon
dioxide, and contribute to short-term control of pH while
talking, whistling and singing.
The anatomy of the respiratory system defines the
major disorders where problems occur, such as obstructive sleep apnea at the level of the naso/oro-pharynx, vocal
cord problems, asthma and COPD, interstitial lung disease/
pneumonia, pleural disease, and respiratory muscle weakness.
Gas exchange
The alveolus is the basic unit of the respiratory system.
The matching of inspired air and venous blood in the
alveolus leads to oxygen uptake and to carbon dioxide
removal.
The level or partial pressure of oxygen and carbon dioxide in each alveolus is determined by the ratio of the
ventilation and the blood flow, not the absolute values.
The ratio of alveolar ventilation to blood flow (V/Q ratio)
for the whole lung is approximately 1.0 in the stable state,
but the V/Q ratios vary across the lung in health, with
higher ratios in the apices and lower ratios in the bases.
The range of V/Q ratios or V/Q inequality is much
greater in lung disease of all types.
Since it is too difficult to measure and identify the V/Q
ratios of all 500 million or more individual alveoli, summary
measures are used. The concept of the alveolararterial
difference for PO2 (PAaO2) is one such measure. Since the
arterial PO2 is influenced by the level of inspired oxygen,
and the level of carbon dioxide is dependent on the alveolar
ventilation, it is not possible to use arterial PO2 alone.
Since it is not possible to make a single measure of
alveolar oxygen pressure (PAO2), this is estimated using a
three-compartment model of the lungs:
1 dead space (V/Q ratio = 0, PAO2 = inspired PO2)
2 shunt (V/Q ratio = infinity; PAO2 = mixed venous PO2)
3 ideal V/Q ratio of 1; PAO2 to be calculated).
Figure 7-1 shows typical values on a PO2/PCO2 graph.
118
Decreasing VA / Q
A
Nor ma
l
I ncr
eas
ing
50
/Q
VA
OVERVIEW OF THE
RESPIRATORY SYSTEM AND
PATHOPHYSIOLOGY
50
PCO 2 mm Hg
Stridor is a harsh inspiratory sound resulting from narrowing of the upper airway.
Causes include tracheal stenosis, upper airway foreign
body, laryngeal disease, and pharyngeal disorders such as
epiglottitis.
100
150
PO 2 mm Hg
Figure 7-1 PO2/PCO2 graph showing the ventilation

perfusion ratio line. The PO2 and PCO2 values of a
lung unit move along this line from the mixed venous
point V to the inspired gas point I as the ventilation
perfusion ratio increases from below (V) to above
(I) normal; A is located at the normal alveolar gas
composition
From West JB. Respiratory physiology: the essentials, 9th ed.
Philadelphia: Lippincott Williams & Wilkins, 2012.
The Aa gradient
The Aa gradient is calculated by estimating the PAO2 first:
PAO2 (mmHg) = [(Pb PH2O) FiO2]
PaCO2[FiO2 + (1 FiO2)]/R
Pb is atmospheric pressure; PH2O is saturated water vapor
pressure at 37C; FiO2 is inspired fraction of oxygen (0.2093
at sea level); R is respiratory quotient, usually 0.8.
At sea level and breathing room air at rest: PAO2 (mmHg)
= 150 PaCO2/0.8.
For a normal PaCO2 of 40 mmHg, the PAO2 will be
100mmHg.
The PAaO2 (Aa gradient) is normally 1020 mmHg.
10 mmHg is normal for a young adult, gradually rising
with age to 20 mmHg in the older adult.
CLINICAL PEARLS
PAaO2 (Aa gradient) is normal in hypoxemia due to
hypoventilation, and with reduced inspired oxygen
fraction such as at altitude.
The Aa gradient is increased in hypoxemia due
to ventilationperfusion (V/Q) inequality, right-to-left
shunting, and diffusion disorder.
V/Q inequality
CLINICAL PEARL
V/Q inequality is the most common cause of hypoxemia, and is responsible for much of the hypoxemia
seen with airways disease such as COPD, and interstitial disease such as idiopathic pulmonary brosis.
Percentage oxygen saturation
100
The curve shifts to the left

with alkalosis and decrease
in temperature, and a decrease
in 2,3-DPG
80
The curve shifts to
the right with fever,
acidosis and an
increase in 2,3-DPG
60
40
20
p50
20
40
60
80
100
Partial pressure of oxygen (mmHg)
The avidity of hemoglobin for oxygen varies
with physiological conditions as well as in
pathological states.
Figure 7-2 Oxygenhemoglobin dissociation curve.

2,3-DPG, 2,3-diphosphoglycerate
From Harward MP and Udden MM. Medical secrets, 5th ed.
Philadelphia: Mosby, 2012.
The major reason that V/Q inequality causes hypoxemia is the shape of the hemoglobinoxygen association
dissociation curve, which relates the partial pressure of
oxygen in the blood to the amount of oxygen carried on
hemoglobin (Figure 7-2). The areas of high V/Q ratio cannot make up for the areas of low V/Q ratio because the
higher areas cannot take on extra oxygen no matter how
high the local PAO2.
Carbon dioxide does not have the same problem; its
pressurecontent curve is linear, so high V/Q areas make up
for the reduced output of low V/Q areas when ventilation is
increased in response to chemoreceptor stimulation.
Right-to-left shunting
There are two forms of right-to-left shunting that will reduce
the level of PaO2 below that expected from the level of PAO2.
An anatomical shunt occurs when blood flows from
the right side to the left side of the circulation without any
exposure to inhaled air. This may be due to:
abnormal connections, such as
atrial or ventricular septal defects
direct pulmonary arteryvein anastomoses/malformations
bronchial veins that drain directly into the left
atrium
a pathophysiological shunt with blood flowing past
completely unventilated alveoli, such as
complete atelectasis
alveoli filled with liquid inflammatory material or blood, as in pulmonary edema and alveolar
hemorrhage.
The PAaO2 of 1020 mmHg found in people without
lung disease is due to some of the right-to-left shunts such
as bronchial veins draining into the left atrium, but also

includes the contribution from the effect of normal V/Q
inequality; this may be called a physiological shunt.
Measuring the size of a right-to-left shunt
This is estimated by measuring PaO2 and PaCO2 while
breathing 100% O2 for 15 minutes. Since the hypoxemia
of hypoventilation, V/Q inequality and diffusion should be
overcome by 100% oxygen, this method measures the anatomical and pathophysiologic shunts; all blood leaving lowV/Q areas will be fully oxygenated.
Normally, the shunt does not exceed 7%.
A shunt >7% is usually due to a significant problem such
as a patent foramen ovale with right-to-left flow, or a
large pulmonary arteriovenous malformation.
A 30% shunt is life-threatening.
Hypoxemia
Summary of causes
1 Ventilationperfusion mismatch is nearly always the
cause of clinically significant hypoxia (increased Aa
gradient; good response to increased inspired oxygen)
2 Hypoventilation (increased PaCO2, normal Aa
gradient)
3 Right-to-left shunt (increased Aa gradient, poor
response to increased inspired oxygen)
4 Impaired diffusion (very rare)
5 Low inspired environmental O2, e.g. high altitude
Note: Desaturation of mixed venous blood (e.g. shock) can
worsen hypoxemia from other causes.
Hypercapnia
Causes
Hypoventilation:
Alveolar hypoventilation is the most common cause
of hypercapnia, in keeping with the relationship
between PACO2 and alveolar ventilation.
PACO2 is inversely proportional to alveolar
ventilation.
If alveolar ventilation is halved, carbon dioxide pressure doubles.
V/Q inequality:
The maintenance of a normal PCO2 in the presence
of V/Q inequality depends on the level of alveolar
ventilation.
One example is the use of high inspired oxygen for
COPD with chronic hypercapnia; since increased
inspired oxygen will increase V/Q inequality by
removing the homeostatic effect on V/Q of hypoxiainduced pulmonary vasoconstriction, ventilation
must increase to avoid further hypercapnia. However, the increased PaO2 reduces the central drive
to respiration, resulting in worsening hypercapnia.
Increased inspired CO2, for instance rebreathing during
a problem with anesthetic equipment.
119
Oxygenhemoglobin association
dissociation curve
Useful points to remember for the relationship between
PaO2 and oxygen saturation:
1 PaO2 of 60 mmHg = saturation 90%
2 PaO2 of 47 mmHg = saturation 70% (normal venous
blood)
3 PaO2 of 26 mmHg = saturation 50%.
Causes of an increased affinity for O2
(Curve shifts to the left, i.e. better oxygen pick-up.)
1 pH
2 PaCO2
3 Carboxyhemoglobin, and abnormal hemoglobin, e.g.
fetal
4 Methemoglobin
5 Decreased 2,3-DPG (2,3-diphosphoglycerate)
6 Hypothermia
Causes of a decreased affinity for O2
(Curve shifts to the right, i.e. better oxygen release.)
1 pH
2 PaCO2
3 Fever
4 Abnormal hemoglobin, e.g. Kansas
5 Increased 2,3-DPG
ACIDBASE DISTURBANCES
FROM A PULMONARY
PERSPECTIVE
Acute respiratory acidosis: reduced pH; increased
PaCO2; normal base excess; increased HCO3 by
approximately 1 mmol/L for every 10 mmHg increase
in PaCO2.
Chronic respiratory acidosis: HCO3 increases by
approximately 3.5 mmol/L for every 10 mmHg increase
in PaCO2. Associated with renal compensation to return
pH toward 7.40; HCO3 > 30mmol/L gives a clue about
chronic hypercapnia.
CLINICAL PEARLS
Base excess (BE) from the arterial blood gas
machine is the BE corrected to a PaCO2 of 40 mmHg
(i.e. normal).
Thus, BE calculation eliminates the respiratory component of the acidbase status and shows only the
metabolic component.
Normal BE is 3. BE >+3 is metabolic alkalosis; BE
<3 is metabolic acidosis.
120
If the HCO3 is lower than the calculated value, there

is a concurrent metabolic acidosis; BE will be , i.e. a
negative value.
If the HCO3 is higher than the calculated value, there
is a concurrent metabolic alkalosis; BE will be , i.e. a
positive value.
Acute respiratory alkalosis: increased pH, reduced
PaCO2, and a decrease in HCO3 by 2mmol/L for every
10 mmHg decrease in PaCO2.
Chronic respiratory alkalosis: chronic decrease in
PaCO2 is associated with renal compensation to return
pH toward 7.40. HCO3 should decrease 5mmol/L for
every 10mmHg decrease in PaCO2.
If the HCO3 is lower than the calculated value, there
is a concurrent metabolic acidosis; BE will be a negative
value.
If the HCO3 is higher than the calculated value, there
is a concurrent metabolic alkalosis; BE will be a positive
value.
MEASUREMENT OF LUNG
FUNCTION
The lung has four fundamental volumes from which lung
capacities are derived:
residual volume (RV)the volume remaining after completing a full active expiration
expiratory reserve volume (ERV)the volume still available after a passive expiration
tidal volume (TV)the volume used for usual ventilation
inspiratory reserve volume (IRV)the volume available by
full inspiration from the end of normal inspiration to the
top of the lungs.
The capacities are combinations of the volumes:
total lung capacity (TLC) is the sum of all four volumes
vital capacity is TLC minus RV
functional residual capacity (FRC) is the resting capacity
RV plus ERV.
Figure 7-3 illustrates lung volumes and other measurements
related to breathing mechanics.
Spirometry
Spirometryor the forced expiratory testis the simplest
test of lung function, and is also one of the most informative
and very easy to do. It should be available to all patients in
every setting, similar to the measurement of blood pressure.
The basic measurements from the forced expiratory
maneuver (Figure 7-4) are:
the forced expiratory volume in 1 second (FEV1)
the forced vital capacity (FVC)
the ratio FEV1/FVC.
TV
IRV
6.0
Inspiratory
capacity
Maximal
inspiratory
level
2.7
TV
ERV
RV
2.2
Resting
expiratory
level
1.2
Maximal
expiratory
level
IRV = inspiratory reserve volume

ERV = expiratory reserve volume
Volume (L)
ERV
IRV
Vital
capacity
RV
Functional
residual
capacity
Total lung capacity
Dead space
TV = tidal volume
RV = residual volume
Figure 7-3 Lung volumes and some measurements related to the mechanics of breathing
Adapted from Comroe JH Jr et al. The lung: clinical physiology and pulmonary function tests 2e. Year Book, 1962.
Normal
(b)
Flow
(c)
2
1
3
4
Time (secs)
Curve (a) Normal spirometry. FEV1 = 4.2 L, FVC = 4.8 L

(b) Obstructive defect. FEV1 = 2.2 L, FVC = 4.5 L
(c) Restrictive defect. FEV1 = 2.4 L, FVC = 2.8 L
Figure 7-4 Example of spirometry

From Adam JG (ed). Emergency medicine: clinical essentials,
2nded. Philadelphia: Saunders, 2013.
While other measures such as flow in the mid-part of the

forced expiration can be taken, the only regular addition is
to repeat the test after administration of a rapid-acting bronchodilator such as salbutamol or albuterol.
The results are compared with predicted normal values
obtained from large surveys.
The normal limits have been defined in the past by general rules for all age groups, such as within 80120% of
predicted for FEV1 and FVC, or >0.70 for FEV1/FVC
ratio.
Recently the lower limit of normal (LLN) has been
introduced, with some changes to the interpretation of
test results. For instance, a cut-off point of 0.7 overestimates the presence of airflow obstruction in the elderly,
and underestimates it in young people.
Spirometry is normal, obstructive, restrictive, or combined
obstructive and restrictive (Figure 7-5).
Look at the FEV1/FVC ratioif the ratio is below the
LLN, this is obstructive.
R(E)
R(P)
TLC
Inspiration
Volume (litres)
Expiration
(a)
Volume RV
Increasing
Figure 7-5 Obstructive and restrictive ow volume

curves. O, obstructive disease; R(P), parenchymal
restrictive disease; R(E), extraparenchymal restrictive
disease with limitation in inspiration and expiration.
Forced expiration is plotted in all conditions; forced
inspiration is shown only for the normal curve.
TLC, total lung capacity; RV, residual volume. By
convention, lung volume increases to the left on
the abscissa. The arrow alongside the normal curve
indicates the direction of expiration from TLC to RV.
From Fauci AS et al. (eds). Harrisons Principles of internal medicine,
14th ed. New York: McGraw Hill, 1998.
Look then at the FVC:

If the FVC is normal, it is obstructive only.
If the FVC is reduced below the LLN, it is a combined
obstructive and restrictive defect on spirometry.
An important point is that obstruction alone can
cause a reduced FVC due to air trapping, but this
cannot be measured with spirometry alone; measurement of lung volumes is required.
If the FEV1/FVC ratio is normal, then look at the FVC.
If the FVC is below the LLN, this is a restrictive
defect. Restriction is best assessed by TLC, but this
is not available on spirometry.
If FVC is normal and FEV1/FVC ratio is normal,
then spirometry is normal.
121

Lung restriction is defined by reduction in TLC below
the lower limit of normal.
Hyperinflation is defined by increase in TLC to above
the upper limit of normal.
Gas trapping is characterized by an increase in RV, or
more accurately by an increase in the RV/TLC ratio.
In restrictive lung disease, TLC is . RV is often ,
but may be normal.
In obstructive lung disease, obstruction is defined
by the FEV1/FVC ratio on spirometry; RV and
TLC are often increased, indicating gas trapping and hyperinflation respectively, but may be
normal.
Table 7-1 Flowvolume loops
PATTERN
EXPIRATORY
PEAK
INSPIRATORY
PEAK
Fixed obstruction
Plateau
Plateau
Variable
intrathoracic
obstruction
Plateau or
concave
Preserved
Variable
extrathoracic
obstruction
Preserved
Plateau
Expiration
6
Diffusing capacity for carbon

monoxide (DLCO test)
Flowvolume loops
Flowvolume loops are a more sensitive way of detecting
airway obstruction than spirometry, and may help to identify
the site of obstruction (Table 7-1). Expiratory and inspiratory flows are plotted against lung volume during maximally
forced inspiration and expiration (Figure 7-6).
Interpretation of pulmonary
functiontests
Table 7-2 summarizes characterisic changes in pulmonary
function in lung disease and in the elderly.
122
Variable
extrathoracic
Variable
intrathoracic
4
Flow (L/sec)
While the DLCO is called a test of diffusing capacity, it is

really a measure of how much carbon monoxide (CO) can
be picked up by the lungs over a certain period of time. This
measure is also known as TLCO (transfer factor of the lung
for CO).
Only very low levels of CO are required due to the
exceptional affinity of hemoglobin for CO; this allows the
assumption to be made that the level of CO in blood leaving
the alveolus is zero.
The DLCO will depend on the volume of air in the lungs
when the CO was taken in, the alveolar surface area available, pulmonary capillary volume, hemoglobin level, and
pulmonary blood flow. It depends to a very minor degree,
if any, on the rate of diffusion of the CO from the alveoli to
the pulmonary capillary.
DLCO is decreased in:
emphysema
anemia
pulmonary hypertension
pulmonary edema
right-to-left shunts.
DLCO is increased in:
polycythemia
diffuse alveolar hemorrhage
left-to-right shunts.
Fixed
lesion
2
0
2
4
6
Inspiration 100 50 0
100 50 0
Vital capacity (%)
100 50 0
Figure 7-6 Flowvolume loops produced by major

airway obstructive lesions
From Fauci AS et al. (eds). Harrisons Principles of internal medicine,
14th ed. New York: McGraw Hill, 1998.
CONTROL OF BREATHING
The system responsible for the control of breathing is summarized in Figure 7-7, which sets out the afferent and efferent aspects of the system.
The role of the upper airway in the control of breathing has
been explored in the investigation of the cause and treatment
of obstructive sleep apnea (OSA) and other forms of sleepdisordered breathing. The coordinated activation of upper airway muscles maintains upper airway patency in normal people
and overcomes upper airway obstruction in OSA.
RESPIRATORY TRACT
DEFENSES
Mechanical defenses
The cough reflex is responsible for clearance of airway
secretions, and defense of the upper airway. The afferent
limb is via a variety of receptors through the upper and lower
respiratory tract. The efferent limb is through inspiratory
and expiratory muscles, and laryngeal muscles.
Table 7-2 Characteristic pulmonary function changes in lung disease and in the elderly
PULMONARY FUNCTION
TEST
CHRONIC
OBSTRUCTIVE
PULMONARY
DISEASE
RESTRICTIVE LUNG
DISEASE
ELDERLY
COMPARED WITH
THE YOUNG*
FEV1/FVC ratio
Decreased
Increased or normal
Decreased
Vital capacity (FVC)
Decreased or normal
Decreased or normal
Decreased
Residual volume (RV)
Increased or normal
Decreased or normal
Maximum mid-expiratory ow
rate (MMFR)
Decreased
Decreased or normal
Decreased
Total lung capacity (TLC)
Increased or normal
Decreased
Unchanged
DLCO
Decreased or normal
Decreased or normal
Decreased
*Less relevant when lower and upper limit of normal (LLN and ULN) are used compared with the older approach of normal being 80% or
more for FEV1 and FVC, and 0.7 for the FEV1/FVC ratio.
DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
Efferent signals
Motor cortex
Afferent signals
Sensory cortex
Chemoreceptors
Air hunger
Upper
airway
Immune system
Brain stem
Upper
airway
Chest
tightness
Ventilatory
muscles
infertility
situs inversus (Kartageners syndrome) in about 50% of
cases.
Chest
wall
Figure 7-7 Efferent and afferent signals that

contribute to the sensation of dyspnea
From Sheel AW, Foster GE and Romer LM. Exercise and its impact
on dyspnea. Curr Opin Pharmacol 2011;11(3);195203.
Mucus is responsible for clearance of micro-organisms

from the airways. Its importance is reflected in cystic fibrosis, where abnormality in the CFTR gene leads to problems
with electrolyte and water transport, leading to viscous,
thickened mucus that facilitates chronic infection and persistent inflammation.
Airway cilia are responsible for moving mucus and its
components throughout the respiratory tract. The importance of cilial function is reflected in disorders such as primary cilial dyskinesia or immotile cilia syndrome, which
lead to multiple problems:
chronic bronchitis and bronchiectasis
otitis and rhinosinusitis
The respiratory tract innate immune system performs the

following roles:
rapid detection and first-line defense against environmental micro-organisms
activation of the adaptive immune system
regulation of inflammation and homeostasis of the
immune system.
Components:
Receptorspattern recognition receptors (PRRs)
such as Toll-like receptors that recognize highly
conserved pathogen-associated molecular patterns
(PAMPs)
Dendritic cells, phagocytes (monocytes, macrophages
and neutrophils) and special non-B, non-T lymphocytes
(natural killer or NK cells, secreting interferon-gamma
and anti-microbial and pro-inflammatory cytokines)
Enzymes, cytokines and peptides, e.g. lysozyme, IL-8
and defensins
Systemic inflammation: C-reactive protein (CRP),
complement system, lectins
The respiratory tract adaptive immune system

Lymphoid tissue is present throughout the respiratory tract,
providing a strong mucosal immune system similar to that
of the gastrointestinal tract, with antigen-presenting cells
(macrophages and dendritic cells) to enable acquired immunity to start in the respiratory tract.
In addition to the usual roles of cell-mediated immunity and specific immunoglobulin (Ig) production through
123
B-lymphocyte proliferation, there are some adaptive

immune roles with specific implications for lung disease:
Airway IgA is important for mucosal immunity of the
upper and lower airways in its dimeric form (monomeric
in serum). Selective IgA deficiency may lead to recurrent infections of the lungs and sinuses including bronchiectasis, although this eventuates in only a minority of
cases.
The balance in lymphocyte development between the
fundamental helper cell classes (Th1/Th2/Th17) may
play a role in the development of diseases such as asthma
where the predominance of Th2 and/or Th17 response
may lead to inappropriate airway inflammation.
DISEASES OF THE AIRWAYS

Asthma
Denition
The Global Initiative for Asthma (GINA) 2011 definition is:
Asthma is a chronic disorder of the airways in which
many cells and cellular elements play a role. The chronic
inflammation is associated with airway hyper-responsiveness
that leads to recurrent episodes of wheezing, breathlessness,
chest tightness and coughing, particularly at night and in the
early morning. These episodes are usually associated with
widespread but variable airflow obstruction within the lung
that is often reversible either spontaneously or with treatment.
GENETICS OF LUNG DISEASE

Only a small number of respiratory diseases are due to single
gene conditions:
Cystic fibrosis is the most common of the single gene
respiratory conditions (see details in the section below).
Deficiency of proteinase inhibition is an autosomal
recessive disorder known as either alpha-1 antitrypsin
deficiency or alpha-1 proteinase inhibitor deficiency,
and causes severe damage to the lungs in the form of
emphysema, and in the liver as cirrhosis. About 95%
ofcases are due to the Z mutation (PiZZ).
PULMONARY DISORDERS
respiratory neuromuscular junctionmyasthenia gravis

respiratory musclesmuscular dystrophy
chest wallkyphoscoliosis; profound obesity
upper airway obstructionepiglottitis, tracheal damage, obstructive sleep apnea.
Bronchial hyper-responsiveness (BHR) can be demonstrated by:

short-term reversal of airflow obstruction, defined as a
12% increase and a 200 mL increase in FEV1 after
administration of bronchodilator
a 15% fall in FEV1 with bronchoprovocation tests (e.g.
hypertonic saline, methacholine, mannitol, histamine).
Respiratory failure
Causes of respiratory failure are classified as shown in

Box7-5.
Upper airway obstruction (inspiratory stridor usually

present rather than expiratory wheeze); includes vocal
cord dysfunction.
Foreign body aspiration, tumor or bronchial stenosis
(resulting in localized wheeze, often monophasic in
character).
Bronchospasm due to acute exacerbation of COPD,
carcinoid syndrome, recurrent pulmonary emboli,
cardiogenic pulmonary edema, systemic vasculitis, or
eosinophilic pulmonary syndromes.
Bronchospasm induced by drugs (e.g. beta-blockers,
aspirin, nebulized drugs such as antibiotics).
Hypoventilation
Causes include disorders of the:
medulla, e.g. inflammation, stroke, tumor, drugs such
as narcotics
spinal cord, e.g. trauma
anterior horn cellspoliomyelitis, motor neuron
disease
respiratory muscle nervesGuillainBarr syndrome
Box 7-5
A clinical classication of causes of respiratory failure

Hypoxemia without CO2 retention,
clear CXR
Pulmonary emboli
Acute airway obstruction
Intracardiac shunt
Hypoxemia without CO2 retention,

inltrate on CXR
Cardiac failure
Interstitial disease
Pneumonia
Adult respiratory distress syndrome
COPD, chronic obstructive pulmonary disease; CXR, chest X-ray.
124
Hypoxemia, CO2 retention, clear CXR

COPD
Severe asthma
CLINICAL PEARL
Wheeze associated with gastroesophageal reux may
have multiple mechanisms, especially vocal cord dysfunction.
Pathophysiology of allergic asthma

Airway response to an inhaled allergen frequently involves
an early bronchoconstrictive response which peaks within
30 minutes and resolves in 12 hours, followed by a latephase response from 3 to 9 hours later.
Early asthmatic responses reflect the concentration of
specific IgE, and the extent of non-specific bronchial
hyper-responsiveness.
Early responses are mediated through degranulation of
mast cells, and release of pre-formed and newly formed
inflammatory mediators.
Late-phase responses are characterized by the influx of
inflammatory cells.
Late-phase responses are IgE-independent, with the
metabolism of mast cell membrane phospholipids such
as leukotrienes, platelet-activating factor and prostaglandins being chemotactic for inflammatory cells.
Inflammatory cells, especially eosinophils, neutrophils
and T-helper cells, then release further inflammatory
mediators.
Occupational exposures can induce asthma (see below).
Signs of a severe exacerbation of asthma

(after GINA, 2011)
1 Breathless at rest
2 Cannot talk in sentences or phrases
3 Agitated, apprehensive, exhausted, drowsy in late stages
4 Increased respiratory rate: >30/min
5 Use of accessory muscles of respiration
6 Loud wheezing; may disappear in late stages
7 Tachycardia: >120/min
8 Pulsus paradoxus >25mmHg
9 Peak expiratory flow: <60% best
10 Normocapnia; hypercapnia in late stages
11 Hypoxemia: pulse oxyhemoglobin saturation <90%,
PaO2 <60mmHg; cyanosis in late stages
The above abnormalities indicate the need for hospital
admission and urgent treatment.
Treatment of acute severe asthma

(after GINA, 2011)
Increased inspired oxygen to achieve an oxyhemoglobin
saturation >90%
Continuous oxygen saturation (SaO2) monitoring
Continuous inhaled beta-agonist via nebulizer for
1hour
Nebulized anticholinergic, e.g. ipratropium
Regular intravenous (IV) hydrocortisone (100mg every

6 hours) or oral prednisoline 1 mg/kg/day to a maximum dose of 50 mg
IV magnesium sulfate
Ventilatory support if worsening respiratory failure, initially with non-invasive ventilation (NIV) using bi-level
continuous positive airway pressure (CPAP) via a mask
or subsequent intubation
Management of chronic asthma

In order to formulate individualized treatment plans for asthmatics, it is necessary to characterize the pattern of disease.
Some patients have intermittent symptoms, followed
by intervening periods without any discernible symptomatology. Lung function may be normal at these
asymptomatic times, or demonstrate some persistent
(subclinical) obstruction. Having an intermittent pattern does not always imply a lack of severity.
Some intermittent asthma is predictable, e.g. exerciseinduced asthma.
Other patients have chronic daily symptoms. Again,
severity of chronic symptoms will vary.
Level of symptoms is an unreliable gauge of lung function.
Objective measurement via spirometry at varying times is
desirable in all patients.
Treatment
Inhaled short-acting beta-agonist therapy is the mainstay of treatment for intermittent asthma.
CLINICAL PEARLS
Inhaled beta-agonist drugs such as salbutamol/
albuterol are used as acute symptomatic treatment
(relievers) for most people with asthma.
They are used as preventative therapy (preventers)
in the setting of exercise-induced asthma, in which
case they should be administered 30 minutes prior
to exercise.
Chronic asthma should be managed with inhaled

corticosteroids.
Inadequate symptom control or suboptimal lung
function despite inhaled corticosteroids can be
treated by the addition of long-acting beta-agonists
such as salmeterol or eformoterol.
The role of leukotriene antagonists is more clearly delineated in children, but some adults with chronic symptoms may benefit.
Intermittent courses of oral corticosteroids will be
required for acute severe exacerbations of asthma.
A small minority of chronic asthmatics require
long-term oral corticosteroids to allow adequacy
of lung function. In these patients, steroid-sparing
agents are sometimes employed, although there is
limited evidence for the efficacy of drugs such as
methotrexate.
125
The utility of monoclonal anti-IgE therapy for chronic

severe asthma is becoming clearer. Drugs such as omalizumab have a good safety profile, but their widespread
use is inhibited by high cost.
There is strong evidence for efficacy of allergen immunotherapy in patients with allergic sensitization to airborne
allergens such as the house dust mite. This treatment
must be used with caution in those with severe or unstable asthma due to the risk of anaphylaxis.
Methylxanthines such as theophylline are rarely used due
to their narrow therapeutic index and limited efficacy.
Inhaled anticholinergics such as ipratropium and tiotropium are generally reserved for patients with COPD, but
can be considered in those with chronic severe disease.
Spacer devices should be encouraged for delivery of
inhaled medication to all asthmatics. Many patients are
unable to adequately coordinate the use of metereddose inhalers.
CLINICAL PEARL
It is important to identify exacerbating factors for
asthma in all patients.
Usual factors include upper respiratory tract infection, cold air, exercise, and airborne allergens such
as house dust mite, animal dander, grass and tree
pollens.
Some 10% of asthmatics will experience exacerbation after ingestion of aspirin or other cyclooxygenase-1 (COX-1) inhibiting drugs.
Vaccination to inuenza and pneumococcus should
be routine in all asthmatics.
Figure 7-8 Chest X-ray of a patient with allergic

bronchopulmonary aspergillosis; note the central and
upper zone distribution of inltrates
From Lazarus AA, Thilagar B and McKay SA. Allergic
bronchopulmonary aspergillosis. Disease-a-Month 2008;54(8):
54764.
necessary. Anti-fungal medication is generally ineffective,

presumably due to the nature of the condition (a hypersensitivity disorder), and the difficulty in maintaining clearance
from colonization of the airways by Aspergillus.
Bronchiectasis
Denition
Allergic bronchopulmonary
aspergillosis (ABPA)
This is an uncommon condition which may complicate
asthma, in which a hypersensitivity reaction to the colonizing organism Aspergillus fumigatus results in cough, dyspnea
and, frequently, worsening asthma control.
There is predominantly central upper lobe bronchiectasis on high-resolution CT scan. See also Figure 7-8.
Diagnostic criteria
1
2
3
4
Asthma
Pulmonary infiltrates
Peripheral eosinophilia
Immediate wheal-and-flare response to Aspergillus
fumigatus
5 Serum precipitins to A. fumigatus
6 Total serum IgE elevated, Aspergillus specific IgE elevated
7 Central bronchiectasis
Treatment
The mainstay of treatment for ABPA is systemic corticosteroid medication. Ideally this can be administered in limited courses, but in some patients long-term treatment is
126
Pathological dilatation of the airways or bronchi presenting as recurrent or chronic airway infection that
often does not respond to initial treatment.
Presence of resistant organisms such as Pseudomonas aeruginosa and Staphylococcus aureus is a common feature.
Clinical features
Daily cough with variable but persistent sputum
production
Varying degrees of dyspnea
Finger clubbing often present
Chest auscultation may be normal, or reveal wheeze,
crackles, or both
Cor pulmonale may develop in late stages
See Figure 7-9.
Causes
Inherited
1 Cystic fibrosis
2 Immotile cilia syndrome (0.5%). There are two major
types of defect in this syndrome:
a Dynein arm lossassociated with sinusitis, bronchiectasis, infertility in males, and situs inversus
(Kartageners syndrome)
Airway treatment with bronchodilators and inhaled

corticosteroids.
Consider anti-inflammatory agentslong-term lowdose macrolide antibiotic.
Lung transplantation may be necessary, especially in the
setting of cystic fibrosis.
Cystic brosis (CF)
Figure 7-9 Chest computed tomography of a patient

with bronchiectasis; note the dilatation of the airways
with marked wall thickening. The bronchi are larger
than the accompanying pulmonary arteries; this is
known as the signet ring sign
From Belada D et al. Diffuse large B-cell lymphoma in a patient
with hyper-IgE syndrome: successful treatment with risk-adapted
rituximab-based immunochemotherapy. Leuk Res 2010;34(9):
e232e234.
Radial spoke deficiencyassociated with sinusitis,

nasal polyps, otitis, mastoiditis, recurrent bronchitis, and infertility in both sexes
2 Immunodeficiency (IgA deficiency, common variable
immunodeficiency)
Acquired/structural
1 Post-infection, e.g. childhood respiratory tract infection including pertussis and measles; necrotizing
pneumonia
2 Localized disease, e.g. bronchial adenoma, tuberculosis, foreign body
3 Airway disease and asthma, e.g. allergic bronchopulmonary aspergillosis, causing central bronchiectasis
4 Inflammatory disorders, e.g. rheumatoid arthritis,
ankylosing spondylitis, systemic lupus erythematosus
(SLE)
5 Inhalation, e.g. gastro-esophageal reflux disease, recurrent pulmonary aspiration, foreign body
This is an autosomal recessive disorder caused by multiple

mutations of a single gene on the long arm of chromosome7.
The most common mutation is a deletion of phenylalanine at position 508, so-called F508, which is
responsible for about 70% of all CF. The gene codes for
a multi-functional protein, cystic fibrosis trans-membrane
regulator (CFTR), which is active in the membrane of epithelial cells. It operates as a chloride channel and regulates
other ion channels. There are more than 1800 mutations
known to reduce the function of chloride channels.
The major effects are on the lungs and pancreatic exocrine function where there are thick, tenacious secretions.
CLINICAL PEARL
Diagnosis of CF is usually made in childhood, but late
presentation may occur, including with:
recurrent respiratory tract infections
bronchiectasis
difficult-to-control asthma, including with ABPA
atypical mycobacterial infections
pancreatitis and liver disease.
Diagnostic tests
1 Gene testing
2 Sweat chloride >60mEq/L
Pathophysiology
Recurrent pulmonary infection, predominantly with
Haemophilus influenzae, Pseudomonas aeruginosa and Staphylococcus aureus
Inspissated secretions
Bronchiectasis
Malabsorption
Progressive respiratory failure and cor pulmonale
Median survival is now approximately 40 years, and is
increasing due to improvements in treatment.
Bronchiolitis
Treatment
Treat the cause if possible, e.g. immunoglobulin replacement in common variable immunodeficiency.
Treat infections with antibiotics, based on airway microbiology. Intravenous antibiotics are often required. Nebulized antibiotics, e.g. tobramycin, may be an option.
Increase sputum clearance:
physicalpostural drainage, physiotherapy
mucolytic agentshypertonic saline, acetylcysteine,
mannitol, DNAase (cystic fibrosis).
Denition
An inflammatory disorder of the small airways (<2 mm
diameter), usually characterized by obstruction with air
trapping, and usually without significant disease of the lung
parenchyma. There is a wide range of causes, including the
following.
1 Infection:
a ViralRSV (respiratory syncytial virus) and
other viruses
127
Bacterialtuberculosis (TB) and atypical TB,

e.g. Mycobacterium avium complex
2 Non-infectious, often causing bronchiolitis obliterans
(see below):
a Inhalational injury
b Connective tissue disease
c Organ transplantation, especially lung
d Drugs, e.g. gold, penicillamine
e Idiopathic
Obliterative bronchiolitis/bronchiolitis
obliterans
(Called bronchiolitis obliterans syndrome if it occurs in a
lung transplant.)
This results from concentric narrowing of small airways
due to intramural fibrotic tissue, causing scarring of bronchiolar walls and surrounding tissue, and airflow obstruction.
The pathology varies and has been divided into
categories:
Constrictive. This results in progressive airflow obstruction, usually following inhalational injury.
Proliferative. This is the more common form, with proliferation of fibroblasts. Extension into the alveoli can
occur to a varying degree. If it is extensive, it is called
bronchiolitis obliterans with organizing pneumonia
(BOOP; Figure 7-10) or cryptogenic organizing pneumonia (COP), and is considered an interstitial lung disease (see later section).
Treatment:
Viral bronchiolitis is treated with respiratory support, as
required.
Other infectious causes require appropriate antimycobacterial or other antibiotic treatment.
Panbronchiolitis
This is a recently identified and uncommon disorder, initially described in Japan, with diffuse bronchiolitis presenting as cough, breathlessness and sputum production.
There are typical high-resolution chest CT findings
of diffuse, small, centrilobular nodular opacities, and a
tree-in-bud pattern.
There is often progressive decline in lung function with
an obstructive defect.
It usually responds well to treatment with a macrolide, possibly due to an anti-inflammatory rather than an antibiotic
mechanism.

(COPD)
Also known as chronic obstructive airway disease (COAD)
and chronic airflow limitation (CAL).
Denition
The GOLD (Global Initiative for Chronic Obstructive
Lung Disease) definition is internationally accepted:
COPD is a common, preventable and treatable disease,
characterized by persistent airflow limitation that is usually
progressive, and associated with an enhanced chronic
inflammatory response in the airways and the lung to
noxious particles or gases. Exacerbations and comorbidities
contribute to the overall severity in individual patients.
Figure 7-10 Chest computed tomography of a patient

with bronchiolitis obliterans with organizing pneumonia
(BOOP). Arrows indicate areas of brosis. Note also
consolidation with air bronchograms
From Muller NL and Silva CIS (eds). Imaging of the chest. Saunders,
2008.
128
The usual criterion for chronic airflow limitation is a

post-bronchodilator FEV1/FVC of <0.7; however, there is a
change in reporting criteria to use the lower limit of normal
(LLN) for the ratio since 0.7 tends to over-diagnose disease
in the elderly and under-diagnose it in the young.
The chronic airflow limitation seen in COPD is due
to a combination of small airways disease, equivalent to an
obstructive bronchiolitis, and to loss of parenchymal support
for airways due to destruction of parenchymal tissue causing
emphysema. Although the most common cause of COPD is
cigarette smoking, there are other causes, including an overlap with chronic asthma.
COPD is an heterogeneous disorder with a phenotype
that can vary with the extent, severity and underlying pathogenesis of disease in four compartments of the lung:
Large airwayschronic bronchitis is defined clinically
as persistent cough and sputum for at least 3 months in
each of 2 consecutive years.
Small airwaysdamage and obstruction at the level
of the bronchioles causes progressive insidious airflow
limitation.
Lung parenchymaemphysema is defined pathologically as an abnormal enlargement in the size of the air
spaces distal to the terminal bronchioles.
Pulmonary blood vesselsincreased pulmonary vascular resistance causing pulmonary hypertension, and
eventually cor pulmonale from arteriolar vasoconstriction by alveolar hypoxia, and destruction of pulmonary
vasculature.
Causes of emphysema
1 Cigarette smoking
2 Alpha-1-antitrypsin deficiency (emphysema/autosomal
recessive)
3 Occupational exposure, e.g. coal, hematite (centrilobular emphysema), bauxite (bullous emphysema),
cadmium (generalized emphysema)
Pathophysiology
Emphysema: Destruction of alveolar walls by enzymes
released from inflammatory cells results in loss of airway
tethering, with airway obstruction, and loss of alveolar
capillary units, which is reflected by a decrease in the
diffusing capacity for carbon monoxide.
Chronic bronchitis: Airway obstruction results from
mucous gland enlargement and smooth muscle hypertrophy, with consequent bronchial wall thickening and
luminal narrowing. Recurrent bacterial infection may
also be an important factor.
1 Adult onset asthmamay be non-smoker, atopic, family history of atopic disease, and attacks may be episodic.
Lung function may be near-normal between exacerbations. However, there may be overlap since long-term
asthma can lead to irreversible airflow limitation.
2 Bronchiectasisdaily large-volume sputum production, clubbing, onset often in childhood, and hemoptysis common.
Treatment
1 Smoking cessation
2 Immunizations (influenza, pneumococcus)
3 Pulmonary rehabilitation program that includes education about the disease, a management plan for an exacerbation, and an exercise program, initially supervised
4 Airway medication with long-acting muscarinic antagonists, long-acting beta-agonists, and inhaled steroids.
Short-acting beta-agonists for symptomatic relief
5 Long-term oxygen therapy (if meeting criteria for
either daytime or nocturnal hypoxemia)
6 Lung transplant may be appropriate in some cases
Complications
Recurrent acute exacerbations, usually caused by viral
infections
Respiratory failure: acute, chronic, acute-on-chronic
Cor pulmonale
Spontaneous pneumothorax
Pneumonia

ILD refers to a broad group of disorders (Box 7-6, overleaf)
where there is inflammation in the alveolar walls, often associated with fibrosis, that causes damage to the blood vessels
in the alveolar walls and to the alveolar epithelial cells.
The mechanism of damage is as broad as the number
of disorders, with some starting with diffuse injury to the
gas exchange units, while in others the pathological process
appears to start in the parenchyma.
Clinical clues to the etiology of diffuse pulmonary disease are:
Raynauds phenomenonscleroderma, pulmonary
hypertension
Symptom onset 46 hours after exposurehypersensitivity pneumonitis
Less dyspnea than expected from chest X-ray
appearancesarcoidosis, silicosis, Langerhans cell
granulomatosis
Erythema nodosumsarcoidosis, histoplasmosis
Dysphagiascleroderma, dermatomyositis, metastatic
cancer
Hemoptysisheart failure, bronchiectasis, Goodpastures syndrome, idiopathic pulmonary hemosiderosis
Clubbingidiopathic pulmonary fibrosis, bronchiectasis, cancer (lymphangitis carcinomatosa)
HematuriaANCA-associated vasculitis, Goodpastures syndrome, systemic lupus erythematosus (SLE),
polyarteritis nodosa (PAN), scleroderma.
CLINICAL PEARL
Causes of pulmonary brosis:
Upper lobe (mnemonic SCATO)
S Silicosis, sarcoidosis
C Coal miners pneumoconiosis
A Ankylosing spondylitis, allergic bronchopulmonary
aspergillosis, allergic alveolitis
T Tuberculosis
O Other: drugs, radiation, berylliosis, eosinophilic granuloma, necrobiotic nodular form of rheumatoid
arthritis
Lower lobe (mnemonic RASHO)
R Rheumatoid arthritis
A Asbestosis
S Scleroderma
H HammanRich syndrome, idiopathic pulmonary
brosis
O Other: drugs, radiation
Chest X-ray patterns of value in differential diagnosis in

interstitial lung disease include:
Adenopathy (hilar, mediastinal)sarcoid, lymphoma,
lymphangitis carcinomatosa, lymphangial carcinoma,
berylliosis
129
Box 7-6
Interstitial lung disease

Connective tissue diseases
Scleroderma/CREST
Polymyositis/dermatomyositis
Systemic lupus erythematosus
(SLE)
Sjgrens syndrome
Mixed connective tissue disease
Rheumatoid arthritis
Ankylosing spondylitis
Coal-workers pneumoconiosis
Berylliosis
Talc pneumoconiosis
Siderosis (arc welding)
Stannosis (tin)
Organic:
Hypersensitivity pneumonitis or
extrinsic allergic alveolitis, e.g.
bird-breeders lung, farmers lung
Drugs
Antibiotics, e.g. nitrofurantoin
Antiarrhythmics, e.g. amiodarone,
procainamide
Anti-inammatories, e.g.
penicillamine, gold
Anticonvulsants, e.g. phenytoin
Chemotherapeutic agents, e.g.
cyclophosphamide, methotrexate,
busulphan, bleomycin
Radiation
Recreational: crack cocaine
Biologicals: rituximab, iniximab
Idiopathic brotic
Idiopathic pulmonary brosis
(usual interstitial pneumonia or
cryptogenic brosing alveolitis)
Acute interstitial pneumonitis
(HammanRich syndrome)
Familial pulmonary brosis
Respiratory bronchiolitis/
desquamative interstitial
pneumonitis
Cryptogenic organizing pneumonia
(COP)/bronchiolitis obliterans with
organizing pneumonia (BOOP)
Non-specic interstitial
pneumonitis
Lymphocytic interstitial pneumonia
(Sjgrens syndrome, connective
tissue disease, acquired immune
deciency syndrome (AIDS),
Hashimotos thyroiditis)
Occupational and environmental

Inorganic:
Silicosis
Asbestosis
Hard-metal pneumoconiosis
Pleural disease-associatedconnective tissue disease

(not dermatomyositis), asbestosis, lymphoma, carcinoma, radiation
Spontaneous pneumothoraxeosinophilic granuloma,
Langerhans cell granulomatosis, lymphangioleiomyomatosis (LAM)
Lytic ribeosinophilic granuloma, carcinoma

Occupational exposure to both organic and inorganic compounds can result in a variety of pulmonary conditions,
including interstitial, obstructive, malignant and pleural
disease.
Inorganic agentspneumoconiosis
Asbestosis
Asbestosis is mainly found in asbestos miners, but also in
workers in the building industry, especially demolition
or ships lagging workers.
Asbestosis is a form of diffuse interstitial fibrosis.
130
Autoimmune pulmonary brosis

(inammatory bowel disease,
primary biliary cirrhosis, idiopathic
thrombocytopenic purpura,
autoimmune hemolytic anemia)
Unclassied
Sarcoidosis
Tuberous sclerosis
Acute respiratory distress syndrome
(ARDS)
Alveolar proteinosis
Primary pulmonary Langerhans
cell histiocytosis (eosinophilic
granuloma)
Amyloidosis
Pulmonary vasculitis
Diffuse alveolar hemorrhage
syndromes
Eosinophilic pneumonia
Piloid pneumonia
Lymphangitic carcinomatosis
Bronchioalveolar cell carcinoma
Lymphangioleiomyomatosis
Gauchers disease
NiemannPick disease
Pulmonary lymphoma
HermanskyPudlak syndrome
Asbestos exposure can also result in pleural plaque formation (Figure 7-11), and is an important risk factor for
carcinoma of the lung, and mesothelioma.
Silicosis
Silicosis is mainly found in the mining and quarrying
industries.
Nodular pulmonary fibrosis may progress to progressive
massive fibrosis (PMF; Figure 7-12).
Calcification of hilar nodes (eggshell pattern) occurs
in 20% of cases. There is also an increased risk of
tuberculosis.
Coal-workers pneumoconiosis (CWP)
CWP is seen in around 10% of all underground
coal-miners.
It is a form of pulmonary fibrosis.
A small percentage also develop PMF.
Berylliosis
Berylliosis results from exposure in the electronics,
computer and ceramics industries.
Figure 7-12 Chest X-ray of patient with progressive

massive brosis
From Mller NL et al. Radiologic diagnosis of diseases of the chest.
Philadelphia: Saunders, 2001.
Asthma
Occupational asthma can occur in:
aluminium smelter workers
grain and flour workers
electronic industry workers (colophory in solder flux)
animal workers (urinary proteins)
paint sprayers and polyurethane workers (isocyanates)
epoxy resin and platinum salt workers.
Organic agentshypersensitivity pneumonitis

(extrinsic allergic alveolitis)
Figure 7-11 Chest X-ray and computed tomography

of patient with pleural plaques (arrows)
From Mller NL and Silva CIS (eds). Imaging of the chest. Saunders,
2008.
Beryllium can rarely cause an acute pneumonitis; more

frequently a chronic granulomatous interstitial pneumonitis occurs.
It is a risk factor for carcinoma of the lung, and a differential diagnosis of sarcoidosis.
This is a type III hypersensitivity reaction to inhaled organic

dusts or animal proteins which can manifest in acute and
chronic forms.
Acute4 to 6 hours after exposure a sensitized person
develops dyspnea, cough, and fever without wheeze.
Chest X-ray reveals nodular or reticulonodular infiltrates with apical sparing.
Chronicrepeated attacks result in lung fibrosis.
Examples are:
farmers lungthermophilic bacteria from moldy hay
bird-breeders lunganimal protein from bird
droppings
hot-tub lungallergic response to inhaled Mycobacterium avium complex
mushroom-growers lung.
Diagnosis depends on a consistent clinical picture in association with serum precipitins to an appropriate antigen.
Pulmonary edema
Can result from irritant gas exposure, e.g. to chlorine.
131
Granulomatous ILD
Sarcoidosis
This is a systemic, non-caseating granulomatous disease of
unknown etiology, typically with a predominant pulmonary
component.
Clinical features
1 Bilateral hilar lymphadenopathy (BHL; Figure 7-13) in
80% of casesalmost always asymptomatic
2 Lung disease stages:
0 No lung involvement
1 BHL only (DLCO may be decreased)
2 BHL and pulmonary infiltrate
3 Fibrosing infiltrate (usually midzone) without
lymphadenopathy
4 End-stage pulmonary fibrosis
3 Skinerythema nodosum (with BHL), lupus pernio,
pink nodules in scars
4 Lymphadenopathy (generalized in 7%)
5 Eyesacute uveitis, uveoparotid fever (uveitis, parotid
swelling, 7th cranial nerve palsy)
6 Nervous systemcranial nerve palsy, neuropathy,
myopathy
7 Liver granulomas
8 Skeletalbone cysts, arthritis
9 Heartheart block, cardiomyopathy
10 Hypercalcemia
11 Splenomegaly
Diagnosis
Requires histological confirmation, usually via lung
biopsy.
Figure 7-13 Chest X-ray of bilateral hilar

lymphadenopathy due to sarcoidosis
From Mason RJ et al (eds). Murray and Nadels Textbook of
respiratory medicine, 5th ed. Philadelphia: Saunders, 2010.
132
Transbronchial biopsy will give a result in the majority

of cases, but at times thorascopic or open lung biopsy, or
biopsy of other involved tissue, is needed.
Pulmonary function tests generally demonstrate a
restrictive pattern and reduced DLCO.
Serum ACE levels are neither sensitive enough nor
specific enough to be consistently useful diagnostically.
However, an elevated level in an otherwise consistent
clinical picture in a patient in whom biopsy is not possible is helpful.
Treatment
Oral corticosteroids are the mainstay of treatment, and
most disease is steroid-sensitive.
BHL alone can be treated with a wait-and-watch
approach, and does not require treatment per se.
Some patients will have a progressive, relentless disease
which requires ongoing therapy.
Others will go into remission, which may or may not be
permanent.
Many patients on long-term corticosteroids will require
addition of a second immunosuppressive agent such as
azathioprine or mycophenolate.
Aggressiveness of immunosuppressive therapy depends
on the severity and location of disease, e.g. sightthreatening ocular disease.

This is a disease of unknown etiology, with inflammation and
fibrosis of alveolar walls. Without treatment there is often an
inexorable deterioration to chronic respiratory failure.
Diagnosis
There is a typical chest X-ray (CXR) and high-resolution
computed tomography (HRCT) appearance of diffuse
interstitial opacities (and honeycombing in more advanced
stages of disease), with pulmonary function tests showing
reduced DLCO, arterial hypoxemia, and a restrictive ventilatory impairment suggesting the diagnosis; but a lung
biopsy is necessary in most cases for definitive diagnosis,
unless the HRCT shows typical changes of usual interstitial pneumonitis with predominantly lower-zone changes.
Treatment
Unfortunately IPF is a progressive disease with no
consistent response to treatment, including immunosuppression.
Most patients eventually develop type I respiratory failure, and require respiratory support in the form of longterm supplemental oxygen therapy. Cor pulmonale
complicates the late stages of the disease.
Immunization to Pneumococcus and influenza should be
kept up to date.
Prompt treatment of superimposed respiratory infection
is required.
There is a small increase in the incidence of lung
carcinoma.
Transplantation may be appropriate in some cases.
Cryptogenic organizing pneumonia (COP)

Also known as bronchiolitis obliterans with organizing
pneumonia (BOOP).
COP results from inflammation of the alveolar spaces,
which often extends into the bronchioli causing plugging of airways by granulation tissue (see Figure 7-10).
COP is the preferred term, as the alveolar changes are
predominant while the bronchiolitis is a minor part of
the condition.
This commonly results in a restrictive pattern of abnormal lung function tests.
Causes
1 Cigarette smoking
2 Post-infectious, e.g. adenovirus, influenza, Mycoplasma
3 Connective tissue disease
4 Toxin inhalation (nitrogen oxides, chlorine, ammonia)
5 Chronic rejection after lung transplantation
6 Chronic graft-versus-host disease
7 Idiopathic (is the commonest cause of COP)
Treatment
COP/BOOP is treated with immunosuppressive drugs.
High-dose corticosteroids are used as first-line.
Steroid-sparing second-line agents are often required, as
treatment may need to be long-term.
EOSINOPHILIC PULMONARY
DISORDERS
This is a rare disease of unknown etiology. It is a differential
diagnosis of non-resolving pneumonia.
Clinical features
Fever
Acute hypoxemic respiratory failure
Diffuse pulmonary (alveolar) infiltrates on CXR
Approximately 25% eosinophils in bronchoalveolar
lavage (BAL) fluid
Peripheral blood eosinophilia (usually)

This is another rare disease with unknown etiology.
Clinical features
Constitutional symptomsfevers, night sweats, malaise, weight loss
Asthma, often pre-dating the disease, in the majority
ofcases
Dyspnea
Bilateral peripheral pulmonary infiltrates, which may be
fleeting
Raised acute phase reactants

Peripheral blood eosinophilia (usually)
Approximately 25% eosinophils in BAL fluid
Definitive diagnosis requires lung biopsy.
Treatment
Oral corticosteroids are used for remission induction.
Long-term use may be required.
Unacceptable side-effects, or inability to wean the dose,
will require addition of a second agent such as azathioprine, methotrexate or mycophenolate.
CLINICAL PEARL
Pulmonary inltrate with eosinophilia
Causes (mnemonic PLATE):
P Prolonged pulmonary eosinophilia, which may be
due to:
1 Drugs, e.g. sulfonamides, sulfasalazine, salicylates, nitrofurantoin, penicillin, isoniazid, paraaminosalicylic acid (PAS), methotrexate, procarbazine, carbamazepine, imipramine
2 Parasites e.g. ascaris
L Loefflers syndromebenign acute eosinophilic inltration with few clinical manifestations
A Allergic bronchopulmonary aspergillosis
T Tropical, e.g. microlaria
E Eosinophilic pneumonia
Other: vasculitis, e.g. polyarteritis nodosa, eosinophilic
granulomatosis with polyangiitis
PULMONARY HEMORRHAGE
Pulmonary hemorrhage can be localized, often due to neoplastic or traumatic conditions, or secondary to diffuse alveolar hemorrhage (DAH).
The most common causes of DAH (Box 7-7) are
immune-mediated, although the differential diagnosis
for DAH is broad. Of the immune-mediated causes, the
ANCA-associated vasculitides are the most common.
Box 7-7
Causes of diffuse alveolar

hemorrhage
Immune-mediated causes
Vasculitides (numerous, including ANCA-associated
vasculitis, Goodpastures syndrome)
Non-immune-mediated causes
Toxic injury, e.g. chemical inhalation
Coagulopathy, including anticoagulant drugs
Increased pulmonary venous hydrostatic pressure,
e.g. mitral stenosis
Idiopathic pulmonary hemosiderosis
133
Diagnostic clues on imaging which suggest DAH

include ground-glass opacities, rapidly changing appearance, perihilar distribution, and consolidation.
PULMONARY INFECTIONS
Bacterial
Organisms commonly implicated in community-acquired
pneumonia:
Streptococcus pneumoniae
Mycoplasma species
Legionella species
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus.
CLINICAL PEARL
Risk factors for nosocomial pneumonia:
increasing age
underlying chronic lung disease
altered neurological state
intubation
immobilization.
Viral
Viruses which may cause pneumonia in adults:
influenza A or B
adenovirus
respiratory syncytial virus
parainfluenza
cytomegalovirus (CMV).
Fungal
Fungi which may cause lung infection:
Histoplasma capsulatum
Aspergillus fumigatus
Cryptococcus neoformans
Blastomyces dermatiditis
Coccidioides immitis
Nocardia species (bacteria)
Actinomyces.
Associations with CXR findings are given in Table 7-3,
those with extrapulmonary disease in Table 7-4, and morphological clues to diagnosis in Table 7-5.
Mycobacterial
Organisms commonly implicated in nosocomial pneumonia:

Gram-negative bacilli
Staphylococcus aureus
anaerobic bacteria
Streptococcus pneumoniae.
Causes of recurrent pneumonia (2 or more episodes in
6months):
Bronchial obstruction, e.g. by a lung cancer, foreign
body, bronchial stenosis
Bronchiectasis
Recurrent pulmonary infarction
Recurrent aspiration of gastric contents
Hypogammaglobulinemia (congenital or acquired)
Pulmonary eosinophilia
HIV (human immunodeficiency virus) infection, or
other immunodeficiency
Tuberculosis (TB)
(Infection with Mycobacterium tuberculosis [MTB].)
1 Primary infectionpatient never previously exposed.
Primary complex consists of Ghon focus in mid or
lower lung zone, and hilar lymphadenopathy.
2 Secondary infectionusually reactivation of dormant
infection. Lesions develop in the upper lobe or the apex
of the lower lobe with minimal lymphadenopathy.
3 Extrapulmonary involvement occurs in up to 20% of
patients.
Table 7-3 Chest X-ray (CXR) ndings in fungal lung
infection
CXR FINDINGS
Lung calcication
Histoplasmosis (spleen often also

calcied)
Hilar
lymphadenopathy
Histoplasmosis, blastomycosis,
coccidioidomycosis
Cavitary disease
Nocardiosis, blastomycosis (thickwalled)
CLINICAL PEARL
Causes of a slowly resolving or non-resolving pneumonia:
1 Bronchial obstruction
2 Complications of pneumoniaabscess, empyema
3 Inappropriate therapy
4 Non-adherence to therapy
5 Non-absorption of antibiotic, e.g. vomiting of tablets
6 Decreased host resistance (immunodeciency)
7 Pneumonia mimic, e.g. cryptogenic organizing
pneumonia (COP), bronchioalveolar cell cancer
134
ASSOCIATED FUNGAL
INFECTION
Coccidioidomycosis (thin-walled)
Round opacity, with
halo of translucency
Aspergilloma
Pleural effusion
Actinomycosis, nocardiosis,
coccidioidomycosis
Table 7-4 Fungal infections of the lung and

extrapulmonary disease
ANATOMICAL
SITES
Lung and skin
POSSIBLE FUNGAL
INFECTION
Blastomycosis (erythema nodosum)
Coccidioidomycosis (erythema
nodosum, morbilliform rash)
Nocardiosis (subcutaneous abscess)
Cryptococcosis (tiny papules,
progress to ulcers)
Lung, nose, palate
Mucormycosis, aspergillosis
Lung, bone
Actinomycosis, blastomycosis,
coccidioidomycosis
Lung, gut
Candida, histoplasmosis,
Aspergillus, actinomycosis
Lung, urinary tract
Blastomycosis (males)
Table 7-5 Morphological clues to diagnosis of fungal

infection
MORPHOLOGY
FUNGUS
45-angled branching
Aspergillus
90-angled branching and nonseptate hyphae
Nocardia
Thick cell wall
Cryptococcus
Broad neck budding
Blastomyces
Acid-fast
Nocardia
Diagnosis
1 Mantoux (purified protein derivative, PPD)an induration >10mm signifies previous or current infection,
or BCG (Bacillus Calmette-Gurin) immunization.
a False-negatives may occur in miliary TB, immunosuppressed patients (e.g. HIV infection, malnutrition, concurrent use of corticosteroids), elderly
individuals, sarcoidosis, coexisting infection (e.g.
lepromatous leprosy), or due to technical error.
b False-positives from non-tuberculosis mycobacteria (NTMB) may occur.
2 Interferon-gamma assayspecific for MTB, except for
false-positives from the NTMB M. kansasii, M. marinum, M. szulgai.
3 CXR/CT (see Figure 7-14).
4 Microbiologyacid-fast staining and culture on sputum, bronchoalveolar lavage fluid, or gastric washings.
Management
1 Chemoprophylaxis with daily isoniazid for 9 months (or
isoniazid and rifampicin for 3 months) is indicated if:
a there is conversion to a positive Mantoux test
(10mm or more >35 years of age, 15mm or more
<35 years of age) within the past 2 years
b patient is HIV-positive with Mantoux reaction
5mm or more
c there has been recent contact with infectious
patient, Mantoux 10mm or more
d patient has chronic illness or is immunosuppressed, Mantoux 10mm or more
e patient is in a high-incidence group, Mantoux
10mm or more, >35 years of age (from endemic
area, nursing home or institution).
2 Standard therapy:
a isoniazid, rifampicin, pyrazinamide and ethambutol (see Table 7-6, overleaf) for 2 months
B
Figure 7-14 Chest X-rays showing (A) Ghon complex and (B) upper lobe tubercular lesions
From: (A) Talley NJ and OConnor S. Clinical examination: a systematic guide to physical diagnosis, 6th ed. Sydney: Elsevier Australia, 2010. (B)
Grant LE and Griffin N. Grainger & Allisons Diagnostic radiology: essentials. Elsevier, 2013.
135
Table 7-6 Drugs for tuberculosis
DRUG
SIDE-EFFECTS
Isoniazid (INH)
Hepatitis (approx. 1%; fast acetylators; increased

>35 years of age)
Peripheral neuropathy (especially slow acetylators)
Flu-like illness, fever
Skin rash, purpura, arthritis, lupus phenomenon
Supplemental vitamin B6 (pyridoxine) reduces the

risk of peripheral neuropathy
Rifampicin
Hepatitis
Fever
Thrombocytopenia, hemolytic anemia (rare)
Light-chain proteinuria
Orange discoloration of urine
Increases metabolism of oral contraceptive

pill, corticosteroids, warfarin, digoxin, and oral
hypoglycemic agents
Ethambutol
Retrobulbar optic neuritis (reversible)

Skin rash
Screen for side-effects with redgreen color

discrimination and visual acuity testing
Pyrazinamide
Arthralgia, gout, hepatitis
(2HRZE) followed by isoniazid and rifampicin

for 4 months (4HR)
b best outcomes are achieved with directly observed
therapy, short course (DOTS).
3 Therapy for patients with drug-resistant TB (multidrug-resistant [MDR] or extensively drug-resistant
[XDR]):
a suspect resistance in HIV-positive patients,
injecting drug users, institutionalized individuals,
and migrants from areas with a high prevalence of
drug-resistant TB
b a regimen with at least four effective drugs,
including an injectable drug, for an initial period
that may be up to 8 months; total duration of
treatment up to 24 months.
Non-tuberculous mycobacterial (NTMB)

infection
Organisms
Mycobacterium avium complex (MAC)M. avium,
M. intracellulare
M. kansasii
Many others
Clinical manifestations in non-immunosuppressed
patients
Upper lobe fibrocavitatory diseasethis mimics TB. It
is more common in patients with COPD
Nodular bronchiectasisbronchiectasis and small nodules typically in the middle lobe, and irregular
Solitary pulmonary nodule
Hypersensitivity pneumonitis, e.g. hot-tub lung
Diagnosis
1 Culturesputum, bronchoalveolar lavage
2 DNA probe for some species
136
COMMENTS
Treatment
Prolonged combination antimycobacterial antibiotics, usually including a macrolide (azithromycin or clarithromycin),
rifampicin, and ethambutol.
Other aspects
Other aspects to consider in pulmonary infections are given
in Tables 7-7 to 7-9.
PLEURAL DISEASE
The analysis of pleural fluid is a mainstay in the diagnosis of
pleural disease (Table 7-10, overleaf).
Pleural effusion
Exudate
CLINICAL PEARL
Biochemical features of a pleural exudate:
protein >3g/100mL (30g/L)
pleural/serum protein >0.5
lactate dehydrogenase (LDH) >200IU/L
pleural/serum LDH >0.6IU/L.
Causes
Pneumonia
Neoplasmlung carcinoma, metastatic carcinoma,
mesothelioma
Tuberculosis
Pulmonary infarction
Subphrenic abscess
Pancreatitis
Connective tissue disease (SLE, rheumatoid arthritis)
Table 7-7 Environmental factors in pulmonary infection
ENVIRONMENTAL EXPOSURE HISTORY
INFECTIONS TO CONSIDER
Water-cooling units
Legionella
Military camps
Mycoplasma
Birds
Psittacosis, histoplasmosis, Aspergillus
Dogs, cats, rats, pigs, cattle
Leptospirosis
Goats, pigs, cattle
Q fever
Abattoirs, vets
Brucellosis, Q fever
Soil
Blastomycosis
Decaying wood, caves, chickens
Histoplasmosis
Potting mix
Legionella lombaechiae
Table 7-8 Pneumonia: underlying diseases and common associated pathogens
DISEASE
COMMON PATHOGENS TO CONSIDER
Obstructing lung cancer
Pneumococcus, oral anaerobes
Chronic obstructive pulmonary disease (COPD)
Pneumococcus, Haemophilus inuenzae
Cystic brosis
Pseudomonas aeruginosa, Staphylococcus aureus
Inuenza virus
Pneumococcus, S. aureus, H. inuenzae A and B
Alcoholism
Klebsiella, oral anaerobes
Alveolar proteinosis
Nocardia
Hypogammaglobulinemia
Encapsulated bacteria (Pneumococcus, H. inuenzae)
Neutropenia
Gram-negative bacilli, Aspergillus fumigatus
Table 7-9 Atypical pneumonias
TYPE
MANIFESTATIONS
DIAGNOSIS
THERAPY
Mycoplasma
Dry cough, headache, fever, bullous

myringitis, patchy pneumonitis with few
chest signs in young adults, hemolysis,
Guillain-Barr, hepatitis, rash, Raynauds
CXR
Cold agglutinins
Specic complement xation test
Culture
Erythromycin
Tetracycline
Roxithromycin
Legionnaires
disease
Dry cough, pleuritic chest pain,

bilateral coarse crackles with
patchy pneumonitis, hyponatremia,
hypophosphatemia, abnormal LFTs,
fever
CXR
Serology (single titer >1:256
suggestive, 4-fold rise at
26 weeks)
Fluorescent antibody sputum test
Erythromycin
Rifampicin (if
immunocompromised)
Tetracycline
Roxithromycin
Q fever
Dry cough, pleuritic chest

pain, headache, fever, myalgia,
granulomatous hepatitis
Livestock workers
Lower lobe consolidation on CXR

Complement xation test in those
with hepatitis/endocarditis
Tetracycline
Psittacosis
Dry cough, pleuritic chest pain,

headache, fever, patchy pneumonitis
Bird-handlers
CXR
Complement xation test
Tetracycline
CXR, chest X-ray; LFT, liver function test.
137
Table 7-10 Pleural uid changes in different disease states
PLEURAL FLUID ANALYSIS
ASSOCIATED DISEASE
pH <7.2
Empyema (except Proteus where pH>7.8), tuberculosis, neoplasm, rheumatoid

arthritis, esophageal rupture
Glucose <3.3mmol/L (<60mg/dL)
Infection, neoplasm, rheumatoid arthritis, mesothelioma
Amylase 200units/100mL
Pancreatitis, ruptured abdominal viscera, esophageal rupture (salivary amylase)
Complement decreased
Systemic lupus erythematosus, rheumatoid arthritis
Chyloustriglycerides >1.26mmol/L
(110mg/dL)
Tumor, thoracic duct trauma, tuberculosis, tuberous sclerosis, primary lymphoid

dysplasia
Cholesterol effusion
Rheumatoid arthritis, nephrotic syndrome, old tuberculosis
Drugs
nitrofurantoin (acute), amiodarone
methysergide (chronic)
chemotherapy
Radiation
Trauma
Traumatic causes include:

rib fracture
penetrating injury
pleural aspiration
high positive end-expiratory pressure (PEEP) or
mechanical ventilation
esophageal rupture.
Transudate
CLINICAL PEARL
Biochemical features of a pleural transudate:
protein <3g/100mL (30g/L)
pleural/serum protein <0.5
lactate dehydrogenase (LDH) <200IU/L
pleural/serum LDH <0.6 IU/L.
Causes
Cardiac failure, iatrogenic fluid overload
Nephrotic syndrome
Liver failure
Meigs syndrome (ovarian fibroma and effusion)
Hypothyroidism
1 Respiratory compromise, e.g. hypoxemia, significant

breathlessness
2 Tension pneumothorax
3 Large pneumothorax, > 2 cm between lung and parietal
pleura
Small bore usually, unless tension pneumothorax.
PULMONARY VASCULAR
DISEASE
Denition
PNEUMOTHORAX
Spontaneous causes include the following.
Primarysubpleural bullae (apical) that rupture, usually in young adults.
Secondary:
Emphysema/COPD
Rare causes:
asthma
eosinophilic granuloma
lymphangioleiomyomatosis
lung abscess
carcinoma
end-stage fibrosis
Langerhans cell granulomatosis
Marfans syndrome
Pneumocystis jirovecii pneumonia.
138
Pulmonary hypertension exists when mean pulmonary

artery pressure is 25mmHg at rest, as assessed by a right
heart catheter study. An estimate by echocardiography of a
pulmonary artery systolic pressure of >50 mmHg is suggestive but not
diagnostic of PH.
Irrespective of cause, all types of PH (Box 7-8) are associated with right ventricular hypertrophy, medial hypertrophy of muscular and elastic arteries, and dilatation with
intimal damage to elastic pulmonary arteries.
Diagnosis
The management of PH depends on an accurate diagnosis of the cause of the pulmonary hypertension, in particular the assessment of left heart function, lung disease,
thrombo-embolic disease, and the presence of hypoxemia
from obstructive sleep apnea and any other sleep-disordered
breathing.
Box 7-8
Causes of pulmonary hypertension

Primary causes
Idiopathic
Hereditary (rare)
Secondary causes
Lung diseases:
Obstructive lung disease, e.g. chronic obstructive
pulmonary disease
Interstitial/parenchymal lung disease, e.g. idiopathic
pulmonary brosis
In association with systemic connective tissue disease,
e.g. CREST syndrome
Drug- or toxin-induced, e.g. by cocaine
Ventilatory disorders:
Apneic syndromes, e.g. obstructive sleep apnea
Musculoskeletal disorders, e.g. chest wall deformity
Heart disease:
Left-sided heart disease, e.g. mitral stenosis
The initial treatment includes general measures and

supportive therapy such as oral anticoagulants, diuretics,
oxygen and digoxin.
Specific targeted therapy is based on three pathways by
which pulmonary vascular resistance can be reduced:
endothelin pathway, where endothelin receptor
antagonists (ERAs) such as bosentan, ambrisentan
and macitentan block the vasoconstrictor and proliferative action of endothelin
nitric oxide pathway, where stimulants of the
pathway such as sildenafil and tadalafil inhibit phosphodiesterase-5 (PDE5 I), leading to an increase in
cyclic guanosine monophosphate (GMP), enhancing its vasodilator effect
prostacyclin pathway, where eproprostenol, iloprost or treprostinil promote vasodilatation systemically or by inhalation.
The sequence in which these agents are used is complex and
depends on the severity of disease according to the WHO
functional classification (Box 7-9), local licensing/funding
arrangements, and tolerance.
When there is inadequate response to combination
therapy, the alternatives include atrial septostomy and lung
transplantation.
Pulmonary vascular disorders:

Recurrent pulmonary thromboembolism
Pulmonary veno-occlusive disease
Hyperviscosity, e.g. myeloproliferative disorders
Other causes, mechanism unknown, e.g.:
Dialysis-dependent renal failure
Portal hypertension
The assessment must include an estimate of whether the

degree of PH is explained by the presence of known causes
or whether there is an element of what is known as Group 1
pulmonary hypertension or pulmonary artery hypertension
(PAH).
In the absence of any known cause for PAH, the term
used is idiopathic PAH (IPAH).
Where other causes are found, the terms include that
cause; for instance connective tissue disease (PAHCTD) or congenital heart disease (PAH-CHD).
A right heart catheter with measurement of pulmonary
vascular resistance and pulmonary capillary wedge pressure is an essential part of the work-up for PAH and is
often required to assess progress.
The prognosis for PAH, a rare disease with a prevalence
of 1550/million, depends initially on the severity at
presentation, with 1-year survival varying from 65% to
95% and overall 5-year survival from 55% to 85%.
Box 7-9
World Health Organization (WHO)

functional classication (FC) of
pulmonary hypertension (PH)
WHO-FC IPatients with PH without limitation of
physical activity: ordinary physical activity does not
cause undue dyspnea or fatigue, chest pain or near
syncope
WHO-FC IIPatients with PH resulting in slight
limitation of physical activity; comfortable at rest but
ordinary activity causes undue dyspnea or fatigue,
chest pain or near syncope
WHO-FC IIIPatients with PH resulting in marked
limitation of physical activity; comfortable at rest but
less than ordinary activity causes undue dyspnea or
fatigue, chest pain or near syncope
WHO-FC IVPatients with PH with inability to carry
out any physical activity without symptoms; evidence
of right heart failure; may have dyspnea and/or fatigue
at rest; discomfort is increased by any physical activity
Treatment
CLINICAL PEARL
The treatment algorithm for Group 1 PH (PAH) is initially

based on whether, at right heart catheter, there is an immediate response to a vasodilator; if this occurs, the first-line
treatment is a calcium-channel blocker.
Pulmonary embolism is the most common cause of

death found at postmortem that was not considered
pre-mortem, and is found in 3040% of autopsies.
139
Symptoms of PE
Dyspnea
Pleuritic chest pain
Hemoptysis (uncommon)
Signs of PE
Often minimal
Tachycardia is the most common finding
Pleural rub
Signs of pulmonary hypertension or deep vein thrombosis (DVT)
idiopathic pulmonary fibrosis (about 20%), and cystic

fibrosis (1520%).
In the past, PAH was a relatively common indication but
this has reduced with the use of targeted therapy.
The overall survival rates are: 1-year approximately
80%; 5-year approximately 50%; 10-year approximately 30%.
Table 7-11 lists selection criteria.
Table 7-11 Selection criteria for lung transplantation
Diagnosis
Before embarking on diagnostic tests, it is important to
make an estimation of the probability of PE, using a thorough clinical evaluation with or without an objective scoring system such as the Wells Score, which includes signs/
symptoms of DVT, heart rate, immobilization due to surgery, previous PE or DVT, hemoptysis, malignancy, and
alternative diagnoses, to provide a high, intermediate or low
probability of PE.
Diagnostic testing includes the following.
Computed tomography pulmonary angiogram (CTPA)
CTPA is very sensitive at detecting centrally located
thromboembolus, but may not detect smaller, peripheral clots. An advantage of CTPA is that it images the
lungs and thorax and can contribute to an alternative
diagnosis.
Ventilationperfusion (V/Q) nuclear scanV/Q scanning is safer in patients with renal impairment who may
be at risk with administration of radiocontrast media.
It is less specific than CTPA when there is pre-existing
lung disease, especially COPD.
Massive PE may cause classic electrocardiographic
(EKG) changes: S1, Q3, T3.
CXR may reveal oligemia of the lung or lungs, or may
show evidence of atelectasis or opacity due to infarction.
D-dimer is sensitive but non-specific in this situation;
only a negative result is of value in estimating the probability of pulmonary thrombo-embolic disease.
Treatment
Prompt anticoagulation.
Consider thrombolysis if hemodynamic compromise
is evident. However, the use of thrombolytic therapy
is controversial, with no convincing evidence that it
improves long-term outcomes.
LUNG TRANSPLANTATION
Lung transplantation is a treatment option for a range of very
severe non-malignant diseases of the lungs.
The most common disorder for which lung transplantation is used is COPD (approximately 40%), followed by
140

BODE index* of 710 or at least one of the following:
History of hospitalization for exacerbation associated
with acute hypercapnia (PCO2 >50 mmHg)
Pulmonary hypertension or cor pulmonale, or both,
despite oxygen therapy
FEV1 <20% of predicted and either DLCO <20% of
predicted or homogenous distribution of emphysema
Histological or radiographic evidence of UIP and any of
the following:
A DLCO <39% of predicted.
A 10% decrement in FVC during 6 months of followup
A decrease in pulse oximetry to <88% during a 6MWT
Honeycombing on HRCT (brosis score >2)
Cystic brosis
FEV1 <30% of predicted, or rapidly declining lung
function if FEV1 >30% (females and patients <18 years
of age have a poorer prognosis; consider earlier listing)
and/or any of the following:
Increasing oxygen requirements
Hypercapnia
Idiopathic pulmonary arterial hypertension
Persistent NYHA class III or IV on maximal medical
therapy
Low (<350 m) or declining 6MWT
Failing therapy with intravenous epoprostenol or
equivalent
Cardiac index <2 L/min/m2
Right atrial pressure >15 mmHg
Sarcoidosis
NYHA functional class III or IV and any of the following:
Hypoxemia at rest
Elevated right atrial pressure >15 mmHg
* The BODE index is a measure that includes body mass index,
degree of dyspnea, and distance walked in 6 minutes (6-minute
walk test).
6MWT, 6-minute walk test; DLCO, diffusing capacity for carbon
monoxide; FEV1, forced expiratory volume in 1 second; PCO2,
partial pressure of carbon dioxide.
Modied from Orens JB, Estenne M, Arcasoy S et al: International
guidelines for the selection of lung transplant candidates: 2006
update. J Heart Lung Transplant 2006;25:74555.
Anticholinergics
Mortality from lung transplantation is highest in the first

year, with primary graft dysfunction (PGD) and infection
being the most common causes.
PGD is the early development of radiographic evidence
of pulmonary edema and hypoxia in the absence of an
obvious cause such as volume overload, acute rejection,
pneumonia or pulmonary venous obstruction.
The cause is unknown, with an ischemic
reperfusion injury being the most likely contributor.
There is no specific treatment; mortality is high and
longer-term outcome is poorer.
The most important determinant of longer-term survival after lung transplantation is the development of
chronic damage to the small airways of the lungs
bronchiolitis obliterans (BOS).
This involves fibroproliferative obliteration of
the small airways that causes progressive airflow
obstruction.
BOS develops in about half of lung transplant recipients by 5 years post-transplant.
One or more episodes of acute rejection has been
identified as a major risk factor for the development
of BOS. Other risk factors include gastroesophageal
reflux and primary graft dysfunction.
The prognosis is poor, with 2-year survival after
onset of about 60%.
Macrolide therapy appears to slow progression.
Aggressive surgical correction of gastroesophageal
reflux is favored in some centers.
Examples
Ipratropium bromide (short-acting)
Tiotropium (long-acting)
PHARMACOLOGY
Bronchodilators
Beta-adrenoceptor agonists
Examples
Salbutamol, terbutaline (short-acting)
Salmeterol, eformoterol, indacaterol (long-acting)
Actions
Relax bronchial smooth muscle
Inhibit mediator release from mast cells
May increase mucus clearance through effect on cilia
Indications
Asthma
Chronic airflow limitation if some reversibility is
present
Side-effects
Tremor
Hypokalemia
Tachycardia
Action
Relax bronchial smooth muscle by inhibiting vagal tone
Indications
Asthma
Chronic airflow limitation
Side-effects
Nil significant
Inhaled corticosteroids
Examples
Budesonide, fluticasone, beclomethasone, ciclesonide
Action
Reduce airway inflammation, predominantly through
inhibition of the generation of leukotrienes and prostaglandins, thereby limiting chemotaxis of inflammatory
cells, especially eosinophils
Indications
Regular inhaled corticosteroids should be used in any
patient with symptoms of chronic asthma, and in the
majority of COPD patients
Patients with episodic asthma will often benefit from
short courses of inhaled corticosteroids during an
exacerbation
Side-effects
Oropharyngeal candidiasis
Dysphonia
Adrenal suppression and systemic steroid side-effects are
unusual, even with high chronic doses
Sodium cromoglycate and nedocromil sodium

Actions
Reduce bronchial hyper-responsiveness and both
immediate and late phases of the asthmatic reaction by
stabilizing mast cells and inhibiting their degradation
These drugs have been largely superseded by inhaled
corticosteroids
Indications
Asthma
Exercise-induced asthma
Side-effects
Nil significant
141
RESPIRATORY SLEEP MEDICINE

The starting point for understanding the breadth of sleep
disorders is the International Classification of Sleep Disorders Second Edition (ICSD-2), revised in 2005 by the
American Academy of Sleep Medicine:
1 Insomniaa common symptom of problems initiating
or maintaining sleep
2 Sleep-related breathing disordersobstructive and
central apneas; hypoventilation and hypoxemia
3 Hypersomnias of central originexcessive daytime
sleepiness not due to sleep restriction, disturbed sleep
or circadian rhythm
4 Circadian rhythm sleep disordersshift work; jetlag;
delayed and advanced sleep phase
5 Parasomniassleep-walking, sleep terrors, sleep paralysis, REM (rapid eye movement) behavior disorder
6 Sleep-related movement disorders
7 Isolated symptoms and normal variants
8 Other sleep disorders.
From an internal medicine context the most important
problems are those of sleep-related breathing disorders, but
a sleep disorder is an important consideration in the differential diagnosis of a number of presentations, especially
excessive daytime fatigue or sleepiness, chronic pain and its
treatment, and the adverse effects of medications.
4 primary disorder of daytime vigilance such as

narcolepsycataplexy syndrome or idiopathic hypersomnolence.
Obesity
The ongoing epidemic of obesity is a major contributor
to the prevalence of obstructive sleep apnea (OSA). It is
the most important risk factor for OSA in middle-aged
adults.
Insomnia
Insomnia is a symptom of dissatisfaction with either the

quality or the quantity of sleep.
It is exceptionally common as an acute problem, especially in response to a stressful event.
Insomnia that lasts for more than 3 months is called
chronic insomnia, and is reported by up to 10% of
adults.
The patterns of insomnia include one or more of difficulty
with initiation of sleep, difficulty with maintenance of sleep,
or awakening too early.
For insomnia to be diagnosed it is necessary to meet
three criteria:
1 adequate opportunity for sleep
2 persistent dissatisfaction with sleep
3 problems with daytime functioning.
Since mood disorders, chronic pain, and advanced disease
of many organs can interfere with sleep and cause insomnia, there is great complexity in assessing and diagnosing
insomnia.
Snoring and apneas
Snoring is the most frequent sleep-related symptom and

often the reason why patients seek medical assessment,
usually through their partners.
Since snoring is the sound generated by airflow through
a narrowed upper airway, there is great variation between
people and within patients as to the loudness, duration,
impact of body position, and exacerbating factors such
as alcohol and nasal obstruction.
To distinguish between simple snoring and snoring
that reflects significant upper airway obstruction causing apneas, hypopneas or increased respiratory effort,
important clinical clues include a history of apneas, episodes of choking, obesity, a thick neck, and oropharyngeal crowding.
Obstructive sleep apnea (OSA)
Excessive daytime sleepiness (EDS)

Excessive daytime sleepiness is a common symptom for
which there are broadly four causes:
1 inadequate sleep or sleep restriction
2 poor-quality sleep due to a range of problems, such as
sleep apnea, restless legs, and chronic pain
3 sedating medications such as benzodiazepines and
narcotics
142
Obstructive sleep apnea is a common syndrome due to

repeated episodes of obstruction of the upper airway during
sleep, causing reduction in oxyhemoglobin saturation,
increased respiratory effort, arousal, and sleep fragmentation. By convention the obstructions must be present for
at least 10 seconds, and can be either complete obstruction
(apnea) or reduced airflow (hypopnea).
Strictly speaking, OSA describes the pathophysiology
and the full syndrome includes the presence of excessive
daytime sleepiness (EDS; see above), as measured by subjective or objective tools.
The usual measure of severity for OSA is the Apnea
Hypopnea Index (AHI), expressing the number of events
per hour of sleep:
normal AHI:
<5/hour
mild AHI:
515/hour
moderate AHI:
1530/hour
severe AHI:
>30/hour
The consequences of OSA are related to the clinical features
and to short-term and long-term impact:
social impact of loud snoring and apneas, mainly on
family members
EDS and unrefreshing sleep, with increased risk of

motor vehicle accidents, poor academic and work performance, and deterioration in personality and cognitive function
cardiovascular impact through systemic hypertension
with consequent increased risk of ischemic heart disease, stroke, and death.
The diagnosis of OSA is made by the measurement
of breathing during sleep. The gold standard test is an
in-laboratory polysomnography (PSG) with recording of
electroencephalography (EEG), electromyography (EMG),
EOG (electro-oculogram), airflow, chest and abdomen
movement, oxyhemoglobin saturation, pulse and limb
movements.
CLINICAL PEARL
It is essential to identify treatable causes of OSA. These
include:
hypothyroidism (large tongue and reduced control
of breathing)
acromegaly (large tongue)
physical obstruction of the upper airway (nasal
polyps, adenoids, tonsillar hypertrophy, vocal cord
paralysis).
Treatment
The treatment of sleep apnea is based on abolishing the
increased resistance of the upper airway during sleep.
Prior to the availability of continuous positive airway
pressure (CPAP), the only available intervention was
a tracheostomy that was kept open during sleep and
occluded during the daytime.
The current treatment options for OSA include the
following.
Weight loss is important for patients with obesity
(BMI>30), and especially for morbid obesity (BMI
>40). For the latter, bariatric surgery may be an
option.
CPAP to keep the upper airway open through functioning as a pneumatic splint. There are technical
variations that provide more sophisticated applications, but the broad principle remains the pneumatic splint. The mask may be nasal or full-face,
or nasal prongs may be used. Acceptance and compliance can be a problem, with possibly only 50%
using the treatment every night.
A mandibular advancement splint to keep the
mandible and the attached tongue forward. This
increases the cross-sectional area of the pharynx; it
reduces upper airway obstruction to a lesser extent
than CPAP, but is better tolerated.
Upper airway surgery. Evidence for the efficacy
of surgical techniques such as uvulopalatoplasty is
lacking.
Central sleep apnea (CSA)

Central sleep apnea is a failure of the respiratory system to
generate the respiratory muscle effort to maintain adequate
minute ventilation. There are two forms of CSA:
1 Hypercapnic CSA occurs in neuromuscular disease,
and causes hypoventilation either only during sleep, or
that is worse during sleep. Causes include amyotrophic
lateral sclerosis/motor neuron disease (ALS/MND),
muscular dystrophy, stroke, and syringomyelia.
2 Hypocapnic CSA seems to arise from instability of
the respiratory control system through changes in
the setting of chemoreceptors, and the response to
those chemoreceptor outputs. The typical pattern is
often CheyneStokes respiration (alternating periods
of hyperventilation and hypoventilation/apnea). The
most common cause is congestive heart failure, but it
also occurs at altitude and with use of high doses of
narcotics.
Treatment
The treatment of CSA will vary with the clinical setting.
For hypercapnic CSA the major treatment is noninvasive ventilation (NIV), using the same mask interface as OSA (see above) but with machines that deliver
pressure support by having a higher pressure during
inspiration than expiration.
There are many sophisticated aspects to NIV machines
that can accommodate the patients condition, including allowance for failure to trigger a breath, and adaptive
servoventilation where the machine does the opposite
of CheyneStokes respiration, providing ventilation
during periods of hypoventilation and none during
hyperventilation.
For CSA associated with heart failure, it is important
that the heart failure is under optimal treatment.
For any potential of an obstruction component, CPAP
may be used.
In some cases, oxygen supplementation alone will be
adequate.
Obesity hypoventilation syndrome (OHS)

This syndrome is being diagnosed more frequently, in
severely obese people. The criteria for diagnosis include:
obesity (BMI >30)
chronic hypercapnic respiratory failure (PaCO2 >45
mmHg), in the absence of another cause such as severe
COPD; an increased HCO3 on serum electrolytes due
to metabolic compensation is a clue for the presence of
chronic hypercapnia
sleep-disordered breathing
a sleep study may reveal OSA, as well as hypoventilation
during sleep or hypoventilation alone.
The major treatment goal is weight loss, but this is often
either difficult or delayed. The usual treatment is NIV, but
often CPAP is tried first to overcome any contribution from
upper airway obstruction.
143

The focus of critical care for internal medicine is the urgent
support of acute organ failure with the aim of maintaining
life, planning the definitive management of the precipitating cause, and keeping organs working while awaiting
the effect of treatment and/or time. While a great deal
of effort is directed to acute problems of the respiratory
system, critical care medicine involves all organs at some
stage.
RESUSCITATION
Cardiac arrest (CA)
Despite improvements in technology and inpatient care,
there has not been a great deal of change in the outcomes for CA over time, as measured by the proportion
of patients discharged from hospital. There may, however,
have been improvements in prognosis after discharge from
hospital.
Out-of-hospital CA
Approximately two-thirds of cases are primarily cardiac, with the others non-cardiac due to causes such as
trauma and near-drowning.
Ventricular fibrillation (VF) and ventricular tachycardia
(VT) have the best prognosis of the cardiac rhythms in
this situation; asystole and pulseless electrical activity
(PEA) confer the worst prognosis.
Approximately one-third of patients make it to hospital,
with time to resuscitation and time to return of spontaneous circulation being the most important of a number
of risk factors.
Approximately 1 in 10 patients is eventually discharged
from hospital.
The most common cause of death is hypoxic brain
damage.
Bystander compression-only cardiopulmonary resuscitation (CPR) contributes significantly to the successful
outcome of out-of-hospital CA.
In-hospital CA
In-hospital CA has a similarly poor outcome to outof-hospital CA, with discharge rates approximately
1015%.
Similarly, the worst outcomes are for asystole, PEA,
non-witnessed CA, and delay to achieving a return of
spontaneous circulation.
CLINICAL PEARL
Time to debrillation is the most important factor in the
outcome of all cardiac arrests.
144
DIAGNOSIS AND DISEASE

MANAGEMENT
Shock
Evaluation and management of shock
Shock is a pathological state defined by the abnormal physiology of reduced delivery of oxygen and other nutrients to
the tissues through a reduction in systemic tissue perfusion.
Cellular impact includes intracellular edema, acidosis,
and loss of ion pumps.
Systemic effects include lactic acidosis and stimulation
of inflammatory and anti-inflammatory processes.
Initial stages of shock are reversible, but later there may be
cellular death, organ damage, multisystem organ failure
anddeath.
There are three types of shock:
1 Hypovolemicinadequate intravascular volume and
reduced cardiac preload, resulting from trauma and
other causes of blood or fluid loss.
2 Cardiogenicresults from cardiac and extra-cardiac
causes of reduced cardiac output, including pulmonary
embolism and cardiac tamponade.
3 Distributivewidespread vasodilatation, reduction
in systemic vascular resistance, and reduced perfusion
of some tissues despite increased cardiac output, occurring due to causes such as sepsis, anaphylaxis, spinal
damage, toxic shock, and neurogenic factors.
There may be combinations of the three types of shock.
The use of right heart catheterization in shock

Although it is now uncommon to use right heart catheterization in the intensive care unit (usually with the flowdirected SwanGanz catheter), it is valuable to understand
its potential diagnostic role in the following situations (see
Table 7-12):
cause of shock
causes of pulmonary edema
cardiogenic
non-cardiogenic
assessment of pulmonary hypertension
pericardial tamponade
intra-cardiac shunt, left to right.
The major measurements on right heart catheterization are
the vascular pressures and the oxygen saturation in each chamber/vessel. Cardiac output can be measured by either a dilution technique such as thermodilution, or the Fick method
based on oxygen consumption. The measures obtained are of
the three components of left heart function preload (based
on pulmonary capillary wedge pressure [PCWP], which is an
estimate of left ventricular filling pressure), afterload (based
on an estimate of systemic vascular resistance [SVR], from
the relationship between systemic blood pressure and cardiac output), and cardiac outputand one of tissue perfusion
(mixed venous oxygen saturation [SVO2]).
Table 7-12 Right heart catheter in shock
DISORDER/
PARAMETER
PCWP
(PRE-LOAD)
SVR
(AFTER-LOAD)
CARDIAC
OUTPUT
SVO2
Cardiogenic shock
increased
increased
decreased
decreased
Hypovolemic shock
decreased
increased
decreased
decreased
Distributive shock
decreased/normal
decreased
increased
increased
PWCP, pulmonary capillary wedge pressure; SVO2, mixed venous oxygen saturation; SVR, systemic vascular resistance.
Acute respiratory distress syndrome

(ARDS)
Acute respiratory distress syndrome refers to stages of acute
lung damage, usually from infective or traumatic shock, that
were described initially in war zones as shock lung but have
subsequently been seen in a wide range of acute illnesses.
The condition was first defined by consensus in 1994, but in
2012 the definition was updated to the following:
Bilateral pulmonary infiltrates consistent with pulmonary edema (see Figures 7-15 and 7-16)
Acute onset
No evidence of left heart failure, e.g. normal PCWP
(18mmHg)
Severity is further defined by the degree of hypoxemia:
mild200 mmHg < PaO2/FiO2 300 mmHg
moderate100 mmHg < PaO2/FiO2 200 mmHg
severePaO2/FiO2 100 mmHg.
Figure 7-16 Computed tomography scan of patient

with ARDS, demonstrating interlobular septal
thickening and a typical crazy paving pattern due
to ne intralobular reticulation superimposed on
ground-glass opacities
From Ichikado K. High-resolution computed tomography ndings
of acute respiratory distress syndrome, acute interstitial pneumonia,
and acute exacerbation of idiopathic pulmonary brosis. Seminars in
Ultrasound, CT and MRI 2014;35(1):3946.
CLINICAL PEARL
To distinguish ARDS from pulmonary edema due to
left heart failure on chest X-ray, check for pulmonary
venous congestion, cardiomegaly (allowing for mobile
chest X-ray), pleural effusions, and Kerley B (septal)
lines. These all suggest left heart failure.
Pathophysiology of ARDS
Figure 7-15 Chest radiograph showing diffuse
alveolar lling in both lungs of a patient with ARDS;
bilateral air bronchograms are marked by arrows, and
endotracheal and nasogastric tubes can be seen
From Port F, Basit R and Howlett D. Imaging in the intensive care
unit. Surgery 2009;27(11):4969.
Diffuse alveolar damage including loss of surfactant and

release of cytokines.
Leakage of cells and protein into the alveolar space overwhelming usual lymphatic drainage.
Three stages of pathology: exudative initially; proliferative after about 7 days; fibrosis later.
145
Severity of hypoxemia is due to severe shunting, where

there is perfusion of areas that have no ventilation due to
alveoli being full of exudate.
Pulmonary hypertension may be marked due to vasoconstriction in response to alveolar hypoxia, and other
mechanisms including destruction of capillaries, microthrombi, and compression of vessels by edema and
inflammation.
There is marked reduction in lung compliance due to
loss of alveoli and loss of surfactant.
Treatment of ARDS
Causes of ARDS
Since the major cause of severe hypoxemia is widespread

occlusion of alveoli by fluid and cellular material, a mainstay of treatment is to keep the alveoli open for as long as
possible during the respiratory cycle, especially in expiration (using PEEP), and to provide enough inspired
oxygen to maintain a satisfactory level of arterial oxygen (PaO2 5580 mmHg or oxygen saturation SpO2
8895%).
When ventilatory support is required, there is no evidence to support the use of non-invasive positivepressure ventilation (NIV), but it can be used to bridge
the time until expert intubation and setting up of invasive ventilation is possible.
The major risk from mechanical ventilation is lung
injury from the positive pressure, volume distension,
and the repeated opening and closing cycles.
This is referred to as barotrauma, volutrauma, or
either ventilator-associated or ventilator-induced
lung injury (VALI/VILI).
Its acute form is pneumothorax.
The longer-term damage from cyclical overdistension of the alveoli is likely to affect those parts
of the lungs less involved with the ARDS, as the heterogeneous loss of compliance in the lungs means
that higher inspiratory pressures will over-distend
the less stiff areas of the lung.
The principle of ventilation in this setting is to use
relatively low tidal volumes (approximately 6mL/kg
ideal bodyweight), with a rate that maintains reasonable but not necessarily normal arterial PaCO2,
and PEEP levels as required to maintain adequate
arterial oxygen levels.
Mild respiratory acidosis through permissive hypercapnia, down to a pH of 7.30, may be accepted.
Due to the effect of positive-pressure ventilation on
venous return, maintenance of adequate cardiac output will require fluid replacement and vascular support
through vasoconstrictors. However, care needs to be
taken not to administer excess fluid, which can worsen
pulmonary edema.
In conditions that occur in ARDS where lung overdistension is likely to occur, tidal volumes and airway
pressures should be limited, and the attendant increase
in arterial CO2 levels is considered to be acceptable
trade-off to prevent lung damage. There is sufficient
evidence now to suggest that lung-protective ventilation, which includes low tidal volume (approximately
Pulmonary causes (ARDS may be more severe and more difficult to treat):
Aspiration and infective pneumonia
Chest trauma
Fat embolism
Adverse drug reaction, e.g. chemotherapeutic agents,
drug overdose
Systemic causes:
Sepsis
Major trauma
Blood transfusion, including massive blood transfusion
Transplantation, both hemopoietic, and lung
Prognosis of ARDS
Initial mortality is usually due to the severity of the precipitating illness, especially if there is multi-organ failure. Subsequent mortality is more likely to be due to complications
such as nosocomial infection than respiratory failure.
ARDS mortality is associated with severity:
mildincreased mortality 27% (95% confidence interval [CI], 2430%)
moderate32% (95% CI, 2934%)
severe45% (95% CI, 4248%),
The duration of mechanical ventilation required is also
related to ARDS severity, with median duration in survivors being:
mild5 days (interquartile range, IQR, 211)
moderate7 days (IQR 414)
severe9 days (IQR 517).
While survivors may have reduced exercise ability and a
number of other physical and mental problems related to
prolonged intensive care, including depression/anxiety, the
majority will return to work if working at the time of illness,
and remain self-caring.
CLINICAL PEARL
Survivors of ARDS usually have normal lung function by
12 months, but frequently have reduced physical quality of life, and neurological complications.
146
General measures
Aggressive treatment of underlying cause(s), including
antibiotic cover for all possible organisms in sepsis.
Maintain cardiovascular function and renal perfusion
but beware of excessive fluid replacement.
Maintain nutrition, by enteral route where possible; the
parenteral route has many side-effects and complications.
Ventilatory support
6 mL/kg), and a plateau airway pressure restricted to

approximately 2830 cmH2O, leads to better outcomes when compared with traditional ventilatory
strategies for ARDS.
The administration of neuromuscular blocking agents
may be associated with decreased mortality when used
early in the course of severe ARDS.
In the patient with very severe ARDS in whom these
measures are not adequate, there are a number of other
strategies used to maintain adequate oxygenation and
limit ventilation-associated lung injury. These include
prone ventilation, high-frequency ventilation and extracorporeal membrane oxygenation (ECMO).
CLINICAL PEARL
In ARDS requiring mechanical ventilation, a tidal volume
(TV) of 6mL/kg is lung-protective.
MECHANICAL VENTILATION OF
THE LUNGS
Mechanical ventilation is the intervention to treat severe
respiratory failure. The lungs are ventilated by a machine
that uses either negative or positive pressure to provide an
adequate tidal and minute volume.
Respiratory failure occurs when the lungs fail to oxygenate the arterial blood and/or do not export enough
carbon dioxide. Strictly speaking, respiratory failure is
present when the PaO2 is below the lower limit of normal and/or the PaCO2 is above the upper limit of normal
for the persons age. It is conventional to define respiratory failure as a PaO2 < 60 mmHg on room air and/or a
PaCO2>50mmHg.
Positive-pressure ventilation (PPV), delivered invasively
through either an endotracheal tube or a tracheostomy, was
refined in war zones during the 1950s and 1960s. PPV via a
nasal or face mask, so-called non-invasive positive-pressure
ventilation (NIV), is now used widely for inpatient and
home-based treatment of respiratory failure, building on the
development of CPAP pumps and masks for the treatment
of obstructive sleep apnea.
Mechanical ventilation can be used to treat severe respiratory failure due to disorders of gas exchange, manifested
by markedly reduced arterial oxygen tension, of alveolar
ventilation, manifested by hypercapnia, or both. It can be
used for either acute or chronic respiratory failure.
Arterial oxygen levels are improved by reducing shunting through opening of alveoli that have either collapsed
or filled with liquid, together with the ability to provide
increased levels of inspired oxygen.
Increased alveolar ventilation is provided by the delivery
of an adequate combination of tidal volume and respiratory rate.
The types of mechanical ventilation have evolved to maximize the correction of hypoxemia and hypercapnia,
to minimize the risk of VALI, to minimize asynchrony
between the patient and the ventilator, and to optimize the

ongoing use of respiratory muscles, thereby reducing disuse atrophy.
The modes of ventilator support are known as:
Controlled or continuous mechanical ventilation
(CMV)the patient is not involved in triggering or
stopping inspiration or in setting the respiratory rate,
and the inspiration is stopped after either a set volume or
a set pressure (volume- or pressure-limited).
Assist-control (AC) allows the patient to take some
additional breaths to which the machine adds the
required volume or pressure.
Intermittent mandatory ventilation (IMV)support is provided to the patients effort as a part of a
set tidal volume/pressure and rate regimen, with the
patients efforts supported to varying degrees. Synchronized IMV (SIMV) ensures concordance between the
patients effort and the machine.
Pressure-support ventilation (PSV)the machine
provides a level of support for each inspiratory effort by
the patient. Since the level of pressure support can be
varied, this form of ventilation is valuable for the process
of weaning off mechanical ventilation.
Bi-level positive airway pressure (BPAP)this is
the mechanical ventilation provided by NIV. The usual
settings are of the inspiratory positive airway pressure
(IPAP), the expiratory positive airway pressure (EPAP),
the rise time or inspiratory flow, and the back-up rate if a
breath is not triggered. There are sophisticated versions
that are used to treat central sleep apnea and Cheyne
Stokes respiration, so-called adaptive servo-ventilation
(ASV).
Continuous positive airway pressure (CPAP)
this is used to overcome the upper airway obstruction
of obstructive sleep apnea by producing a pneumatic
splint of the upper airway. It is also very effective for
acute pulmonary edema, and for severe vocal cord
dysfunction.
Non-invasive positive-pressure
ventilation (NIV)
Successful NIV requires trained staff and appropriate
equipment. It can be started in the emergency department,
intensive care or high-dependency unit and wards for inpatients, and in outpatient clinics and sleep laboratories for
non-inpatients. The interface between the patient and the
machine for NIV may be a nasal mask, nasal cushions, a full
face mask or a combination. The nasal mask provides the
more physiological airflow, and allows talking and removal
of secretions. The benefits of NIV have been shown to be
best for acute exacerbations of COPD:
reduced mortality
reduced need for invasive ventilation
reduced length of stay and complications, including
nosocomial infections
reduced re-admission to hospital.
147
Indications
Acute exacerbations of COPD with respiratory acidosis
(pH<7.35)
Acute pulmonary edema where CPAP is not adequate
Obesity hypoventilation syndrome
Respiratory failure from neuromuscular disease
Acute exacerbation of asthma
Neutropenic septic patients may have a better outcome
with NIV than with invasive ventilation
Contraindications
Impaired consciousness
Inability to cooperate
High risk of pulmonary aspiration
Recent esophageal or upper gastrointestinal surgery
Facial injury or any problem that would prevent application of a mask
Invasive positive-pressure ventilation

(IPPV)
Interface
The endotracheal tube should be of a size that provides
maximum cross-sectional fit.
The cuff should be inflated to the lowest pressure that
provides a seal, to minimize the risk of damage to the
wall of the trachea.
The position of the endotracheal tube should be checked
clinically from the presence of breath sounds bilaterally,
and with a chest X-ray.
The timing for moving from an endotracheal tube to a
tracheostomy depends on the causal problems for respiratory failure, comorbidity and the prognosis.
A tracheostomy may be considered after 7 days if not
weaned off the ventilator.
Auto-PEEP
This can be a problem in the early stages of ventilating a patient when, due to the respiratory rate and
difficulty with expiration, the breaths stack up with a
gradual increase in the expiratory lung volume, causing
hyperinflation.
It is most likely to occur in patients with COPD and
asthma, and carries the risk of hypotension and shock
due to impedance of venous return to the right atrium.
There is also the risk of VALI, especially pneumothorax,
that can worsen or mimic the cardiovascular problem.
The treatment includes changes in ventilator parameters to allow a longer expiratory period, and maximizing
treatment of the underlying problem.
148
CLINICAL PEARL
Treatment of auto-PEEP may include decreasing tidal
volume, decreasing respiratory rate, or increasing expiratory time.
Difficulty in weaning from IPPV

This is a relatively common problem and its potential is an
important part of the discussion with a patient and/or their
family prior to or just after starting IPPV, especially in someone with severe underlying cardiopulmonary or neuromuscular disease.
Causes of delayed weaning or difficulty with weaning:
incomplete resolution of the causal illness or of a complicating illness
reduced drive to breatheresidual sedation, metabolic
alkalosis, central nervous system problems
reduced neuromuscular strengthmyopathy, malnutrition/sarcopenia, electrolyte abnormalities, neuropathy, and medication such as corticosteroids
reduced compliance of the lungs and chestfluid overload, fibrosis, pleural disease, obesity
obstruction to breathingventilator tubing, secretions,
airway inflammation and edema, bronchial muscle
spasm
increased respiratory and metabolic demandanxiety,
fever, delirium, hypoxia.
While a number of cardiac problems can complicate prolonged
IPPV, cardiogenic pulmonary edema should be considered in
the situation of slow or difficult weaning. The change from
positive pressure to negative pressure in the lungs and pleural space as the ventilator support is reduced will lead to an
increase in venous return, making Starling forces in the lung
parenchyma more favorable to edema formation.
Extracorporeal membrane oxygenation

(ECMO)
Extracorporeal membrane oxygenation is a term used for
the process of providing oxygenation outside the body inthe
setting of severe lung disease, such as ARDS.
An extracorporeal circuit directly oxygenates and
removes carbon dioxide from the blood.
To use ECMO in patients with ARDS, a cannula is
placed in a central vein, and blood is withdrawn from
the vein into an extracorporeal circuit by a mechanical
pump and then enters an external oxygenator.
Within the oxygenator, blood passes along one side of a
membrane, which provides a bloodgas interface for the
diffusion of gases.
The oxygenated extracorporeal blood is then warmed
or cooled as needed and returned to the central vein.
Box 7-10 outlines indications and contraindications for use
of ECMO.
Box 7-10
Indications and contraindications for ECMO

Indications
Severe hypoxemia (e.g. PaO2/FiO2 ratio <80) despite
the application of high levels of PEEP (typically 1520
cmH2O) for at least 6 hours in patients with potentially
reversible respiratory failure
Uncompensated hypercapnia with respiratory
acidemia (pH <7.15) despite the best accepted
standard of care for management with a ventilator
Excessively high end-inspiratory plateau pressure
(>3545 cmH2O, according to the patients body
size) despite the best accepted standard of care for
management with a ventilator
Relative contraindications
High-pressure ventilation (end-inspiratory plateau
pressure >30 cmH2O) for >7 days
High FiO2 requirements (>0.8) for >7 days
Limited vascular access
Any condition or organ dysfunction that would limit the
likelihood of an overall benet from ECMO
Absolute contraindications
Any condition that precludes the use of anticoagulation
therapy
ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; PEEP, positive
end-expiratory pressure.
Modied from Brodie D and Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med 2011;365(20):190514.
149
1
A 55-year-old obese patient (body mass index = 42) complains of morning headaches and daytime sleepiness. His
family reports that he snores very loudly. He has a history of systemic hypertension, and a small myocardial infarction
3 years ago with no residual cardiac dysfunction. He is a non-smoker. An overnight oximetry study shows signicant
hypoxemia with 20% of the night spent with an oxygen saturation below 90% and an oxygen desaturation index (3%)
of 38/hour. Arterial blood gases show a pH of 7.38, PaCO2 of 57 mmHg, PaO2 66 mmHg and bicarbonate of 32 mmol/L.
Which is the most likely diagnosis?
A CheyneStokes respiration
B Severe obstructive sleep apnea
C Late-stage chronic lung disease
D Obesity hypoventilation syndrome
E Central sleep apnea
A 39-year-old HIV-positive male is found to have a tuberculin skin test (Mantoux) of 8 mm induration. He has no
symptoms, has not had a BCG vaccination, and has had no contact with tuberculosis. Chest X-ray is normal. Which of
the following treatment approaches is the most appropriate?
A Isoniazid treatment for latent tuberculosis for 9 months
B Full treatment for tuberculosis with 4 drugs for 2 months and 2 for 4 months
C Interferon-gamma release assay for tuberculosis (IGRA)
D No further action
E Annual chest X-rays for 3 years
For a 63-year-old male patient with severe COPD (FEV1 0.8 L, 32% of predicted; PaO2 53 mmHg), which of the following
has been shown to prolong his life expectancy?
A Inhaled long-acting muscarinic antagonists (LAMAs)
B Inhaled corticosteroid therapy
C Pulmonary rehabilitation
D Domiciliary oxygen
E Long-term macrolide antibiotic
4 A 78-year-old man presents with chronic cough and breathlessness that has been increasing over the past 12 months.
He is a lifelong non-smoker. On examination he has clubbing of the ngers and crackles over the lower half of
both lungs. Lung function tests show an FVC of 75% of predicted with an FEV1/FVC ratio of 0.86; carbon monoxide
transfer is 45% of predicted. A chest X-ray shows an interstitial pattern mainly in the lower lobes with a suggestion of
honeycombing. A high-resolution CT of the chest shows symmetrical bilateral reticular opacities with honeycombing,
predominantly in the bases of the lungs. Laboratory tests for connective tissue disease are negative. The patient wants
to know what type of treatment has been shown to be of long-term benet for his lung disease.
A High-dose parenteral corticosteroids
B Azathioprine and prednisone
C No current treatment
D Cyclophosphamide and prednisone
E Pirfenidone
5
A 45-year-old woman with a long history of asthma presents with gradually progressive cough and breathlessness,
and with fever and mild weight loss. There is no history of rhinosinusitis, rash, or focal neurological symptoms.
On examination there is bilateral wheeze; pulse oximetry is 92%. A chest X-ray shows diffuse alveolar inltrates,
predominantly peripheral. A high-resolution CT scan of the chest conrms alveolar inltrates and mediastinal
lymphadenopathy. Blood eosinophils are 5.4 109/mL (normal <0.4 109/mL). Serum precipitins for Aspergillus are
negative. Which of the following is the most likely diagnosis?
A Acute eosinophilic pneumonia
B Allergic bronchopulmonary aspergillosis (ABPA)
C Tuberculosis
D Chronic eosinophilic pneumonia
E Eosinophilic granulomatosis with polyangiitis (EGPA/ChurgStrauss syndrome)
6 A 55-year-old man suddenly collapses while cycling with friends. He has no previous medical history. The friends
attempt CPR with mouth-to-mouth resuscitation, but he vomits and they are unable to effectively clear his airway.
An ambulance arrives on the scene. The man is in asystole, and there is no pulse or respiratory effort. Attempts are
made to continue resuscitating, but they are unsuccessful. This mans outcome may have been improved if?
A The bystanders were able to effectively secure his airway and prevent aspiration.
B Irrespective of giving mouth-to-mouth resuscitation, compression-only CPR had been carried out.
C Bystanders had had access to an automatic debrillator.
D The ambulance had arrived sooner and established an airway and intravenous access.
150
A 60-year-old female presents to hospital with 3 days of breathlessness, cough and fevers. She has a history of asthma,
but has had no prior admissions. At presentation she is diaphoretic, but her peripheries are warm. She has a pulse of
140 beats/min and sinus rhythm, blood pressure 70/40 mmHg, temperature 38.4C. A chest X-ray shows consolidation
involving the right lower and middle lobes. Electrocardiography demonstrates ST depression in leads V3V5 with
Twave inversion. Troponin level is elevated. Arterial blood gases demonstrate a pH of 7.29, PaO2 50mmHg, and PaCO2
30mmHg. Serum biochemistry reveals Na 130 mmol/L (reference range [RR] 135145), K 4.9 mmol/L (RR 3.55.6), urea
11.4 mmol/L (RR 2.19.0), creatinine 120 micromol/L (RR 4090), and HCO3 14mmol/L (RR 2333). You decide that she
is in shock. From your ndings you should institute the following treatment based on the probable cause of her shock:
A Stabilize her, transfer her to intensive care, and place a SwanGanz catheter to guide resuscitation.
B Commence broad-spectrum antibiotics for community-acquired pneumonia, support circulation with intravenous
uids and commence support with non-invasive ventilation.
C Commence broad-spectrum antibiotics for community-acquired pneumonia, support circulation with intravenous
uids, and avoid vasopressors until an urgent cardiac echo can be performed.
D Commence broad-spectrum antibiotics for community-acquired pneumonia, support circulation with intravenous
uids, and use vasopressors as needed.
8 A 78-year-old ex-smoker with a history of COPD presents to the emergency room by ambulance. He has an FEV1 of
40% of predicted. He does not use home oxygen. His pulse is 120/min and regular, blood pressure 110/60 mmHg,
respiratory rate 12/min, and Glasgow Coma Scale score reduced at 12. He is breathing 10L of oxygen via a mask.
Arterial blood gases (ABGs) demonstrate pH 7.21, PaO2 103mmHg, PaCO2 90mmHg, HCO3 35mmol/L (RR 2333).
Your approach to treatment should be:
A To reduce oxygen concentration, aiming for SaO2 8892%, give nebulized bronchodilators, and commence
treatment with non-invasive ventilator support via a mask
B With his reduced level of consciousness, to secure his airway and intubate
C To commence treatment with intravenous salbutamol, reduce oxygen, and repeat ABGs
D To give continuous nebulized salbutamol, intravenous hydrocortisone, and titrate oxygen to maintain SaO2 of
9295%
9 A 52-year-old diabetic woman, with a background of retinopathy and hypertension, is admitted with pyelonephritis.
She is febrile at 39C, her pulse is 130/min in sinus rhythm, BP is 90/50mmHg, respiratory rate is 18/min, and SpO2 is
93% on room air. Electrolytes demonstrate Na 130 mmol/L (reference range 135145), K 4.3 mmol/L (RR 3.55.6), urea
15.6 mmol/L (RR 2.19.0), creatinine 224 micromol/L (RR 6090), and blood glucose 20.3mmol/L (RR 3.66.0). Urine
analysis shows nitrites 2+, blood 3+, protein 3+, glucose 4+, and ketones +. Urine microscopy shows WCC>100 106/L.
Blood culture isolates a Gram-negative rod. She is commenced on treatment with intravenous (IV) third-generation
cephalosporin, a single dose of gentamicin, IV insulin infusion, and IV uids. That night she becomes breathless, with
pulse rate 130/min, BP 120/70mmHg, temperature 37.8C, respiratory rate 35/min, and SpO2 85% despite FiO2 0.5 via a
mask. Chest X-ray shows bilateral airspace consolidation. Electrocardiography shows sinus tachycardia with no other
changes. She deteriorates, is intubated and transported to intensive care. Your next action should be:
A Broaden antibiotic cover to cover community-acquired pneumonia
B Organize an urgent abdominal CT scan to determine whether she has a renal abscess that requires surgical
drainage
C Continue antibiotics and a protective ventilator strategy to support, without attempting to normalize oxygenation
D Commence on dopamine and IV uids to maintain a urine output greater than 30mL/hour
ANSWERS
1
D.
The blood gases show chronic hypercapnic respiratory failure, as evidenced by hypercapnia and raised bicarbonate. This is
a clue to the presence of the obesity hypoventilation syndrome, especially in a patient with marked obesity. This patient may
also have obstructive sleep apnea in view of the loud snoring and daytime sleepiness. The lack of cardiac dysfunction makes
CheyneStokes less likely. The history gives no risks for central sleep apnea. The high oxygen desaturation index suggests the
episodic sleep-disordered breathing of sleep apnea rather than REM-related hypoxemia seen in chronic lung disease.
A.
In the absence of a history of BCG vaccination, the explanation for a positive Mantoux test is previous tuberculosis (TB)
infection and there is thus the risk of reactivation of latent infection, especially in a patient at risk of immunosuppression.
It would be dangerous not to treat. Therefore, it is appropriate to treat with single-agent therapy for 9 months. If there
were signs of active TB (e.g. abnormal chest X-ray, or productive cough), multi-drug therapy would be required. The IGRA
would not give any further information in this setting.
D.
Unfortunately, apart from lung transplantation, the only treatment proven to prolong life in severe COPD is the use of
continuous domiciliary oxygen in those with persistent hypoxemia. This is probably due to the reduction in hypoxic
pulmonary vasospasm, and the consequent lessening of pulmonary hypertension. This may then delay the onset of
cor pulmonale.
151
4 C.
This is a description of a case of idiopathic pulmonary brosis, for which there has been no demonstration of reduced
progression of disease with the use of immunosuppressant drugs, or with the anti-brotic agent pirfenidone.
5
D.
EGPA is unlikely in the absence of a history of rhinosinusitis, rash or neurological symptoms. ABPA should be associated
with the demonstration of both serum precipitins and specic IgE to Aspergillus, so negative precipitins makes this unlikely.
Eosinophilic pneumonias generally cause peripheral lung inltrates. The very high blood eosinophil count and history
of asthma and fevers make one form of these the most likely diagnosis. The progressive nature of the dyspnea, and the
lymphadenopathy, make chronic eosinophilic pneumonia most likely. Tuberculosis should not cause marked eosinophilia.
6 B.
Compression-only CPR is the only approach available to the bystanders in this situation that could have potentially led to
successful resuscitation.
7
D.
The patient is in septic shock with evidence of a metabolic acidosis and compensatory respiratory alkalosis. This is likely
to be secondary to community-acquired pneumonia. Treatment should include early empirical antibiotic therapy, and
treatment to restore the circulation. There is evidence of an acute coronary syndrome, but it is unlikely to account for
the cause of shock alone and is not the primary event. The aim should still be to support the circulation and resuscitate
appropriately, with vasopressors as needed. Treatment guided by SwanGanz catheter has not been shown to improve
outcomes.
8 A.
A case can be made for reducing oxygen and giving bronchodilators, then repeating ABGs before commencing NIV, but
already with a reduced level of consciousness this may not be enough. It is likely that NIV has better long-term outcomes
than intubation with IPPV in this setting, with equivalent acute efficacy. There is no role for continuous nebulized or
intravenous salbutamol in this setting. Maintaining oxygen saturation at 9295% is unnecessary, and is likely to promote a
reduced respiratory drive with worsened hypercapnia.
9 C.
This picture is consistent with acute respiratory distress syndrome (ARDS) secondary to septic shock. There is no reason to
propose another infection in this context and in this timeframe. While she is diabetic and may be at risk for ischemic heart
disease, unless she has a severe myocardial infarction, acute pulmonary edema is less likely. Treatment for ARDS aims to
treat the underlying cause and support respiratory function.
152
CHAPTER 8
CARDIOLOGY
Peter Thompson
ACUTE CORONARY SYNDROMES
CHAPTER OUTLINE
CLINICAL EVALUATION OF THE PATIENT
Taking the historypossible cardiac symptoms
INVESTIGATION OF CARDIAC DISEASE
Chest X-ray (CXR)
Echocardiography
Radionuclide myocardial perfusion imaging
catheterization
Coronary CT angiography (CTCA) and calcium
scoring
DYSLIPIDEMIA
Dyslipidemia and cardiovascular disease (CVD)
CORONARY ARTERY DISEASE (CAD)

Prevalence
Pathophysiology
STABLE CORONARY ARTERY DISEASE

Investigation
Management of symptoms in the stable CHD
patient
Terminology
Pathophysiology of acute coronary syndromes
Management of STEMI
Pharmacological therapy in acute coronary
syndromes
VALVULAR HEART DISEASE

MITRAL VALVE DISEASE
AORTIC VALVE DISEASE

TRICUSPID VALVE DISEASE

PULMONARY VALVE DISEASE

Assessing the severity of valvular heart disease
and deciding on surgery
CARDIOMYOPATHIES

153
CARDIAC ARRHYTHMIAS

Sick sinus syndrome
Supraventricular premature complexes (ectopics)
Atrial utter
CONDUCTION DEFECTS

Treatment
Devices
INFECTIVE ENDOCARDITIS
Microbiology
Diagnosis
Management
Prevention
PERICARDIAL DISEASES

Acute pericarditis
CARDIAC FAILURE
Denition
Causes
CLINICAL EVALUATION OF
THE PATIENT
Taking the historypossible cardiac
symptoms
CLINICAL PEARL
Localized chest pain with a palpable area of tenderness
indicates a non-cardiac origin, but the nding does not
necessarily exclude underlying coronary heart disease.
Chest pain or discomfort
Dyspnea
Eliciting an accurate history of chest pain or discomfort is an

important skill in the evaluation of patients with suspected
cardiac disease. The central challenge in the evaluation of
chest discomfort (Table 8-1) is to assess whether it indicates
myocardial ischemia.
Typical angina is a central chest pain or tightness usually
described as a heavy squeezing sensation, sometimes a
burning, or a vague sensation of discomfort which eludes
precise description. It is usually brought on with exertion
and relieved with rest. Relief on resting is usually immediate, and if the discomfort persists for more than a few
minutes, non-cardiac causes should be considered.
Atypical angina can occasionally present with pain in
the lower jaw, left arm, right arm, epigastrium, and
occasionally in the interscapular area of the back. Eliciting a history of exacerbation by exertion and relief with
rest is a very valuable clue that the pain is an atypical
form of angina.
Relief with nitroglycerin usually indicates myocardial
ischemia but can occur with esophageal spasm.
While angina can present with localized pain, finding an
area of tenderness on the chest wall makes it more likely
that the pain is arising from the structures of the chest
wall, such as with costochondritis. Costochondritis can
coexist with coronary heart disease (CHD), so finding
chest wall tenderness does not exclude CHD.
Worsening of the pain with inspiration (pleuritic pain)
indicates a pericardial or pleural cause for the chest pain.
The possibility of esophageal reflux or other gastrointestinal causes may be raised if the chest pain or discomfort
comes on after meals or bending over.
The sensation of shortness of breath (dyspnea) and its

variants orthopnea and paroxysmal nocturnal dyspnea
are very common, and in patients with cardiac disease
usually indicate the presence of cardiac failure or significant valvular heart disease.
Evaluating dyspnea presents a diagnostic challenge, as
the same symptom can be associated with respiratory
disease, anxiety and simply lack of fitness.
The sudden onset of paroxysmal nocturnal dyspnea,
particularly with the production of frothy sputum,
is usually due to cardiac failure.
Orthopnea is also usually due to cardiac failure but
respiratory causes cannot be ruled out entirely.
Dyspnea with wheezing can occur with cardiac
failure (so-called cardiac asthma), but exacerbation
with a recent respiratory infection makes respiratory
disease more likely to be the cause.
154
Palpitations
The term palpitation means different things to different people, and the term is best avoided in direct questioning. Terms
such as irregular heart rhythm or skipping of the heart beat
are much more likely to be understood by the patient. It is
often helpful to distinguish regular tachycardias, ectopic beats
and atrial fibrillation by having the patient tap out on their
chest or on the desk how they experience the irregularity.
CLINICAL PEARL
Asking the patient to tap out the rhythm on their chest or
a desktop can help elucidate the cause of palpitations.
Chapter 8 Cardiology
Table 8-1 Differential diagnosis of chest discomfort
DIAGNOSIS
CHARACTER
LOCATION
COMMENT
Coronary heart disease

Exertional angina
Heavy, squeezing pressure
Retrosternal with
radiation to neck or left
arm
Worse with exertion, relieved

with rest; relieved rapidly with
nitroglycerin
Unstable angina
Similar to above but may be

more intense
Similar to above
Occurs with minimal exertion

or at rest; usually responds to
nitroglycerin
Acute myocardial
infarction
Similar to above but more

severe, and associated with
sweating, clamminess, dyspnea,
nausea, light-headedness
Similar to above
Sudden onset at rest,

incomplete relief with
nitroglycerin
Cardiovascular, non-coronary
Pericarditis
Pleuritic, worse with inspiration
Central, parasternal
Variable with change in position;

no relief with nitroglycerin;
associated with pericardial rub
Aortic dissection
Severe, tearing or ripping

sensation
Anterior chest, often

with radiation to
interscapular area
Occurs in patients with

uncontrolled hypertension or
Marfan syndrome
Pulmonary embolism
Abrupt onset, usually severe

and can be pleuritic
Usually retrosternal
but can be left or right
chest
Marked dyspnea, tachypnea,

tachycardia, and hypotension;
marked oxygen desaturation
Pneumonia with pleural

involvement (pleurisy)
Variable, usually pleuritic
Unilateral localized, on
side of infection
Dyspnea, cough, fever, crackles,

pleural rub
Spontaneous
pneumothorax
Sudden onset, variable severity
Lateral on side of
pneumothorax
Pleuritic, dyspnea, reduced

breath sounds on side of
pneumothorax
Gastroesophageal reux
Dull, can be sharp or dull
Retrosternal,
sometimes with
radiation to neck or jaw
Often comes on after food,

may be relieved by antacids or
proton-pump inhibitors
Cholecystitis
Dull, aching
Usually subcostal but

can be retrosternal
May come on after fatty food

consumption; associated with
right subcostal tenderness and
disordered liver function tests
Costochondritis
Often sharp, can be dull and

aching
Localized over
costochondral joint
Localized chest wall tenderness;

NB: does not exclude coronary
heart disease
Rib fracture
Localized, pleuritic
Very localized pain over

fracture
Usually after chest trauma

but can occur after vigorous
coughing
Herpes zoster (shingles)
Dull, disturbing, may be

associated with typical blistering
eruption
Unilateral in
dermatome distribution
Pain is often worse before

eruption of vesico-papular rash
Thoracic
Gastrointestinal
Chest wall pain
155
Syncope
A sudden episode of collapse can be a very threatening
symptom, and can indicate a major bradyarrhythmia
requiring urgent treatment, or a life-threatening tachyarrhythmia such as ventricular tachycardia.
The patient should be asked if the episode was preceded
by any disturbance of the heart rhythm.
A history of similar episodes occurring while standing
or getting up from a sitting or lying position may indicate postural hypotension.
Metabolic causes, such as hypoglycemia, should be
sought by checking for recent commencement or dose
change of hypoglycemic treatments.
General examination
The patients level of distress, the rate of breathing,
degree of pallor, presence of sweating (diaphoresis), cyanosis, and coolness or warmth of the peripheries are all
valuable observations which offer important diagnostic
clues.
Careful examination of the hands and lips can help identify the presence of cyanosis, which is traditionally classified as central (mainly in the lips) or peripheral (mainly in
the extremities).
Pulse
The radial pulse can give valuable clues to the regularity
of the heart rhythm and rate.
An irregularly irregular pulse is usually due to atrial
fibrillation, but differentiation from frequent ectopic
beats may require an electrocardiogram.
Pulsus paradoxus (a fall in systolic blood pressure of
>10 mmHg with inspiration) and pulsus alternans
(alternating weak and strong beats) are often clinically evident on palpation of the brachial pulse, and
confirmed by checking the brachial pulse with the
sphygmomanometer.
Evaluation of the pulse contour usually requires careful
examination of the carotid pulse.
The femoral pulse can be examined to detect aortofemoral delay in aortic coarctation, and may accentuate some
signs of aortic regurgitation.
Jugular venous pulse

The jugular venous pulse (JVP) is evaluated to estimate the
central venous pressure and to draw conclusions on right
heart function from the pulse contour.
An elevated JVP is a useful indicator of right heart pressure overload.
The external jugular vein is best for measuring the
height of the JVP, and the internal jugular for assessing
pulsations and contour of the pulse.
A JVP height of >4.5 cm above the angle of Louis with the
patient at 45 to the horizontal, or a JVP visible above the
clavicle with the patient at 45, is considered abnormal.
The finding of an elevated JVP on the right should
always be confirmed by checking the left.
The normal response to inspiration is a fall in the jugular
pressure; a rise or lack of fall in the JVP with inspiration
is referred to as Kussmauls sign and may be a sign of
pericardial tamponade.
Hepato- or abdomino-jugular reflux (an increase in JVP
with pressure over the liver or upper abdomen) is used
to elicit borderline signs of increased central venous
pressure.
CLINICAL PEARL
The external jugular is better for measuring the venous
pressure; the internal jugular is better for measuring the
venous pulse contour.
CLINICAL PEARL
Evaluate all pulses: radial pulse for rhythm, brachial
for pulsus paradoxus and alternans, femoral for aortofemoral delay, and carotid for pulse contour.
Blood pressure measurement

Blood pressure should be measured in a sitting or lying
position.
A small cuff will underestimate blood pressure, and vice
versa.
156
The ideal cuff should have a bladder length that is

80% and a width that is at least 40% of arm circumference (a length-to-width ratio of 2:1).
The systolic pressure is denoted by the 1st Korotkoff
sound; there is now general agreement that the diastolic pressure is denoted by the 5th Korotkoff sound
(disappearance of the sound) rather than the 4th Korotkoff sound (muffling of the sound). However, when the
diastolic pressure using the 5th Korotkoff sound is very
low, the 4th Korotkoff sound should be recorded, and
noted as such.
There is evidence that measurement in both arms adds
to the assessment. This is rarely done as routine, but
should be sought if aortic dissection with involvement
of the left subclavian artery is suspected.
Orthostatic hypotension is defined by a fall in systolic
pressure >20 mmHg in response to assuming of the
upright posture from a supine position within 3 minutes.
Examination of the contour of the pulsations in the internal jugular vein can provide valuable information. The
correlations between the jugular pulse and the phases of
the cardiac cycle are shown in Figure 8-1, and the mechanism and interpretation summarized in Table8-2.
Carotid pulse
The carotid pulse should be examined in all patients,
but especially when trying to assess the severity of aortic
Table 8-2 Venous pulse contours and interpretation
VENOUS PULSE
MECHANISM
INTERPRETATION
a wave
Atrial contraction
Prominent in situations of increased atrial

compliance such as COPD and pulmonary
hypertension. Absent in atrial brillation
Cannon or giant a wave
Right atrium contraction against a closed

tricuspid valve
May indicate atrioventricular block or

ventricular tachycardia
v wave
Does not represent ventricular contraction; is

a reected wave from late lling of the right
atrium
Combines with c wave and is prominent with

tricuspid regurgitation
c wave
Small wave, represents ventricular

contraction
Usually difficult to see in clinical examination
x descent
Downward movement of the tricuspid

valve during ventricular contraction; occurs
between the a wave and the v wave,
interrupted by the c wave
y descent
Ventricular lling after opening of triscupid

valve; occurs after the v wave
Steep y descent said to be typical of

pericardial constriction
COPD, chronic obstructive pulmonary disease.
stenosis. Pressure over the carotid pulse should be gentle

to avoid initiating a bradycardic response, and both
carotids should not be examined together.
The clinically important carotid pulse contours are
summarized in Table 8-3.
Carotid pulse
A
Venous pulse
V
Y
Cardiac inspection, palpation and percussion
Heart sounds
S1
S2
EKG
P
QRS
Figure 8-1 The jugular venous pressure and pulse

contour
From Walker HK, Hall WD and Hurst JW, eds. Clinical methods:
The history, physical, and laboratory examinations, 3rd ed. Boston:
Butterworths, 1990.
Inspection of the precordium is often overlooked but can

provide valuable clues.
Prominent pulsations in the precordium may indicate
a left ventricular aneurysm or marked right ventricular
overload.
Prominent pulsations in the suprasternal notch may
indicate an aortic arch aneurysm.
Palpation of the precordium should include documentation of the location of the apex beat. The location of the
apex beat should be recorded with the patient lying flat,
but examination in the left lateral decubitus position
Table 8-3 Summary of carotid pulse contours and their interpretation
PULSE CHARACTER
TERMINOLOGY
CAUSE
A slow-rising, low-amplitude pulse,

sometimes with shuddering
Slow-rising pulse (pulsus parvus et tardus)
Severe aortic stenosis
Sharp rise and fall in the carotid

pulse regurgitation
Corrigans pulse
Collapsing pulse
Waterhammer pulse
Severe aortic regurgitation
A double-amplitude pulse
Bigeminal pulse (pulsus bigeminus)
Frequent ectopic beats
Prominent secondary pulsation
Bisferiens pulse (pulsus bisferiens)
Severe aortic regurgitation or

hypertrophic cardiomyopathy
157
(patient lying half on the left side with support from the
examiners arm or a pillow) should also be performed to
fully evaluate the character of the cardiac impulse.
A diffuse apex beat may indicate marked left ventricular systolic dysfunction.
Palpation of the left parasternal space should be routine
to search for right ventricular overload.
A systolic thrill over the left parasternal space may be
felt in severe aortic stenosis, and, more rarely, a diastolic thrill may be felt in severe aortic regurgitation.
Percussion of the precordium is occasionally helpful
when trying to identify displacement of the heart or a
large pericardial effusion.
Ewarts sign is an area of dullness on percussion at
the lower angle of the left scapula, indicating a large
pericardial effusion.
CLINICAL PEARL
The location of the apex beat should be recorded with
the patient lying at, as should the character of the cardiac pulsation in the left lateral decubitus position.
It is a valuable clue to the increasingly recognized condition of diastolic dysfunction of the left
ventricle.
A 3rd heart sound invariably indicates significant left ventricular dysfunction. It is usually lowpitched, but in the presence of a tachycardia may
be of medium pitch and more readily heard. This is
referred to as gallop rhythm.
Systolic murmurs
During auscultation, systole should be carefully examined
to determine the pitch, character, timing, amplitude (loudness), location and radiation of any murmur.
The amplitude should be recorded on a scale of 14 or
16.
The location in which a murmur is best heard is often a
guide to which valve is producing the murmur. However, careful studies comparing skilled clinicians with
echocardiographic findings have shown that a murmur
in the apical region can be aortic in origin and mitral
regurgitation can sometimes be heard best in the aortic
or pulmonary parasternal location.
CLINICAL PEARL
Cardiac auscultation
Auscultation at the apex, left sternal border, right upper
sternal border and right lower border is essential for full
evaluation.
Abnormalities of the heart sounds give important clues
to underlying pathophysiology (Table 8-4).
Added sounds in systole or diastole can also assist to
identify abnormalities in systolic and diastolic function
(Table 8-5).
The 4th heart sound indicates reduced left ventricular compliance from multiple causes, including
aortic stenosis, left ventricular hypertrophy, ischemic heart disease, and restrictive cardiomyopathy.
Murmurs are best described by their precise location

on the chest (left sternal border/apical/right parasternal), rather than the traditional aortic/pulmonary/
mitral/tricuspid locations, as these may not accurately
reect the origin of the murmur.
The character and timing of the murmur can be

described as pansystolic (holosystolic) or crescendo/
decrescendo (often described as diamond-shaped from
its configuration on phonocardiography).
A pansystolic (holosystolic) murmur is usually an indication of mitral regurgitation, but can
be due to a ventricular septal defect. If it radiates
Table 8-4 Variations in the 1st and 2nd heart sounds
SOUNDS
MECHANISM
SIGNIFICANCE
Increased amplitude of the 1st heart

sound
Vigorous mitral and tricuspid valve

closure
Hyperkinetic circulation or a short PR

interval
Wide splitting of the 2nd heart sound
Delay in closing of the pulmonary

valve or right ventricular overload
Right bundle branch block (some

variation in the degree of splitting with
respiration) or large atrial septal defect
(xed splitting)
Reverse splitting of the 2nd heart

sound
Aortic valve closure can be so delayed

that the aortic component of the
sound occurs after the pulmonary
component
Left bundle branch block or severe left

ventricular dysfunction
Increase in amplitude of the

pulmonary component of the 2nd
heart sound
Vigorous pulmonary valve closure
Tic-tac mechanical character
Mechanical valve closure or opening
Mechanical prosthetic valve
158
Table 8-5 Added sounds in systole and diastole
ADDED SOUND
MECHANISM
SIGNIFICANCE
Systole
Early systolic click
Aortic or pulmonary valve opening; can

occur alone or preceding a systolic bruit
Dilated aortic root or pulmonary artery
Mid-systolic click
Arises from the mitral valve apparatus;

may be single or multiple
Usually indicates mitral valve prolapse;

can occur with normal mitral valve
function
4th heart soundmoderate- to

low-pitched sound occurring just
before the 1st heart sound
Atrial systole into a non-compliant left

ventricle
Reduced compliance of the left ventricle
3rd heart soundlow-pitched

sound in mid diastole
Abrupt deceleration of left ventricular (LV)

inow during early diastole
Indicates signicant systolic dysfunction

with cardiac failure
Opening snaphigh-pitched
sound which may precede the
mid-diastolic rumble
Diastolic opening of the mitral valve
Mitral stenosis associated with mobile

valve leaets
Mid-diastolic rumblelonger and

lower-pitched than the 3rd heart
sound
Diastolic ow across a stenosed mitral

valve
Indicative of mitral stenosis; needs to be

distinguished from 3rd heart sound
Diastole
to the axilla, it favors mitral regurgitation as the

cause.
A softer pansystolic murmur heard at the left lower
sternal area may indicate tricuspid regurgitation.
An increase in amplitude with inspiration strengthens the evidence for tricuspid regurgitation, but this
is an unreliable sign, and supportive evidence of a
prominent v wave in the JVP and hepatic pulsation
should be sought.
A crescendo/decrescendo (ejection type,
diamond-shaped) murmur usually indicates aortic
stenosis but can represent mitral regurgitation.
On occasions, mitral regurgitation associated with prolapse of the posterior mitral valve leaflet can be heard
best in the parasternal area.
Radiation to the neck indicates origin from the aortic
valve, and radiation to the axilla indicates origin from
the mitral valve.
It is sometimes difficult to distinguish aortic valve
sclerosis from stenosis on clinical grounds alone, and
other features of aortic stenosis (especially a slowrising pulse) on examination of the carotid pulse
should be sought before reaching aconclusion.
A murmur which has features of aortic stenosis and
mitral regurgitation may truly reflect both conditions.
Occasionally, hypertrophic cardiomyopathy can reproduce features of aortic stenosis from outflow tract
obstruction from the septal hypertrophy, as well as
mitral regurgitation from the disruption of the mitral
valve apparatus.
CLINICAL PEARLS
A harsh mid-systolic murmur at the left sternal border
with radiation to the neck indicates aortic stenosis.
A pansystolic murmur with radiation to the axilla
indicates mitral regurgitation.
The only exception is anteriorly directed mitral
regurgitation which may be heard in the left parasternal region.
Diastolic murmurs
The two main diastolic murmurs are an early diastolic murmur due to aortic regurgitation, and a mid-diastolic murmur
heard in mitral stenosis.
The early diastolic murmur of aortic regurgitation is
high-pitched with a characteristic decrescendo character heard best at the left sternal border.
The length, not the amplitude of the murmur, indicates
the severity of the regurgitation:
a short early diastolic murmur indicates mild
regurgitation
a murmur persisting to mid diastole or greater indicates severe regurgitation.
the murmur may be enhanced by sitting the patient
forward and listening in expiration.
An early diastolic murmur heard best well to the left of
the sternum may be a sign of pulmonary regurgitation.
The mid-diastolic murmur of mitral stenosis has a
low-pitched, rumbling character, and must be sought
with the patient in the left lateral decubitus position.
159
Again, the length, not the amplitude, of the middiastolic rumble is an index of the severity of the
mitral stenosis.
It needs to be distinguished from a 3rd heart sound
(usually associated with other signs of cardiac failure), and from the Austin Flint murmur associated
with severe aortic regurgitation (associated with
other signs of aortic regurgitation such as collapsing
pulse or wide pulse pressure).
Abdomen
Examination of the abdomen from the cardiac perspective
includes:
palpation of the liver for pulsatile hepatomegaly indicating tricuspid regurgitation
gentle pressure over the liver to elicit the hepatojugular
reflux
a search for ascites and free fluid which may indicate
chronic right heart failure.
CLINICAL PEARL
A diastolic rumble is usually found with other features
of mitral stenosis; a 3rd heart sound usually has other
features of cardiac failure.
Continuous murmurs
Occasionally a continuous murmur is heard. This can
indicate a patent ductus arteriosus or other cause of aorticpulmonary connection such as from infective endocarditis,
trauma, or post-operative fistula.
It is important to recognize that these are rare, and a
continuous-sounding murmur is more likely to be due to
amore mundane cause, such as aortic stenosis and regurgitation, or a loud pericardial friction rub (see below).
Pericardial friction rubs
A pericardial friction rub can be heard anywhere over
the heart, but usually best at the left sternal border.
Pericardial rubs vary in pitch, and usually but not always
have a leathery, scratching, to-and-fro character.
They can often vary with different positions and phases
of respiration, and can be variable from hour to hour.
Respiratory examination
Chest percussion and auscultation of the chest are essential components of the clinical examination of the cardiac
patient.
Percussion can identify the presence and extent of a
pleural effusion which may be a sign of chronic cardiac
failure.
Auscultation for crackles at the lung bases and for areas
of dullness may reveal signs of cardiac failure.
While the presence of crackles does not confirm
cardiac failure, rapid resolution with diuretic treatment is a clear sign that the crackles were due to
cardiac-related pulmonary congestion, and not a
respiratory cause such as chest infection or pulmonary fibrosis. The extent of crackles (scattered only,
extensive but confined to below mid-scapula, or
throughout the whole of the lung fields) should be
documented.
The identification of whistling or wheeze may indicate that dyspnea is more likely to be due to asthma
or chronic obstructive pulmonary disease, but does
not rule out the possibility of cardiac asthma due
to pulmonary congestion.
160
INVESTIGATION OF CARDIAC
DISEASE
For the assessment and investigation of cardiac disease, many
tests can be employed, and optimal use of testing requires an
appreciation of what each test can offer. It is helpful to distinguish tests which are mainly for imaging the heart and
those which test functional capacity (Table 8-6).
The EKG is the most useful and widely used investigation for evaluating the cardiac patient. While the increasing sophistication and miniaturization of the EKG, and the
readily available automated analysis, are welcome technological developments, a clear understanding of the basics of
EKG interpretation remains essential (Table 8-7).
Table 8-6 Cardiac investigations
TEST
IMAGING
FUNCTIONAL
Electrocardiogram
(EKG)
Chest X-ray
++
Echocardiogram
+++
Exercise EKG
+++
Radionuclide
scintigraphy
++
Stress
echocardiography
++
++
Radionuclide
myocardial
perfusion imaging
++
++
Invasive coronary
angiography
+++
Coronary computed
tomography
angiography
++
Cardiac
catheterization
++
Magnetic resonance
imaging
++
++
Table 8-7 A guide to electrocardiographic (EKG) interpretation
EKG
OBSERVATION
INTERPRETATION
Quality of the tracing
Baseline stable? Minimal interference? Correct voltage standardization? Correct lead placement?
Heart rate
Heart rate: can be documented from the interpretative EKG; the simplest method is to use a heart
rate ruler or to divide 300 by the number of big squares between R waves
Heart rhythm
Regular or irregular?
Frontal axis
The normal axis is 30 to +90; left-axis deviation is < 30, right-axis deviation is > +90
P waves
Present? Normal morphology? Notched, tall?
PR interval
Normal = 120200ms
Prolonged = 1st degree atrioventricular block
Short = WolffParkinsonWhite (WPW) syndrome if associated with delta wave
Variable PR interval indicative of Wenckebach block
QRS complex
Normal duration <110ms

Notched but <120ms = intraventricular conduction defect
>120ms = bundle branch block (BBB). Tall R in V1: usually RBBB; no tall R wave in V1: usually
LBBB. Other causes of tall R wave in V1: right ventricular hypertrophy, type A WPW, true posterior
infarction
Non-pathological Q waves: can occur in lateral leads, and small narrow Q waves in inferior leads.
If in doubt, may need echocardiography for evaluation.
Pathological Q waves usually >25% of the R wave, and >40ms wide
Poor R wave progression or QS waves in anterior leads: may indicate old anterior infarction, but
may be normal. Often shown to be benign on echocardiography
QT interval
Measure QT and QTc (corrected QT interval)

Abnormal QTc in an adult male is >450ms, and in an adult female >470ms
ST segment
ST-segment elevation: physiological ST elevation in anterior leads and early repolarization usually
<2mm
Abnormal ST elevations:
ST elevation concave upwards: usually pericarditis but can indicate a normal variant of early
repolarization
acute ST elevation in 2 contiguous leads with >1mm elevation in the anterior leads or >2mm in
the anterior leads is indicative of ST-elevation myocardial infarction (STEMI)
ST-segment depression: transient with myocardial ischemia; permanent with left ventricular
hypertrophy, digoxin effect
T wave
Minor T wave inversion can be due to multiple causes, including electrolyte disturbances,
hyperventilation, and certain drugs. The most common cause is myocardial ischemia
Deep T wave inversion: acute myocardial ischemia, but other causes include intracerebral events,
hypertrophic cardiomyopathy
Tall peaked T waves: acute ischemia or hyperkalemia
U wave
Usually hypokalemia, but may be normal
Localization of
myocardial damage
The localization of EKG abnormalities:

inferior: II, III and aVF
lateral: aVL, V5, V6
anterior: V2V5
161
Exercise EKG stress testing (EST)

The EST is a well-validated diagnostic procedure in
which exercise is used to increase myocardial oxygen
demand, and continuous EKG is used to detect evidence of myocardial ischemia or arrhythmia.
The exercise EKG is frequently used to evaluate a
patients risk of coronary heart disease, but is also
useful to reveal residual myocardial ischemia after a
coronary event or intervention.
It can also be used to assess cardiac arrhythmias, and
to assess functional capacity in patients with valvular heart disease and inform timing of intervention.
It is widely available and relatively inexpensive.
It is relatively safe, but deaths or myocardial infarctions
can occur in up to 5 per 100,000 tests.
Complications can be minimized by adherence to
the usual safety and quality standards, with particular emphasis on assessment of symptoms and meticulous monitoring of EKG changes.
In modern practice, continuous monitoring of the
12-lead EKG is standard, and careful surveillance
for cardiac arrhythmias and systolic blood pressure
is essential.
Exercise testing can be done with a bicycle ergometer or
treadmill protocol. The most widely used protocol is the
Bruce Treadmill Protocol with an increase in workload
each 3 minutes.
Drugs can affect the exercise test result. Beta-blockers
affect the heart rate response to exercise, and may mask
the EKG or symptomatic response to exercise. Digoxin
can affect the shape of the ST segments.
The shape of the ST-segment depression can provide useful clues (see Figure 8-2). If the ST-segment
depression is up-sloping, it is less significant than flat or
down-sloping depression.
The greater the extent of ST-segment depression, the
greater is the likelihood of myocardial ischemia. STsegment depression of >2 mm is usually taken to be a
strong indication of myocardial ischemia. If the abnormality persists for >5 minutes and occurs during recovery, this indicates more-severe disease.
There are important caveats in interpreting ST-segment
changes with exercise. Females often have more labile
ST segments, and can have normal coronary arteries even with an exercise test showing >2 mm of STsegment depression.
ST-segment elevation may indicate acute myocardial
ischemia, and is an indication for immediate cessation of the
test and careful post-exercise monitoring.
T wave changes with exercise are common and not
usually indicative of myocardial ischemia; however, extensive deep T wave inversion, particularly if persistent, can be
a marker of extensive ischemia.
Cardiac arrhythmias are common with exercise. The
development of short runs of ventricular tachycardia may be
of no clinical significance.
CLINICAL PEARL
Exercise EKG interpretation requires not only careful
analysis of the exercise EKG, but also observation of
clinical state during exercise, blood pressure response,
and exercise duration.
EKG criteria
ST-segment depression on exercise electrocardiography
can be indicative of underlying myocardial ischemia, but
needs to be interpreted with care.
Abnormal
Other clinical observations

While the EKG provides crucial diagnostic data, other observations are important in interpreting the exercise EKG.
Borderline
Upsloping
Flat or down sloping
J-junction
(ST0)
Flat or down sloping

deviation greater than
or equal to
1.0 mm is Abnormal
Flat or down sloping deviation

greater than or equal to
0.5 mm and less than 1.0 mm
is Borderline
Slope is determined over

60 msec (1.5 boxes)

60 msec (1.5 boxes)
ST deviation amplitude is
relative to the isoelectric
line and measured at the
J-junction
ST deviation amplitude is
relative to the isoelectric
line and measured at the
J-junction
Flat
Downsloping
(worse)
(ST60)
J-junction
(ST0)
Isoelectric line
Upsloping depression with
ST60 greater than or equal
to 2.0 mm is Borderline
Flat
Downsloping
(worse)
(ST60)

60 msec (1.5 boxes)
Note: to be borderline, ST
depression at ST0 must be
greater than 2 mm
J-junction
(ST0) (ST60)
Figure 8-2 Interpretation of the exercise electrocardiogram

From Fletcher GF et al. AHA Scientic Statement. Exercise standards for testing and training: a statement for healthcare professionals.
Circulation. 2001;104:16941740.
162
The patients symptoms and their response to exercise

need to be carefully recorded. The development of
typical angina with exercise is diagnostic of ischemia,
but other chest pains may develop from other causes,
e.g. musculoskeletal pain. Careful interpretation and
observation can provide valuable information.
The blood pressure response to exercise is usually a
steady rise with increasing exercise, but an exaggerated
response may have adverse prognostic significance.
A drop in blood pressure of >10 mmHg can indicate
extensive myocardial ischemia, and is an indication for
prompt cessation of the test.
Observation of the patient for dyspnea, pallor, cyanosis
and facial expression indicating distress can all provide
valuable diagnostic clues.
Sensitivity, specicy and predictive value

The sensitivity (percentage of persons who have disease who will have a positive test) and specificity (percentage of persons who do not have disease who will
have a negative test) of the exercise EKG depend largely
on the type of patient undergoing the test.
The positive predictive value (percentage of those
with or without disease who are identified correctly) is
high in patients who are likely to have coronary artery
disease (CAD), e.g. those with multiple risk factors or
suggestive symptoms.
The use of the exercise EKG is not recommended as a
screening test in the large number of persons at low risk
in the community.
With careful selection of patients, careful conduct of
the test, and informed interpretation, the exercise EKG
continues to provide valuable information despite
the rapid growth of more technologically advanced
procedures.
Chest X-ray (CXR)

A CXR allows structural assessment of the heart in relation to the other organs within the thoracic cavity and
mediastinum.
Cardiomegaly, aortic root abnormalities, and valvular
calcifications can be identified, but this assessment has
been largely supplanted by echocardiography in modern
practice.
Pulmonary abnormalities that are a result of cardiac dysfunction, such as acute pulmonary edema and pleural
effusions, can be identified on CXR (see Figure 8-3).
CLINICAL PEARL
An important role of the chest X-ray is to identify the extent
of pulmonary congestion and the response to treatment.
Echocardiography
Echocardiography is now the most widely used imaging
procedure in cardiology. It has the advantage of being relatively inexpensive and readily available. With modern echocardiographic equipment, reliable imaging can be obtained
at the bedside even in a critically ill patient.
Echocardiography relies on reflection and processing of
ultrasound waves from the cardiac structures.
The ultrasound probe is placed on the patients chest,
and emits and receives high-frequency ultrasound.
Probes of 2 to 10 megahertz (MHz) are usually used for
echocardiography; higher frequencies achieve greater
definition, but at the loss of tissue penetration.
The ultrasound waves are then processed into M mode
(assessing motion in a single narrow view) or into a
two-dimensional image which represents the moving
cardiac structures (2D echo).
Figure 8-3 Chest X-ray in patient with pulmonary edema (left), showing shadowing and bats wing congestion
appearance; and after treatment (right)
Image courtesy of Dr Angela Worthington
163
More recent processing developments have enabled the

development of three-dimensional echocardiography,
which can provide remarkable anatomical detail for particular views of the heart. This has been of advantage
in the analysis of complex congenital heart disease, and
the planning and monitoring of valve function during
mitral valve surgery.
The addition of Doppler imaging and analysis allows the
pattern of blood flow and tissue movement to be analyzed.
The Doppler signal can be displayed as a black and white
spectral image display equivalent to flow, or color-coded
using the convention of motion towards the transducer =
red, motion away from the transducer = blue.
A fully optioned modern echocardiographic examination therefore uses a combination of 2D echocardiography with Doppler color-flow imaging.
CLINICAL PEARL
In viewing Doppler ow images on echocardiography,
red = ow towards the transducer, blue = away from
the transducer.
The usual transthoracic echocardiogram is performed with

imaging from the left parasternal area, apical area, suprasternal area and subcostal area.
The left parasternal long-axis view can provide valuable
information equivalent to a sagittal section from the
apex to the origin of the aorta.
The left parasternal short-axis view can provide
cross-sectional imaging of the left ventricular chamber
and en face views of the mitral valve and aortic valve.
Apical views are usually used to analyze the left and right
ventricular shape and function.
Subcostal views are particularly valuable for assessing
pericardial disease, and suprasternal imaging is used for
assessing the anatomy of the ascending aorta and aortic
valve.
Transesophageal echocardiography (TEE) provides
remarkably high-resolution images of the cardiac chambers,
particularly of the left atrium (including left atrial appendage), mitral and aortic valves. This is of particular value in
assessing left atrial appendage thrombus formation.
CLINICAL PEARL
Transesophageal echocardiography is invaluable for
assessment of the mitral valve, and thrombus in the left
atrial appendage.
Stress imaging with exercise or intravenous dobutamine

(stress echo) can provide valuable information on wallmotion abnormalities and assess whether there is inducible
ischemia as a result of the stress.
Even further miniaturization of ultrasound probes has
resulted in the capacity for intracardiac imaging (ICE)
and intravascular imaging (IVUS) for imaging the interior of the coronary arteries.
164
Enhancement of the images can be obtained by injection of agitated saline to identify microbubbles passing
across intracardiac shunts.
The use of ultrasound contrast media can be employed
for the enhancement of left ventricular endocardial borders, to better define global and regional systolic function.
Major uses of echocardiography

Analysis of systolic function of the left ventricle
Global left ventricular function is usually expressed as
the left ventricular ejection fraction (LVEF), calculated
from the left ventricular end-diastolic volume (LVEDV)
minus the systolic volume (LVESV), divided by the
diastolic volume (LVEDV), i.e. (LVEDV LVSEV)/
LVEDV.
Regional wall motion is graded as normal, hypokinetic
(reduced systolic function), akinetic (no wall motion),
or dyskinetic (paradoxical outward rather than inward
motion). An akinetic segment of left ventricular wall is
usually echogenic, indicating scar tissue.
The thickness of the heart muscle can be identified (usually no greater than 1 cm in the septum and posterior
walls), and the left ventricular mass overall calculated.
Left ventricular diastolic function
On occasions, systolic function may be within normal limits but the left ventricle is pumping inefficiently
because of reduced compliance or stiffness of the left
ventricle. This can be associated with a variant of cardiac failure (heart failure with preserved systolic function [HFPSF], also known as heart failure with preserved
ejection fraction [HFPEF]). This may occur in infiltrative
processes or with significant left ventricular hypertrophy.
Measurement of diastolic dysfunction is complex; it is
usually measured from the rate of inflow during mitral
valve inflow.
CLINICAL PEARL
Echocardiography is an essential tool for the assessment of left ventricular function and should be performed in every patient suspected of cardiac failure.
Assessment of the right ventricle

Patients with advanced left-sided valvular heart disease or
pulmonary hypertension need careful evaluation of their
right ventricular function.
Intracardiac masses
Intracardiac tumors or thrombus can be readily identified
and monitored on echocardiography.
Pericardial disease
Echocardiography is of particular value in assessing the presence of a pericardial effusion, and whether it is associated
with cardiac tamponade.
Assessment of the cardiac valves

Tricuspid valve. A minor degree of regurgitation
through the tricuspid valve is physiological. Significant
tricuspid regurgitation may reflect tricuspid valve abnormality, dysfunction of the right ventricle, or increased
pulmonary artery pressure. The pulmonary artery pressure can be estimated indirectly from the flow through
the tricuspid valve during regurgitation.
Pulmonary valve. The pulmonary valve is well imaged
with several echocardiographic views.
CLINICAL PEARL
Trivial pulmonary and tricuspid regurgitation are often
seen on echocardiography and are not signicant.
Mitral valve. The mitral valve is well seen in transthoracic echocardiography (TTE), but even more clearly
with transesophageal echocardiography (TEE). In the
left parasternal long-axis view, the mitral valve apparatus
and the anterior and posterior valve leaflet morphology
and motion can be examined in detail.
The degree of mitral regurgitation can be measured
by assessment of the Doppler flow signal.
Mitral stenosis can be suspected from reduced
motion of the leaflets on the parasternal long-axis
views, and confirmed by planimetry on the parasternal short-axis view.
The pattern of inflow through the mitral valve can
be calculated to estimate the degree of diastolic
dysfunction.
A degree of calcification in the mitral annulus is
normal and increases with age.
TTE with 2D and 3D imaging is frequently used
before and during mitral valve surgery to assess
which leaflets require repair, and to guide the surgical approach.
Aortic valve. The aortic valve is well visualized in both
parasternal and apical views.
The degree of thickening and the mobility of the
valve can be assessed with the 2D views, but the
function of the valve and the extent of stenosis or
regurgitation needs assessment of the Doppler colorflow images, and detailed analysis of the Doppler
spectral data.
The transvalvular velocities are used to calculate the
peak and mean gradients, and, with consideration of
the stroke volume, the valve area can be calculated.
The best parameter for monitoring the progress of
aortic stenosis remains undetermined, but in practice peak velocity, gradients, valve area, and symptoms are all evaluated in deciding on the timing of
intervention.
The assessment of aortic regurgitation also requires
careful evaluation of the 2D echo and the Doppler
flow analysis. Most echo labs report the degree of
regurgitation as trivial (minimal jet), mild (visible
regurgitation into the ventricle), moderate (regurgitation reaching the mid-ventricle) or severe (regurgitation towards the apex of the left ventricle).
Assessment of the aorta

The parasternal and apical echo windows do not allow for
assessment of more than the aortic root, coronary sinuses
and the first 34 cm/11.5 in of the ascending aorta. The
normal aortic root in adults should not exceed 3.6 cm/1.4
in. The Doppler technique can be used to assess a gradient
within the aorta and may allow the diagnosis of aortic coarctation. A more detailed assessment of the ascending aorta
and arch may require computed tomography (CT) or magnetic resonance imaging (MRI).
Assessment of congenital heart disease
Echocardiography has been a major advance in the evaluation of congenital heart disease.
The most common anomaly, foramen ovale, can be
recognized from careful examination of the interatrial
septum. The anomaly is recognized with increasing frequency with improving technical imaging capability. It
is a benign finding, but has been associated with stroke,
transient ischemic attack (TIA), and migraine.
A bicuspid aortic valve is usually recognized from a typical bicuspid appearance of the valve on the parasternal
short-axis view.
An atrial septal defect may be recognizable from identifying a defect in the interatrial septum, but requires
imaging after intravenous injection with agitated saline
for accurate assessment. The passage of micobubbles
across the interatrial septum confirms the location and
size of the defect. Evidence of right ventricular overload
can further confirm the presence of a large defect.
Ventricular septal defects, being associated with a
high-velocity jet, are usually recognized from analysis of
the Doppler signal, particularly in the substernal views.
Contrast echocardiography
Contrast agents which release microbubbles on contact
with the ultrasound beam can be used to enhance the
blood pool, and are of particular value to enhance endocardial borders in difficult-to-image patients, including
during stress echocardiography.
Contrast agents are also used to image for specialized conditions which may not be clear on standard
imaging, including left ventricular non-compaction,
an apical variant of ventricular hypertrophy, or structural complications of myocardial infarction such as
pseudo-aneurysm.
Contrast echo has been of particular value in distinguishing apical shadowing suggestive of apical thrombus
from physiological appearances, and for cardiac tumors.
Exercise (pharmacological) stress

echocardiography (ESE)
Exercise stress echocardiography (ESE) is a functional test
that aims to detect changes in cardiac function between
rest and exercise. This is usually done by displaying images
simultaneously on the screen (quad screen display) to compare before and after images in different views.
165
It is commonly used for the assessment of myocardial

ischemia, but can also be used for the functional assessment of moderate aortic stenosis, diastolic function and
pulmonary artery pressures.
Standard echocardiographic images of the left ventricle
are taken from different imaging windows at rest, and
the patient is then exercised to their peak capacity using
a treadmill or bicycle. Repeat images are then taken at
the peak of the patients exercise. If pulmonary pressures, valvular gradients and diastolic parameters are of
interest, these are also included in both the resting and
peak acquisition phases.
If the patient is unable to exercise, for reasons such as
orthopedic limitations, frailty or chronic illness, dobutamine can be used to stimulate tachycardia.
Radionuclide myocardial perfusion

imaging
Radionuclide myocardial perfusion imaging uses
technetium-99m or thallium. Both are taken up by the
myocardium, and the flow through the myocardial tissue
is detected by a gamma scanner which creates an image of
multiple planes and segments.
The test is conducted in two stages: a stress stage at which

time the radionuclide is injected, and a post-stress stage
which is usually 4 hours after stress to allow restoration
of resting conditions. The stress stage employs either a
treadmill/bicycle ergometer or a chemical agent, such as
dipyridamole, adenosine or dobutamine, to stimulate
tachycardia and thus myocardial oxygen demand.
Radionuclide myocardial perfusion imaging is typically
done when there is doubt about the interpretation of
the stress EKG, to distinguish viable from non-viable
myocardium, or when the functional significance of a
coronary stenosis is being evaluated.
The resting and stress images are compared to detect
defects in arterial perfusion during the stress phase.
Decreased perfusion during the stress phase represents
arterial disease, whereas a defect at both stress and rest
indicates infarcted myocardial tissue (see Figure 8-4).

catheterization
Coronary angiography is performed by the injection of
radio-opaque contrast into the coronary arteries to identify
their anatomy. The coronary artery nomenclature as seen in
the usual projections is shown in Figure 8-5, and the appearances on angiography are seen in Figure 8-6.
It is used for the diagnosis of CAD, and it also enables
the insertion of coronary artery stents.
When stents are inserted, the procedure is termed percutaneous coronary intervention (PCI).
Left anterior oblique
Right anterior oblique

1
1
5
4
5
5
5
6
1. Left main
2. Left anterior descending
(LAD)
3. Circumflex
4. Diagonals
5
5. Septals
6. Obtuse marginals
4
2
3
Left anterior oblique
Right anterior oblique

1
2
1. Sino-atrial (SA) nodal
2. Conus
3. Right ventricular (RV)
branch
4, Acute marginals
5. Postero-lateral ventricular
(PLV) branch
6. Posterior descending
artery (PDA)
Figure 8-4 Radionuclide myocardial perfusion

scans; stress images are in the upper rows and
delayed images (4 hours later) in the lower rows.
There are extensive anteroseptal and lateral defects
(white arrows) with near-total restoration of blood
ow 4 hours post exercise (red arrows). Coronary
angiography conrmed severe stenoses in the left
anterior descending artery, moderate disease in the
mid circumex artery, and severe disease in the distal
right coronary artery
Figure 8-5 Nomenclature of the coronary arteries in

the typical coronary angiography projections
Image courtesy of Dr Geoffrey Bower, Nuclear Physician, Mount

Nuclear Medicine, Perth, Australia.
From Thompson PL (ed), Coronary care manual,

2nd ed. Sydney: Elsevier Australia, 2011.
166
3
4
6
6
CLINICAL PEARL
Coronary angiography is the gold standard for assessing coronary artery disease. Its main limitation is that it
images the lumen and cannot estimate the extent of
disease in the wall of the vessel.
Figure 8-6 Normal coronary arteries. The left coronary

artery system as seen on coronary angiography is
shown in A and B. In the right anterior oblique (RAO)
view (A) the vertebral column is to the left of the cine
frame, and in the LAO view (B) it is to the right. In both
projections, the circumex artery is adjacent to the
vertebral column; the left anterior descending artery
reaches the cardiac apex. The right coronary artery
system and its branches is shown in C and D
From Thompson PL (ed), Coronary care manual, 2nd ed. Sydney:
Elsevier Australia, 2011..
Cardiac catheterization involves insertion of catheters

into the chambers of the heart or great arteries to allow pressure assessment and size analysis of these chambers.
When catheters are placed into the left ventricle and
aorta, this is called left heart catheterization (LHC),
whereas when placed in the right ventricles and pulmonary artery it is called right heart catheterization (RHC).
Bedside insertion of a right heart catheter can allow
measurement of pulmonary artery pressure, by inserting the SwanGanz catheter into the pulmonary artery,
inflating the balloon at the tip, and feeding the balloon
forward until it wedges into a sub-segmental pulmonary
artery. The balloon occludes any forward blood flow,
obliterating the pressure from the right ventricle, and
can measure the pulmonary capillary wedge pressure
(PCWP).
Coronary CT angiography (CTCA) and

calcium scoring
Coronary computed tomography angiography (CTCA) is
becoming more readily available, and has a role in identifying the extent of coronary artery disease without the need
for invasive catheterization (Figure 8-7). However, the technique does require injection of contrast medium and may be
contraindicated in the presence of renal dysfunction.
Interpretation of the images requires a high level of
skill, and limitations include perturbing of the CT image
Figure 8-7 (A) Coronary angiogram showing severe stenoses in the left anterior descending (LAD) artery, with
very poor distal ow in the artery, of a patient with an acute STEMI (ST-elevation myocardial infarction). (B) The
same patient following balloon angioplasty and stenting of the LAD lesion
Images courtesy of Dr Angela Worthington.
167
by calcification, and over-interpretation of the severity of

narrowing. Nevertheless, CTCA has proven to be of assistance in the urgent assessment of patients with chest pain,
and is being increasingly used as an alternative to invasive
angiography to detect the presence or absence of coronary
atherosclerosis.
Coronary calcification scoring has been shown to be an
accurate index of prognosis, adding incremental information to the assessment of coronary risk factors.
A normal calcium score on CT indicates freedom from

coronary disease, and is an excellent indicator of a
good medium-term prognosis.

Cardiac MRI performs both static and dynamic imaging of the heart, allowing precise assessment of structure
and of volumes, plus very sensitive analysis of myocardial tissue.
It is primarily used in the assessment of complex congenital heart disease, infiltrative heart disease, and
cardiac tumors or thrombi.
While it is capable of distinguishing healthy from ischemic from scarred myocardium, the complexity and cost
of MRI means that it is not routinely used in the assessment of acute ischemia.
It can be used for the assessment of myocardial viability in the context of chronic ischemia being assessed
for revascularization. The injection of gadoliniumenhanced contrast is of particular use in assessing myocardial scarring.
CLINICAL PEARL
Cardiac MRI has an important role in assessing brosis
and prognosis in cardiomyopathies.
DYSLIPIDEMIA
The strong relationship between cholesterol levels and cardiovascular outcome has been well known for decades.
Meta-analysis of observational studies has shown that
each 1 mmol/L lower of total cholesterol is associated
with a reduced risk of cardiovascular events: by a half for
those aged in their 40s, a third for those in their 50s and
a sixth for those in their 70s and 80s. The relationship is
linear, with no apparent threshold for an increase in risk
in any level of cholesterol or age group (Figure 8-8).
Statin therapy can safely reduce the 5-year incidence of
major coronary events, coronary revascularization and
stroke by, on average, about one-fifth for each mmol/L
reduction in low-density lipoprotein (LDL) cholesterol.
168
8089
256
128
7079
64
6069
Hazard ratio (95% Cl)
CLINICAL PEARL
Age at risk
(years)
32
5059
16
4049
8
4
2
1
0.5
4.0
5.0
6.0
7.0
8.0
Usual total cholesterol (1mmol/L)
Figure 8-8 Ischemic heart disease mortality (33,744

deaths) vs usual total cholesterol; meta-analysis of
61 observational studies. Note that the scale is log
linear, with each mark on the vertical axis indicating
a doubling of risk
From Prospective Studies Collaboration, Blood cholesterol and
vascular mortality by age, sex, and blood pressure: a meta-analysis
of individual data from 61 prospective studies with 55,000 vascular
deaths. Lancet 2007;370:182939.
CLINICAL PEARL
For each 1 mmol/L of LDL lowering with statin therapy,
the risk of coronary events and stroke is reduced by
about 20%.

Lipid fractions vary greatly in size and density.
They are transported by circulating lipoproteins.
The protein structure that carries the lipid is referred
to as the apoprotein. The apoproteins responsible for
each of the circulating lipoproteins are summarized in
Table 8-8.
CLINICAL PEARL
Atherogenic lipoproteins are carried on ApoB, and
antiatherogenic lipoproteins are carried on ApoA. A
mnemonic is B = Bad, A = AOK.
Table 8-8 Circulating lipids and their related

apoproteins
CIRCULATING LIPID
MAJOR APOPROTEIN
Chylomicron
B48
Chylomicron remnants
B48, E
VLDL (very-low-density
lipoprotein)
B100
IDL (intermediate-density
lipoprotein)
B100, E
LDL (low-density
lipoprotein)
B100
HDL (high-density
lipoprotein)
A-I, A-II
Lipoprotein(a)
B100, (a)
From Miller M et al. Triglycerides and cardiovascular disease:

a scientic statement from the American Heart Association.
Circulation 2011;123:2292333.
Which lipid should be measured?

Total cholesterol predicts coronary risk in large
cohorts, but the wide distribution of total cholesterol
levels and variations in serial testing make individual risk stratification based on total cholesterol alone
unreliable.
The total cholesterol level includes low-density
lipoprotein (LDL) and high-density lipoprotein
(HDL) cholesterol, combining atherogenic and
possibly protective fractions.
Low-density lipoprotein (LDL) cholesterol
LDL is generally regarded as the atherogenic lipid
fraction. It is usually recommended for more accurate risk assessment, and is a valid predictor of coronary risk.
Its role in atherogenesis has been confirmed by
many trials showing that lowering LDL reduces
risk. However, the measurement LDL-C most
widely used in clinical practice is a derived measurement calculated from the Friedewald equation
[LDL cholesterol = total cholesterol HDL cholesterol (triglyceride (mmol/L) 0.45)]. The estimation of LDL cholesterol by this method requires a
fasting sample for accurate measurement of the triglyceride level, and is invalid if the triglyceride level
is too high.
Direct measurement of the main apolipoprotein
of LDL, ApoB100 (usually abbreviated to ApoB),
can overcome these difficulties. It does not require
fasting and has been shown to be a more reliable
predictor of risk than indirectly measured LDL
cholesterol.
Non-HDL cholesterol (= total cholesterol minus
HDL cholesterol) overcomes the difficulty that
triglycerides can perturb the derived LDL cholesterol

measurement, but despite several guidelines recommending its wider use it is not currently used as a routine replacement for estimating LDL cholesterol.
High-density lipoprotein (HDL) cholesterol is
related inversely and independently to risk (i.e. even
after adjustment for other risk factors). Multiple studies
have confirmed the inverse linear relationship to future
coronary risk, including patients taking statins and with
low levels of LDL cholesterol.
This is widely interpreted as being due to the role of
HDLs in reverse cholesterol transportation, but it is
increasingly appreciated that HDL cholesterol has
relevant antioxidant, anti-inflammatory, and antithrombotic properties.
Despite its key role in limiting atherogenesis, elevation of HDL cholesterol in clinical trials has not
shown any benefit. Measurement of the major apolipoprotein of HDL cholesterol, ApoA-I, may offer
more specific information.
CLINICAL PEARL
Increased HDL levels are associated with an apparent
protective effect, but to date it has not been possible to
reduce risk by raising HDL.
Triglyceride measurements correlate with cardiovascular risk, but interpretation of the role of triglycerides
is confused because of multiple confounding associated
risk factors, especially obesity, and other features of the
metabolic syndrome and diabetes.
Adjustment for these confounding factors flattens
the relationship between triglyceride measurements
and cardiovascular disease outcomes.
Triglyceride itself is non-atherogenic, but the
correlations between risk and triglyceride measurement may reflect atherogenic remnants of chylomicrons and VLDLs.
There is evidence that an elevated triglyceride level
increases the risk of cardiovascular disease when
associated with a low HDL cholesterol level.
Apolipoproteins
Apolipoprotein B100 (ApoB) is the chief protein in the
atherogenic VLDL, IDL and LDL particles.
Plasma ApoB levels reflect total numbers of atherogenic
particles.
ApoA-I is the major apolipoprotein constituent of the
anti-atherogenic HDLs.
The measurement of the apolioproteins has significant
advantages in more accurate prediction; it avoids the need
for a fasting sample, but testing is not widely available.
Ratios
The total cholesterol:HDL cholesterol ratio may offer a
more accurate prediction of risk.
169
The ratio of ApoB:ApoA-I was an excellent predictor

of risk in a large international study, and the use of a
non-fasting blood sample in large community studies is
an obvious advantage.
CLINICAL PEARL
CLINICAL PEARL
All patients with established cardiovascular disease
should be on a statin if possible.
A widely used target for patients with coronary heart
disease is to lower LDL cholesterol to <1.8mmol/L
(<70mg/dL).
The ratio of ApoB:ApoA-I is a good predictor of risk and

can be used without fasting.
Normolipidemia in patients with a high risk

of CVD
Dyslipidemia and cardiovascular

disease (CVD)
It is important to recognize that treatment decisions are not
made on the basis of a single measurement of cholesterol or
LDLs. The clinical setting and cardiovascular risk level need
to be considered carefully. However, the higher the level of
LDL cholesterol, the greater the need to institute therapy
(Figure 8-9).
Normolipidemia in patients with established

CVD
Patients with established CVD are at very high risk of
progression of atherosclerosis and future cardiovascular
events irrespective of their lipid levels.
There is convincing evidence from clinical trials that all
patients with CVD should be treated with a statin.
The clinical trials which have guided this conclusion
have shown that the lower the better is probably correct, with no evidence of a safe baseline level of LDL
cholesterol.
A widely used target level for significant reduction of
risk is <1.8 mmol/L (<70 mg/dL), or a 50% reduction in
LDL cholesterol when this target cannot be reached.
Total CV risk
(SCORE)
%
Treatment decisions for patients with a high absolute risk

of CVD are made similarly to those with established CVD.
Those patients with a 5-year absolute risk of CVD events
of >10% (based on calculation of risk based on age, gender, cholesterol or LDL level, HDL level, systolic blood
pressure and smoking habit) should be commenced on a
statin.
The target level for high-risk patients is similar to that
for patients with established CVD.
In patients at moderate risk (510%), an LDL cholesterol goal of <3.0 mmol/L (less than 115 mg/dL) should
be considered.
CLINICAL PEARL
Patients at high risk (absolute 5- to 10-year risk of CVD
event of >10%) should be started on a statin.
Non-CVD patients with fasting LDL

>3.5 mmol/L (135 mg/dL)
The usual causes of elevated LDL at this level are inappropriate dietary habits, polygenic hypercholesterolemia,
LDL-C levels
<70 mg/dL
<1.8 mmol/L
70 to <100 mg/dL
1.8 to <2.5 mmol/L
100 to <155 mg/dL

2.5 to <4.0 mmol/L
155 to <190 mg/dL

4.0 to <4.9 mmol/L
>190 mg/dL
>4.9 mmol/L
No lipid
intervention
No lipid
intervention
Lifestyle intervention
Lifestyle intervention,
consider drug if
uncontrolled
1 to <5
consider drug if
uncontrolled
consider drug if
uncontrolled
consider drug if
uncontrolled
>5 to <10, or
high risk
consider drug
consider drug
and immediate
drug intervention
and immediate
drug intervention
and immediate
drug intervention
10 or very
high risk
consider drug
and immediate
drug intervention
and immediate
drug intervention
and immediate
drug intervention
and immediate
drug intervention
<1
Figure 8-9 Lipid treatment in patients with cardiovascular risk

Adapted from Perk et al. The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice. ESC recommendations for treatment based on LDL. Eur Heart J 2012;33(13):16351701.
170
or mixed dyslipidemia (i.e. elevated LDL with elevated

triglyceride/VLDL).
Initial treatment is with a low-fat diet, and if the LDL
level remains high then statin therapy should be started.
Very high LDL cholesterol, >5.0mmol/L

(190mg/dL)
In these patients, a genetic disorder such as familial
hypercholesterolemia is very likely.
There may be non-vascular deposition of xanthomas or
xanthelasma.
Family testing to detect affected relatives should be routine in these patients.
Elevated triglycerides
May be caused by:
obesity and overweight
physical inactivity
excess alcohol intake
high-carbohydrate diet (>60% of energy intake)
type 2 diabetes
chronic renal failure
nephrotic syndrome
drugs (corticosteroids, estrogens, retinoids, higher doses
of beta-blockers)
genetic dyslipidemias.
Triglyceride level ranges are:
normal <1.7mmol/L (<150 mg/dL)
borderline high 1.72.2 mmol/L (150199 mg/dL)
high 2.25.6 mmol/L (200499 mg/dL)
very high >5.6 mmol/L (>500 mg/dL).
CLINICAL PEARL
Markedly elevated triglycerides can often be lowered
with cessation of alcohol intake and reduction of carbohydrate intake.
Low HDL cholesterol

A low HDL cholesterol level is defined as <1.0 mmol/L
(<40 mg/dL).
It may be associated with an elevated triglyceride, partly
due to biochemical interactions and partly to laboratory
measurement interference.
The common causes are:
overweight and obesity
physical inactivity
type 2 diabetes
very high carbohydrate intake (>60% energy)
drugs (beta-blockers, anabolic steroids, progestational
agents).
Diet therapy
All guidelines on lipids encourage adherence to a low-fat
diet, regular exercise, and weight reduction. While this
advice is sensible and an accepted part of good medical management, the clinical trial evidence shows that the benefits
are limited.
CLINICAL PEARL
While the trial evidence for reducing risk with diet is not
strong, all patients being considered for statin therapy
should have detailed dietary advice.
Statins
The statins (HMG CoA reductase inhibitors) are the
most widely used drugs for lowering LDL cholesterol.
For each 1 mmol/L reduction in LDL cholesterol due
to statin therapy, there is a significant reduction in allcause mortality and coronary mortality.
As a result, all guidelines recommend the liberal use of
statins, not only in persons with hypercholesterolemia,
but also in those with proven or a high risk of vascular
disease.
Non-statin therapies
Ezetimibe
Ezetimibe inhibits the reabsorption of cholesterol by the
intestine. It is well tolerated, and reduces the concentration
of LDL cholesterol by 1520% when given either as monotherapy or added to a statin. It is available in combination
with simvastatin.
At present, ezetimibe remains second-line treatment
for the patient who has refractory LDL elevation despite
intensive statin therapy, or who has a contraindication to
statins.
Fibrates
The LDL-lowering effect of fibrates (gemfibrozil, bezafibrate) is relatively weak, although they have a role in the
patient with hypertriglyceridemia and in the patient with
the mixed dyslipidemia which accompanies the metabolic
syndrome and diabetes.
CLINICAL PEARL
The combination of brates with statin therapy has
been associated with an increased risk of myopathy,
and close monitoring of creatine kinase is mandatory
in these patients.
Omega-3 fatty acids

Certain fish oils have high concentrations of omega-3 fatty
acids, and are widely promoted for lipid control.
171
There is some evidence that prognosis in post-coronary

patients is improved with consumption of omega-3 fatty
acids, but the effects on lipids are modest and the mechanism of the benefit remains unclear.
Lowering triglycerides
The evidence that lowering moderately elevated triglycerides
is beneficial is generally lacking.
Despite this, some guidelines, on the basis of the epidemiological association, suggest that it is reasonable to
recommend a triglyceride target of <1.5 mmol/L.
A markedly elevated triglyceride level is a significant
risk factor for pancreatitis, and this itself is an indication for treatment if the triglyceride level exceeds
5mmol/L.
Treatment of marked hypertriglyceridemia is with verylow-fat diets (15% of caloric intake), strict avoidance of
alcohol, and early institution of an effective triglyceridelowering drug such as a fibrate or nicotinic acid.
CLINICAL PEARL
Evidence for improved outcomes with all the non-statin
therapies is weak, but they are sometimes needed for
lipid control if a patient is unable to take a statin.
rapidly to unstable angina, acute coronary syndromes,

or sudden death.
New biomarkers and imaging techniques have been
developed to identify the unstable plaque, but to date no
markers are reliable enough for widespread clinical use
and have not been shown to be superior to risk stratification based on the well-recognized risk factors of
hypertension, hypercholesterolemia and smoking, all of
which have direct adverse effects on the atherosclerotic
plaque.
STABLE CORONARY ARTERY

DISEASE
Investigation
The approach to investigating the patient with suspected
CAD with stable, minimal or absent symptoms is directed
to assessing their overall cardiovascular (CVD) risk, in particular the identification of the high-risk patient who may
benefit from coronary revascularization.
Screening asymptomatic outpatients for coronary disease is not necessary in the general population, but is justified in those in certain high-risk occupations.
CLINICAL PEARL
CORONARY ARTERY DISEASE

(CAD)
Risk stratication using standard risk factors can identify

the absolute risk of cardiovascular events in the next
510 years with reasonable accuracy. This assessment
should be done before more complex risk markers are
considered.
Prevalence
Coronary heart disease is one of the most common health
disorders in modern life, accounting for nearly one-third of
all deaths. It may be silent or may manifest as angina, acute
coronary syndromes or sudden death. It is already a major
cause of disability, and the World Health Organization
has estimated that it will be by far the major health burden
worldwide within the next two decades.
Pathophysiology
Coronary artery disease is usually due to atherosclerosis.
It is now well recognized that the atherosclerotic process
is more complex than simple steady accretion of lipid
deposits, but the unpredictable clinical course of the
patient with CHD is not fully understood.
In addition to lipid deposition, the processes of cellular infiltration, degenerative and inflammatory changes,
and associated endothelial dysfunction all have the
potential for fluctuations in coronary flow.
Interactions between multiple factors in the plaque,
including a large lipid pool, thin cap, inflammatory infiltrate, and mechanical forces explain the fact that atherosclerosis is likely to increase in step-like stages, and
the patient who has been stable for months or years may
develop an unstable atherosclerotic plaque and progress
172
Initial assessment of risk factors

The initial evaluation should assess the patients risk and
the need for further investigation. It includes a detailed history, including family history, physical examination, resting
EKG, lipid profile and a marker of dysglycemia. From this,
the patient can be categorized into a low, intermediate or high
risk of a coronary event in the next 510 years.
The most widely used risk assessment protocols categorize a patients absolute cardiovascular risk by assessing
age, gender, LDL cholesterol, HDL cholesterol, systolic
blood pressure, smoking habits, and presence of diabetes
or hyperglycemia.
Other factors include a strong family or racial propensity for premature CHD, and a measure of obesity,
particularly the waist circumference or waist:hip ratio.
An example of a risk calculator (the Australian absolute
risk calculator) is shown in Figure 8-10.
Further testing for identifying coronary heart disease is
ideally determined by the patients risk assessment and
symptoms. Often the initial assessment is focused on identifying the small proportion of patients who may benefit from
revascularization to prolong survival.
The resting EKG is helpful if signs of ischemia such as
T wave inversion are identified, but the EKG is normal in
Sex
Male
Age
48
Systolic blood pressure

Smoking status
Yes
Female
years
140
mmHg
No
Total cholesterol
5.5
mmol/L
HDL cholesterol
mmol/L
Diabetes
Yes
No
ECG LVH
Yes
No
Sex
Male
Female
Age
48
Systolic blood pressure

Smoking status
Yes
Unknown
Your heart and stroke risk score is
4%
years
155
No
Total cholesterol
5.5
mmol/L
HDL cholesterol
1.0
mmol/L
Diabetes
Yes
No
ECG LVH
Yes
No
mmHg
i
Unknown
Your heart and stroke risk score is
20%
Figure 8-10 Examples of absolute risk assessment, comparing a 48-year-old female with marginal elevation of
total cholesterol and normal HDL levels with and without elevated blood pressure, diabetes and smoking
Adapted from National Vascular Disease Prevention Alliance. www.cvdcheck.org.au
the majority of patients with CHD and should never be

used to rule out CHD.
Novel risk factors

A large number of alternative risk factors have been considered, but demonstrating their incremental value over the
Framingham-derived risk factors has been challenging.
Lipid subfractions have been evaluated in detail, but
apart from Lp(a) they do not add predictive value to the
LDL and HDL levels.
Since the importance of inflammation in the development and destabilization of atherosclerosis has been
accepted, the use of high-sensitivity C-reactive protein
(hs-CRP) has been studied extensively. Despite extensive evidence that it is a valuable marker of inflammation
and by itself indicates an increased risk, it has not been
shown to be incremental to established risk factors.
Other markers of inflammation are even less predictive
than hs-CRP.
Homocysteine is a predictive marker in some studies,
but does not add incremental value to risk assessment.
CLINICAL PEARL
None of the novel risk factors have been shown to add
incremental risk prediction to the standard risk factors;
high-sensitivity C-reactive protein is now thought to be
less useful than previously thought.
Exercise EKG
Despite the wide availability of more complex and
expensive methods for assessment, the treadmill exercise test remains a very useful, widely used and relatively
cost-efficient method of identifying the patient at high
risk of having significant CHD.
The role, limitations and interpretation of the exercise
EKG are discussed in detail in the earlier section on
investigation of cardiac disease.
Since the exercise EKG depends on inducing myocardial ischemia, a significant obstructive lesion must be
present in the coronary arteries to result in a positive
test.
173
The exercise EKG is not able to identify the atherosclerotic burden of non-occlusive disease, and in particular cannot recognize an unstable plaque which may be
non-occlusive at the time of the test, but it is still capable
of initiating an acute coronary event in the future.
Alternative imaging modalities such as intravascular

ultrasound (IVUS) or optical coherence tomography
(OCT) have the advantage of identifying intramural
atherosclerosis, but the disadvantage that they require
an invasive approach.
Stress imaging studies (radionuclide

myocardial perfusion imaging and stress
echocardiography)
Stress myocardial perfusion imaging or stress echocardiography may be performed in asymptomatic patients with an
intermediate risk, or an exercise score suggesting high risk. In
patients not capable of exercise, pharmacological testing may
be required, using adenosine or dipyridamole myocardial perfusion imaging or dobutamine stress echocardiography. (See
the earlier section on investigation of cardiac disease.)
Weight control, regular exercise, tight blood pressure

control, and cessation of smoking are mandatory for
patients with stable CHD, and an improvement in the
risk factor profile is likely to improve prognosis.
A supervised exercise program improves the quality of
life for patients who are prepared to persist.
Education of the patient to report changes in the pattern
of angina is essential, as risk of an acute coronary event
is greatly increased when this happens.
Coronary artery imaging

Invasive coronary angiography is regarded as the gold
standard for the evaluation of the location and extent of
coronary artery disease (see the earlier section on investigation of cardiac disease).
Invasive coronary angiography to identify lesions suitable
for revascularization is not essential for patients with a
low overall risk who have been shown to have a normal
exercise capacity and normal left ventricular function.
Indeed, recent studies have failed to show any advantage of revascularization over medical therapy in these
patients. However, if revascularization is contemplated,
invasive coronary angiography is the modality of choice.
Newer imaging technologies are being used increasingly
for patients with suspected CHD. The calcium score on
high-speed CT scanning has been shown to add to the
Framingham risk assessment.
CLINICAL PEARL
The calcium score has been shown to add incremental value to the standard risk factors. A coronary calcium score of 0 indicates an excellent medium-term
prognosis.
Coronary CT angiography has the advantage that it is

able to identify atherosclerotic deposition in the walls of
the coronary arteries, and can identify soft (uncalcified)
plaque as well as calcified plaque. Its value for establishing the long-term prognosis has not been established,
and despite reductions in radiation exposure with modern imaging, there are still concerns about the long-term
carcinogenic effect of radiation. Identification of a heavy
atherosclerotic load may be an incentive for aggressive
management of risk factors, including LDL lowering in
a patient with a normal lipid profile.
Magnetic resonance imaging has the advantage that it
can provide additional anatomical detail, but it has not
proven to be as effective as CT imaging for coronary
imaging, and may be more suitable for monitoring atherosclerotic progression in larger vessels.
174
Risk factor management
CLINICAL PEARL
Tight control of risk factors can signicantly improve
prognosis and should be the basis of treatment in all
patients.
Antiplatelet medications
Aspirin (75325 mg daily) should be used in all patients
with coronary heart disease without contraindications.
Meta-analyses have shown that the benefit for
patients with known CHD is an absolute benefit of
25 fewer serious vascular events per 1000 patients
treated. This is similar for dosages in the range of
75325 mg per day.
There is a small risk of gastrointestinal bleeding
from daily aspirin. Although the gastrointestinal
side-effects are lower with the lower doses, daily
doses below 75 mg have not been shown to be
beneficial.
Clopidogrel has a clear role in the patient recovering
from an acute coronary syndrome or after implantation
of a coronary stent, but in stable patients it delivers marginal benefits on improving cardiovascular prognosis,
with an increased risk of bleeding.
CLINICAL PEARL
Low-dose aspirin can reduce vascular events by 25 per
1000 patients treatedone of the most cost-effective
treatments in medicine.
Newer antiplatelet agents such as prasugrel and ticagrelor have better efficacy in post-coronary patients, but
with increased risks of bleeding.
Dipyridamole has vasodilatory and antithrombotic
effects, but can exacerbate angina and should not be
used as an antiplatelet agent in coronary heart disease.
Beta-adrenergic blockers
On the basis of their potentially beneficial effects on
morbidity and mortality when used as secondary prevention in post-infarction patients, beta-blockers should
be strongly considered as initial therapy for chronic stable angina, although their role in stable patients has not
been confirmed in clinical trials.
Beta1-selective drugs are preferred, and metoprolol and
atenolol are the most widely prescribed.
If significant left ventricular dysfunction is identified, it
is preferable to use one of the beta-blockers which have
been shown to be effective in cardiac failure (carvedilol,
bisoprolol, nebivolol or extended-release metoprolol),
commencing at a low dose and titrating to response.
Lipid-lowering agents
A large number of clinical trials have shown that reduction of LDLs with statins can decrease the risk for adverse
ischemic events in patients with established coronary artery
disease.
Meta-analysis of the trials in patients with established CHD has shown that reduction of LDL cholesterol by 23 mmol/L with statins reduces risk by
about 4050%.
CLINICAL PEARL
In patients with known CHD, statin therapy can reduce
risk by 20% for each 1 mmol/L reduction in LDL cholesterol; the target should be to reduce the LDL level to
below 2 (or 1.8) mmol/L.
Evidence from clinical trials suggests that the benefit exists no matter what the baseline LDL level.
Each of the statins has been shown to be effective.
The risks of major adverse events associated with statins
are generally low, although myalgias and abnormalities
of liver function are common, and usually respond to
lowering the dose or cessation.
Risks with the widespread prescribing of statins for
CHD are still being monitored, but to date there is
no indication of any increased risk of cancer or other
adverse effects.
Myopathy is an occasional side-effect of statins, and can
be severe.
Concerns about cognitive dysfunction with statins are
widespread among patients, but there is no evidence of
this from the large number of patients included in clinical trials over the past 20 years.
Angiotensin-converting enzyme inhibitors

(ACEIs) and other inhibitors of the renin
angiotensinaldosterone system (RAAS)
The role of ACEIs in improving prognosis in stable CHD
patients is unclear.
Several trials have shown that they may have a vasculoprotective benefit in high-risk patients.
Angiotensin receptor blockers (ARBs) may be used

when the patient is unable to take an ACEI.
Aldosterone antagonists do not have a role in the asymptomatic normotensive patient who is free of cardiac
failure.
Nitrates and calcium-channel blockers

Nitrates have not been shown to improve outcomes in
patients with CAD.
Immediate-release or short-acting dihydropyridine
calcium-channel blockers increase adverse cardiac
events, and should not be used.
Long-acting or slow-release dihydropyridines may be
prescribed for hypertension without increasing the risk.
Non-dihydropyridines (verapamil, diltiazem) are contraindicated if there is left ventricular dysfunction.
Coronary revascularization
In stable CHD patients, coronary revascularization with
coronary artery bypass surgery (CABG) has been shown
to deliver clear-cut prognostic benefits in patients with
left main coronary disease or three-vessel disease with
significant left ventricular dysfunction. The benefits of
CABG in other patient groups are less clear.
Percutaneous coronary intervention (PCI) has not been
shown to deliver a prognostic benefit above optimal
medical therapy. In patients with multivessel disease
or diabetes who are suitable for either CABG or PCI,
CABG delivers a better long-term prognosis but with a
higher peri-procedural risk of stroke.
Management of symptoms in the

CHD patient
In patients experiencing angina, beta-blockers relieve symptoms by lowering the heart rate with possibly an effect on
blood pressure and myocardial oxygen consumption.
The anti-anginal effect closely correlates with the effect
on lowering the heart rate at rest, and especially on
exercise.
Occasionally, patients with conduction system disease
may develop high grades of atrioventricular (AV) block.
This usually responds to cessation of the beta-blocker,
but may indicate the need for a pacemaker.
Other side-effects include lethargy, reduced exercise
capacity due to the slow heart rate, cold peripheries,
and possible mild effects on raising of blood glucose and
LDL levels.
CLINICAL PEARL
Left ventricular dysfunction is no longer considered
a contraindication to beta-blockers, but caution is
required at commencement to avoid bradycardia and
hypotension.
175
All calcium-channel blockers have mild coronary vasodilating effects, and can be used for symptomatic relief when
beta-blockers are contraindicated.
Nitrates
Organic nitrates such as glyceryl trinitrate (GTN,
nitroglycerin) and isosorbide mono- and dinitrates are
donors of nitric oxide (NO), the potent endothelialderived vasodilator. The anti-ischemic effect results
from reduced venous return and cardiac work, and a
direct coronary vasodilating effect.
Nitroglycerin/GTN can be taken for symptoms of
angina by sublingual tablets or spray.
The sublingual tablets need constant renewal as
they are subject to sublimation with loss of the
active ingredient over 34 months, especially with
an open bottle or a plastic container and in bright
light. The spray formulation lasts longer.
Nitroglycerin/GTN should be taken immediately at the onset of angina. Relief of angina usually
occurs within 30 seconds but can be accompanied
by a headache.
The anti-anginal effect is quite short-lived, lasting
about 15 minutes.
Nitroglycerin patches can elute GTN over 1224 hours.
The effect of isosorbide dinitrate lasts about 30 minutes,
and extended-release isosorbide mononitrate (ISMN)
in a dose of 30120 mg/day has a longer duration of
actionup to 12 hours or longer.
All long-acting nitrates are susceptible to the induction of nitrate tolerance, with a progressive loss of
the beneficial effect after 24 hours of continuous
therapy. Therefore, nitroglycerin patches or ISMN
must be interspersed with nitrate-free periods of
1012 hours per day.
There is cross-tolerance between nitrates and agents
with nitrate moieties such as nicorandil (see below).
Patients should be warned that nitrates interact with
cyclic GMP phosphodiesterase, and co-administration
with sildenafil, vardenafil or tadalafil can result in severe
hypotension.
CLINICAL PEARL
Treatment with all long-acting nitrates needs to include
a nitrate-free interval of 1012 hours in each 24-hour
period.
Coronary revascularization
In many patients in modern practice, early revascularization
with percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) can be considered a first
option for patients with angina. This can deliver immediate
relief of symptoms and improved quality of life.
The choice of revascularization technique may be determined by the coronary anatomy, patient preference, or
comorbidities.
In patients who are not initially suitable for revascularization, medical therapy may need to be maximized and
then the patient reconsidered for revascularization in
light of the response.
Patients with single-vessel disease are best managed
with PCI.
Multiple-vessel disease or left main disease has been usually treated with CABG until recently, when advances
in technology have allowed these lesions to be tackled
with PCI.
CLINICAL PEARL
Multi-vessel and left main coronary disease can now be
managed with PCI, but long-term outcomes are better
with CABG, with reduced need for repeat procedures.
Novel anti-anginal agents

Ranolazine may reduce myocardial ischemia and angina
by inhibition of the late inward sodium channel (late
INa), which remains open in myocardial ischemia, and
can achieve an improvement in myocardial blood flow
without effects on heart rate or blood pressure. It can be
used to complement agents which reduce O2 demand.
The usual oral dose is 7501000 mg twice a day either
176
as monotherapy or in combination with beta-adrenergic

blockers, calcium-channel blockers or nitrates.
Nicorandil has dual effects as an ATP-dependent
potassium channel (KATP) opener with a nitrate moiety.
Opening of the KATP reduces the Ca2+ overload associated with myocardial ischemia, as well as dilating
peripheral and coronary resistance arterioles, and the
nitric oxide donor action has a coronary vasodilating
effect.
It has been shown to reduce CHF death, non-fatal
myocardial infarction, and hospital admission for
angina.
The dose is 1020mg twice daily.
Ivabradine is a member of a new class of selective
heart-rate-lowering agents that act specifically on the
sinoatrial (SA) node.
It selectively inhibits the If, a primary SA node pacemaker current, reducing the heart rate at rest and
during exercise. By this mechanism, it has been
shown to be effective in reducing angina, particularly when other therapies are ineffective.
It has also been shown to be effective in improving outcomes in patients with left ventricular dysfunction, particularly in patients with heart rates of
70beats/min or more.
The usual dose is 5mg twice daily.

In patients with apparently refractory angina symptoms
who are unsuitable for revascularization, a check on
adherence to medications can be revealing.
Errors in use of nitroglycerin/GTN and long-acting

nitrates are common.
A persistently high heart rate may reveal lack of
adherence or misunderstanding about the dose of
beta-blocker or, alternatively, undiagnosed hyperthyroidism or tachyarrhythmia.
Adjusting the timing of nitrate administration to the
period of the day when the symptoms are occurring is
essentiallong-acting nitrates cannot be possibly effective during the day if the angina occurs at night during
the nitrate-free period.
Encouraging the patient to use nitroglycerin/GTN
spray or sublingual tablets before undertaking exercise
or physical or emotional stress can help limit the frequency of distressing angina.
Other, less common causes of persistent angina include
unrecognized anemia, undiagnosed hypertrophic
cardiomyopathy, severe aortic valve disease, or pulmonary hypertension.
CLINICAL PEARL
Most patients with angina can have their symptoms
managed with medical therapy; failure to respond
to maximal anti-anginal therapy should prompt a reexamination of the diagnosis.
Undiagnosed cardiac failure may also cause refractory

angina, and empirical treatment with a diuretic may
help.
Careful review of the patient history to ensure that the
angina is not arising from the chest wall, or the gastrointestinal tract, or anxiety, may be needed.
Palliative measures with spinal cord stimulation or narcotics for pain management are rarely needed.
ACUTE CORONARY
SYNDROMES
Terminology
The patient who presents with new-onset or worsening
chest pain typical of myocardial ischemia is best treated as
having an acute coronary syndrome until proven otherwise.
The terminology of the acute coronary syndromes is
summarized in Figure 8-11. The diagnosis and subsequent
categorization demands not only a brief history, but also a
12-lead EKG.
The initial working diagnosis depends on the findings
on the EKG. If there is ST-segment elevation or new
left bundle branch block, the patient is categorized as
having an ST-elevation myocardial infarction (STEMI),
Acute coronary syndrome
Electrocardiogram
Aborted myocardial
infarction
ST or new LBBB
ST
STEMI
NSTEACS
Working
diagnosis
Troponins
STEMI
Myonecrosis
confirmed
Myonecrosis
not confirmed
NSTEMI
Unstable angina
Final
diagnosis
Figure 8-11 Classication of acute coronary syndromes. LBBB, left bundle branch block; NSTEACS, non-STelevation acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation
myocardial infarction
Adapted from White HD and Chew DP. Acute myocardial infarction. Lancet 2008;372:57084.
177
which may revert to an aborted myocardial infarction

after treatment.
If the ST segments are not elevated, the patient is categorized as having a non-ST-elevation acute coronary
syndrome (NSTEACS).
Following further evaluation with troponin levels at
6hours (normal troponin) or 34 hours (high-sensitivity
troponin), the patient is then further categorized as
having had a non-ST-elevation myocardial infarction
(NSTEMI), or unstable angina.
The rationale for the separation based on the appearance
of the initial EKG is that STEMI and NSTEACS have
a different pathophysiology, and this determines the
direction and urgency of treatment.
The definition of myocardial infarction has changed as
increasingly sensitive biochemical markers for the identification of myocardial necrosis have become available (see
Box 8-1).
CLINICAL PEARL
An elevated troponin level in a patient with chest pain
should be assumed to indicate myocardial necrosis.
Pathophysiology of acute coronary

syndromes
It is now widely accepted that the cause of acute coronary syndromes in atherosclerotic CAD is rupture of
an advanced atherosclerotic lesion with superimposed
thrombus.
The acceptance of the link between ruptured coronary plaque and coronary thrombosis has led to the
concept of the vulnerable plaque, which has a large
lipid pool, a thin cap separating the atheromatous
material from the lumen, inflammatory infiltration, activation of matrix metalloproteinases, and
reduced expression of collagen.
Box 8-1
Denition of acute myocardial infarction

Any one of the following criteria meets the diagnosis for myocardial infarction.
1 Detection of elevated values of cardiac biomarkers (preferably troponin) above the 99th percentile of the upper
reference limit (URL) together with evidence of myocardial ischemia with at least one of the following:
a ischemic symptoms
b EKG changes indicative of new ischemia (new STT changes or new LBBB)
c development of pathological Q waves in the EKG
d imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
2 Sudden unexpected cardiac death, including cardiac arrest, with symptoms suggestive of myocardial ischemia,
accompanied by new ST elevation, or new LBBB, or denite new thrombus by coronary angiography but dying before
blood samples could be obtained, or in the lag phase of cardiac biomarkers in the blood.
3 For percutaneous coronary interventions (PCIs) in patients with normal baseline values, elevations of cardiac
biomarkers above the 99th percentile of the URL are indicative of peri-procedural myocardial necrosis. By convention,
increases of biomarkers greater than 3 99th percentile of the URL have been designated as dening PCI-related
myocardial infarction.
4 For coronary artery bypass graft (CABG) in patients with normal baseline values, elevations of cardiac biomarkers
above the 99th percentile of the URL are indicative of peri-procedural myocardial necrosis. By convention, increases
of biomarkers greater than 5 99th percentile of the URL plus either new pathological Q waves or new LBBB, or
angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable
myocardium have been designated as dening CABG-related myocardial infarction.
5 Pathological ndings post-mortem of an acute myocardial infarction.
Prior myocardial infarction
1 Development of new pathological Q waves with or without symptoms.
2 Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a
non-ischemic cause.
3 Pathological ndings post-mortem of a healed or healing myocardial infarction.
EKG, electrocardiograph; LBBB, left bundle branch block.
Modied from Thygesen K, Alpert JS, Jaffe AS, et al. Joint ESC/ACCF/AHA/WHF Task Force for the Universal Denition of Myocardial
Infarction. Third universal denition of myocardial infarction. Circulation 2012;126:2020-35.
178
Rupture or erosion of the plaque usually occurs at

the surface of the eroded or thinned cap, or at the
site of maximum strain at the junction with the vessel wall.
Exposure of thrombogenic atherosclerotic material
in the ruptured or fissured unstable plaque initiates
thrombus.
The initially formed thrombus may fragment, leading to
a variable clinical course.
Accumulation of platelets over a ruptured site can lead
to further growth of the thrombus and further impairment of flow, leading to further stenosis and thrombotic
occlusion.
Limiting the formation of thrombus in the coronary
artery is a major target of modern therapy of acute coronary syndromes.
The effects on the myocardium from the reduction
in blood flow are immediate, starting with reduced
contractility.
Cardiac arrhythmias can occur in this early stage and
ventricular fibrillation, the most common cause of sudden cardiac death, may occur.
If coronary occlusion with total myocardial ischemia
persists, myocardial necrosis is inevitable.
Necrosis generally begins after 3045 minutes of
total ischemia, and is complete after 46 hours.
If reperfusion occurs in time to limit the amount of
necrosis, the size and morphology of the infarct can
be modified. Therefore, early reperfusion after coronary occlusion is a major aim of the modern treatment of STEMI.
Management of STEMI
The aim of treatment in STEMI is to achieve successful
reperfusion of the totally occluded coronary artery with
fibrinolytic therapy or PCI as soon as possible.
While comparative randomized clinical trials have
shown a clear superiority of PCI over fibrinolysis, due
to the more certain achievement of successful reperfusion (98% in PCI versus 65% in fibrinolysis), the choice
of reperfusion modality in a particular case depends on
the timing of presentation and the facilities available.
If coronary reperfusion with PCI cannot be achieved
within 90 minutes after presentation by a team experienced in emergency PCI, fibrinolytic therapy is recommended to attempt early reperfusion, albeit with a
lower rate of successful reperfusion. The basis for this
recommendation is shown in Figure 8-12.
Several agents are available for fibrinolysis, including
streptokinase, alteplase (r-TPA), reteplase, and tenecteplase. Of these, the single-bolus administration of
tenecteplase offers clear advantages.
CLINICAL PEARL
In STEMI, primary PCI is superior to brinolytic therapy
when it can be achieved in 90 minutes from presentation; otherwise reperfusion should be started with lytic
therapy.
In hospitals offering PCI, all obstacles to delaying the

door to balloon time (i.e. the time from presentation at
the emergency department to successful reperfusion in
PCI better
1.5
1.25
1.0
Fibrinolysis better
Odds of death with fibrinolysis
2.0
0.8
0.5
60
75
90
105
114
135
150
165
180
PCI-related delay (DBDN) (min)
Figure 8-12 Declining superiority of percutaneous coronary intervention (PCI) with hospital delays. This study
showed the benets crossing at 114 minutes after presentation of patient to hospital and thereafter brinolysis
achieved better outcomes. DB, door to ballon for PCI; DN, door to needle for brinolysis
From Pinto DS et al. Coronary heart disease hospital delays in reperfusion for ST-elevation myocardial infarction. Implications when selecting
a reperfusion strategy. Circulation 2006;114:201925.
179
the cardiac catheterization laboratory) should be removed

by encouraging direct transfer to the catheter laboratory.
The choice of PCI modality depends on the clinical
situation.
It is possible to achieve excellent results with a drugeluting stent (DES) as well as a bare metal stent (BMS).
The risk of re-stenosis will be reduced with the use of
a DES, but the patient receiving a DES will need to
take dual antiplatelet therapy for 12 months post-stent
insertion.
CLINICAL PEARL
Despite the urgency of the need to achieve early
reperfusion, the patients clinical situation needs to be
considered. A drug-eluting stent (DES) will require dual
antiplatelet therapy for 12 months; if major surgery is
planned, a bare metal stent (BMS) or balloon angioplasty may be preferable.
Complications of STEMI
If the period of total myocardial ischemia is prolonged,
myocardial necrosis progresses. With extensive infarction of more than 40% of the left ventricle, cardiac failure and cardiogenic shock may occur.
The severity of myocardial infarction and pump failure are often graded according to the Killip classification, with an increase in case fatality from <5% in
Killip class I (no signs of left ventricular dysfunction),
to 3040% for classes II (clinical or radiological signs
of pulmonary congestion) and III (severe pulmonary
edema), and over 80% in class IV (established cardiogenic shock without reperfusion).
Cardiogenic shock and severe cardiac failure as a
complication of STEMI have declined with wide
use of early reperfusion.
Mechanical complications including rupture of the free
wall, development of a ventricular septal defect (VSD)
from rupture of the interventricular septum, and severe
mitral regurgitation from rupture of a papillary muscle
have also declined, but are still seen.
Intra-aortic balloon pumping and inotropic therapy
have limited benefits on improving outcomes.
CLINICAL PEARL
Sudden development of a harsh systolic murmur may be
due to severe mitral regurgitation from papillary muscle
rupture or to development of a ventricular septal defect;
urgent echocardiography can distinguish the two.
Other complications of STEMI include ventricular

arrhythmias, including ventricular fibrillation and ventricular tachycardia, atrial arrhythmias, and conduction
disturbances.
Apical thrombus with the potential for stroke may occur
in the ventricle damaged by infarction or aneurysm.
In the early days post-STEMI, inflammation of the
180
epicardial surface may produce pericardial pain and a

pericardial rub.
Right ventricular infarction may occur in patients with
large inferior infarction due to occlusion of the right
coronary artery.
Subsequent to the initial injury, the infarcted tissue and the non-infarcted residual myocardium
undergo a remodeling process in which the ventricular wall becomes thinner and the infarct zone
lengthens.
Late adverse remodeling can result in dilatation of
the left ventricle or localized ventricular aneurysm
formation with late arrhythmias and cardiac failure. ACEIs have been shown to limit the extent of
adverse remodeling.
Dresslers syndrome is a late form of pericardial inflammation with marked elevation of inflammatory indices. It is treated with anti-inflammatory drugs, usually
non-steroidal, but occasionally corticosteroids are
needed.
In NSTEACS/NSTEMI, the pathophysiology differs from
STEMI and demands a different management approach.
While the initiating event of plaque rupture is common
to both STEMI and NSTEMI, in the patient presenting
with a NSTEACS it is likely that the coronary occlusion will be incomplete, and the likelihood of extensive
myocardial necrosis is less.
The major aim of treatment is to ensure that the patient
does not progress to total occlusion of the coronary
artery. Antithrombotic therapy is therefore essential.
Surprisingly, fibrinolysis has been shown to be ineffective or even harmful, possibly because of enhancement
of thrombin activity.
CLINICAL PEARL
Counter-intuitively, brinolysis is not benecial and
may be harmful in NSTEACS. Other antithrombotic
(antiplatelet, antithrombin) treatments are benecial.
The role of invasive therapy for NSTEACS has been

clarified in recent years. There is now clear evidence that
early coronary angiography and progression to coronary
revascularization if appropriate is superior to medical
management.
Angiography and PCI or CABG (if needed) are best
done during the initial hospital admission, but there
is not the same urgency as in STEMI as extensive
necrosis is not occurring.
Patients with elevated biomarkers, persistent symptoms, variable EKG changes, and hemodynamic
instability should be regarded as high risk and
undergo coronary angiography as soon as possible
after hospital admission.
Patients without these features are at lower risk
and can be managed conservatively, but should be
investigated further with exercise testing or stress

echocardiography.
Recent studies have shown that CT imaging of the
coronary arteries may be a valuable method of distinguishing low- from high-risk patients in the emergency
department.
Pharmacological therapy in acute

coronary syndromes
All patients experiencing an acute coronary syndrome
should receive the combination of drugs which have been
shown in clinical trials to improve outcomes. These are
described below.
and consistent antithrombin effect, but may increase the

risk of bleeding from invasive procedures.
CLINICAL PEARL
Switching from unfractionated heparin to enoxaparin or vice versa should be avoided because of an
increased risk of bleeding.
Many cardiac catheterization laboratories prefer to

maintain IV heparin in patients who are going to the
laboratory for catheterization or PCI, and there is
increasing uptake of the radial approach to minimize
bleeding from the groin which may occur with the femoral approach.
Aspirin
In patients not already taking aspirin, treatment should commence with 300 mg followed by 100150 mg per day. This
has been shown in large clinical trials to improve short- and
long-term outcomes by 2030%.
Other antiplatelet agents

Clopidogrel has been shown to have a benefit in
patients with acute coronary syndromes. For patients
likely to undergo PCI, a loading dose is required to
ensure platelet inactivation. 300mg has been standard
therapy, but with increasing recognition of genetic
variations in clopidogrel responsiveness, 600 mg is
increasingly used.
Prasugrel (60mg loading dose and 10mg daily maintenance) has been shown to be more effective than clopidogrel in patients in whom the coronary anatomy is
known, without the genetic variation in response but at
a higher risk of bleeding.
Ticagrelor has been shown to be superior to clopidogrel
and can be given in the early stages of an acute coronary
syndrome before the coronary anatomy is known. It also
has a higher risk of bleeding than clopidogrel.
In patients who do not receive a stent, dual antiplatelet
therapy can be continued for 12 months, although the
major effect is in the first 3 months.
In patients who receive a bare metal stent, dual antiplatelet therapy should be continued for 34 months.
In patients who receive a drug-eluting stent, dual antiplatelet therapy should be continued for 12 months.
Heparin/enoxaparin
There is strong supportive evidence for the widespread
routine use of heparin in acute coronary syndromes.
Intravenous (IV) unfractionated heparin (UFH)
can be given and has the advantage that it can be
withheld if needed, but requires monitoring of the
effect with the activated partial thromboplastin time
(APTT). The ideal APTT in acute coronary syndromes has been shown to be 6080 seconds.
Subcutaneous enoxaparin 1mg/kg twice daily has been
shown to be equally effective and gives a more potent
Beta-blockers given orally have been shown to improve
outcomes in patients with myocardial infarction, and
by extrapolation are recommended for all patients with
CHD.
IV beta-blockers may have a role in patients with persistent tachycardia or hypertension, but have been shown
to have adverse effects in patients who are hypotensive.
Metoprolol and atenolol are the most widely used
beta-blockers in this clinical situation.
Statins
Early administration of high-dose statins has been shown to
improve outcomes. The statin shown in clinical trials to be
effective is atorvastatin, given in a dose of 80 mg/day.
CLINICAL PEARL
Aspirin, beta-blockers and statins should be commenced as early as possible for all patients with STEMI
or NSTEACS.
Angiotensin-converting enzyme inhibitors

(ACEIs)
ACEIs may have some anti-atherosclerotic effect, but their
main benefit is in patients with known left ventricular
dysfunction.
Nitrates
In patients with persistent angina pain or other evidence
of ongoing ischemia, intravenously infused GTN is
used to reduce the frequency of ischemic episodes.
Nitrates can also be effective in pulmonary edema,
because of their venodilating effects.
VALVULAR HEART DISEASE

Valve disease may be of no consequence when mild, but can
cause severe symptoms and adversely affect prognosis when
severe.
181
The typical murmurs of valvular heart disease are summarized in Table 8-9.
CLINICAL PEARL
Table 8-9 Summary of the typical murmurs of

valvular heart disease
Rheumatic heart disease is the most common cause of

mitral stenosis; it is seen less commonly in developed
countries.
CAUSE
TYPICAL PRESENTATION
Mitral
stenosis
Mid-diastolic rumble heard best at the

apex with the bell or low-frequency
diaphragm of the stethoscope; the longer
the murmur, the more severe the stenosis
Mitral
regurgitation
Usually pansystolic (holosystolic) and

heard best at the cardiac apex with
radiation to the axilla
Murmurs of mitral valve prolapse may
be mid-systolic or late systolic, and are
occasionally heard better at the left
sternal border than the apex
Aortic
stenosis
Harsh, mid-pitch crescendo/decrescendo

murmur at the left sternal border with
radiation to the neck; can be loud
enough to be heard at the apex
Aortic
regurgitation
Early diastolic murmur heard best at the

left sternal border; may require expiration
or leaning forward to hear clearly; the
length, not the loudness, indicates the
severity of the regurgitation
In rheumatic MS, progressive fibrosis and calcification of the valve leaflets leads to narrowing of the valve
orifice.
With further progression, involvement of the valve
commissures and chordae disrupts valve function,
leading to obstruction of blood flow from the left
atrium to the left ventricle.
Subsequent dilatation of the left atrium can predispose to development of atrial fibrillation, and thrombus formation within the left atrial appendage.
On occasions, a hugely dilated left atrium can
impinge on thoracic structures including the left
recurrent laryngeal nerve, with dysphonia.
Increasing left atrial pressure results in pulmonary congestion with dyspnea and reduces exercise capacity.
Pulmonary hypertension may result from reactive pulmonary vascular changes, further worsening dyspnea.
Symptoms
Sudden changes in cardiac workload or heart rate, as in
pregnancy, fever and thyrotoxicosis, can bring on symptoms of MS suddenly.
The development of atrial fibrillation can suddenly
exacerbate the symptoms and lead to a rapid decline
in the clinical course of a patient with MS. Sometimes
a cardioembolic stroke can be the first manifestation
ofMS.
Pulmonary
stenosis
Soft blowing murmur heard to the left of

the sternum
Pulmonary
regurgitation
Short early-diastolic murmur;

distinguished from aortic regurgitation
because other features of right heart
overload may be present
Tricuspid
stenosis
Similar to mitral stenosis, but features of

right heart failure are very obvious
CLINICAL PEARL
Tricuspid
regurgitation
Blowing murmur at lower left or right

sternal border; increases with inspiration
There is usually a latent period of several decades from

development of rheumatic mitral stenosis to onset of
symptoms, with many patients experiencing the onset
in their 40s.
MITRAL VALVE DISEASE
Clinical signs

The incidence of MS has declined in recent decades, but
remains an important cause of disability, particularly in
developing countries and low socioeconomic groups susceptible to rheumatic fever.
Etiology and pathogenesis

Rheumatic fever is the leading cause of MS.
Post-rheumatic valvular heart disease results in predominant MS in about 40% of cases, with involvement of the aortic and tricuspid valves in the
remainder.
Rarer causes include congenital MS, and encroachment onto the mitral valve orifice from mitral valvular
calcification.
182
A malar flush with erythema and a tendency to cyanosis

over the cheeks and nose (mitral facies) is a classical
feature only seen in patients with severe MS.
On auscultation, the 1st heart sound (S1) may be
prominent. The pulmonic component of the 2nd heart
sound (P2) may be accentuated if pulmonary hypertension has developed. An opening snap can be heard if
the valve leaflets have not become heavily calcified and
immobile.
The typical auscultatory finding of MS is a low-pitched,
rumbling, diastolic murmur, heard best at the apex with
the patient in the left lateral recumbent position. Generally, the longer the murmur, the more severe the MS.
In patients in sinus rhythm, the murmur may become
louder with atrial systole, resulting in presystolic
accentuation of the diastolic rumble. This feature is not

present in patients with atrial fibrillation.
Clinical signs of right ventricular overload and tricuspid
regurgitation may be present, with hepatomegaly, ankle
edema, ascites, and pleural effusion.
CLINICAL PEARL
In mitral stenosis, the longer the murmur, the more
severe the stenosis.
Management
Many patients with MS can be managed with regular
clinical and echocardiographic review.
Patients with MS frequently adjust their activity downward with the gradual progression of their symptoms,
and may need to be pressed to accurately identify a
decline in physical capacity.
The role of anticoagulants for patients in sinus rhythm
is controversial. Patients with large left atrial size and
spontaneous echo contrast may be at risk of thromboembolism while in sinus rhythm.
Investigations
In sinus rhythm, the EKG may show features of left atrial
enlargement with notching and bifid appearance, best
seen in lead II. A large negative terminal component of
the P wave in lead V1 may be a confirmatory finding of
left atrial enlargement. With pulmonary hypertension,
right-axis deviation and right ventricular (RV) hypertrophy may be present.
The chest X-ray may show evidence of left atrial
enlargement with filling in of the gap between the aorta
and left ventricle, and straightening of the upper left
border of the cardiac silhouette. Evidence of pulmonary
congestion may be present.
Mitral stenosis is well visualized on echocardiography
in the long-axis left parasternal views, with thickening
ofthe leaflets, and reduced motion and doming of the
leaflets during ventricular filling. The left parasternal
short-axis views can visualize and measure the mitral
orifice by planimetry.
The severity of the MS is calculated from the mitral
valve orifice area and transvalvular peak and mean gradients. The mean gradient is the more reliable index of
severity in MS.
Transesophageal echocardiography (TEE) is used to
obtain more detail on the valve anatomy and function, to
assess suitability for mitral balloon valvuloplasty, and to
assess the presence of left atrial appendage thrombus.
CLINICAL PEARL
Intervention for mitral stenosis (MS) is recommended when there are symptoms, and severe
MSwith valve area of <1.5cm2.
Mitral balloon valvuloplasty is the preferred intervention for MS but is not suitable when there is signicant mitral regurgitation.
The timing of intervention depends on assessing symptoms and echocardiographic progression.

Successful valvuloplasty can halve the mean gradient
and double the valve area, accompanied by significant
improvements in symptoms.
Patients with extensive chordal involvement, significant
mitral regurgitation, and left atrial thrombus are not
considered ideal for valvuloplasty, and will need open
(surgical) mitral valvuloplasty. Surgery can clear extensive calcification and improve valve function by freeing
the scarred chordate and papillary muscles. Attempts are
made to preserve the subvalvular mitral valve apparatus.
In patients with atrial fibrillation, mitral valve surgery
is often accompanied by a maze procedure to reduce
the risk of atrial fibrillation, and oversewing of the left
atrial appendage to reduce the risk of thromboembolic
complications.

A large atrial septal defect (ASD) may be associated with
RV enlargement; however, the absence of radiographic
evidence of pulmonary congestion, the presence of a
systolic murmur over the pulmonary artery, and fixed
splitting of the 2nd sound are more indicative of ASD.
Rarely, a left atrial myxoma may obstruct the mitral
valve orifice and mimic the clinical signs of MS; however, myxoma can be identified from its characteristic
echocardiographic appearance.
CLINICAL PEARL
The Austin Flint murmur with severe aortic regurgitation can be confused with the murmur of mitral stenosis, but these patients have other obvious signs of
aortic regurgitation.
While mitral stenosis is usually a result of rheumatic fever

with a predictable clinical course, MR has multiple causes
and, because of the complex structure and function of the
mitral valve, may have a variable course.

MR can result from disruption of any component of the
mitral valve apparatusmitral valve leaflets, annulus, chordae tendineae, papillary muscles, or subjacent myocardium.
Acute MR can result from papillary muscle dysfunction or rupture in myocardial infarction, chordal rupture in myxomatous degenerative mitral valve disease,
or valve destruction in endocarditis. Transient papillary
muscle dysfunction may occur from papillary muscle
dysfunction in myocardial ischemia.
Chronic MR usually results from mitral valve prolapse (MVP) in younger patients, and ischemic heart
183
disease or extensive mitral annular calcification in older

patients.
MVP is due to myxomatous degeneration of the
mitral valve leaflets, with progressive lengthening of
the mitral chordae.
Chronic MR in ischemic heart disease may be due to
localized scarring of the papillary muscles or myocardium controlling the papillary muscles, or to generalized ischemia with functional MR as the mitral valve
annulus becomes dilated with left ventricular (LV)
dilatation and dysfunction. Other causes of myocardial dilatation such as cardiomyopathies have a similar effect.
Mitral annular calcification is an aging process exacerbated by renal dysfunction or diabetes.
Rheumatic mitral disease, less common now than previously, results in scarring and deformity of the mitral
valve leaflets and chordae.
Dynamic, variable MR can occur in hypertrophic
cardiomyopathy when there is involvement of the LV
outflow tract, and results from systolic anterior motion
of the anterior mitral valve leaflet into the high-velocity jet in the narrowed LV outflow tract; it varies
in severity with heart rate and hemodynamic loading
conditions.
Congenital MR can occur with a cleft anterior mitral
valve leaflet in ostium primum atrial septal defect.
Irrespective of the cause of the MR, the progressive enlargement of the left ventricle that accompanies MR can exacerbate the degree of regurgitation.
Symptoms
Acute MR may present with rapid onset of dyspnea or
acute pulmonary edema.
Chronic MR may be asymptomatic for years if mild to
moderate.
Chronic, severe MR may cause fatigue, exertional dyspnea, and orthopnea. Palpitations are common and may
be due to atrial ectopic beats or may indicate the onset
of atrial fibrillation.
On occasions, the presentation may be with symptoms of right heart failure with abdominal bloating due
to hepatic congestion and ascites, and with peripheral
edema.
Clinical signs
The typical clinical feature of MR is a loud, harsh systolic murmur heard best at the cardiac apex. Auscultation in the left lateral decubitus position may help to
clarify the features of the murmur.
Multiple variants on the classic pansystolic (holosystolic)
murmur may occur depending on the mechanism of the
MR. In patients with MVP, the murmur may be initiated with a mid-systolic click, followed by a late systolic
murmur.
184
CLINICAL PEARL
The usual murmur of mitral regurgitation (MR) is a harsh
apical pansystolic (holosystolic) murmur at the apex;
the chief exception to this is posterior leaet MR which
directs the jet anteriorly and the murmur is heard at the
left sternal border.
Acute MR due to valve perforation in endocarditis, ruptured chordae, or papillary muscle rupture may cause a
musical high-pitched or squeaking murmur.
Occasionally in patients with chronic severe MR with
left ventricular dysfunction, the murmur may be softer
as the left atrial pressure increases to reduce the differential with the systolic left ventricular pressure.
Differential diagnosis may include aortic stenosis (AS);
the murmur of AS is typically crescendo/decrescendo in
the left parasternal area but this can also be produced by
MR with an anteriorly directed jet.
In acute myocardial infarction, development of a harsh
systolic murmur may indicate acute MR or possibly
development of a ventricular septal defect. Urgent echocardiography may be needed to distinguish these.
Investigations
The EKG may show left-axis deviation, a left ventricular
strain pattern with T wave inversion in the lateral leads,
and left atrial enlargement with P mitrale.
MR is usually recognized readily on the echocardiogram from the Doppler flow pattern in the left parasternal long-axis and apical four-chamber views. The
severity of the regurgitation can be ranked as mild
(regurgitant jet just into the left atrium), moderate (regurgitant jet reaches the mid-atrium) or severe (regurgitant
jet reaches the posterior wall). In chronic MR, enlarged
left atrium or elevated pulmonary pressure may indicate
greater severity.
Transesophageal echocardiography (TEE) is used to
identify more detail of the location of the regurgitation
to assist surgical repair.
Management
Patients with mild MR can be reassured that they do
not need any intervention on their valve. They may
require occasional clinical or echocardiographic review
to monitor the progress of the MR.
Most patients with moderate MR can also be monitored with clinical and echocardiographic review and do
not need intervention.
Patients with severe MR may present with symptoms
and will require early intervention. Many patients,
however, remain asymptomatic for years and can be
managed conservatively. Eventually, most patients will
develop symptoms of dyspnea and reduced exercise
capacity, and there is now a trend to intervene earlier in
asymptomatic patients to avoid the development of left
atrial enlargement, propensity for atrial fibrillation, and

development of pulmonary hypertension.
Acute MR with hemodynamic deterioration requires
urgent clinical stabilization of cardiac failure and early
intervention.
Ideally, MR is best treated with surgical reconstruction of
the valve and minimization of the MR.
If repair of the valve is not possible, a decision has to
be made between insertion of a bioprosthesis (avoiding
the need for anticoagulation but with the prospect of reoperation in 1015 years) or a mechanical valve (anticoagulation required but minimal need for re-operation).
The decision-making process needs to involve cardiologist, surgeon and patient.
Recent developments with valve-preserving operations
and minimally invasive approaches, including transcatheter, percutaneous techniques to reduce regurgitation,
have minimized the morbidity and improved outcomes
with mitral valve surgery.

MVP syndrome is a common, occasionally familial syndrome resulting from redundant mitral leaflet tissue,
associated with myxomatous degeneration of the valve.
It is a frequent accompaniment of Marfan syndrome and
may be associated with thoracic skeletal deformities.
The posterior mitral leaflet is usually more affected than
the anterior, and elongated or ruptured chordae tendineae cause or contribute to the variable clinical course
of the mitral regurgitation.
Clinical features
MVP is more common in young women.
The clinical course is most often benign with no more
than a systolic click and murmur, with mild prolapse of
the posterior leaflet.
In some patients, however, it can progress over years or
decades and can worsen rapidly with chordal rupture
orendocarditis.
Palpitations and occasionally syncope can result from
ventricular premature contractions and paroxysmal
supraventricular and ventricular tachycardia, or atrial
fibrillation.
Sudden death has been reported in patients with severe
MR and depressed LV systolic function.
Some patients with MVP may have substernal chest
pain which may occasionally resemble angina pectoris.
Transient cerebral ischemic attacks secondary to emboli
from the mitral valve have been reported.
CLINICAL PEARL
The course of mitral valve prolapse is usually benign,
but syncope or major arrhythmias indicate an adverse
prognosis.
The typical finding on auscultation is a mid- or late systolic click, generated by the sudden tensing of elongated
chordae tendineae or by the prolapsing mitral leaflets.
Systolic clicks may be multiple and followed by a highpitched, late systolic crescendo/decrescendo murmur at
the cardiac apex.
Investigations
The EKG may show biphasic or inverted T waves in the
inferior leads.
Echocardiography shows displacement of the mitral
valve leaflets. The usual echocardiographic definition
of MVP is displacement of the mitral leaflets in the
parasternal long-axis view by at least 2 mm. Doppler
imaging can evaluate the associated MR and estimate
its severity. The jet lesion of MR due to MVP is most
often eccentric, and accurate assessment of the severity
of MR may be difficult.
Transesophageal echocardiography (TEE) provides
more accurate information, especially when repair or
replacement is being considered.
Management
Serial echocardiography can be used to monitor progress of MVP.
Beta-blockers may be required if there are documented
arrhythmias causing symptoms.
Patents with a history of TIA may require treatment
with aspirin.
The timing of surgery is usually determined by the severity of mitral regurgitation and associated symptoms.
CLINICAL PEARL
Transcatheter repair of mitral regurgitation is not ideally
suitable for mitral valve prolapse because of the myxomatous degeneration of the leaet tissue.
AORTIC VALVE DISEASE

Most cases of AS in younger patients result from progressive deterioration and fibrosis of the valve in patients
born with a bicuspid valve.
A bicuspid aortic valve is usually part of a more
diffuse aortopathy, and coarctation and ascending
aortic aneurysm are common associations.
Calcific aortic stenosis is the usual cause in older patients.
There has been controversy over whether the process
of aortic valve degeneration with fibrosis and stenosis is
related to atherosclerotic disease. There are similarities
in the histological appearances of calcific aortic valve
disease and atherosclerosis, and the two conditions share
185
several common risk factors, but trials to delay progression with statins have generally been ineffective in calcific aortic stenosis.
Rheumatic valve disease rarely affects the aortic valve by
itself. Usually stenosis is associated with regurgitation,
and occurs in association with mitral valve disease.
Rare causes of AS include a localized sub-aortic membrane, or a supra-aortic stenosis.
With progressive narrowing of the aortic valve there is
an increase in the transvalvular pressure gradient, reduction of the valve area, and LV hypertrophy.
Increase in intramyocardial pressure may cause
myocardial ischemia, and reduced compliance may
lead to diastolic heart failure.
Symptoms
Aortic stenosis usually remains asymptomatic until the
aortic valve area is reduced below 1cm2.
CLINICAL PEARL
Aortic stenosis usually progresses slowly, but can
accelerate in older patients.
Progressive dyspnea and reduced exercise capacity may

occur as the stenosis progresses.
The development of cardiac failure is a bad prognostic
sign, and indicates either that the valve stenosis is very
severe or that there is associated LV dysfunction.
Angina pectoris may develop as a result of the severity of
the stenosis with LV hypertrophy, but more often indicates the presence of associated coronary disease.
The development of syncope is also a bad prognostic
sign indicating very severe stenosis, or associated conduction system disease.
Clinical signs
A delayed upstroke and reduced amplitude in the carotid
pulse are the typical pulse features of AS, but these are
usually seen only in severe AS.
The murmur of AS is characteristically a crescendo/
decrescendo (mid-) systolic murmur that commences
shortly after the 1st heart sound, increases in intensity to
reach a peak at mid-systole, and ends just before aortic
valve closure.
It is characteristically harsh and loud, and can be
high- or medium-pitched.
It is loudest in the 2nd right intercostal space, and
may be transmitted to the base of the neck or into
the carotids.
Usually a loud murmur, particularly if associated
with a systolic thrill, indicates severe stenosis, but
in some patients with significant left ventricular
dysfunction the murmur may be relatively soft and
short.
The heart sounds are usually well heard, but the aortic component of the 2nd heart sound may be delayed,
186
leading to a single 2nd heart sound or even reverse splitting. The latter is more likely to indicate the presence of
a left bundle branch block. A 4th heart sound reflecting
LV hypertrophy and reduced LV compliance may be
audible at the apex.
CLINICAL PEARL
A delayed upstroke and reduced amplitude in the carotid pulse (pulsus parvus et tardus) are typical of aortic
stenosis. If they are present, the stenosis is severe.
Investigations
The EKG may show LV hypertrophy with STT
changes in the lateral leads.
With severe AS, the chest X-ray may show an enlarged
heart, and calcification of the aortic valve and annulus is
usually readily visible on a lateral projection.
The characteristic echocardiographic appearance of
calcified and immobile valve leaflets is readily seen on
the left parasternal long-axis view. The calcified valve
and features of a bicuspid valve are best seen en face on
the parasternal short-axis view. The gradients across the
valve are measured using Doppler measurements of the
transaortic velocity. The valve area can be calculated
from these measurements.
CLINICAL PEARL
A valve area of <1 cm2 indicates severe aortic stenosis
(AS), 11.5 cm2 moderate AS, and 1.52 cm2 mild AS.
When decisions are being made about the timing of

valve surgery or transcatheter intervention, and there is
a discrepancy between clinical and echocardiographic
assessment, there may be a need to check these valve gradients using cardiac catheterization. In modern practice
this is uncommonly performed, as there are concerns
that attempts to cross the valve may cause dislodgement
of calcific particles. However, coronary angiography or
more recently coronary CT angiography is routinely
performed in older patients to assess the presence of
associated coronary artery disease.
Management
Patients with severe AS should avoid excessively heavy
lifting or other isometric exercise.
Usual treatments for cardiac failure or angina can be
used, but excessive diuresis with hypovolemia should
be avoided if possible as this can increase the risk of
syncope.
Statin therapy should follow usual guidelines, and has
no additional benefit in AS. The timing of intervention
with surgery or transcatheter intervention is determined
by symptoms and the severity of the AS.
Severe AS (mean gradient>40mmHg) and symptoms

of syncope, heart failure or angina, or an asymptomatic patient with LV dysfunction (LVEF <50%) or an
adverse response to exercise, are indications for surgery
or intervention.
In patients who remain asymptomatic, serial echocardiography should follow the rate of progression of the
stenosis.
CLINICAL PEARL
Patients with a biscuspid aortic valve should undergo
aortic imaging with computed tomography or magnetic resonance imaging to rule out coarctation or
other aortic pathology.
Open valve replacement remains the standard for intervention in most centers.
The operation can be performed with a mortality risk of about 5% depending on age and
comorbidities.
Choice of valve is usually determined by age.
A bioprosthetic valve will avoid the need for anticoagulants (unless there is an established indication
such as atrial fibrillation). However, despite improvements in bioprosthetic valve technology, there is a
high rate of failure and need for re-operation after
1015 years. Therefore, bioprosthetic valves are usually chosen for older patients with a limited life expectancy, and mechanical valves for younger patients.
The rapidly increasing availability of transcatheter aortic valve replacement (TAVR) has changed the indications for intervention. While the early experience with
TAVR was limited to older patients too ill to safely
undergo surgery, there are rapidly widening indications
for this approach.
Palliation of severe AS with balloon valvuloplasty is an
option in patients not suitable for surgery or TAVR, but
rapid recurrence limits this as a definitive treatment.

Aortic regurgitation can occur as a result of primary valve
disease, or from dilatation of the aortic root.
Direct involvement of the aortic valve with regurgitation may occur from rheumatic disease, but usually in
association with mitral valve disease.
A congenital bicuspid aortic valve can progress to predominant AR, but usually with extensive thickening of
the valve and associated stenosis.
AR may result from infective endocarditis, usually on a
valve previously deformed with rheumatic disease or
acongenital bicuspid valve.
Rarer causes include ankylosing spondylitis or blunt
chest trauma.
AR is often due to marked aortic dilatation; while the
valve leaflets may not be involved in the primary disease
process, widening of the aortic annulus and separation

of the aortic leaflets may cause the AR.
Aortic root causes of regurgitation include cystic medial
degeneration of the ascending aorta, with or without
Marfans features, idiopathic dilatation of the aorta,
and atherosclerotic or hypertensive degeneration of the
aortic architecture with an ascending aortic aneurysm.
Acute AR may occur as a result of retrograde aortic root
dissection.
In chronic AR, the regurgitation gradually leads to
compensatory mechanisms which may be effective in
maintaining cardiac output and preventing the development of symptoms for decades. An increase in the
LV end-diastolic volume is followed by dilatation, and
hypertrophy of the LV allows the heart to maintain a
normal stroke volume and an apparently normal ejection fraction. Further progression leads to failure of
these compensatory measures, with reduction in stroke
volume and LVEF and an increase in systolic volume.
Deterioration of LV function often precedes the development of symptoms.
Exercise testing may unmask compensated LV
dysfunction.
Symptoms
Patients with chronic AR may remain asymptomatic
for as long as 1015 years, even when the regurgitation
is hemodynamically severe on clinical examination and
echocardiography.
Subtle symptoms including an increased awareness of
the heartbeat, sinus tachycardia or ventricular premature beats during exertion may be present and hardly
noticed by the patient.
Patients may present with exertional dyspnea or reduced
exercise capacity.
Chest pain suggestive of angina may occur in patients
with severe AR.
With progression of LV dysfunction, symptoms of cardiac failure may develop quite rapidly.
In patients with acute severe AR, rapid onset of pulmonary edema and/or cardiogenic shock may be the initial
presentation.
CLINICAL PEARL
Aortic regurgitation (AR) can result from pathology of
the valve or the aortic root. Both should be considered
when AR is detected.
Clinical signs
The typical feature of severe AR is a prominent collapsing pulse, and an early diastolic murmur. The pulse is
often described as a waterhammer pulse, and can manifest with several eponymous variants, including bobbing of the head (Corrigans sign), pulsation of the nail
bed (Quinckes sign), pistol-shot sound (Traubes sign)
187
or a to-and-fro murmur (Duroziezs sign) over the femoral arteries.

There is usually a wide pulse pressure, and generally a
pulse pressure of >100 mmHg indicates very severe AR.
The murmur commences in early diastole, is best heard
at the left sternal border, and is typically a high-pitched,
blowing, decrescendo murmur.
The length of the murmur correlates with the
severity of the AR, with a short murmur indicating mild AR, a murmur to mid-diastole indicating
moderate AR, and a murmur filling diastole indicating severe AR.
The murmur is more easily heard with the diaphragm of the stethoscope, with the patient sitting
forward, and auscultating in expiration.
The loudness of the murmur is not an indication of
the severity of the regurgitation.
In severe AR, the murmur may blend with a diastolic
rumble (the Austin Flint murmur) due to vibration of
the anterior leaflet of the mitral valve, and may cause
confusion with mitral stenosis.
Investigations
EKG signs of left anterior hemiblock or LV hypertrophy
with T wave inversion in inferior and lateral leads may
be obvious.
On the chest X-ray, the cardiac silhouette is enlarged, the
apex is displaced downward and leftward in the frontal
projection, and aortic root enlargement may be visible.
On the echocardiogram, minor degrees of AR are frequently seen when not clinically or hemodynamically
relevant.
With more severe AR, increased LV size but normal systolic function may be seen.
With progression, an increase in the end-systolic
dimension or a subtle deterioration of the apparently normal LVEF may be the first signs of
decompensation.
The regurgitant jet can be assessed by color-flow
Doppler imaging.
A high-frequency fluttering of the anterior mitral leaflet
during diastole produced by the regurgitant jet is a characteristic finding (and the genesis of the Austin Flint
murmur).
The aortic root can be evaluated with echocardiography
to assess if aortic root dilatation is the cause of the AR.
However, the echocardiographic window is limited to
the first 34 cm (11.5 in) of the ascending aorta, and
anatomical detail of the remainder of the aorta needs to
be established with cardiac CT or MRI.
Management
Careful observation with clinical and echocardiographic
surveillance is needed for patients with mild to moderate regurgitation. The rate of progression varies, with
many patients remaining symptom-free without evidence of decompensation for a decade or more.
In patients with more severe degrees of regurgitation,
echocardiographic monitoring of the LV response to the
regurgitation is crucial.
188
In the symptom-free patient, a degree of LV dilatation

may be acceptable as part of the physiological compensation, but any increase in systolic dimension needs to
be carefully evaluated, as this may indicate impending
decompensation.
Control of blood pressure is important.
The development of symptoms is a late development and
indicates that decompensation has already developed. Once
symptoms develop, mortality in patients without surgical treatment may be as high as 1020% per year. Symptoms of cardiac failure may need stabilization with diuretics
and ACEIs, but improvement in symptoms should not be
regarded as avoiding the need for surgical intervention.
Surgery is recommended when there are symptoms
or LV dysfunction (LVEF <50%), or normal LV function but marked LV dilatation with a left ventricular
end-diastolic diameter of >70 mm, or left ventricular
end-systolic diameter of >50 mm or >25 mm/m2 body
surface area.
Surgery with a mechanical or bioprosthetic valve has
been the only option until recently, but valve-sparing
surgery, particularly for acute AR or in valves without
extensive calcification, has been explored with success
in many centers.
When the AR is associated with marked aortic root
dilatation, reconstruction of the aortic root may also be
required.
Patients with acute severe AR require early intervention
with surgery.
CLINICAL PEARL
Surgical intervention in chronic aortic regurgitation is
determined more by the response of the ventricle than
by the severity of the regurgitation.
TRICUSPID VALVE DISEASE

Tricuspid stenosis is usually rheumatic in origin, and is
usually associated with mitral stenosis. Rarely, isolated
congenital TS can occur.
The clinical features are those of systemic venous congestion with hepatomegaly, ascites, and edema.
Although a rare condition, the diagnosis may
be missed if not considered in a patient showing
venous congestion in excess of that expected with
their mitral valve disease.
The jugular veins are distended, and in patients with
sinus rhythm there may be giant a waves.
A diastolic murmur of TS may be present but
attributed to the murmur of mitral stenosis. However, it is generally heard best along the left lower
sternal border and over the xiphoid process rather
than at the apex of the heart, and may be accentuated with inspiration.
The EKG shows features of right atrial enlargement
including tall, peaked P waves in lead II, in the absence
of EKG signs of right ventricular (RV) hypertrophy.
Echocardiography shows a thickened tricuspid valve
which domes in diastole.
Treatment is with valvuloplasty or valve replacement at
the same time as mitral valve surgery.

Functional tricuspid regurgitation is due to marked
dilatation of the tricuspid annulus from RV enlargement in patients with severe pulmonary hypertension.
Other causes of RV enlargement may result in functional TR, including right ventricular infarction.
Direct TR due to valve involvement is less common but
may result from a congenitally deformed tricuspid valve,
with defects of the atrioventricular canal, as well as with
Ebsteins anomaly of the tricuspid valve, endocarditis or
trauma.
The clinical manifestations are those of right-sided heart
failure with prominent v waves and rapid y descents in
the jugular pulse, and pulsatile hepatomegaly.
The murmur of TR is a blowing pansystolic murmur
along the lower left sternal margin which is intensified
during inspiration.
correction, and this can now be achieved with balloon

valvuloplasty.
Acquired pulmonary stenosis may result from the carcinoid syndrome.
Trivial or mild pulmonary regurgitation is a common finding on echocardiography and does not require
any further investigation.
More severe pulmonary regurgitation may occur as a
result of dilatation of the pulmonary artery due to severe
pulmonary arterial hypertension, producing a highpitched, decrescendo, diastolic blowing murmur in the
2nd left intercostal space (Graham Steell murmur).
Moderate pulmonary regurgitation is an almost invariable result of corrected Fallots tetralogy.
Assessing the severity of valvular heart

disease and deciding on surgery
The usual indications for surgery and intervention in mitral
and aortic valve disease are summarized in Table 8-10.
Table 8-10 Indications for surgery or transcatheter
intervention in aortic and mitral valve disease
DISEASE
TYPE
Mitral
stenosis
Progressive symptoms, valve area

<1.5cm2 (1cm/m2 body surface area),
mean gradient >10mmHg, development
of pulmonary hypertension
Mitral
regurgitation
Flail leaet, ruptured papillary muscle,

large coaptation defect
Symptomatic patients with LVEF >30%
and LVESD <55 mm
Asymptomatic patients with left
ventricular dysfunction (LVESD 45 mm
and/or LVEF 60%), development of
pulmonary hypertension, or new-onset
atrial brillation
Aortic
stenosis
Severe aortic stenosis (mean gradient

>40mmHg, valve area <1.0 cm2,
maximum jet velocity >4m/s)
Symptoms of syncope, heart failure, or
angina
Asymptomatic patients with left
ventricular dysfunction (LVEF <50%) or
adverse response to exercise
Aortic
regurgitation
Abnormal/ail large coaptation defect

Symptoms of cardiac failure or reduced
exercise capacity
Asymptomatic patients with left ventricular
dysfunction (LVEF <50%), or normal LV
function but marked LV dilatation (LVEDD
>70 mm, or LVESD >50 mm or LVESD
>25 mm/m2 body surface area)
CLINICAL PEARL
The diagnosis of tricuspid regurgitation is usually
established on the basis of the jugular venous pressure
(JVP) and pulsatile hepatomegaly; the murmur may be
difficult to hear.
A trivial or mild degree of tricuspid regurgitation is a

normal finding on echocardiography, but severe TR
produces Doppler features of torrential regurgitation,
often accompanied by hepatic-vein flow reversal. Continuous wave Doppler of the TR velocity profile is useful in estimating pulmonary arterial systolic pressure.
Functional TR associated with heart failure may
improve dramatically with control of the cardiac failure,
and does not require surgical intervention. Addition of
an aldosterone antagonist to diuretic therapy may help
if there is secondary hyperaldosteronism from hepatic
dysfunction.
In patients in whom the TR is due to rheumatic valve
disease, tricuspid valve annuloplasty at the time of surgical repair may be indicated.
PULMONARY VALVE DISEASE

Pulmonary stenosis is a relatively common congenital
anomaly which produces a systolic murmur at the upper
left sternal border, and a characteristic doming appearance
of the valve on echocardiography. It only rarely requires
INDICATIONS FOR SURGERY/

INTERVENTION
LVEF, left ventricular ejection fraction; LVEDD, left ventricular enddiastolic diameter; LVESD = left ventricular end-systolic diameter.
189
CARDIOMYOPATHIES
Cardiomyopathy is a chronic disease of the heart muscle
(myocardium), in which the muscle is abnormally enlarged,
thickened and/or stiffened. The weakened heart muscle loses
the ability to pump blood effectively, resulting in increased
risk of arrhythmias and heart failure.
The cardiomyopathies are a diverse group of conditions
affecting the heart muscle. The traditional classification
of cardiomyopathies is into three types: dilated, hypertrophic and restrictive cardiomyopathies.
New genetic and molecular biology information has
shown a degree of overlap between the types, but it
remains the most widely used and understood classification. Some more recently recognized cardiomyopathies
do not fit into this standard classification.

The main causes of dilated cardiomyopathy are shown in
Table 8-11.
Idiopathic dilated cardiomyopathy

Idiopathic DCM usually presents with progressive cardiac failure or with radiographic or echocardiographic
evidence of cardiac enlargement.
Patients with this condition are at increased risk of cardiac arrhythmias and sudden death.
Whether the etiology is due to undiscovered genetic
defects in myosin, actin and other muscle proteins, to
Table 8-11 Causes of dilated cardiomyopathy
DILATED
CARDIOMYOPATHY
CLINICAL FEATURES
Idiopathic
Any age, usually

progressive
Familial/genetic
May manifest at a
young age; may be a
complication of muscular
dystrophy
Alcoholic
Usually with alcohol

excess, but with wide
individual variation
Chemotherapy
Usually anthracyclines
Viral myocarditis
Can be severe or lifethreatening but may be

transient with complete
recovery
Parasitic infection
Chagas disease
Inltrative disorders
Hemochromatosis,
sarcoidosis
Peripartum
cardiomyopathy
Usually self-limiting but can

be severe
190
a disordered immunological response, or to a reaction

to a viral illness remains the subject of conjecture and
investigation.
The pathology varies with distorted myofibrils and
varying degrees of fibrosis.
Progressive dilatation and hypertrophy of the left ventricle leads to LV dysfunction, usually systolic.
Echocardiography typically shows global depression of
LV function, in contrast to ischemic causes which are
usually regional.
Treatment with beta-blockers, ACEIs, and aldosterone
antagonists may delay progression, and can lead to significant improvements in some cases.
Patients with marked depression of LV function are at
increased risk of sudden death, and implantation of an
implantable cardioverter-defibrillator (ICD) is usually
recommended when the ejection fraction is consistently
below 35%. Implantation of an ICD has been shown to
significantly improve prognosis.
CLINICAL PEARL
The diagnosis of idiopathic dilated cardiomyopathy is
made only after all correctable causes have been ruled
out.
Familial/genetic cardiomyopathies
In some families there is a pattern of early development
of dilated cardiomyopathy with echocardiographic evidence of LV dysfunction and dilatation, and a propensity to early death.
Early treatment with beta-blockers and ACEIs, and
implantation of an ICD, may significantly improve the
prognosis.
A genetic susceptibility to development of dilated
cardiomyopathy and viral myocarditis has long been
suspected but poorly understood. A specific form of
cardiomyopathy may complicate Duchenne and Becker
muscular dystrophy, with the myocardial abnormality
localized to the posterior wall of the left ventricle. There
is a characteristic tall R wave in lead V1 on the EKG,
and hypokinesis of the posterior wall can be seen on
echocardiography.
Mitochondrial myopathies may also rarely involve
the heart, with progressive cardiac failure and LV
dysfunction.
A familial form of cardiomyopathy with conduction system abnormalities may present with atrioventricular block,
and symptoms of cardiac failure as a late development.
CLINICAL PEARL
Despite advances in understanding the molecular
biology of cardiomyopathy, there is no advantage in
genetic testing, even in families with a strong history of
cardiomyopathy.
Alcoholic cardiomyopathy
In some communities this is the most common form of
dilated cardiomyopathy.
All types of alcohol consumption can cause alcoholic
cardiomyopathy, and the volume and duration of excess
drinking varies greatly, but six standard drinks daily for
510 years is usually regarded as the usual dose required
to damage the heart.
It may be associated with nutritional deficiencies, which
can exacerbate the severity of the cardiomyopathy, and
is often associated with other alcohol-related cardiac
conditions including atrial fibrillation and hypertension.
but MRI with gadolinium contrast is increasingly used

to identify tissue edema and fibrosis.
In some cases, the condition can progress to an established cardiomyopathy, but in many cases complete resolution can occur over a period of 36 months.
Viruses implicated include coxsackievirus and Epstein
Barr virus, and cardiac involvement can be seen in HIV.
CLINICAL PEARL
In patients with probable viral myocarditis, decisions
about implantation of an implantable cardioverterdebrillator should be deferred to assess whether the
LV dysfunction is permanent.
CLINICAL PEARL
Alcoholic cardiomyopathy can improve or, rarely, even
resolve with complete cessation of alcohol.
Chemotherapy-induced cardiomyopathy
Anthracyclines (most commonly doxorubicin) may
directly damage the myocardium and cause clinically
evident cardiac failure in 5% or more of patients treated.
Lesser degrees of LV dysfunction are seen more
frequently. The left ventricle may show a reduced
LVEF without cardiac dilatation.
Total cessation of the anthracycline can allow recovery in many cases, but permanent reduction in LV
function may result.
CLINICAL PEARL
Patients having anthracycline chemotherapy should
have baseline and serial echocardiography to monitor
for development of cardiomyopathy.
The monoclonal antibody trastuzumab also has some

cardiotoxic effect, particularly when co-administered
with anthracyclines.
Cardiotoxicity, usually transient, can occur with very
high doses of cyclophosphamide.
5-fluorouracil, and cisplatin, can cause coronary spasm
with depressed contractility.
Viral myocarditis
Myocarditis can present with mild cardiac failure,
but on occasions can cause severe rapid-onset cardiac
failure, and occasionally cardiogenic shock. In such
patients with fulminant disease, urgent consideration
of implantation of a left ventricular assist device is
required.
It often commences with a nonspecific viral illness,
and there may be a latent period between the flulike illness and the onset of the myocarditis.
It can be associated with pericardial involvement.
The typical clinical pattern with echocardiographic features of LV dysfunction usually establish the diagnosis,
Parasitic infection
Infection with Trypanosoma cruzi can involve the heart in
Chagas disease, resulting in LV dysfunction with a particular propensity to thromboembolic complications and cardiac
arrhythmias.
Inltrative disorders
Hemochromatosis is a rare but important cause of cardiomyopathy. It occurs only in advanced hemochromatosis and can cause severe cardiac failure and cardiac
arrhythmias, but can be reversible with venesection.
Chelation with desferrioxamine has been used, but
may transiently exacerbate arrhythmias and cardiac
failure.
Sarcoidosis can involve the heart, with cardiac failure
and cardiac arrhythmias. MRI may demonstrate infiltration of the heart with granulomas. Occasionally positron emission tomography (PET) is used to identify the
extent and localization of the granulomas. Treatment
with high-dose corticosteroids may limit the extent of
cardiac involvement.
Peripartum cardiomyopathy
Cardiomyopathy in the post-partum mother, usually with
mild cardiac failure, occurs in 1 in 10,000 deliveries. The
cause remains poorly understood, but an inflammatory
infiltrate may be seen on biopsy. With supportive measures
and standard treatment of LV dysfunction, the prognosis is
usually for complete recovery within several months.

Hypertrophic cardiomyopathy is defined as marked cardiac hypertrophy in the absence of an obvious cause such as
hypertension or valvular heart disease.
Systolic function is usually normal, but diastolic dysfunction can be a significant clinical problem.
The usual pattern is asymmetric hypertrophy with
enlargement of the septum, with many cases showing obstruction of the outflow tract of the left ventricle (hence the previous terminology of hypertrophic
obstructive cardiomyopathy, HOCM).
191
It is now recognized that the hypertrophic pathology

is generalized in the cardiac muscle, with different distribution in different patients. A variant with predominantly hypertrophy in the apical region is thought to
have a more benign course.
CLINICAL PEARL
Not all patients with hypertrophic cardiomyopathy
have outow tract obstruction, hence the terminology
HCM rather than HOCM.

The pathological features are marked disarray of individual fibers in a characteristic whorled pattern, with
fibrosis of varying degree.
The prevalence is 1 in 500 adults, with approximately
half having a distinct heritable pattern.
Multiple genetic mutations have been identified in the
sarcomeric genes, mostly in the beta-myosin heavy
chain, the cardiac myosin-binding protein C, or cardiac
troponin T.
The prognosis varies between families; but at this stage,
despite considerable advances in understanding the
molecular biology of the condition, a specific genetic
mutation to assist with targeted management of the
patients at highest risk has eluded investigators.
of hypertrophy of the posterior wall as well. A gradient

across the outflow tract is seen in many patients, and in
more severe cases the characteristic echocardiographic
finding of systolic anterior motion of the anterior leaflet of the mitral valve results from a Venturi effect in
the outflow tract. This further compounds LV outflow
obstruction, and contributes to disruption of the mitral
valve apparatus with mitral regurgitation.
The echocardiographic measurement of the gradient
can be highly variable depending on loading conditions
(reduced preload with diuretics or dehydration, reduced
afterload with vasodilators) and heart rate. For these reasons, serial measurement of the outflow gradient is not a
reliable method of monitoring progress. It has, however,
been established that patients with a consistently high
gradient have a worse prognosis than those without.
CLINICAL PEARL
Signs of gross enlargement of the septum, a history of
syncope, a family history of sudden death and highgrade arrhythmias are indicative of an adverse prognosis in hypertrophic cardiomyopathy.
The diagnosis of a generalized hypertrophy variant may

be suspected in a patient with hypertension who appears
to have excessive hypertrophy for the degree of blood
pressure elevation.
Management
Symptoms and clinical ndings
Common symptoms are mild dyspnea or atypical chest
pain, but many patients remain asymptomatic throughout, and have the diagnosis made on incidental EKG or
echocardiographic findings.
Syncope is a rare but troubling presentation, as this can
indicate a high risk for sudden death.
Tragically, the initial presentation may be with sudden
death, and this is the most common cause of sudden
death in otherwise healthy young athletes.
Typical physical findings include a systolic murmur, but
this is not always present in milder cases.
EKG anomalies include LV hypertrophy and deep
T wave inversion in the anterior or inferior leads. On
occasions, well-developed Q waves in the inferior leads
(from activation of the hypertrophic septum) may cause
confusion with inferior myocardial infarction.
CLINICAL PEARL
Deep T-wave inversions and inferior-lead Q waves in
the EKG of hypertrophic cardiomyopathy may (incorrectly) suggest a diagnosis of myocardial infarction.
The echocardiogram shows features of LV hypertrophy, often with evidence of diastolic dysfunction. In the
typical septal hypertrophy variant, the hypertrophy of
the septum is prominent, but there is usually a degree
192
Many patients require no further management than serial

clinical and echocardiographic review to ensure that
there is no progression of their mild septal hypertrophy.
Drug treatments have generally not been effective in
slowing the rate of hypertrophy, although ACEIs have
been proposed for this purpose. In patients with significant outflow tract obstruction, it may be possible
to improve symptoms, particularly palpitations, with
beta-blockers or calcium-channel blockers (verapamil/
diltiazem).
Patients with proven severe hypertrophy, advanced gradients and symptoms may obtain symptom relief from
surgical resection of the hypertrophied septal tissue
(myectomy). A valid alternative method of reducing the
septal hypertrophy has been the use of alcohol ablation
by injecting alcohol in controlled doses into the septal
perforator artery. While symptoms of obstruction can
be improved, neither myectomy nor alcohol septal ablation have been shown to improve long-term prognosis.
Patients with a strong family history of sudden death,
a history of syncope, septal thickness in excess of 3 cm
(1.2 in), or documented ventricular tachycardia should
be considered for implantation of an ICD.
Restrictive cardiomyopathies result from infiltration
of the myocardium with a varying degree of fibrotic
reaction.
Reduced compliance of the left ventricle with abnormal diastolic function is seen, usually with only mildly
depressed systolic function.
Left atrial enlargement is common, with a propensity to
atrial fibrillation.
A mild reduction in exercise capacity is the usual presenting symptom.
Clinical signs may show predominant right-sided heart
failure with characteristic steep y descent in the jugular venous pulse. A prominent 4th heart sound in sinus
rhythm reflects the reduced compliance.
Amyloidosis is the most frequent cause of restrictive
cardiomyopathy.
Cardiac amyloidosis may be due to AL (amyloid
light-chain) amyloidosis with abnormal production
and infiltration of immunoglobulin light chains, or
transthyretin-related (TTR) amyloidosis in which
the amyloid infiltrate is derived from transthyretin, a small molecule mainly produced by the liver.
TTR may be due to a genetic form known as hereditary TTR amyloidosis, and a non-hereditary form
called senile systemic amyloidosis (SSA). The latter
has a more benign course, usually occurring in men
in their 70s or 80s.
Waxy deposits of amyloid infiltrate the myocardium and restrict filling.
The EKG shows typical low voltages, and the echocardiogram shows a restrictive pattern of diastolic
dysfunction with a characteristic brightly speckled
appearance best seen in the septum. Due to this appearance being neither sensitive nor specific, MRI is more
reliable for diagnosis.
Cardiac transplantation has been temporarily successful in some cases, but re-infiltration of the transplanted
myocardium may be a limitation.
Patients with the more common SSA variant of TTR
amyloidosis often require no active treatment apart from
management of their cardiac failure.
Patients with the rarer familial TTR may need to be
considered for liver transplantation as the liver is the
source of the TTR.
Other causes of restrictive cardiomyopathy

Rare glycogen storage and other infiltrative conditions can affect the myocardium and cause a restrictive
cardiomyopathy.
Of these, Fabrys disease, due to alpha-galactosidase
deficiency, is the most significant as it can be recognized
with an enzyme assay to measure the level of alphagalactosidase activity and is correctable with enzyme
replacement therapy.
In tropical countries, eosinophilic endomyocardial disease and myocardial involvement in Lfflers endocarditis can be common causes of restrictive cardiomyopathy
and cardiac failure.
Thoracic radiation therapy for breast or lung cancer can cause the late development of a restrictive
cardiomyopathy.
Some cardiomyopathies more recently described have not
been fully characterized but do not fit the dilated/hypertrophic/restrictive classification. These are summarized in
Table 8-12.
CLINICAL PEARL
Diabetes/obesity
Echocardiographic speckling is a widely discussed

sign of cardiac amyloid inltration, but not sufficiently
reliable for making a diagnosis.
There is controversy as to whether the diastolic LV dysfunction which frequently complicates diabetes and obesity
Biopsy of the abdominal fat pad may confirm the diagnosis, but the abnormal tissue may be overlooked, and
cardiac biopsy may be needed to confirm the diagnosis.
If AL amyloidosis is the likely diagnosis, a screening of
the peripheral blood for light chains and bone marrow
biopsy is done to assess the numbers of plasma cells,
to establish the diagnosis. If there is no confirmation
of AL, screening for a mutation in transthyretin may
demonstrate the familial form.
The treatment of AL and TTR amyloidosis differs.
The aim of treatment in AL amyloidosis is to prevent
the production of light chains by the plasma cells with
the use of chemotherapy, but this does not affect the
cardiac prognosis.
The prognosis in AL is often poor, due to both progressive cardiac failure and progressive involvement of other
organs.
Implantation of an ICD may improve the prognosis.
Table 8-12 Cardiomyopathies which do not t into

the classication of dilated, hypertrophic or restrictive
CARDIOMYOPATHY
FEATURES
Diabetes/obesity
More likely to cause

diastolic dysfunction; may
be reversible
Ventricular noncompaction
Usually benign, but

arrhythmias and
thromboemboli can occur
Arrhythmogenic rightventricular cardiomyopathy
May cause ventricular

tachycardia and sudden
death
Takotsubo cardiomyopathy
Also known as apical

ballooning or stressinduced cardiomyopathy;
may mimic myocardial
infarction
193
represents a true cardiomyopathy, or is simply fatty infiltration, but there is increasing evidence that diabetes is associated with specific changes in myocardial metabolism.
infarction. It often but not exclusively occurs in elderly

females after a sudden stress, and has also been termed stress
cardiomyopathy. The usual pattern is for restoration of the
apical ballooning to normal within several months.
Ventricular non-compaction
Ventricular non-compaction was originally identified as
an echocardiographic finding of prominent trabeculae at
the cardiac apex. It is now recognized as a distinct form of
cardiomyopathy, with an increased risk of thrombosis and
major cardiac arrhythmias. Anticoagulation and implantation of an ICD may need to be considered in more severe
cases.
Arrhythmogenic right-ventricular
cardiomyopathy
CARDIAC ARRHYTHMIAS
Cardiac arrhythmias may vary from benign ectopic beats
to incapacitating heart block and lethal ventricular arrhythmias. The assessment and planning of management requires
not only a detailed examination of the EKG but also a full
and detailed clinical assessment of the patient.
This condition, now known as ARCM and previously known

as arrhythmogenic right-ventricular dysplasia (ARVD), can
be fatal and contribute to early sudden death. It is associated
with fibromuscular dysplasia and fatty infiltration of the outflow tract of the right ventricle. It can be overlooked on echocardiography and requires MRI for ruling out the diagnosis
in a young person with syncope and/or a family history of
sudden death.
Takotsubo cardiomyopathy
This condition, recognized only recently, is associated with
the sudden development of chest pain, T-wave inversion in
the anterior leads of the EKG, and a characteristic ballooning
of the cardiac apex seen on echocardiography or ventriculography. The unusual name derives from the ventriculographic
appearance of the ventricle, which is similar to a Japanese
lobster pot. Coronary angiography does not show any culprit lesion and the condition is distinct from myocardial
Sinus tachycardia is usually defined as sinus rhythm

at a rate above 100/min. Correction of the underlying
abnormality, including blood loss, hyperthyroidism,
anxiety, alcohol withdrawal, hypoxemia or worsening
cardiac function, is usually sufficient.
Sinus arrhythmia is a normal physiological response
of variation of the heart rate with respiration. There is
phasic variation of the PP interval with preservation
of normal P-wave contour. When atrial activity arises
from multiple sites, the P-wave morphology and the
PP interval vary. No specific treatment is necessary.
Treatment of underlying lung disease (if present) should
be optimized.
Sinus bradycardia is usually defined as a sinus rhythm
below 50/min. It can be a normal variant and is often an
indication of a high level of physical fitness. However,
it can also be due to medications such as beta-blockers,
calcium-channel blockers or digoxin, or may occur as
Sinus arrest
Blocked atrial
premature beat
Figure 8-13 Pauses in heart rhythm due to sinus arrest (no P-wave activity) and a blocked atrial premature beat
(P wave, but conduction blocked)
From Thompson P (ed). Coronary care manual, 2nd ed. Sydney: Elsevier Australia, 2011.
194
a result of increased vagal tone. The patients therapy

should be reviewed for heart-rate-slowing medications
which should be reduced or discontinued. If it is persistent and affects cardiac output or causes symptoms,
atrial or dual-chamber cardiac pacing may be required.
Sinus arrest (or sinus pause) (Figure 8-13) may occur
as an isolated phenomenon in patients with sinus node
dysfunction. If recurrent and symptomatic, especially if
causing syncope, a permanent pacemaker is necessary.
Drug therapy is ineffective.
CLINICAL PEARL
Sinus tachycardia responds, usually slowly, to correction of the underlying problem.
Supraventricular tachycardia responds rapidly to
vagal maneuvers.
Sick sinus syndrome
For some patients (with AV reciprocating tachycardia), there is evidence of ventricular pre-excitation on
12-lead EKG (WolffParkinsonWhite syndrome).
There are three major types of SVT:
Atrioventricular node re-entrant tachycardia
(AVNRT). This commonest type of SVT occurs as
a result of longitudinal dissociation (of conduction)
within the compact AV node, or may involve a small
portion of perinodal atrial myocardium.
Atrioventricular reciprocating (re-entrant) tachycardia (AVRT). This occurs when there is an accessory pathway participating in the tachycardia circuit.
When associated with ventricular pre-excitation on a
resting 12-lead EKG, patients are described as having
the WolffParkinsonWhite syndrome. The accessory
pathway may be concealed and not visible on the surface
EKG when there is only retrograde conduction.
CLINICAL PEARLS
The sick sinus syndrome is a term encompassing sinus bradycardia, chronotropic incompetence, and the tachy-brady
syndrome.
Bradycardia may be persistent and stable, or occur intermittently, particularly at the termination of supraventricular tachyarrhythmiasusually atrial fibrillation.
In this situation it results from suppression of the sinus
node.
Drugs used to treat the tachyarrhythmia component
of this disorder often provoke bradycardia, making
back-up pacing necessary.
CLINICAL PEARL
The sick sinus syndrome includes sinus bradycardia,
chronotropic incompetence, and the tachy-brady syndrome. It is the most common reason for pacemaker
insertion.
Supraventricular premature complexes

(ectopics)
Supraventricular ectopic beats can arise in the atria or the
AV junction. They are very common and typically benign,
but can be of concern if they provoke palpitations. They can
be exacerbated by caffeine, tobacco and alcohol.
Reassurance and removal of stimulants is the best treatment for supraventricular ectopy. For highly symptomatic
patients, a low-dose beta-blocker may provide relief. For
intractable symptoms, antiarrhythmic drugs are occasionally used.

The usual clinical presentation of SVT is sudden-onset,
regular, rapid palpitations. There may be associated dyspnea, pre-syncope, chest tightness or anxiety.
SVT occurs most often in otherwise healthy individuals, and usually the resting EKG is normal.
AVNRT is due to a re-entrant circuit conned to the

AV node.
AVRT uses an accessory pathway for the re-entrant
circuit.
AT is not a re-entrant tachycardia.
Atrial tachycardia (AT). Atrial tachycardia is a focal

arrhythmia arising in the atrial tissue. It may be congenital and is more often associated with underlying structural heart disease.
Supraventricular tachycardias usually have a regular, narrow,
complex appearance on 12-lead EKG, but may be associated with a wide QRS complex when there is a pre-existing
bundle branch block, the development of rate-related bundle branch block (aberrancy), or anterograde conduction
over an accessory pathway.
Management
Immediate treatment can commence with the application of various vagal maneuvers such as the Valsalva
maneuver, carotid sinus massage, breath-holding/
coughing, or cold-water immersion. Carotid sinus massage is the most effective.
If vagal maneuvers are ineffective, the treatment of
choice is intravenous adenosine. An initial dose of 3mg
should be given by rapid injection into a large-bore cannula via an antecubital vein (or central access if available), then 6mg followed by 12mg if needed. Correctly
administered adenosine will successfully terminate the
majority of SVTs.
An alternative to adenosine is intravenous verapamil
given in a total dose of 510 mg. Verapamil should not
be given as a single bolus, and is given in boluses of
12mg at 1-minute intervals.
For patients with known accessory pathways (Wolff
ParkinsonWhite syndrome), episodes of SVT can be
treated in the same manner, although calcium-channel
blockers and digoxin are best avoided as they can, rarely,
195
accelerate conduction in the accessory pathway. Adenosine will terminate tachycardia and does not accentuate anterograde conduction in the accessory pathway.
SVTs which do not respond to vagal maneuvers or adenosine may be due to a focal atrial tachycardia.
CLINICAL PEARL
After vagal maneuvers, intravenous adenosine is the
preferred treatment. AVNRT and AVRT will respond; AT
will not.
Synchronized direct-current (DC) cardioversion with

200 joules can be used if there is hemodynamic
compromise.
Many patients with SVT can be observed long term and
treated without medications.
The pill in the pocket therapy approachissuing the patient with an antiarrhythmic drug to use
as required is an alternative for patients having
infrequent episodes.
Drug therapy taken on a regular basis may control recurrent episodes, but may be associated with side-effects
unacceptable to the typically relatively young patients.
Options include a beta-blocker or calcium-channel
blocker.
Digoxin is an alternative, although less effective.
Flecainide can be used if there is clear evidence of
normal LV function.
If drug therapy does not reliably control the episodes of
tachycardia, the patient should be considered for catheter ablation.
Catheter ablation is the treatment of choice for
patients with recurrent SVT, particularly if highly
symptomatic or frequent. In patients with AVNRT,
the slow pathway in the AV node is ablated. In
AVRT, the target is the accessory pathway.
Catheter ablation for AVNRT and AVRT is highly
successful, with a cure rate exceeding 90% for
experienced operators and a risk of serious complications of <1%. Focal atrial tachycardias respond
less well to ablation.
Non-paroxysmal AT (AT with block) due to digitalis
intoxication is unusual in modern practice, but requires
special attention because of the potential to cause harm
with inappropriate treatment. Cardioversion should be
avoided.
Chaotic (multi-focal) AT is usually seen in patients with
respiratory disease, especially cor pulmonale, or infiltrative disease of the atrium. Treatments include optimization of the patients respiratory status, and reduction of
sympathomimetic bronchodilators. Amiodarone may be
helpful.
Atrial utter
Atrial flutter usually arises in the right atrium and utilizes a re-entrant circuit in the region of tissue between
the inferior vena cava and the tricuspid annulus, known
as the cavotricuspid isthmus.
Typical atrial flutter (Figure 8-14) is usually
counter-clockwise around the tricuspid valve,
resulting in negative flutter waves in the inferior
EKG leads (II, III, aVF).
Atrial flutter involving other regions of the left and
right atria is called atypical atrial flutter (Figure
8-14).
Typical atrial flutter is more readily amenable to
catheter ablation therapy.
Atrial flutter usually occurs in the presence of underlying structural heart disease such as ischemic heart
disease, cardiomyopathy, or valvular heart disease. It
occasionally occurs in the apparently normal heart.
CLINICAL PEARL
The typical saw-tooth pattern of atrial utter can be
exposed with carotid sinus massage.
Figure 8-14 (A) Typical atrial utter showing typical saw-tooth pattern in lead II and exposed by carotid sinus
massage. (B) Atypical atrial utter showing upright utter waves in lead II
From Thompson P (ed). Coronary care manual, 2nd ed. Sydney: Elsevier Australia, 2011.
196
Typical atrial flutter is recognized by the presence of a

saw-tooth pattern of the flutter waves on the 12-lead
EKG. Usually there is 2:1 block of the flutter complexes
at the AV node, resulting in a ventricular rate of 130150
beats/min. There may be variable conduction through
the AV node, resulting in irregular QRS complexes.
The saw-tooth pattern may be obscured by the QRS
complex and T wave, and therefore when assessing
a patient with an unexplained tachyarrhythmia it is
important to consider the possibility of atrial flutter.
The typical saw-tooth pattern on the EKG can be frequently demonstrated by increasing the degree of atrioventricular block with vagal maneuvers such as carotid
sinus massage.
CLINICAL PEARL
The atrial utter pattern can be obscured by the T wave
of the preceding beat; atrial utter is a masquerader
and should be considered in every case of unexplained
tachycardia.
Management
Intravenous AV nodal blocking agents may achieve
slowing of the heart rate.
Amiodarone is effective in slowing AV conduction and
may achieve reversion to sinus rhythm, but the rate of
reversion to sinus rhythm is variable.
Intravenous ibutilide achieves high rates of reversion
to sinus rhythm, but with a risk of inducing polymorphic ventricular tachycardia, and should be avoided
in patients with structural heart disease or a long QT
interval.
If the patient is unstable, it is preferable to restore sinus
rhythm as soon as possible with synchronized DC cardioversion. Alternatively, reversion of atrial flutter can
be achieved with rapid overdrive atrial pacing.
Left atrial thrombus can occur in atrial flutter, and the

same precautions to avoid thromboembolism should be
followed as for atrial fibrillation (see below).
Typical atrial flutter is usually easily amenable to catheter ablation, with a success rate of approximately 90%
and a low complication rate. Atypical atrial flutter can
also be treated with catheter ablation, although with a
lower rate of success.

Atrial fibrillation is the most common sustained cardiac arrhythmia, with a prevalence of 12% of the general population, 5% of patients aged 6074 years, and
approximately 10% of patients aged over 75 years.
Atrial fibrillation can be classified as paroxysmal (occurring intermittently), persistent (lasting for more than
48hours) or permanent (likely to be longstanding).
There have been considerable recent advances in understanding the mechanism of AF, and the recognition that
the origin of AF is in the ostia of the pulmonary arteries
and amenable to ablation has dramatically widened the
therapeutic options.
Atrial fibrillation is more likely to occur in patients with
underlying heart disease, but lone AF can also occur in
patients without any demonstrable cardiac disease.
An important consideration with AF is an increased risk
of thrombus formation in the left atrial appendage and
systemic thromboembolism.
The risk increases with increasing age, past history of
stroke or transient ischemic attack (TIA), hypertension, cardiac failure and diabetes, summarized in two
widely used scoring systems (see Table 8-13, below).
P waves are not visible on the EKG (Figure 8-15) and
are replaced by fibrillation waves on the baseline. The
ventricular response is usually irregular, due to varying
degrees of conduction of the atrial fibrillation into the
AV node.
a VR
V1
V4
II
a VR
V2
V5
III
a VR
V3
V6
Figure 8-15 Typical example of atrial brillation, with rapid irregular ventricular response and absent P wave
activity
197

I
a VR
V1
V4
II
a VL
V2
V5
III
a VF
V3
V6
Figure 8-16 Very rapid atrial brillation with wide bizarre complexes in a patient with an atrioventricular
accessory conduction pathway (WolffParkinsonWhite syndrome). Digoxin can accelerate the abnormal
conduction and should be avoided
CLINICAL PEARL
The irregularity of the ventricular response in AF is a
more reliable EKG sign than attempting to see brillation waves
An important variant of AF is rapid conduction with

aberration (wide QRS complexes; Figure 8-16). This
may indicate AF with WolffParkinsonWhite syndrome, indicating a high-risk situation which should not
be treated with digoxin or calcium-channel blockers.
Management
The treatment of atrial fibrillation is directed at:
slowing the ventricular response
achieving reversion to normal sinus rhythm if
possible
reducing the frequency and hemodynamic effects of
subsequent atrial fibrillation
preventing further episodes
reducing the risk of stroke.
In recent-onset AF, a significant number of patients will
revert to sinus rhythm spontaneously.
If there is significant hemodynamic compromise, urgent
DC cardioversion should be considered.
The ventricular rate can be slowed with beta-blockers or
(non-dihydropyridine) calcium-channel blockers if the
increased cardiac rate is causing problems, or digoxin or
amiodarone.
If reversion to sinus rhythm does not occur when the
heart rate has been slowed, cardioversion should be
considered. Although there are no clear data to guide
198
clinical practice, cardioversion is thought to have a negligible risk of thromboembolism if performed within 48
hours of onset.
CLINICAL PEARL
Synchronized cardioversion can usually be performed
within 48 hours of onset of atrial brillation without risk
of thromboembolism.
All patients should have intravenous heparin or subcutaneous enoxaparin on presentation, to reduce the risk of
thromboembolism.
If more than 48 hours have passed since the onset of
AF or the time since onset is uncertain, an alternative
approach is to commence oral anticoagulation and
arrange elective DC cardioversion after at least 3 weeks
of formal anticoagulation.
If it is preferable to restore sinus rhythm sooner, a
transesophageal echocardiogram (TEE) can be performed to exclude thrombus in the left atrium prior
to cardioversion of the fully anticoagulated patient.
Due to the possibility of left atrial stasis with slow
return of atrial contractility, it is currently recommended that anticoagulation be continued for at
least 3 weeks after DC cardioversion.
Patients with paroxysmal atrial fibrillation who
revert spontaneously or with pharmacological
treatment after an episode longer than 48 hours
previously should also be anticoagulated for at least
3weeks.
For long-term management, the decision to use antiarrhythmic drugs and repeated cardioversion to attempt
to maintain sinus rhythm (rhythm control approach)
versus controlling the rate to minimize symptoms (rate

control approach) requires a careful and individualized
analysis of the likely riskbenefit ratio for each patient.
Recent studies comparing rhythm control with rate
control concluded that rate control is equivalent in
patients with minimal or no symptoms.
Exceptions to the rate control approach include
younger symptomatic patients and those with complicated atrial fibrillation (stroke or cardiomyopathy). In these patients, rhythm control, including by
catheter ablation, should be considered.
CLINICAL PEARL
The rate control and rhythm control approaches to
managing atrial brillation have similar long-term prognoses.
In addition to repeated cardioversion, drugs which may

be considered for rhythm control include beta-blockers,
calcium-channel blockers, class I antiarrhythmics (flecainide, propafenone), and class III antiarrhythmics
(amiodarone, dofetilide, ibutilide).
Flecainide is successful for reversion, less so for
maintenance of sinus rhythm; it cannot be prescribed for patients with significant coronary heart
disease or LV dysfunction.
Propafenone has been used for reversion of AF but a
risk of provoking ventricular arrythmias (proarrythmia) has limited its use.
Amiodarone is effective in preventing recurrences,
but long-term administration is fraught with a high
risk of complications.
Dofetilide has been used for reversion and maintenance of AF, and ibutilide for reversion of AF. Both
have a risk of proarrhythmia.
Sotalol is an attractive alternative, with beta-blocker
and type II effects, but the development of proarrhythmia, particularly in the elderly with impaired
renal function, can be a serious drawback.
Vernakalant is a new drug with a high rate of success for
reversion of acute AF, and without risk of proarrhythmia.
Drugs which may be considered for rate control include
digoxin, beta-blockers and calcium-channel blockers.
Digoxin is widely used for rate control and is effective for control of the rate at rest, but is less effective
with exercise and with stress. It may be preferable to
combine it with a beta-blocker.
Antithrombotic therapy is effective in reducing the risk

of stroke, but at the expense of bleeding.
Until recently, warfarin has been the most effective
agent for reduction of risk of stroke.
Aspirin has been shown to be less effective than
warfarin in the prevention of stroke.
Clopidogrel has also been shown to be less effective, but may be an alternative if warfarin is
contraindicated.
The recommended INR (international normalized
ratio) range for warfarin therapy in non-valvular AF
is 2.03.0.
Recent comparisons of warfarin with novel oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban and edoxaban, have shown that each
of the newer agents is at least equivalent to warfarin in antithrombotic effect, with the advantage of
avoiding the need for frequent INR monitoring.
The decision to commence antithrombotic therapy is
based on consideration of the risk of stroke, the likely
risk of bleeding, and a range of other factors including
the patients likely adherence and comorbidities.
The patients risk of stroke can be assessed from
consideration of the CHADS2 or the CHA2DS2VASC scores (Table 8-13, overleaf).
The CHADS2 score is simple and readily applicable. However, it does not include many common
stroke risk factors, and some patients incorrectly
classified as low risk are better identified with the
CHA2DS2-VASC score.
Patients with a CHADS2 or CHA 2DS2 -VASC
score of 1 should be anticoagulated.
CLINICAL PEARL
The CHADS2 score is simple to use, but may rate a
patient at low risk when they are at intermediate risk on
the CHA2DS2VASC score. For this reason, the CHA2DS2VASC is preferable and is the recommended scoring
system in all modern AF guidelines.
Atrial appendage occlusion devices designed to

reduce the risk of thromboembolism can be inserted
percutaneously to isolate the left atrial appendage.
These devices are only considered in patients who are
considered at high risk of thromboembolism, and who
cannot tolerate anticoagulation. They can reduce the
risk of stroke, but their role needs to be better defined
with longer follow-up.
Anticoagulation decisions
The decision-making process for deciding on anticoagulation to reduce the risk of stroke with antithrombotic therapy
can be challenging.
CLINICAL PEARL
Atrial brillation is an important cause of stroke, and
all patients should be considered for anticoagulation
based on their risk prole.
Ablation therapy (pulmonary vein isolation

and related procedures)
Catheter ablation of the ostia of the pulmonary veins isolates
the atrial fibrillation trigger, and (in selected cases) substrate
modification is also performed within the atria.
Success rates of 7085% can be expected in patients
with paroxysmal AF in experienced, high-volume centers, but often a second or third procedure is needed to
completely abolish AF.
199
Table 8-13 Comparison of the CHADS2 and CHA2DS2VASC scores for assessing the risk of stroke in a patient
with atrial brillation
STROKE RISK FACTOR
CHADS2 SCORE
CHA2DS2VASC SCORE
Cardiac failure
Hypertension
Age
1 (>75 y)
1 (6574 y)
2 (>75 y)
Diabetes
Stroke/TIA, systemic embolism
Sex
1 (female)
Vascular disease
Maximum score
TIA, transient ischemic attack.
Persistent AF is less successfully treated with catheter

ablation.
Following ablation, all patients are anticoagulated with
warfarin for at least 1 month (usually 3 months). Many
authorities recommend indefinite anticoagulation after
ablation because of the risk of AF recurrence.
Ventricular ectopic beats are almost always benign,

but can be frustratingly symptomatic and patients frequently need a lot of support.
Ventricular tachycardia (VT)
CLINICAL PEARL
Catheter ablation can be highly effective in abolishing
atrial brillation, but the patient needs to be warned of
the risk of recurrence, and advised that a course of
treatments may be needed.
Ablation of the His bundle with implantation of a permanent ventricular or biventricular pacemaker may achieve rate
control of AF in patients who are highly symptomatic and
intolerant of medications.
Ventricular ectopic beats (VEBs)
Ventricular ectopic beats arise from enhanced automaticity
or localized re-entry circuits in the ventricles.
Specific treatment of asymptomatic VEBs is generally
not necessary. Possible contributing factors such as cardiac stimulants, electrolyte disturbance and myocardial
ischemia should be corrected.
In patients who are troubled with symptomatic VEBs,
administration of oral beta-blocking drugs may be
effective in reducing the frequency and the patients
awareness of the irregular heart rhythm, especially when
there is associated anxiety or evidence of excess circulating catecholamines.
Antiarrhythmic drug therapy is best avoided for this
largely benign rhythm disturbance.
200
CLINICAL PEARL
Ventricular tachycardia is a tachyarrhythmia arising in

either the right or the left ventricle:
VT is usually due to a re-entrant circuit in a damaged heart. Processes such as chronic myocardial
infarction, or cardiomyopathy which causes myocardial damage and scar may lead to VT.
VT may also occur in patients with arrhythmogenic right ventricular cardiomyopathy.
Accelerated idioventricular rhythm may occur due
to disturbed automaticity in damaged Purkinje
fibers in acute myocardial infarction.
VT may also occur in patients with an otherwise normal heart with congenital abnormalities
of ion channels, including long QT and Brugada
syndromes.
Heart rates in VT may range from 100300 beats/min.
Multiple morphologies of VT and varying rates of VT
commonly occur in an individual patient.
Non-sustained VT has a better prognosis than
sustained VT.
As a general rule, salvos of a few ventricular beats are
not treated as VT.
Sustained VT (lasting at least 30 seconds) is the
most important form of VT, in that it usually
requires prompt intervention.
Prolongation of the QT interval may be precipitated by
a variety of drugs, and torsades de pointes may occur in
susceptible individuals.
Many so-called antiarrhythmic drugs may have proarrhythmic side-effects, particularly in patients with
structural heart disease.
Diagnosis
The clinical manifestations of VT can range from
asymptomatic, to syncope, to sudden death.
The EKG features of VT (Figure 8-17) are a regular
tachycardia with broad QRS complexes. Frequently, P
waves can be seen dissociated from the QRS complexes
and this can be a useful clue that the arrhythmia is not a
conducted supraventricular arrhythmia.
The torsades de pointes variant of ventricular tachycardia commences as an early ventricular beat during repolarization (QT interval), and is rapid, polymorphic and
frequently self-reverting.
Accelerated idioventricular rhythm is a slow, regular,
wide QRS complex at a rate exceeding the sinus rate.
CLINICAL PEARL
Identifying P wave activity independent of the QRS
complex can be a valuable clue that the tachyarrhythmia is ventricular tachycardia.
Due to the risk of proarrhythmia, antiarrhythmic drugs

must be used cautiously. All predisposing and triggering
factors should be addressed before considering administration of antiarrhythmic drugs.
If antiarrhythmic drugs are needed, intravenous beta-blockers may be effective. Intravenous
amiodarone (5 mg/kg) over 510 minutes may
be used in patients with sustained VT and hemodynamic compromise if VT is refractory to DC
cardioversion.
Magnesium may be of benefit in patients with torsades de pointes, particularly if serum magnesium is
low, but is not of benefit otherwise. Pacing at ~100/
min may also be used to prevent torsades de pointes.
For long-term management, first-line therapy for VT
is implantation of an implantable cardioverter defibrillator (ICD). These devices can deliver a short burst of
anti-tachycardia pacing, and have back-up defibrillation capability if there is a deterioration to ventricular
fibrillation.
Oral antiarrhythmic therapy is rarely used for maintenance treatment of VT, and usual treatment is with
device therapy.
Ventricular brillation (VF)

Management
For initial treatment, patients experiencing loss of
consciousness from VT require immediate resuscitation, including early DC cardioversion/defibrillation.
Ventricular fibrillation is the usual cause of sudden death

in ischemic heart disease. It is often preceded by short runs
of polymorphic VT, which may spontaneously terminate;
however, once VF is established, it is not self-terminating in
the human heart. The patient with VF will rapidly lose consciousness. If left untreated, it will be fatal within minutes.
The EKG shows a coarse irregular rhythm. Pseudo VF
patterns due to artifact, tremor, or a displaced electrode
affecting the EKG should not be confused with VF, and
are not associated with any change in conscious state.
The only effective management is immediate, unsynchronized defibrillation with a DC shock of 200 joules
(360 joules if monophasic defibrillator). If the cardiac
arrest is witnessed it is reasonable to administer up to
3maximum-energy DC shocks. If these prove ineffective, advanced cardiac life support is initiated.
CLINICAL PEARL
Ventricular brillation requires immediate debrillation,
even before CPR if possible.
Figure 8-17 (A) Rapid, wide-complex tachycardia

typical of ventricular tachycardia. (B) Torsades de
pointes initiated by an ectopic beat on the T wave;
has the potential to self-revert or deteriorate into
ventricular brillation. (C) Accelerated idioventricular
rhythm exceeding the sinus rate
From Thompson P (ed). Coronary care manual, 2nd ed. Sydney:
Elsevier Australia, 2011.
CONDUCTION DEFECTS
Right and left bundle branch blocks are due to delayed
conduction through the bundle branches or distal radicles of the conduction system. They can indicate underlying heart disease, but may be benign, particularly right
bundle branch block.
201
QRS notching and prolongation of <0.12 seconds is

referred to as a partial or incomplete BBB if the EKG pattern is typical of right or left bundle branch block.
Nonspecific widening of the QRS complex is referred
to as an intraventricular conduction defect (IVCD).
In BBB, the QRS complex is wide with duration >0.12
seconds (3 small squares) at the widest point.
It is sometimes necessary to examine several different EKG leads to determine the maximum width of
the QRS complex.
The QRS appearances in lead V1 can usually discriminate: a tall R with RSR pattern indicates a
right bundle branch block; no tall R wave in V1
indicates a left bundle branch block.
Typical lead V1 patterns are shown in Figure 8-18.
cardiomyopathy, ischemic heart disease, myocardial

infarction or LV hypertrophy.
On occasions it can be due to localized calcific or fibrotic
disease in the conduction system and, like RBBB, can
be intermittent.
The QRS is prolonged, and measures >0.12 seconds.
There is a small (or no) R wave in lead V1 and slurring or notching of leads I, aVL and V6. There is often
left-axis deviation. The direction of the ST segment and
Twave vectors is opposite to that of the QRS vector.
Right bundle branch block (RBBB)
Management is directed towards the underlying

cardiac problem.
Right bundle branch block may have no prognostic

significance, but may reflect right heart disease. If it
is associated with left-axis deviation, it indicates more
advanced conducting system disease (bifascicular block;
see below).
Right bundle branch block shows slurring and notching
of the QRS, with widening >0.12 seconds, a dominant
R wave in V1 with a typical RSR pattern, and a slurred
S wave in the lateral leads.
Benign RBBB needs to be differentiated from the Brugada syndrome, which has a RBBB-like pattern with
persistent ST-segment elevation (coved appearance) in
the right precordial leads. This is associated with susceptibility to ventricular tachyarrhythmias, and sudden
cardiac death.
No management is necessary for RBBB except
in the presence of bifascicular block and symptoms.
Patients with bifascicular block and syncope warrant
further investigation and consideration of pacemaker
implantation.
CLINICAL PEARL
The code for distinguishing RBBB from LBBB is: RSR in
lead V1 = RBBB.

The intraventricular conduction system consists of three
fascicles.
Involvement of the anterior/superior division of the
left bundle will produce a left anterior fascicular block
(hemiblock).
Involvement of the posterior/inferior division of the
left bundle will produce a left posterior fascicular block
(hemiblock).
Left anterior fascicular block (left anterior

hemiblock)
Left bundle branch block (LBBB)
The QRS complex may not be widened, but the main frontal axis will be directed leftwards to greater than 30, i.e.
the QRS complex will be positive in lead I, negative in lead
III, and predominantly negative in lead II.
Left anterior fascicular block by itself requires no treatment, but may indicate a risk of atrioventricular block if
associated with RBBB (bifascicular block).
Left bundle branch block is usually associated with

diffuse disease involving the left ventricle such as
Left posterior fascicular block (left posterior

hemiblock)
In left posterior hemiblock the conduction through the posterior/inferior division of the left bundle is affected. It is less
common than anterior fascicular block.
Bifascicular block
Figure 8-18 Comparison of right bundle branch and

left bundle branch patterns in lead V1. The QRS is
upright with an RSR pattern in right bundle branch
block (A) and downwards in left bundle branch
block (B)
202
The combination of RBBB with left anterior hemiblock is referred to as bifascicular block. In this situation,
depolarization of the left ventricle is solely via the left
posterior/inferior division of the left bundle and cardiac
conduction becomes less reliable.
There is a low risk of developing high-grade atrioventricular (AV) block in a stable patient with bifascicular block, but in circumstances where further stresses
on the cardiac conduction system are possible, such as
myocardial ischemia, infarction, general anesthesia or
surgery, cardiac pacing may be necessary.
CLINICAL PEARL
Right bundle branch block with left-axis deviation (left
anterior hemiblock) indicates the presence of conduction system disease, and the risk of complete atrioventricular block.

Atrioventricular block can occur as a result of conduction delay in the AV node, bundle of His, or the bundle
branches.
Usually AV block with a narrow QRS complex indicates delay in the AV node, whereas AV block with associated bundle branch block indicates disease below the
bundle of His in the ventricular conduction system.
First-degree AV block
Prolongation of the PR interval >0.2 seconds (5 small
squares) constitutes first-degree AV block.
If the first-degree AV block is drug-induced, withdrawal
or dosage reduction of the drug causing AV conduction
delay is the only management necessary. Future administration of these drugs should be avoided.
between the conducted QRS and the ventricular escape

beat.
Patients with symptomatic AV block require cardiac pacing.
If there is a correctable cause such as myocardial infarction or drug toxicity, temporary pacing may suffice, but
usually permanent pacing is required. Transcutaneous
pacing can be used in the emergency situation.
CLINICAL PEARL
Pacing is the only effective treatment for symptomatic
complete AV block. Drug treatments are ineffective.
CARDIAC FAILURE
Overall, cardiac failure (congestive heart failure, CHF)
occurs in 1.52.0% of the population in Western communities, with marked racial and community differences.
The incidence and prevalence rises markedly with age, with
CHF occurring approximately in <1% in people aged below
60 years, 10% in people aged over 65, and >50% in people
aged over 85 years in Western countries. It is one of the most
common reasons for hospital admission and doctor consultation in people aged 70 and older.
Second-degree AV block
Second-degree AV block can occur as a result of delay
through the AV node, or in the HisPurkinje system.
Delays in the AV node characteristically show the
Wenckebach phenomenon, whereas block at the level of
the HisPurkinje system characteristically does not.
The two types of second-degree AV block are referred
to as Mobitz types I and II.
Type I block is more commonly referred to as
Wenckebach AV block; there is gradual prolongation of the PR interval, leading eventually to a
dropped beat before the cycle restarts. It may be
due to drugs affecting AV node function, and may
be self-limiting. Permanent pacing is usually not
necessary.
In type II block there is no lengthening of the PR
interval prior to the sudden loss of AV conduction. It
is associated with disease of the conduction system,
and requires a permanent pacemaker. The risk of
developing complete AV block and syncope is high.
Third-degree (complete) AV block

In third-degree (complete) AV block there is no conduction of atrial impulses to the ventricle, which maintains its
rhythm by a junctional or ventricular escape rhythm.
The clinical features depend primarily on the rate of the
ventricular escape rhythm. Rates below 40/min are frequently associated with syncope or near-syncope.
The EKG abnormality is readily recognized, with total
dissociation of the P waves and QRS complexes. The
QRS complexes are usually regular. On occasion there
may be partial AV conduction, producing fusion beats
Denition
The diagnosis of CHF requires both clinical features and an
objective measure of abnormal ventricular function, as outlined in the definition reproduced in Box 8-2.
Systolic heart failure refers to a weakened ability of
the heart to contract in systole, and remains the most
common cause of CHF. This reflects the prevalence of
coronary heart disease (CHD) in the Western world,
although hypertension is still a significant contributor
to systolic heart failure. Other important causes include
cardiomyopathies.
HFPSF (heart failure with preserved systolic function),
also known as HFPEF (heart failure with preserved
Box 8-2
Denition of cardiac failure

Heart failure is a complex clinical syndrome that can result
from any structural or functional cardiac disorder that
impairs the ability of the ventricle to ll with or eject blood.
It is a syndrome in which the patients should have the
following features: symptoms of heart failure, typically
breathlessness or fatigue, either at rest or during exertion,
or ankle swelling and objective evidence of cardiac
dysfunction at rest.
European Task Force on Heart Failure, 2005. Adapted from
Byrne J, Davie AP and McMurray JJV. Clinical assessment and
investigation of patients with suspected heart failure. In StewartS,
Moser DK and Thompson DR (eds). Caring for the heart failure
patient. London: Martin Dunnitz, 2004.
203
ejection fraction) or diastolic heart failure, refers to

the clinical syndrome of heart failure due to impaired
diastolic filling of the left ventricle, with or without
impaired systolic contraction. It is more common in the
elderly. Ischemia, LV hypertrophy from hypertension,
age-related fibrosis, and cardiac infiltration may all act
to impair diastolic filling of the heart.
Causes of systolic heart failure

Common
Coronary heart disease and prior myocardial infarction
Hypertension
Less common
Non-ischemic idiopathic dilated cardiomyopathy
Causes
While the clinical manifestations may closely resemble each
other, the causes of systolic and diastolic heart failure differ.
The common, less common and uncommon causes of systolic and HFPSF (HFPEF) heart failure are summarized in
Boxes 8-3 and 8-4.

Symptoms and signs
Symptoms of cardiac failure include exertional dyspnea, orthopnea and paroxysmal nocturnal dyspnea
(PND).
A dry, irritating cough may occur, particularly at night,
and this may be difficult to distinguish from asthma or
bronchitis. A therapeutic trial of diuretic therapy may be
useful in these patients.
Symptoms related to fluid retention, such as abdominal distension, ascites, and sacral and peripheral edema,
occur when there is associated right heart failure.
Fatigue and weakness may be prominent.
Patients with CHF may show no abnormal physical
signs, as these are often a late manifestation of cardiac
failure, and on occasion the diagnosis must be made on
the history alone.
Signs of fluid retention may be present, including basal
inspiratory crackles which do not clear with coughing,
and increased resting respiratory rate.
Signs of right heart failure include raised jugular venous
pressure (JVP), ankle and sacral edema, ascites or tender
hepatomegaly.
On auscultation, a 3rd heart sound may be audible.
Clinical signs of LV dysfunction or enlargement may be
present, including a displaced apex beat, or a murmur
may indicate underlying valvular heart disease.
CLINICAL PEARL
Uncommon
Valvular heart disease, especially mitral and aortic
incompetence
Non-ischemic dilated cardiomyopathy secondary to
long-term alcohol misuse
Inammatory cardiomyopathy, or myocarditis
Chronic arrhythmia
Thyroid dysfunction (hyperthyroidism, hypothyroidism)
HIV-related cardiomyopathy
Drug-induced cardiomyopathy, especially
anthracyclines (daunorubicin, doxorubicin)
Peripartum cardiomyopathy
Box 8-4
Causes of HFPSF (HFPEF)

Common
Hypertension (especially systolic hypertension)
Coronary heart disease
Diabetes
Less common
Valvular disease, particularly aortic stenosis
Uncommon causes
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy, either idiopathic or
inltrative, such as amyloidosis
HFPEF, heart failure with preserved ejection fraction; HFPSF, heart
failure with preserved systolic function.
most widely used being the New York Heart Association

(NYHA) grades summarized in Table 8-14.
Electrocardiogram
Clinical diagnosis of congestive heart failure may be

challenging, and drug therapy can cause confusion.
Beware cough which can be caused by angiotensin-converting enzyme inhibitors, edema by dihydropyridine calcium-channel blockers, and dyspnea and
reduced exercise capacity by beta-blockers.
It is standard practice to grade the severity of cardiac failure using an internationally recognized grading system; the
204
Box 8-3
Abnormalities on the EKG include nonspecific ST-segment

and T wave changes. Conduction abnormalities, including
intraventricular conduction delays or LBBB, signs of previous infarction, or LV hypertrophy may be seen.
Chest X-ray
A normal chest X-ray does not exclude the diagnosis, but
confirmatory signs of pulmonary congestion with upper
lobe diversion may help to distinguish the cause of dyspnea
Table 8-14 NYHA classication of cardiac failure

severity
GRADE
SYMPTOMS
No symptoms and no limitation in ordinary

physical activity, e.g. shortness of breath
when walking, climbing stairs, etc.
II
Mild symptoms (mild shortness of breath

and/or angina) and slight limitation during
ordinary activity
III
Marked limitation in activity due to

symptoms, even during less-than-ordinary
activity, e.g. walking short distances (20
100m). Comfortable only at rest
IV
Severe limitations. Experiences symptoms

even while at rest. Mostly bedbound patients
The Criteria Committee of the New York Heart Association

(NYHA). Nomenclature and Criteria for Diagnosis of Diseases of
the Heart and Great Vessels, 9th ed. Boston, Mass: Little, Brown
& Co; 1994:253-6.
from respiratory causes. Evidence of interstitial edema with

pleural effusions or septal lines further confirms that the
cause of dyspnea is due to cardiac failure.
Echocardiography
All modern guidelines for assessing patients with cardiac failure recommend that patients with suspected CHF should
have an echocardiogram.
The echocardiogram can distinguish between systolic
and diastolic dysfunction.
Systolic dysfunction is present when the ejection
fraction is reduced. There is incomplete agreement
on a cut-off for the lower level of LVEF, but a measurement below 50% makes systolic dysfunction
likely, and a measurement below 40% is definite
systolic dysfunction.
LV diastolic function is diagnosed from estimation
of filling pressures via transmitral and pulmonary
venous pulsed-wave Doppler and tissue Doppler
studies. More recently, strain measurements have
made the recognition of diastolic dysfunction more
reliable.
Identification of valvular heart disease is an added benefit of echocardiography and the extent of mitral regurgitation can be measured. This is of importance in patients
with advanced CHF, some of whom may respond to
correction of the mitral regurgitation.
CLINICAL PEARL
All patients with cardiac failure should have echocardiography to identify the extent of systolic dysfunction,
identify patients with diastolic dysfunction, and identify
correctable valvular heart disease.
Gated radionuclide measurement of LV function can

provide a reliable estimate of LVEF, but has been largely
supplanted by echocardiography for this purpose.
Hematology and biochemistry

Mild anemia may occur in patients with CHF, and is
associated with an adverse prognosis.
Measurement of plasma urea, creatinine and electrolytes
provide a simple index of renal function, and this should
be performed in all patients.
In advanced CHF, dilutional hyponatremia can occur.
Diuretic therapy may also affect sodium levels. Persistent hyponatremia may indicate a loss of homeostasis
and indicate a poor prognosis.
Hyperkalemia may occur with impaired renal function,
especially in the presence of ACEIs, aldosterone antagonists or aggressive diuretic therapy. Hypokalemia can
occur with thiazide or loop diuretics.
Congestive hepatomegaly may cause abnormal liver
function tests, and hypoalbuminemia, potentially indicating cardiac cirrhosis, may occur with longstanding
CHF.
Natriuretic peptides
Plasma levels of brain-type natriuretic peptide (BNP) indicate the severity of CHF.
Both BNP and N-terminal proBNP levels have been
shown to predict all-cause mortality, including death
from pump failure and sudden death; however, BNP
and N-terminal proBNP levels vary with age, gender
and renal function.
Measurement of BNP or N-terminal proBNP is not
recommended as routine in the diagnosis of CHF, but
is particularly useful for clarifying whether dyspnea is
due to CHF or to respiratory causes. A normal BNP or
N-terminal proBNP level makes the diagnosis of heart
failure unlikely.
Treatment
The dual aims for treatment of cardiac failure are to relieve
symptoms and improve prognosis.
Symptom relief
Fluid and salt management
The most prominent symptoms in cardiac failure are due to
fluid retention. Careful monitoring of salt and fluid intake
can be sufficient in many patients to control these symptoms
without recourse to diuretics.
For patients with mild symptoms (NYHA grade II or
less), limiting sodium intake to 3 g/day assists with control of fluid balance.
For patients with moderate to severe symptoms (NYHA
grade III/IV) and requiring diuretics, a restricted sodium
intake of 2 g/day should be applied.
In most patients with cardiac failure, a fluid intake of less
than 2.0 L/day is recommended. If symptomatic fluid
205
retention is obvious, fluid intake should be restricted to

<1.5 L/day.
Fluid restrictions should be liberalized in warmer
weather to avoid dehydration and hypotension.
CLINICAL PEARL
Daily weighing is an important discipline in heart failure management. A weight gain of more than 2 kg in
2days is a reason to increase diuretic therapy.
Diuretics
Diuretics are an essential tool in managing symptoms of cardiac failure, although they have not been shown to improve
survival. Diuretics increase urine sodium excretion and can
rapidly decrease the symptoms and physical signs of fluid
retention.
In fluid-overloaded patients, treatment is usually initiated with a loop diuretic (e.g. furosemide 4080 mg/
day) until edema and relief of dyspnea is achieved. The
diuretic dose should be decreased when symptoms and
signs indicate euvolemia.
Thiazide diuretics are an alternative in patients who find
the rapid diuresis with loop diuretics unappealing.
Occasionally loop and thiazide diuretics can be combined, but this requires careful monitoring of response
to avoid hypovolemia and hypokalemia.
Long-term use of loop and thiazide diuretics may also
contribute to magnesium depletion, potentially contributing to cardiac arrhythmias.
In patients with persistent fluid retention, especially
when right heart failure and hepatic congestion and ascites are prominent, addition of an aldosterone antagonist,
e.g. spironolactone, may be helpful. Aldosterone antagonists, particularly in combination with ACEIs, can
increase the risk of renal dysfunction and hyperkalemia.
Angiotensin-converting enzyme inhibitors (ACEIs)
and angiotensin-receptor blockers (ARBs)
These have a mild diuretic effect and can contribute to
symptom relief.
Digoxin and other inotropic agents
Oral digoxin and its digitalis predecessors have been
used for more than 200 years in the symptomatic treatment of cardiac failure. In the past few decades, however, it has been established that its role in the patient
in sinus rhythm is limited, and its inotropic effect may
not be helpful. Despite this, digoxin may have a role
in the management of the patient with advanced cardiac failure in which other therapies are not controlling
symptoms.
Other oral inotropic agents have been used, but the
apparent logic of enhancing contractility of the failing
heart has not translated into clinical benefit, and their
use is now abandoned because of adverse effects on
outcomes.
206
In selected patients with severe decompensated heart

failure, short-term use of intravenous inotropic agents
may have a role in improving symptoms.
Dobutamine can be used for short-term support,
and may achieve clinical stability.
Levosimendan is a calcium-sensitizing inotropic
agent possibly superior to dobutamine, but its use
may be limited by hypotension in some patients.
Improving prognosis in systolic heart failure

An improved understanding of the pathophysiology of the
failing heart has led to substantial advances in treatment
over the past 30 years. The primary paradigm of therapy
has advanced from attempting to improve contractility
with inotropic agents to blocking the adverse neurohumoral
response to heart failure.
Reninangiotensinaldosterone system (RAAS)
blockade
Inhibition of the RAAS and the use of angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin II
receptor antagonists (ATRAs) are central to the management of systolic heart failure.
ACEIs have been shown in large randomized clinical
trials to prolong survival and reduce the need for hospitalization in patients with moderate to severe heart failure (NYHA grades IIIV), and to moderately increase
ejection fraction.
All patients with systolic heart failure should be started
on a low dose of ACEIs if tolerated, and the dose
increased if possible.
Angiotensin-receptor blockers (ARBs) are generally better tolerated and are an alternative for patients
who experience ACEI-related adverse effects, such as a
cough.
ACEIs and ARBs in heart failure show similar outcomes in comparative trials. Combinations of ACEIs
and ARBs have been trialed, but may have adverse
effects on renal function.
CLINICAL PEARL
Multiple trials have shown that angiotensin-converting
enzyme inhibitors (ACEIs) and beta-blockers are the
ideal combination to improve prognosis in cardiac failure. Angiotensin-receptor blockers (ARBs) can be substituted if there is ACEI intolerance.
Beta-adrenergic blockade
Beta-blockers inhibit the adverse effects of chronic
activation of the sympathetic nervous system, and
its adverse effects on the myocardium. Although the
benefits of beta-blockade may be a class effect, only
four beta-blockers have been shown to improve
prognosis in clinical trials. The unique properties of
these drugs and their usual doses are summarized in
Table 8-15.
Table 8-15 Beta-blockers shown in clinical trials to be effective in improving outcomes in cardiac failure
DRUGS
UNIQUE PROPERTIES
USUAL DOSE
Bisoprolol
Cardio (beta-1) selective
2.510 mg once daily
Carvedilol
Non-cardio (beta-1) selective, vasodilating alphablocker effect, antioxidant
2.525 mg twice daily
Metoprolol
Cardio (beta 1) selective
Succinate (XL preparation)

25100 mg once daily
Nebivolol
Non-cardioselective, vasodilating effect mediated by

the endothelial nitrous oxide pathway
5 mg once daily
XL, extended-release.
Beta-blockers should be started cautiously, especially

in patients who are hypotensive or recently decompensated. They should be started at low doses with gradual
increases, to limit adverse effects of hypotension, bradycardia and reduced cardiac contractility.
Clinical trials have shown no difference in outcomes
with the order of commencing ACEIs (ARBs) and
beta-blockers in heart failure.
Improving prognosis in heart failure with

preserved systolic function (HFPSF)
In contrast to the many proven treatments in systolic
heart failure, there have not been any convincing drugs
to improve outcomes in HFPSF (see Box 8-4, above).
Trials of ARBs and calcium-channel blockers have
shown no benefit.
Devices
CLINICAL PEARL
While the benets of beta-blockade in cardiac failure may be a class effect, only carvedilol, bisoprolol,
extended-release metoprolol and nebivolol have been
shown to be effective in randomized clinical trials.
Aldosterone antagonists
Aldosterone can promote fibrosis, hypertrophy and
arrhythmogenesis in the failing heart, and antagonism
of these effects with spironolactone provides benefit.
Spironolactone reduces all-cause mortality and results
in symptomatic improvement in patients with advanced
CHF. The usual dose is 25 mg/day, increasing gradually
to 50mg twice a day.
There is a risk of hyperkalemia with higher doses,
particularly in the presence of ACEIs and/or renal
impairment.
The use of spironolactone is also limited by the
development of gynecomastia.
Eplerenone, a more selective aldosterone antagonist
without feminizing effects, has been found to reduce
mortality in patients with LV systolic dysfunction and
symptoms of heart failure.
Direct sinus-node inhibition
As beta-blockers may improve heart failure outcomes with
heart rate slowing, an alternative method of heart rate
slowing with the sinus-node inhibitor ivabradine has been
trialed, and has been shown to reduce cardiovascular mortality and heart failure hospitalization in patients with heart
rates above 70/min; this drug may be a useful alternative to
beta-blockade.
Implantable cardioverter-debrillator (ICD)

Patients with cardiac failure and LV dysfunction are
prone to high-grade, potentially lethal arrhythmias such
as ventricular tachycardia and ventricular fibrillation.
Implantation of an ICD is associated with a 2030%
relative reduction in mortality at 1 year, with improved
survival maintained over subsequent years.
Benefits have also been shown in patients with LV dysfunction without overt cardiac failure.
Current guidelines recommend implantation of an ICD
in cardiac failure patients with LVEF <35%.
Many patients are untroubled by the implantation of the
ICD and appreciate the security of knowing that they
have received a lifesaving device. However, ICDs are
expensive and can worsen quality of life, particularly in
patients experiencing frequent painful shocks.
Biventricular pacingcardiac
resynchronization therapy (CRT)
Patients with symptomatic dilated heart failure may
have asynchronous contraction of the left ventricle. A
widened QRS complex (>120 ms) may be an electrocardiographic marker of this.
Systolic function is improved by pacing simultaneously
in the left and right ventricles. This can improve symptoms and frequency of hospitalization in patients with
symptomatic dilated CHF and prolonged QRS duration, and a mortality benefit of biventricular pacing in
patients with heart failure has also been shown.
The improvement in prognosis is greater when CRT is
combined with ICD, compared with ICD alone.
207
CLINICAL PEARL
Implantable cardioverter-debrillator devices are indicated in patients with cardiac failure and LVEF <35%.
Cardiac resynchronization therapy is benecial when
the QRS complex is widened to >120 ms.
Left ventricular assist devices (LVADs)

The use of LVADs to assist or replace LV function is now
well established as a temporary bridge to cardiac transplantation. With improving technology and the development of
continuous flow devices with fewer moving parts, the prospect of LVADs as destination (permanent) therapy is feasible, but not yet widely available.
INFECTIVE ENDOCARDITIS
The incidence of infective endocarditis varies greatly
between different populations and systems of medical care, and ranges from 3 to 10 episodes/100,000
person-years.
The profile of endocarditis has changed in recent
years from a condition largely affecting young people
with rheumatic valve disease, to now occurring more
frequently in older persons, especially those with
prosthetic valves or degenerative valve conditions.
The changing profile has been associated with a
change in the pathogenic organisms. While streptococcal endocarditis has been the most common
cause in the past, there is an increasing prevalence
of staphylococcal endocarditis and more exotic
bacteria and fungi, particularly among immunocompromised patients and intravenous drug users.
The infection may be confined to superficial involvement of the valve leaflets, but can erode the valve tissue
and cause valve perforation, and involve the paravalvular
structures with the formation of paravalvular abscesses.
There is the potential for embolic events, with minor
effects including splinter hemorrhages in the nail beds
(Figure 8-19) and subconjunctival hemorrhages, or
major neurological consequences with formation of
intracranial mycotic aneurysms.
There may be an immunological reaction responsible for vasculitis, Roth spots and Janeway lesions
(Figure8-19).
CLINICAL PEARL
The pattern of endocarditis has changed from predominantly viridans streptococci (strep viridans) affecting rheumatic valves to a more complex prole.
Microbiology
Streptococci and enterococci
Oral streptococci (strep viridans or beta-hemolytic
strep) form a mixed group of micro-organisms; they
208
C
Figure 8-19 (A) Roth spots, (B) Janeway lesions, and
(C) splinter hemorrhages
From: (A) Goldman L and Schafer AI. Goldmans Cecil medicine,
24th ed. Philadelphia: Saunders, 2012. (B) James WD, Berger T and
Elston D. Andrews Diseases of the skin: clinical dermatology, 11th
ed. Saunders, 2011. (C) Baker T, Nikolic G and OConnor S. Practical
cardiology, 2nd ed. Sydney: Churchill Livingstone, 2008.
remain a common cause of infective endocarditis and

are almost always susceptible to penicillin.
A subgroup, members of the Streptococcus milleri and S.
anginosus groups, comprises a more aggressive form with a
propensity to form abscesses, and requires a longer period
of treatment. Some newly classified subspecies (Abiotrophia and Granulicatella) may be tolerant to penicillin.
Enterococci (Enterococcus faecalis, E. faecium) can also
cause endocarditis and are usually sensitive to penicillin.
Staphylococci
Community-acquired native-valve staphylococcal infective
endocarditis is usually due to Staphylococcus aureus, which is
most often susceptible to flucloxacillin (previously methicillin). However, staphylococcal prosthetic-valve endocarditis
is more frequently due to coagulase-negative staphylococci
(CNS) with flucloxacillin resistance (methicillin-resistant
Staphylococcus aureus, MRSA).
CLINICAL PEARL
Community-acquired staphylococcal endocarditis
may be ucloxacillin-sensitive, but MRSA is an increasingly frequent and difficult-to-treat pathogen.
Fastidious and exotic organisms

Initial blood cultures may be negative in endocarditis
which has been previously treated with antibiotics, or
is due to infections of the HACEK (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella and Kingella) group,
Brucella, and fungi.
Rarely, persistently blood-culture-negative endocarditis may be due to intracellular organisms such as Bartonella or Chlamydia. In these cases, diagnosis depends on
cell culture or gene amplification.
Infections are more common in immunocompromised
patients and intravenous drug users.
Diagnosis
The diagnosis of endocarditis can be challenging and
requires a high level of awareness, particularly in patients
with prosthetic valves or in immunocompromised patients,
where missing the diagnosis even for a short time can have
serious consequences.
The traditional symptom complex of a fever and a new
murmur may be a form of presentation, but is unreliable for accurate diagnosis in modern practice. There
is increasing reliance on combining the findings from
echocardiography and blood cultures.
The diagnosis is confirmed if 2 major criteria, or 1
major criterion and 3 minor criteria, or 5 minor criteria
are fulfilled.
The two major criteria are:
1 A positive blood culture for endocarditis.
a Micro-organisms typical of endocarditis from
2 separate blood cultures can establish the
diagnosis.
b Organisms consistent with, but not typical of,
endocarditis require at least 2 positive cultures of
blood samples drawn >12 hours apart, or all of 3
or a majority of >4 separate cultures of blood with
the first and last samples drawn at least 1 hour
apart, to establish the diagnosis.
c There is no justification for the practice of synchronizing blood sampling with peaks of fever.
2 Echocardiographic evidence of endocardial
involvement.
a An oscillating intracardiac mass or vegetation
on a valve or supporting structure, in the path of
regurgitant jets, or new partial dehiscence of prosthetic valve, or new valvular regurgitation.
b It is important to note that an echocardiogram negative for vegetations does not exclude
endocarditis.
Transesophageal echocardiography (TEE) may be

required if there is doubt about the diagnosis on
transthoracic echo, or if surgery is contemplated.
CLINICAL PEARL
The diagnostic criteria for infective endocarditis are fullled if there is blood culture evidence and echocardiographic evidence of mobile vegetations.
Minor criteria include:

a predisposing heart condition
intravenous drug use
fever with a temperature >38C
vascular phenomena including major arterial emboli,
septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
immunological phenomena such as glomerulonephritis,
Oslers nodes, Roth spots, positive rheumatoid factor
microbiological evidence with positive blood culture
but not meeting a major criterion as noted above
serological evidence of an active infection with an
organism consistent with endocarditis.
Management
Early diagnosis is an important part of the management
of infective endocarditis.
Antibiotic treatment is informed by the microbiological findings.
Initial treatment may be necessary when the diagnosis
has been established on clinical and echocardiographic
criteria but the blood culture is not available.
CLINICAL PEARLS
While awaiting denitive blood culture information
in the patient not sensitive to penicillin and without a
prosthetic valve, treatment should commence with
IV amoxicillin/clavulanate 12 g/day in 4 doses, and
gentamicin 3mg/kg/day in 2 or 3 doses.
While awaiting denitive blood culture information in the patient with a prosthetic valve, treatment
should commence with vancomycin 30 mg/kg/day
in 2 doses, gentamicin 3 mg/kg/day in 2 or 3 doses,
and rifampin 1200 mg/day orally in 2 doses.
The standard treatment for organisms fully susceptible

to penicillin is penicillin 1218 million units/day, maintained for 4 weeks.
Alternative regimens maintained for 4 weeks are
amoxicillin 100200 mg/kg/day IV or ceftriaxone
2g/day IM or IV.
2-week regimens with these drugs supplemented with
gentamicin or netlimicin have been used and shown to
be as effective as the 4-week regimens, but need careful
monitoring of the gentamicin levels.
209
In beta-lactam-allergic patients, vancomycin 30mg/kg

in 2 divided doses can be used.
Monitoring of the benefits of treatment should be
undertaken with serial echocardiography and assessment
of inflammatory parameters. If these are not showing
convincing evidence of improvement, reassessment of
antibiotic sensitivities and antibiotic regimens is needed.
CLINICAL PEARL
Following initial treatment, IV treatment should continue for 4 weeks; regimens of shorter duration have
been used successfully, but require more aggressive
and higher-dose antibiotics.
Surgery has an important role in the management of

endocarditis. It may be difficult to time the surgery, as
early surgery may be complicated by operating with an
active infection, whereas late surgery may allow irreversible destruction of the valve.
Immediate surgery is indicated if there is clear evidence
of valve destruction or the development of cardiac
failure.
Box 8-5
Dening the high-risk patient for

endocarditis prophylaxis
Antibiotic prophylaxis should only be considered for
patients at highest risk of IE:
1 Patients with a prosthetic valve or a prosthetic
material used for cardiac valve repair
2 Patients with previous IE
3 Patients with congenital heart disease
a cyanotic congenital heart disease, without
surgical repair, or with residual defects, palliative
shunts or conduits
b congenital heart disease with complete repair
with prosthetic material whether placed by
surgery or by percutaneous technique, up to
6months after the procedure
c when a residual defect persists at the site of
implantation of a prosthetic material or device by
cardiac surgery or percutaneous technique
Antibiotic prophylaxis is no longer recommended in
other forms of valvular or congenital heart disease
Prevention
IE, infective endocarditis.
It is important to take careful steps to prevent endocarditis in susceptible patients. In recent years, however, it has
been realized that the evidence to justify the previous practice of widespread use of antibiotics for prophylaxis in all
dental procedures in patients with heart murmurs was based
on minimal evidence, and was exposing the community to
unnecessary overuse of antibiotics. Recent guidelines have
defined more carefully the high-risk patient and the situations where prophylaxis is required.
The high-risk patient is now defined as in Box 8-5.
From The Task Force on the Prevention, Diagnosis, and Treatment

of Infective Endocarditis of the European Society of Cardiology.
Guidelines on the prevention, diagnosis, and treatment of infective
endocarditis. Eur Heart J 2009;30:2369413.
The specific situations which require treatment for

those identified as high-risk are defined in Box 8-6. Of
note, the only procedure requiring antibiotic prophylaxis, even in the high-risk patient, is dental work with
gingival or oral mucosal disruption.
Box 8-6
Recommendations for prophylaxis of infective endocarditis in highest-risk patients

according to the type of procedure
A. Dental procedures
Antibiotic prophylaxis should only be considered for
dental procedures requiring manipulation of the gingival
or periapical region of the teeth or perforation of the oral
mucosa.
Antibiotic prophylaxis is not recommended for local
anesthetic injections in non-infected tissue, removal
of sutures, dental X-rays, placement or adjustment of
removable prosthodontic or orthodontic appliance or
braces. Prophylaxis is also not recommended following the
shedding of deciduous teeth or trauma to the lips and oral
mucosa.
B. Respiratory tract procedures

Antibiotic prophylaxis is not recommended for respiratory
tract procedures, including bronchoscopy or laryngoscopy,
transnasal or endotracheal intubation.
C. Gastrointestinal or urogenital procedures
Antibiotic prophylaxis is not recommended for
gastroscopy, colonoscopy, cystoscopy or transesophageal
echocardiography.
D. Skin and soft tissue
Antibiotic prophylaxis is not recommended for any
procedure.
From The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology.
Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Eur Heart J 2009;30:2369413.
210
Minor dental work, respiratory, gastrointestinal or

urogenital procedures do not require prophylactic
antibiotics.
The antibiotic regimens recommended for prophylaxis
if it is necessary are shown in Table 8-16.
The standard dose of amoxicillin should be taken about
1 hour before dental procedures.
PERICARDIAL DISEASES
The pericardial space is usually a thin layer of fluid. Having
two surfaces (parietal and serosal), it is subject to inflammation, fluid accumulation and fibrosis.
Acute pericarditis
Acute pericarditis occurs when the serosal and parietal surfaces of the pericardium become inflamed for any reason.
The most common cause is viral pericarditis. This
often occurs during a viral illness, sometimes after a
delay of several weeks from the onset of the flu-like
illness.
Viral causes include the coxsackieviruses, but

other influenza and parainfluenza viruses may be
implicated.
The pathogenesis may involve an immunological reaction which results from the inflammatory
response to the viral illness.
There may also be associated myocardial involvement
(myopericarditis).
The usual clinical course is benign with resolution
within days or weeks, responding rapidly to antiinflammatory medication. Some cases, however, can
progress to the development of pericardial effusion or
tamponade.
Some cases can become relapsing, with multiple episodes during subsequent months, and may progress to
constrictive pericarditis.
CLINICAL PEARL
Viral pericarditis is common and usually has a benign
self-limiting course, but can be complicated by the
development of an effusion and late development of
pericardial constriction.
Table 8-16 Antibiotic regimens for prophylaxis of endocarditis in high-risk patients
ADULT DOSE
PEDIATRIC DOSE
Standard general prophylaxis

Amoxicillin
2 g PO
50 mg/kg PO; not to exceed

2 g/dose
2 g IV/IM
50 mg/kg IV/IM; not to exceed

2 g/dose
Clindamycin
600 mg PO

600 mg/dose
Cephalexin (cefalexin) or other rst- or second-generation

oral cephalosporin in equivalent dose (do not use with a
history of severe penicillin hypersensitivity)
2 g PO

2 g/dose
Azithromycin or clarithromycin
500 mg PO

500 mg/dose
Clindamycin
600 mg IV
20 mg/kg IV; not to exceed

600 mg/dose
Cefazolin or ceftriaxone (do not use cephalosporins in

patients with a history of severe penicillin hypersensitivity)
1 g IV/IM
50 mg/kg IV/IM; not to exceed

1 g/dose
Unable to take oral medication

Ampicillin
Allergic to penicillin
Allergic to penicillin and unable to take oral medication
IM, intramuscularly; IV, intravenously; PO, orally.

From Wilson W et al. American Heart Association Guideline: prevention of infective endocarditis. Circulation 2007;116:173654.
211
Pericarditis is common after myocardial infarction,

usually in association with extensive infarction and
often associated with atrial arrhythmias.
A variant of post-infarction pericarditis is Dresslers
syndrome, a serositis complicating myocardial
injury. It is related to post-cardiotomy syndrome,
a pericardial (and occasionally pleural) inflammatory syndrome complicating cardiac surgery. Both
Dresslers syndrome and post-cardiotomy syndrome are now seen less frequently.
Pericarditis may also be a reaction to uremia or to neoplastic infiltration of the pericardium, and may occur
as part of a systemic inflammatory illness such as exacerbation of rheumatoid disease or lupus.
Rarer causes include myxedema, drugs, and tuberculosis.
Treatment
Clinical features and investigations
The rate of accumulation, rather than the volume of

fluid, determines the degree of cardiac compression
which results from pericardial effusion.
The typical symptom of pericarditis is an anterior chest

pleuritic pain which increases with inspiration. The
pain is often relieved by sitting up or changing posture.
It can also be a dull pain without the typical pleuritic
features, and can radiate to the jaw or arms and shoulders, causing confusion with the pain of myocardial
infarction.
The characteristic clinical examination finding is a
pericardial rub, usually heard best in systole, but often
with a diastolic as well as a systolic component. The
rub has a characteristic scratching, to-and-fro quality.
It can vary from hour to hour. The rub is often accentuated by listening in expiration, or with the patient
sitting forward.
CLINICAL PEARL
A pericardial rub may be transient, can be enhanced
during expiration, and should be carefully sought when
the diagnosis of pericarditis is suspected.
The typical feature of the EKG in pericarditis is concave

upwards ST-segment elevation, described as a Mexican
saddle appearance. It differs from the ST-elevation of
myocardial infarction which is more typically (but not
always) convex upwards.
The normal variant of early repolarization may
cause confusion in interpreting ST-segment elevation, but in this case the EKG remains unchanged
on serial EKGs, whereas the EKG in pericarditis can
change as the pericarditis evolves.
Echocardiography may be normal or may show a
small amount of pericardial fluid.
Cardiac biomarkers may be mildly elevated if the
pericarditis is associated with myocardial injury in
myopericarditis, but are usually only modestly elevated
in typical viral pericarditis.
212
Treatment is usually with an anti-inflammatory drug.

In all patients who have had evidence of a vigorous inflammatory response accompanying the pericarditis, serial
echocardiography is wise to ensure that the pericarditis is
settling and a pericardial effusion is not developing.
CLINICAL PEARL
Although the echocardiogram is usually normal in
acute viral pericarditis, it should be used to check that
an effusion is not developing.
CLINICAL PEARL
With slow build-up of pericardial uid, stretching of the
pericardium may accommodate a large effusion, but
a small increase in volume can suddenly increase the
intrapericardial pressure and cause tamponade.
All of the causes of pericarditis listed above can cause

pericardial effusions, but they are most commonly seen
in patients who are severely uremic or with extensive
neoplastic infiltration.
Echocardiography is a reliable and valuable tool for the
assessment of pericardial effusions. Features of tamponade on echocardiography commence with mild flattening
of the right atrium, followed by compression of the right
ventricle. These echocardiographic features usually occur
before clinical signs of tamponade are evident.
The classical clinical signs of tamponade are a rising
jugular venous pressure (JVP), with Kussmauls sign
(an increase rather than a decrease in the height of the
venous pulse with inspiration), and pulsus paradoxus
(an increase in amplitude of the respiratory variation in
pulse amplitude of >10mmHg).
CLINICAL PEARL
Pericardiocentesis needs to be done urgently when tamponade is present; a large effusion may need tapping if
there are warning signs of tamponade developing.
Pericardiocentesis for tamponade can be lifesaving. It

is usually done through the subxiphoid approach, but
if the echocardiogram shows a loculated effusion, alternative approaches may be used. A drainage catheter is
usually left in place overnight to allow completion of
drainage of the effusion. If there is rapid reaccumulation
of pericardial fluid, a surgical approach with creation of

a pericardial/pleural window may be needed.
CLINICAL PEARL
Pericardiocentesis is not a benign procedure. A medium-sized effusion without tamponade should not be
tapped.
Apparently unexplained severe right heart failure is the

most common presentation, and clinical signs of pericardial constriction may be subtle.
Echocardiography with features of constriction can
confirm the clinical suspicion, but CT or MRI are often
required to delineate the cause.
Surgical release of the constriction, and resection of
the thickened pericardium can dramatically abolish the
symptomatic right heart failure.

Constrictive pericarditis can result from progressive
pericarditis.
Tuberculosis is the classic cause, but relapsing viral pericarditis, scarring following cardiac surgery, radiotherapy
and uremia are increasingly frequent causes.
CLINICAL PEARL
In severe unexplained right heart failure, pericardial
constriction should be considered, as it is a potentially
correctable cause of the right heart failure.
213
1
In atrial brillation, the A wave in the jugular venous pulse is:

A More prominent than usual
B Absent
C Present but cannot be seen
D Replaced by visible brillation waves
On the electrocardiogram, a right bundle branch block is represented by a widened QRS complex and:
A An M shape in the lateral leads
B Left-axis deviation
C Right-axis deviation
D RSR with a tall R wave in the V1 lead
A patient presents with clinical features of ST-elevation myocardial infarction (STEMI). The hospital does not have
facilities for percutaneous coronary intervention (PCI), and there is a 1-hour ambulance drive to the nearest
PCI-capable hospital. The best treatment for this patient is:
A Conrm the diagnosis with an immediate and a 3-hour troponin level.
B Check with the PCI-capable hospital if they can receive a PCI patient in 90 minutes and transfer them there for PCI.
C Administer thrombolytic therapy and transfer the next morning for PCI.
D Check the cholesterol levels, admit to the coronary care unit and observe.
4 A 56-year-old woman presents with shortness of breath, and the clinical examination demonstrates a long,
low-pitched rumbling diastolic sound in mid-diastole. The likely diagnosis is:
A Borborygmi
B Mild mitral stenosis
C A 3rd heart sound indicating heart failure
D Severe mitral stenosis
5
A 68-year-old female patient presents to the emergency department (ED) with her second episode of atrial brillation
(AF). The episode has been going on for 18 hours, she is not distressed, and the AF reverts shortly after arrival in the ED.
She has no history of hypertension, cardiac failure or diabetes.
A She should be reassured and sent home.
B She should be started on aspirin 100 mg/day.
C She should be started on an oral anticoagulant.
D She should be started on aspirin 100 mg/day and clopidogrel 75 mg/day.
6 A patient with a loud murmur and echocardiography showing moderately severe mitral regurgitation is going to see
the dentist for dental extraction and requires advice on antibiotic prophylaxis. The patient is allergic to penicillin. They
should be advised that they need:
A Amoxycillin 2 g with antihistamine cover just before the procedure
B Clindamycin 600 mg 1 hour before the procedure
C Azithromycin 500mg just before the procedure
D No antibiotic cover
ANSWERS
1
B.
The A wave in the jugular venous pulse represents atrial contraction. As atrial contraction is absent in atrial brillation, there
is no A wave seen in the jugular venous pulse.
D.
A tall R wave in lead V1 is a reliable marker of a right bundle branch block. A simple mnemomic is R tall in V1 = RBBB.
The slurred and tall R wave is due to delayed activation of the right ventricle. Other causes of a tall R wave in V1 are right
ventricular hypertrophy, true posterior infarction and type A WolffParkinsonWhite syndrome.
B.
In STEMI, time is muscle and urgent reperfusion of the occluded coronary artery is the aim. If PCI can be delivered by a
skilled team within 90 minutes of presentation, this is the preferable mode of reperfusion. If skilled PCI cannot be delivered
in this time, reperfusion therapy should be commenced with a lytic agent.
214
4 D.
The severity of mitral stenosis can be determined by auscultation. In general, the longer the diastolic murmur, the more
severe the mitral stenosis. For mitral stenosis to cause dyspnea, it is usually severe.
5
C.
All the recent clinical trial evidence shows that patients with atrial brillation, even if reverted, should be anticoagulated
with warfarin or a new oral anticoagulant (NOAC) such as dabigatran, rivaroxaban or apixaban. Aspirin provides insufficient
antithrombotic effect for atrial brillation, and the combination of aspirin and clopidogrel has been shown to be inferior to
an oral anticoagulant.
6 D.
The latest guidelines recommend that antibiotic cover for valve lesions should be limited to patients at highest risk (those
with prosthetic valves, patients with prior endocarditis). Mitral regurgitation is no longer regarded as sufficiently high risk for
endocarditis to warrant antibiotic prophylaxis.
215
CHAPTER 9
HYPERTENSION
Annemarie Hennessy
CHAPTER OUTLINE
MECHANISMS OF HYPERTENSION
EPIDEMIOLOGICAL EVIDENCE FOR
HYPERTENSION AND ITS EFFECTS
DEFINITIONS OF HYPERTENSION
CLINICAL PRESENTATIONS AND
INVESTIGATIONS
TARGET-ORGAN EFFECTS OF HYPERTENSION
Blood vessels
Cardiac effects
Retinopathy
Renal changes secondary to hypertension
Brain
TREATMENT AND TARGETS FOR

HYPERTENSION CONTROL
Specic targets linked to comorbid conditions
TREATMENT FOR CHRONIC PRIMARY

HYPERTENSION
Normal adult
High-normal
TREATMENT IN AN ACUTE SETTING
Hypertension remains a common, widespread and increasing problem in all countries around the world. It contributes to overall cardiovascular risk, including that of stroke,
cardiac disease and other vascular disease, as well as chronic
kidney disease and retinopathy. It interacts strongly with diabetes, obesity, hyperlipidemia, smoking, and renal disease to
accelerate the progression to irreversible organ damage.
MECHANISMS OF
HYPERTENSION
Physiological determinants of hypertension are:

volume overload/salt overload
increased systemic vascular resistance
increased central drive to increase BP
increased sympathetic nerve stimulation.
The pressureflowresistance relationship helps us understand that an increase both in cardiac output (CO) and in
total peripheral resistance (TPR) can lead to an increase
in BP.
BP = CO TPR
The mechanisms of hypertension are best defined by the

physiological processes that lead to blood pressure elevation.
These mechanisms are true whether the elevated blood
pressure (BP) is primary or is secondary to other conditions.
We also need to remember that cardiac output is a function

of stroke volume (SV) and heart rate (HR).
CO = HR SV
217
Knowing these relationships helps us understand why the

pharmacological targets for hypertension include reducing
the systemic vascular resistance, decreasing the heart rate, or
decreasing the circulating volume.
Hypertension is considered to be primary if the BP is
elevated due to family history, or due to lifestyle issues such
as sedentary lifestyle, obesity, and dietary indiscretion (diets
high in sodium and fats). The term essential was coined in
the 1800s when it was thought that the pressure was essential to perfuse damaged kidneys; we now know this to be the
reverse, i.e. damaged kidneys cause hypertension. The term
essential has no place in modern medical language and the
terms chronic hypertension or primary hypertension have
better meanings. Secondary hypertension occurs when
an underlying medical condition explains the origin of the
hypertension, and there are many of these (see below).
Hypertension causes a vicious cycle of damage to the
endothelium, and then the vascular smooth muscle, such
that the tendency to hypertension and high shear stress
within the blood vessel is reinforced with time. As a result
of longstanding undertreated hypertension, a range of structural changes occur (Box 9-1).
The molecular mechanisms behind these physiological
changes are divided into two categories: those acting in the
periphery, and those arising from the brain (Box 9-2).
Genetic contributions to primary hypertension are the
subject of much research. The search for single or multiple probable genetic explanations is important in defining
mechanisms and designing new targets for treatment, but
they are not widely used in everyday clinical practice. Some
genetic causes, although rare, give us insight into the mechanisms of disease at a molecular level (Table 9-1).
Secondary hypertension is caused by conditions across
many domains of internal medicine (Box 9-3). These are
best classified as:
endocrine
arterial abnormalities
renal disease
medication-induced
malignancy-related.
Box 9-1
Structural changes due to ongoing

and progressive blood pressure
elevation
Amplication:
Vascular remodeling as a result of hypertension
Vascular smooth muscle hypertrophy
Increased arterial stiffness
Rarefaction:
Loss of capillary density
Not all antihypertensives reverse this phenomenon
Change in autoregulatory set points of the major organs,
especially the kidneys:
Potential targets of therapy
It is also seen as a direct consequence of autoimmune disease

processes such as vasculitides, thyroiditis, and malignancy,
with associations with parathyroid malignancies, endothelinomas, reninomas, and adrenal tumors.
Newer anticancer drugs which control the angiogenesis
axis (VEGF inhibitors) are associated with hypertension.
EPIDEMIOLOGICAL EVIDENCE
FOR HYPERTENSION AND ITS
EFFECTS
Figure 9-1 (overleaf) gives an example of the increasing
prevalence of hypertension with age in Western society.
These rates of chronic hypertension are similar to those
seen in most developed and developing countries. There
is no fundamental effect of age per se on increasing blood
pressure outside of the effect of modern life. These increases
are linked to decreasing rates of physical activity, increasing
Box 9-2
Mechanisms behind physiological changes in hypertension

Peripheral determinants of hypertension
Paracrine effects of local hormones:
Endothelial derived, e.g. decreased nitric oxide,
endothelin, endothelium-derived hyperpolarizing factor
Local mitogens causing vascular smooth muscle
hypertrophy, e.g. angiotensin II
Aging and structural effects on cell function:
Prenatal imprintingethnic differences, reduced
glomerular number, and volume
Low birthweightleads to increased risk of adult
hypertension
Telomere shorteningmay represent early aging
Postnatal growth patternsgrowth spurts may be
accompanied by increases in blood pressure, perhaps
when renal growth does not match systemic growth
218
Central determinants of hypertension

Activation of the sympathetic nervous system:
Alpha-1 effects include arterial constriction
Beta-adrenergic effects include increased heart rate,
cardiac contractility, and activation of the renin
angiotensin system
Activation of the reninangiotensinaldosterone system
results in volume expansion, and vasoconstriction
Chapter 9 Hypertension
Table 9-1 Examples of genetic causes of hypertension
GENETIC DISEASE CAUSING

HYPERTENSION
GENE ABNORMALITY
KEY CLINICAL FEATURES
Polycystic kidney disease
PKD1 and PKD2 polycystin genes
Polycystic kidneys, liver
Liddles syndrome
Sub-units of the epithelial sodium

channel SCNN1B and SCNN1G genes
(gut-dominant)
Metabolic alkalosis, hypokalemia,

suppressed renin and
aldosterone
Multiple endocrine neoplasia type 2a
RET proto-oncogene
Pheochromocytoma,
medullary thyroid cancer,
hyperparathyroidism.
Box 9-3
Causes of secondary hypertension

Endocrine causes
Epinephrine excess
Aldosterone excess
Thyroid disease
Pregnancy
Vascular causes
Coarctation of the aorta
Atherosclerosis (smokers, diabetes mellitus, advancing age)
Renal disease
Inherited
Inammationglomerulonephritis
Diabetes mellitus
Drug reactions
Renal tumors (renal-cell carcinoma, reninoma)
Medication-induced
NSAIDs
Corticosteroids
Analgesics
Ethanol
Cyclosporine (ciclosporin)
SSRIs
Oral contraceptives
Malignancy-related
Skin lesions such as endothelinomas
PTH- and PTHRP-producing cancers
Anti-VEGF-related cancer treatment
Adrenal tumors
Multiple endocrine neoplasia
NSAIDs, non-steroidal anti-inammatory drugs; PTH, parathyroid hormone; PTHRP, parathyroid-hormone-related protein; SSRI, selective
serotonin reuptake inhibitor; VEGF, vascular endothelial growth factor.
rates of poor dietary fruit and vegetable intake, and increasing rates of high blood cholesterol (Box 9-4).
Acute exacerbation of hypertension is seen when events
of enormous stress occur, and have been associated with
increased rates of cardiovascular events (e.g. the San Francisco
earthquake).
Untreated malignant hypertension was in the past associated with a rapidly fatal prognosis. This was due to clear
end-organ effects such as papilledema, hypertensive heart
disease/cardiac failure, and nephrosclerosis, with a 79%
mortality at 1 year.
There are many large-scale, modern population studies
which have identified the importance of hypertension in
various populations, and its association with cardiovascular
disease, dementia, and death.
Box 9-4
Identied lifestyle risk factors for

hypertension
Overweight and obesity
Diabetes mellitus (due to being overweight)
Sedentary lifestyle
Recreational drugs, e.g. cocaine, amphetamines
Alcohol
Contraceptive pills (estrogen, progesterone)
219
Percent
80
70
60
Males
Females
50
40
30
20
10
0
2534
3544
4554
5564
Age group (years)
6574
75+
Figure 9-1 Proportion of Australians aged 25 years and over with high blood pressure, by age group,
19992000
Australian Institute of Health and Welfare (http://www.aihw.gov.au/prevalence-of-risk-factors-for-chronic-diseases
DEFINITIONS OF
HYPERTENSION
The mainstay of chronic hypertension management is to:
1 establish the diagnosis as primary, and treat any secondary cause
2 establish the extent of target-organ effects from the
hypertension, while paying attention to
3 the importance and complications caused by additional
cardiovascular risk factors and lifestyle (Figure 9-2).
Blood pressure definitions of hypertension are well supported by evidence for a continual relationship between
higher blood pressures and increasing cardiovascular morbidity and mortality, as shown above. Thus, as the relationship between even moderate increases in blood pressure
and stroke becomes evident, tighter BP limits and targets
are set.
Current guidelines define hypertension as shown in
Table 9-2.
Resistant hypertension is defined as that which is controlled with more than three medications, and refractory
hypertension is that which cannot be controlled even on

multiple medications (Box 9-5).
Establishing the validity of any single BP reading is the
source of much discussion. The BP readings need to be
reliably taken on machines that are validated for the circumstance, and by an experienced operator. Because of the
potential flaws in such an approach, there is a move towards
automated readings and self-taken readings, even in the
Box 9-5
Denition of refractory
hypertension
Blood pressure that is elevated despite the use of three
drugs:
of different classes
of which one is a diuretic
in a patient who is adherent/compliant with their
regimen, and
where there is an accurate and sustained increase in
blood pressure
Table 9-2 Hypertension classications
CLASSIFICATION
SYSTOLIC BP (mmHg)
DIASTOLIC BP (mmHg)
Normal
<120
<80
High-normal (prehypertension)
120139
8089
Stage 1
140159
9099
Stage 2
160179
100109
Stage 3
>180
>110
Hypertension
220
G^hàZkZaldbZc
6
7 8
Non-smoker
Smoker
4 5
7 8
Non-smoker
Smoker
4 5
180
Age
6574
160
140
Systolic blood pressure (mm Hg)
120
Age
5564
160
140
180
160
160
140
140
120
120
160
140
120
120
180
180
Age
4554
160
140
160
140
120
120
Age
3544
160
140
120
7 8
4 5
Total cholesterol:HDL ratio
7 8
4 5
>30%
2530%
2025%
High
1520%
Moderate
1015%
510%
7 8
Smoker
4 5
8
180
Age
6574
160
140
120
180
Age
5564
160
140
120
180
180
Age
4554
160
140
160
140
120
140
140
120
120
120
180
Age
3544
160
140
120
8ZgiV^c\gdjehbVn]VkZ8K9g^h`jcYZgZhi^bViZYjh^c\i]ZhZX]Vgih#
HZZ8VgY^dkVhXjaVg<j^YZa^cZh=VcYWdd`'%%.:Yî^dc[dgYZiVâh#
Diabetes
Non-smoker
Smoker
120
160
CdiZ/I]Zg^h`X]Vgihcdl^cXajYZkVajZh[dgH7EVadcZ!Vhi]^h^hi]Zbdhi^c[dgbVi^kZ
d[XdckZci^dcVaanbZVhjgZYWaddYegZhhjgZeVgVbZiZgh[dgXVgY^dkVhXjaVgg^h`#
9^Vhida^XegZhhjgZhbVnVYYhdbZegZY^Xi^kZedlZg!ZheZX^VaanVindjc\ZgV\Zh
Z\!VY^Vhida^XegZhhjgZXdch^hiZcian3&%%bb=\^cVeVi^Zcilî]H7EkVajZh
WZilZZc&)%VcY&,%bb=\#
140
180
Lî]^ci]ZX]VgiX]ddhZi]ZXZaacZVgZhiidi]ZeZghdchV\Z!hnhida^XWaddYegZhhjgZH7E
VcYidiVaX]daZhiZgdaI8I8/=9AgVi^d#EZdeaZl]d[VaaZmVXiandcVi]gZh]daYWZilZZc
XZaahVgZeaVXZY^ci]ZXZaa^cY^XVi^c\]^\]Zgg^h`#
160
160
>YZci^[ni]ZX]VgigZaVi^c\idi]ZeZghdchhZm!Y^VWZi^XhiVijh!hbd`^c\]^hidgnVcYV\Z#
180
180
Jh^c\i]Z8]Vgih
Key
5-year cardiovascular
disease (CVD) risk
(fatal and non-fatal)
Mild
180
180
180
180
Very high
No diabetes
Non-smoker
4
G^hàZkZabZc
Diabetes
No diabetes
G^hàZkZa/
*"nZVg8K9g^h`
[ViVaVcYcdc"[ViVa
7 8
4 5
7ZcZih/CCI[dg*nZVghidegZkZcidcZZkZci8K9ZkZcihegZkZciZYeZg&%%eZdeaZigZViZY[dg*nZVgh
&^ciZgkZci^dc
'*g^h`gZYjXi^dc
'^ciZgkZci^dch
)*g^h`gZYjXi^dc
(^ciZgkZci^dch
**g^h`gZYjXi^dc
(%
&(,#*eZg&%%
,&)eZg&%%
+&+eZg&%%
'%
'%*eZg&%%
&&.eZg&%%
.&&eZg&%%
&*
',)eZg&%%
&*,eZg&%%
&'-eZg&%%
&%
)%'#*eZg&%%
'')#*eZg&%%
&-*#*eZg&%%
*
-%&#'*eZg&%%
))'#'*eZg&%%
(+(eZg&%%
CCI2CjbWZgcZZYZYidigZVi
7VhZYdci]ZXdchZgkVi^kZZhi^bViZi]ViZVX]^ciZgkZci^dc/Vhe^g^c!7EigZVibZciadlZg^c\H7EWn&%bb=\dgaê^YbdY^XVi^dcadlZg^c\A9A"8Wn'%
gZYjXZhXVgY^dkVhXjaVgg^h`WnVWdji'*dkZg*nZVgh#
CdiZ/8VgY^dkVhXjaVgZkZcihVgZYZcZYVhbndXVgY^Va^c[VgXi^dc!cZlVc\^cV!^hX]VZb^Xhigd`Z!igVch^Zci^hX]VZb^XViiVXÌ>6!eZgê]ZgVakVhXjaVg
Y^hZVhZ!Xdc\Zhi^kZ]ZVgi[VâjgZVcYXVgY^dkVhXjaVg"gZaViZYYZVi]#
2.55%
<2.5%
djgXZ/CZlOZVaVcY<j^YZa^cZh<gdje#CZlOZVaVcY8VgY^dkVhXjaVg<j^YZa^cZh=VcYWdd`/6hjbbVgngZhdjgXZ[dgeg^bVgnXVgZegVXiî^dcZgh#'cYZY#LZaa^c\idc/CZlOZVaVcY<j^YZa^cZh<gdje0'%%.#
Figure 9-2 The New Zealand Risk Calculator, indicating that the risk prole for the effect of hypertension is
modied by sex, age, smoking and lipid status. These sorts of risk calculator can indicate the risk of stroke in the
next 5 years, and can be a powerful tool in focusing the patient on the need to reduce the risk by controlling
hypertension. Blue scale: 5-year risk <2.5% up to 2.55%. Green scale: 510% and 1015%. Yellow: 1520%.
Orange: 2025%. Red: 2530%. Purple >30%. In the purple category, that means that <10 are needed to be
treated to prevent 1 event; and >10 cardiovascular events are prevented per 100 patients treated for 5 years
From the New Zealand Guidelines Group, http://www.nzgg.org.nz/guidelines/0035/CVD_Risk_Full.pdf
physicians consulting room. Whenever the technique of the

diagnostic reading is changed, it is likely that the goalposts
will need to be moved in terms of classifications and targets
for treatment. 24-hour BP monitoring is most useful in those
with unpredictable or highly variable readings, and in those
with possible white-coat hypertension.
hypertension is achieved by a detailed history, and examination to identify those with diagnostic clues.
CLINICAL PRESENTATIONS
AND INVESTIGATIONS
Hypertension associated with recent-onset diabetes,

truncal obesity, and depression should trigger investigation for corticosteroid excess.
Excluding secondary causes is the mainstay of establishing

the diagnosis of primary hypertension.
Given the list of secondary causes outlined above, the
establishment of a diagnosis of secondary versus primary
Labile hypertension may indicate pheochromoytoma

(rarely).
Episodic hypertension associated with tachycardia and
sweating could suggest a pheochromocytoma.
Radio-femoral pulse delay, a precordial systolic bruit,

or a lower BP in the legs may indicate coarctation of the
aorta.
Renal enlargement is present with polycystic kidneys.
221
An epigastric bruit can in some cases indicate renal

artery stenosis.
Investigations specific to a directed diagnostic possibility are more relevant than testing for all of the above.
As an example, in endogenous corticosteroid excess in
Cushings syndrome, hypertension alone is rarely the
presentation of this illness. Hypertension in the context
of diabetes, depression and changing body shape (buffalo hump, truncal obesity, and purple striae) will lead
to an appropriately directed investigation for adrenal
sources of excessive corticosteroid production.
Isolated systolic hypertension is a more likely sign in
renal disease and in aldosterone excess syndrome.
The presence of hypokalemia should be a trigger for
investigating for secondary causes.
CLINICAL PEARLS
A renal (glomerular) diagnosis is excluded by a normal urine analysis and normal renal tract ultrasound.
There is a 60% chance that a renal bruit represents a
case of renal artery stenosis.
In the absence of any symptoms or signs suggestive of secondary hypertension, some basic biochemical and radiological screening is warranted to further exclude the secondary
causes.
Serum potassium concentration: hypokalemia occurs in
primary aldosteronism, renovascular disease, and corticosteroid excess syndromes.
Serum thyroid-stimulating hormone (TSH) to exclude
hyperthyroidism.
Serum calcium to exclude primary hyperparathyroidism.
Serum creatinine and urine dipstick to exclude glomerular disease.
Renal ultrasound to identify renal cystic disease, renal
tumors, and renal parenchymal status.
A targeted investigation for renal artery stenosis should
occur when there are clinical clues for renovascular disease:
New onset of diastolic hypertension before the age of
35, or after the age of 55.
Failure to adequately control hypertension with maximal doses of three antihypertensive agents with appropriate synergy.
Sudden deterioration in previously well-controlled
hypertension.
Any episode of malignant hypertension.
Acute rise in creatinine after therapy with an angiotensinconverting enzyme inhibitor (ACEI).
Discrepancy in renal size found on ultrasonography,
computed tomography (CT), or magnetic resonance
imaging (MRI).
Hypertension and papilledema.
Presence of hypertension and aorto-iliac atherosclerosis,
abdominal aortic aneurysm, or infra-inguinal peripheral
arterial disease.
222
Hypertension and unexplained rise in creatinine levels.

Hypertension and multivessel coronary artery disease.
CLINICAL PEARL
Hypertension and hypokalemia should signal that this
could be primary hyperaldosteronism.
Once the diagnosis of secondary hypertension has been

excluded, primary hypertension (by far the most common
diagnosis) is defined.
The next step is to establish the target-organ effects of
hypertension and direct treatment and expected outcome improvements accordingly.
Initial investigation in primary hypertension includes an
electrocardiogram (EKG), urine analysis, and echocardiogram if there is persistent or prolonged elevation of
blood pressure, in order to identify target-organ effects.
TARGET-ORGAN EFFECTS OF
HYPERTENSION
Blood vessels
Blood vessels themselves are the first target of hypertension:
Vascular smooth muscle hypertrophy is evident in cardiac and renal changes with longstanding hypertension.
Small-vessel leak is manifested as proteinuria and
retinopathy.
Hypertension contributes to atherosclerosis, and therefore myocardial ischemia, cerebrovascular disease, and
peripheral vascular disease (peripheral artery occlusive
disease).
Cardiac effects
Atrial enlargement
Left ventricular hypertrophy (Figures 9-3 and 9-4).
Retinopathy
Retinal changes from hypertension are an easily identified
and important bedside test of severity (Figure 9-5, overleaf).
At their simplest, retinal arterial changes include:
silver wiringindicates Grade 1 hypertensive retinopathy (generalized arterial constriction).
AV nippingindicates Grade 2 hypertensive retinopathy (irregular constriction of the retinal vein at the point
of arterial crossing).
In more severe cases there are also:
Hemorrhages and cotton-wool spotsindicate Grade
3 hypertensive retinopathy (areas of retinal ischemia or
bleeding related to vessel occlusion or rupture).
Grade 4 changes, which are dramatic and more likely
to be associated with visual loss, and increased overall
patient mortality.
Grade 4 changes include:

ischemic optic neuropathy
papilledema
retinal artery occlusion
retinal vein occlusion
retinal detachment
macular damage and therefore loss of vision.
Renal changes secondary to

hypertension
Figure 9-3 Short-axis view of an autopsied heart

showing severe left ventricular hypertrophy; note
the thickened wall
From Seward JB and Cassaclang-Verzosa G. Inltrative cardiovascular diseases: cardiomyopathies that look alike. J Am Coll
Cardiol 2010;55(17):1769-79
Macroscopically both kidneys appear atrophic, with

irregular scars, a granular subcapsular surface, and cortical thinning. This is described as benign nephrosclerosis, but the wisdom of the term is being questioned.
Microscopically, there are small cortical infarcts, glomeruli show focal sclerosis, afferent arterioles show hyaline
sclerosis, and small arteries show intimal proliferation
and elastic re-duplication. Arteries also show fibrosis
of the wall with medial hypertrophy. Larger arteries
develop atheroma.
These changes all result in an increased tendency for proteinuria; initially as microscopic and then as manifest
proteinuria.
It may be challenging to separate proteinuria due to
longstanding hypertension from that due to an underlying renal disease. The additional finding of hematuria
will help make this distinction.
Figure 9-4 Electrocardiogram for a young professional cyclist, demonstrating sinus bradycardia, voltage criteria
for left ventricular hypertrophy, and large-amplitude precordial T waves
From Saksena S and Camm AJ, eds. Electrophysiological disorders of the heart, 2nd ed. Philadelphia: Saunders, 2012.
223
Figure 9-5 A normal retina (left) and a retina indicating the presence of hemorrhages, hard exudates,
papilledema and cotton-wool spots in severe hypertension (right)
(Left) http://stanfordmedicine25.stanford.edu/the25/fundoscopic.html. (Right) http://www.theeyepractice.com.au/optometrist-sydney/high_
blood_pressure_and_eye_disease
The timing of hypertension relative to the development

of albuminuria may give a clue. If the hypertension is
present for >5 years before the onset of proteinuria, then
the renal disease is unlikely to be primary. If there are
markers of renal failure, hematuria or other systemic
evidence of vasculitis, then the renal disease is likely to
be primary.
An acute rise in serum creatinine can indicate rapidly progressive renal disease (usually glomerular) or acute kidney injury, or alternatively that malignant hypertension is
occurring.
Brain
Arterioles develop hyaline sclerosis and Charcot
Bouchard aneurysms.
Arteries develop atheroma.
The basal ganglia and pons show expanded perivascular
spaces, small infarcts and hemorrhages.
Dementia is linked to poorly controlled hypertension,
and is likely to be due to small vessel complications.
TREATMENT AND TARGETS FOR

HYPERTENSION CONTROL
The mainstay of chronic hypertension management is to:
1 Develop a plan to manage important lifestyle factors.
2 Achieve a level of appropriate BP control relative to
cause, with targeted antihypertensive medication treatment, and generic antihypertensive treatment.
3 Correct correctable or secondary causes of hypertension.
It is important that BP control is the mainstay of all treatments, given that secondary causes are often diagnosed late,
and correction of the underlying lesion is very likely not to
correct the BP completely. This is especially the case if the
BP has been elevated for a period of >5 years. It is also likely
224
that the timeframe for diagnosis, given the need for metabolic testing and advanced imaging techniques, will be of
the order of months, and during this time the BP should be
controlled as well as possible.
Treatment strategies for hypertension require consideration of a number of factors:
1 What is the target BP?
2 How is this influenced by comorbidities?
3 Is there another diagnosis or compelling indication to
use one treatment over another?
4 Is there a contraindication to the treatment being
proposed?
5 What combination of therapies is appropriate, and are
there additional side-effects to look out for?
6 How can these be managed with regard to managing
the other cardiovascular risk factors simultaneously?
Specic targets linked to comorbid

conditions
Acute hypertension or exacerbation of
hypertension in a hospital setting
Often, acute medical review is required for review of acute
hospital-related hypertension. Reversible factors in this setting can easily be identified through a thorough history,
patient file review and physical examination.
In the first 48 hours of admission to hospital, factors such
as pain and distress are important and reversible with analgesia
and reassurance. Confusion about home medications (doses
and timing) should also be taken into account when considering the diagnosis and the immediate need for treatment.
Iatrogenic contribution to hypertension from intravenous (IV) fluids, especially infusion of excessive normal
saline (0.9%), should be treated with appropriate fluid management and perhaps a diuretic (IV furosemide), if supported
by the physical examination findings.
Diabetes mellitus
In diabetes, for chronic hypertension the goal for antihypertensive treatment is a BP below 130/80 mmHg, although
this depends on age. This tight target achieves a clear benefit for stroke prevention, as well as for renal protection and
overall cardiovascular benefit in some age groups.
Renal disease
In general there is evidence that a lower than usual target for proteinuria is beneficial in decreasing the risk of
progressive renal disease.
The targets depend on the extent of the proteinuria and the age of the patient. With urinary protein
excretions of <100 mg/mmol Cr, BP targets should
be <140/90 mmHg; and if >100 mg/mmol Cr, the
target is <130/80 mm Hg.
These targets are very difficult to achieve in everyday clinical practice.
There are special considerations for ACEIs or angiotensin II receptor antagonists (ATRAs)but not bothas
part of the therapy. Although there is a theoretical advantage of blocking the reninangiotensinaldosterone
system (RAAS) at two locations (enzyme and receptor),
there is an increased rate of potentially lethal hyperkalemia, and the combination is not recommended.
Postural effects of increasing doses of medication need
to be taken into account, especially in elderly patients,
or those with autonomic neuropathy.
Pregnancy
Pregnancy is a special case for hypertension control.
Drugs need to be category A or B in terms of fetal toxicity, need to have stood the test of time in terms of
safety, and need to be flexible enough to cope with rapid
changes in requirement, especially at the time of delivery and the immediate post-partum period.
CLINICAL PEARLS
Do NOT use an angiotensin-converting enzyme
inhibitor (ACEI) or an angiotensin II receptor antagonist (ATRA) in any pregnant patient.
ACEIs or ATRAs reduce the progression of chronic
kidney disease but may reduce the glomerular ltration rate in bilateral renal artery obstruction.
ACEIs may cause hyperkalemia and cough.
Optimal targets for control in pregnancy are uncertain.

Current theory suggests that very tight targets of BP
control (<85 mmHg) can be associated with loss of
fetal weight and birthweight.
This is counterbalanced by a concern that a higher
target BP is associated with more episodes of severe
hypertension, greater escalation to preeclampsia,
and therefore greater risk of prematurity due to
urgent requirement for delivery.
There is no best suggestion for an antihypertensive agent
in pregnancy.
The most common regimens include alphamethyldopa, oxprenolol, clonidine, labetalol, nifedipine and hydralazine.
The use of pure vasodilators in the setting of hypertension in pregnancy can cause headache, which can
confuse the clinical picture as headache is a diagnostic feature of preeclampsia.
Treatment of the acute severe elevation of BP in fulminant preeclampsia (>170/110 mmHg) requires an expert
team, IV medication and, usually, IV magnesium sulfate
to prevent maternal seizure and maternal mortality.
TREATMENT FOR CHRONIC

PRIMARY HYPERTENSION
The target for treatment and medication rests with the absolute BP, as well as the additional risk factors (cholesterol,
smoking, sex and age).
Normal adult
Systolic BP <120 mmHg and diastolic <80 mmHg.
Recommendation is to recheck in 2 years.
Lifestyle changes:
weight reduction
adoption of a diet rich in vegetables and low-fat
dairy products, with reduced saturated and total fats
dietary sodium restrictiononly if very-highcontent fast foods are frequently consumed
physical activityengage in regular aerobic exercise at least 30 minutes per day
moderation of alcohol intake.
High-normal
Systolic BP 120139 mmHg and diastolic 8089 mmHg
Recheck in 1 year.
Assess absolute risk of cardiovascular disease.
BP 140/90 mmHg.
Consider lifestyle interventions.
Identify important drug causes:
estrogen-containing medication
NSAIDs
illicit drug use.
Commence medication if there are multiple risk factors
or if the readings are sustained.
While the cheapest and most effect antihypertensive
agents remain beta-blockers and diuretics, there is
substantial evidence that initial treatment with an
ACEI, or in fact any other antihypertensive where
there is a compelling indication (Table 9-3, overleaf), are reasonable choices.
Other compelling indications might include:
migrainebeta-blocker
or
calcium-channel
blocker
225
Table 9-3 Antihypertensive choice in the setting of cardiovascular comorbidity
COMPELLING
INDICATION
DIURETIC
9
Heart failure
Post myocardial infarction
BB
ACEI
ATRA
9
Diabetes
Recurrent stroke
prevention
ALDO ant
9
9
High risk of coronary artery

disease
Chronic kidney disease
CCB
9
9
ACEI, angiotensin-converting enyzme inhibitor; ALDO ant, aldosterone antagonist; ATRA, angiotensin II receptor antagonist,
BB, beta-adrenoceptor antagonist; CCB = calcium-channel blocker.
prostatismalpha-adrenergic
antagonist
prazosin)
anxiety disorderbeta-blocker.
(e.g.

Stages 2 and 3 hypertension require a more aggressive
approach, using the agents outlined in Table 9-3. Treatment
needs to be immediate and take into account other comorbidities and target-organ effects to achieve the required
target blood pressure response. Targets are given in Box 9-6.
Box 9-6
Targets for hypertension

management
226
Control of blood pressure to a pre-set target

Minimal medication side-effects
Reversal of left ventricular hypertrophy over 2 years
(improved echocardiogram and electrocardiogram)
Decrease cardiovascular events, especially stroke and
serious adverse events
Decrease progressive loss of cerebral function
(dementia)
Decrease progression of renal disease
Different guidelines exist around the world with recommendations for treatment of different levels of hypertension
in different target groups. Guidelines attempt to use the
best available evidence to make recommendations, but all
are subject to interpretation and need to be viewed in the
context of treating unique individual patients with varying
comorbidities. One such example is from the Eighth Joint
National Committee (JNC8) (Box 9-7).
TREATMENT IN AN ACUTE
SETTING
Control of hypertension acutely should take into account
the relevant comorbidities and the risk of rapid decrease in
BP which can occur in the setting of relative hypovolemia.
Consideration should be given to:
age
likelihood of postural effects
background/previous medication choicespatients
on long-acting medications, and especially ACEIs and
ATRAs, are at potential risk of acute kidney injury, and
hyperkalemia from hypovolemic shock.
Overall, it is advisable to use short-acting agents with minimal renal effects. Regular monitoring of BP and side-effects,
and potentially frequent antihypertensive dose adjustments,
will be required.
Box 9-7
Recommendations for management of hypertension

Recommendation 1
In the general population aged 60 years, initiate
pharmacological treatment to lower BP at SBP 150 mmHg
or DBP 90 mmHg and treat to a goal SBP <150 mmHg
and goal DBP <90 mmHg. (Strong Recommendation
Grade A)
Recommendation 6
In the general nonblack population, including those with
diabetes, initial antihypertensive treatment should include
a thiazide-type diuretic, CCB, ACEI, or ARB. (Moderate
RecommendationGrade B)
Corollary recommendation: In the general population

aged 60 years, if pharmacological treatment for high
BP results in lower achieved SBP (e.g. <140 mmHg) and
treatment is well tolerated and without adverse effects
on health or quality of life, treatment does not need to be
adjusted. (Expert OpinionGrade E)
Recommendation 7
In the general black population, including those with
diabetes, initial antihypertensive treatment should include a
thiazide-type diuretic or CCB. (For general black population:
Moderate RecommendationGrade B; for black patients
with diabetes: Weak RecommendationGrade C)
Recommendation 2
In the general population <60 years, initiate
pharmacological treatment to lower BP at DBP 90 mmHg
and treat to a goal DBP <90 mmHg. (For ages 3059 years,
Strong RecommendationGrade A; for ages 1829 years,
Expert OpinionGrade E)
Recommendation 8
In the population aged 18 years with CKD, initial (or addon) antihypertensive treatment should include an ACEI or
ARB to improve kidney outcomes. This applies to all CKD
patients with hypertension regardless of race or diabetes
status. (Moderate RecommendationGrade B)
Recommendation 3
In the general population <60 years, initiate
and treat to a goal SBP <140 mmHg. (Expert Opinion
Grade E)
Recommendation 9
The main objective of hypertension treatment is to attain
and maintain goal BP. If goal BP is not reached within
a month of treatment, increase the dose of the initial
drug or add a second drug from one of the classes in
recommendation 6 (thiazide-type diuretic, CCB, ACEI, or
ARB). The clinician should continue to assess BP and adjust
the treatment regimen until goal BP is reached. If goal BP
cannot be reached with 2 drugs, add and titrate a third
drug from the list provided. Do not use an ACEI and an ARB
together in the same patient. If goal BP cannot be reached
using only the drugs in recommendation 6 because of a
contraindication or the need to use more than 3 drugs to
reach goal BP, antihypertensive drugs from other classes
can be used. Referral to a hypertension specialist may
be indicated for patients in whom goal BP cannot be
attained using the above strategy or for the management
of complicated patients for whom additional clinical
consultation is needed. (Expert OpinionGrade E)
Recommendation 4
In the population aged 18 years with CKD, initiate
and goal DBP <90 mmHg. (Expert OpinionGrade E)
Recommendation 5
In the population aged 18 years with diabetes, initiate
and goal DBP <90 mmHg. (Expert OpinionGrade E)
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium-channel blocker;
CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.
The strength of recommendation grading system is based on the National Heart, Lung, and Blood Institutes Evidence-based Methodology
Lead.
From 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to
the Eighth Joint National Committee (JNC 8). JAMA 2014;311(5):50720. doi:10.1001/jama.2013.284427
227
1
A 78-year-old woman presents to the hospital with acute left lower lobar pneumonia. She is noted at the time of
admission to have blood pressure (BP) readings of 110/80 mmHg lying and 90/60 mmHg sitting, with a postural
tachycardia. She is diagnosed appropriately and treated with intravenous (IV) antibiotics and IV uids. At 48 hours
in hospital, you are called to see her because she has a BP of 180/110 mmHg and has met the criteria for a clinical
(medical) review. Your strategy after thorough review of the medical record, and physical examination demonstrating
an elevated jugular venous pressure (JVP), ne bi-basal crepitations, and ankle pitting edema, should be which of the
following?
A Continue the IV uids and antibiotics and administer a diuretic.
B Withhold the IV uids, monitor urine output and review in 4 hours.
C Administer an oral long-acting calcium-channel blocker (e.g. amlodipine 50mg daily) as a regular treatment option.
D Reduce the IV uids and cease the antibiotics due to the possibility of drug allergy.
E Treat her with IV morphine for respiratory distress and continue the treatment as prescribed by the admitting team.
A 65-year-old man who has had diabetes mellitus for 11 years presents for review of hypertension. You are considering
which of the treatments available for blood pressure control are best indicated in his case. Which of the following
would be the most appropriate treatment?
A He has prostate symptoms: suggest prazosin 2 mg three times daily.
B He has protein excretion of 0.16 mg/mmol Cr: suggest an angiotensin-converting enzyme inhibitor (ACEI)
(perindopril) 10 mg daily.
C He has a baseline potassium of 5.8 mmol/L (reference range 3.55.0 mmol/L): suggest an angiotensin II receptor
antagonist (ATRA) (irbesartan) 150 mg daily.
D He has urinary incontinence: suggest indapamide (a diuretic) 1.5 mg daily.
E He has intermittent asthma: suggest atenolol 50mg daily.
A 55-year-old businessman presents to the emergency department with altered vision and headache. He has been
told for 10 years that his blood pressure is borderline and, although treatment has been suggested, he has declined
medications. He drinks 6 standard alcoholic drinks per night, every night of the week. Which of the following features
suggests that he has a hypertensive emergency?
A A reading of 180/110 mmHg
B The presence of retinal bleeding
C The presence of +protein on urine dipstick
D The presence of a 4th heart sound (S4) on cardiac auscultation
E An electrocardiogram showing atrial brillation
4 A 56-year-old woman presents with new-onset hypertension of 260/160 mmHg. She has never had hypertension
identied in the past, but she does not like doctors. Her history reveals an alcohol intake of 1 L/day, a stressful job,
and a history of childhood sexual abuse that has not previously been disclosed. She has no signs of secondary
hypertension; her thyroid function is normal. You start treatment with ramipril (an angiotensin-converting enzyme
inhibitor [ACEI]) and add a calcium-channel blocker (amlodipine), and have sent her for addiction counseling and
psychological support, which she has found valuable. She returns 3 months later and her blood pressure is still
elevated, at 170/90 mmHg. What diagnosis and treatment options would you now consider?
A Add an angiotensin II receptor antagonist (ATRA) without any further biochemical investigation.
B Increase the ramipril to twice the recommended dose.
C Add a short-acting vasodilator (e.g. hydralazine), ensuring that her ANA (antinuclear antibody) is normal.
D Add a beta-blocker after ensuring that her cardiac hypertrophy has resolved.
E Add a diuretic after ensuring that her renal function is normal.
ANSWERS
1
B.
Acute changes in BP are commonly associated with acute medical illness, in this case pneumonia. It is likely that the
initial BP is a reection of the acute illness, and her ongoing BP management needs to be considered in the context
of her chronic BP state. Is she chronically hypertensive? Is she on antihypertensive medications? This might have been
exacerbated by the IV uids (including normal saline) used in her initial treatment plan. Treating the hypertension now
with diuretics or calcium-channel blockers will compound the uncertainty about the IV volume and the contribution of
the sepsis. Options A and C are therefore incorrect. Allergy does not usually present as hypertension, rendering option D
incorrect. Controlling pain and distress are important in the setting of any hospitalization, but narcotics should be used
judiciously in those with respiratory illness. Therefore, option E is incorrect.
228
A.
Compelling indications for antihypertensive use suggest that management of other symptoms, e.g. control of prostate
symptoms for older men, increases the benet of the medication, including the likely adherence. If there was a noncompelling indication, then targeting overt proteinuria or microscopic proteinuria with ACEIs or ATRAs is appropriate. For
options C, D, and E there are relative contraindications for these medications.
B.
Absolute blood pressure readings (especially single readings) do not generally constitute an emergency. Proteinuria is an
indication of an end-organ effect of chronic hypertension, rather than an acute emergency. Hypertensive heart disease
is associated with an S4, but this does not usually indicate that there is imminent heart failure or other adverse cardiac
event. Atrial brillation is also a possible consequence of chronic hypertension, not constituting an emergency. However,
thyrotoxicosis should be excluded in this instance. Retinal bleeding indicates an acute blood pressure emergency and can
indicate impending intracerebral bleeding, including white-matter hemorrhage. This should indicate that urgent treatment
is required.
4 E.
Resistant hypertension is dened as blood pressure that is still elevated after the use of three medications at maximum
doses from different classes of drugs, including a diuretic. This case assumes that the calcium-channel blocker and ACEI
are at maximal doses. Therefore, a diuretic should be added. Additional dosing above the recommended dose range is
associated with increased risk of side-effects (option B), but if carefully managed is sometimes used as a strategy. Use of
target-organ damage to inform treatment decisions is important, but not likely to be effective in the 3-month timeframe
here (option D). Short-acting medications are generally not considered to be of best adherence value in long-term
management (option C). Combining an ACEI and an ATRA should not be employed due to the high risk of hyperkalemia
and increased mortality (option A).
229
CHAPTER 10
NEPHROLOGY
Annemarie Hennessy
VASCULAR RENAL DISEASE
CHAPTER OUTLINE
INHERITED CYSTIC KIDNEY DISEASE
Autosomal dominant polycystic kidney disease
(ADPCKD)
Medullary cystic disease and autosomal recessive
polycystic disease
ACQUIRED KIDNEY CYSTIC DISEASE

Simple renal cysts

THROMBOTIC THROMBOCYTOPENIC
PURPURA (TTP)/HEMOLYTIC UREMIC
SYNDROME (HUS)
MALIGNANT HYPERTENSION
Mechanisms of renal injury in hypertension
Clinical presentation, investigation and diagnosis
SCLERODERMA KIDNEY
KIDNEY AND URINARY TRACT INFECTION

Treatment and targets for urinary tract infection
INHERITED RENAL BASEMENT MEMBRANE

DISEASE
Alports disease
GLOMERULONEPHRITIS (GN)
Classication
Primary glomerular inammatory disease
Secondary glomerular inammatory disease
SCLEROSING GLOMERULAR DISEASE

Diabetes mellitus
Focal sclerosing glomerular nephropathy (FSGN)
Mechanisms of scleroderma kidney and renal

crisis
REFLUX NEPHROPATHY
CHRONIC KIDNEY DISEASE (CKD)

Early stages of CKD
Clinical presentations of stages 4 and 5 CKD
End-stage renal disease (ESRD) and renal
replacement therapy
ACUTE RENAL FAILUREACUTE KIDNEY

INJURY (AKI)
231
TUBULO-INTERSTITIAL DISEASES
Hypokalemic alkalosis (with and without

hypertension)
ELECTROLYTE DISORDERS
INHERITED CHANNELOPATHIES
ASSOCIATED WITH HYPERTENSION OR
HYPERKALEMIA
Hypernatremia
Hyponatremia
Hyperkalemia
Hypokalemia
THE KIDNEYS IN PREGNANCY AND

PREGNANCY-RELATED DISEASES
INHERITED CYSTIC KIDNEY

DISEASE
Autosomal dominant polycystic kidney
disease (ADPCKD)
Genetics and molecular mechanisms
Autosomal dominant (AD) polycystic kidney disease
(PCKD) is one of the most common inherited diseases seen
in human populations.
The medical interest in this condition arises from its
classical presentation, its extrarenal manifestations, its
prevalence in any dialysis population (7%), and the possibility in future that treatment could lead to a decrease
in renal cyst formation, and therefore a reduction in
renal parenchymal loss.
Several randomized controlled trials testing cyst
number/volume reduction strategies are appearing in
the literature presently and may indicate a significant
improvement in renal prognosis for affected individuals.
The genetic abnormalities of polycystin genes (PKD1,2,3)
are mutations that lead to alterations in epithelial cell proliferation and polarization to the apical and lateral membranes.
The unaffected gene products are transmembrane proteins localized to the primary cilia of renal epithelial cells,
with extracellular domains which co-localize with other
surface markers such as E-cadherin, a transmembrane
protein responsible for calcium-dependent cell adhesion.
Cysts are not present at birth due to the protective effect
from the good allele (from the non-affected parent).
With time there is somatic mutation of this protective
gene, leading to cyst accumulation.
The somatic mutation effect relates to mutation, or an
environmental effect.
The result is a clonal expansion of epithelial cells due to
deficiency in cell cycle regulation.
Clinical presentations
The most usual clinical presentations occur in patients with a
known family history of cystic disease, although 20% occur
in individuals with no or unknown family history.
The usual symptoms are:
flank pain
232
back pain
(macroscopic) hematuria.
The common signs are:
gross or microscopic hematuria
hypertension
progressive renal failure
increase in abdominal girth, secondary to massive renal
enlargement
associated hepatomegaly from liver cysts in some cases.
Downstream complications of hypertension also occur
in this population, and include headache, left ventricular
hypertrophy, retinopathy, and eventual ischemic heart disease, stroke and renal failure. Patients with PCKD are prone
to renal calculus formation.
CLINICAL PEARL
The clinical sign of ballottement, which is thought to be
critical in the diagnosis, is often done poorly because of
too-lateral palpation. The kidneys rest in a more medial
position and require that the ballotting hand sits completely under the patient at the time of ballottement.
Examination
Physical examination should include abdominal palpation for renal enlargement.
Tenderness is a feature of cystic disease and great care
should be taken not to disrupt the cysts with physical
examination.
A right upper quadrant mass arising from the kidney
can be confused with liver enlargement from hepatic
involvement.
Cystic disease in the pancreas and spleen rarely leads to
demonstrable physical findings.
Additional clinical findings relate to the extrarenal
manifestations, including circle of Willis aneurysms
(visual field defects), optic atrophy, aortic stenosis, or an
apical systolic murmur (mitral valve prolapse).
Features of longstanding hypertension can include renal
bruits, carotid bruits, peripheral vascular arterial stenosis, left ventricular hypertrophy with a displaced apex
beat, and left or right ventricular failure.
Chapter 10 Nephrology
Figure 10-1 This patient (male) has autosomal dominant polycystic kidney disease, and his serum creatinine level
is within the normal range. An oral contrast agent was given to highlight the intestine. (A) Computed tomography
(CT) scan without contrast. (B) CT scan at the same level as A but after intravenous infusion of iodinated
radiocontrast material. The cursor (box) is used to determine the relative density of cyst uid, which in this case
is equal to that of water. Contrast enhancement highlights functioning parenchyma, which here is concentrated
primarily in the right kidney. The renal collecting system is also highlighted by contrast material in both kidneys
From Taal MW et al. (eds). Brenner and Rectors The kidney, 9th ed. Philadelphia: Elsevier, 2012.
Occasional cysts which are pendulous can cause ureteric

obstruction, and this should be excluded by ultrasound
examination.
The presence of urinary tract infection complicating cystic disease is best diagnosed by urine microscopy and culture, although a walled-off collection might require blood
cultures or cyst aspiration, and drainage for diagnosis.
Progressive renal injury is reflected in a classical progression of uremic symptoms and biochemistry, and will be
discussed later in the chapter.
Genetic testing, though available, is expensive, and not
generally used in routine clinical practice when family
history is already present.
Figure 10-2 Autosomal dominant polycystic kidney
disease. Sagittal scan of right kidney. Normal renal
parenchyma is replaced by cysts of varying sizes
From Pretorius ES and Solomon JA (eds). Radiology secrets plus, 3rd
ed. Philadelphia: Elsevier, 2011.
Investigations
Ultimately, diagnosis is made by demonstrating multiple
renal cysts, usually by ultrasound.
When many bilateral cortical renal cysts are present
(usually in individuals over 35 years of age), there is no
doubt about the diagnosis (Figures 10-1 and 10-2).
The defining, or minimum, number of cysts to establish
the diagnosis is dependent on the age of the patient. As
an example, the presence of at least two cysts in each
kidney by age 30 in a patient with a family history of the
disease can confirm the diagnosis of PCKD.
In acute episodes, the presence of cyst hemorrhage can
be determined by ultrasound or computed tomography
(CT) scan, but this should only be done when there is
diagnostic confusion, as cyst hemorrhage is very common.

While the principal burden of this disease is progressive renal
failure and eventual dialysis, there is much interest currently
in the mechanisms of disease and thus targets for preventing
cyst development.
To this end, recent trials have been undertaken in the
target age group (2545 years) to prevent cyst formation. The decrease in cyst volume was measurable, but at
this time not clinically significant. It remains to be seen
whether other cyst-reduction trials will be able to show
improvement in parenchymal survival in the future.
Renoprotective therapy with tight blood pressure (BP)
control, usually by the use of angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin II receptor
antagonists (ATRAs), is warranted in patients with
PCKD; these drugs should not be used together because
of the risk of hyperkalemia.
Appropriate treatment of hypercholesterolemia and
timely treatment of obstruction and infections are
important for preservation of functional glomerular
mass and function.
233
Box 10-1
Targets for polycystic kidney disease
Screen for and treat urinary tract infection

Screen for cerebral aneurysm once, and on a 5-yearly
basis, in those families with a strong history of
Monitor for deterioration in renal function
Control hypertension to reduce progressive renal
damage
Screen for and manage proteinuria with ACEI/ATRA
therapy
Limit other nephrotoxic insults (e.g. NSAIDs) or renal
vasoconstrictors (illicit drugs)
Prepare for dialysis in progressive disease
Provide pre-pregnancy counseling for women to
reduce the risk of superimposed preeclampsia
Treat lower tract obstruction (prostatomegaly)
appropriately in older men
ACEI, angiotensin-converting enzyme inhibitor; ATRA,

angiotensin II receptor antagonist; NSAID, non-steroidal antiinammatory drug.
Other imaging modalities are less helpful in MSK.

CT may be helpful for medullary calcification, but
not for tubular ectasia, as seen in the IVP.
Magnetic resonance imaging (MRI) is useful in
those allergic to iodinated contrast medium, but is
insensitive for detecting calcification.
The typical appearance of medullary striation indicates
the disease (Figure 10-3).
MSK can be associated with renal tract infections and
stone formation, but is not usually associated with
hypertension or progressive renal failure.
Medullary cystic disease and autosomal

recessive polycystic disease
Medullary cystic disease is also an inherited disease, with
cysts in the inner medulla. The progression to renal failure is seen between 20 and 50 years of age. This is an
uncommon condition.
Other cystic diseases include autosomal recessive polycystic disease, which is rare. These cysts form in utero,
and in the early months of life, and lead to early-life
renal failure.
ACQUIRED KIDNEY CYSTIC

DISEASE
Simple renal cysts
Figure 10-3 Intravenous pyelogram showing

the brushlike pattern (arrows) that is indicative of
medullary sponge kidney disease
From Schmitz PG and Maddukuri G. Kidneys, ureters, and bladder
imaging; intravenous pyelography. Medscape Reference: Drugs,
Diseases and Procedures; 2011. http://emedicine.medscape.com/
article/2165400-overview#aw2aab6b5

Medullary sponge kidney disease is a developmental abnormality with cystic dilatation of collecting tubules. It is often
an incidental diagnosis made on intravenous pyelography
(IVP) (1/500).
It is usually asymptomatic but can be discovered when
investigating stone formation, nephrocalcinosis or
hematuria.
234
A common abnormality identified when investigating renal

disease is a simple renal cyst.
These are not inherited.
The risk factors for simple renal cysts include age and
chronic renal damage.
Cysts generally get larger with older age, and are very
rarely symptomatic.
If bleeding has occurred or pain is thought to be due
to size, cyst aspiration by an experienced interventional radiologist is a reasonable approach.
There are no septa, thickenings or calcifications in a
simple cyst.
The presence of these abnormalities implies a
complex cyst, and renal malignancy needs to be
excluded.
They are identified on ultrasound, CT and MRI scan
and, as the name implies, are an even, thin-walled,
spherical or elliptical fluid-filled cavity, usually in the
renal cortex.
CLINICAL PEARL
Simple renal cysts are present in 30% of renal scans, and
50% of the 50-year-old population.
Angiomyolipomas of the kidney are benign lesions of the

kidney containing fat, muscle and blood vessels. They have a
cystic appearance, although with irregular features, and often
need to be differentiated from more sinister renal masses.
Oncocytomas, similarly, are benign tumors arising

from the intercalated cells of the collecting duct. They can
be large, and require resection for diagnosis and treatment.

Metabolic environments that promote renal
calculus disease
Renal calculus disease occurs in 420% of the population of
developed countries, and 9% of that in undeveloped countries. There is also an increase in incidence in children in
developed countries.
Where infection was implicated in the past, metabolic
causes are now the main concern.
The contribution of chronic dehydration is thought
to be a contributory factor in the general population,
and it is postulated that with global warming there will
be a 10% increase in incidence, and a 24% increase
in healthcare costs associated with kidney stones. The
most common cause is idiopathic, and relates to hypercalciuria and hypocitraturia.
Other medical causes of renal calculus include hypercalcemia and hyperuricemia.
Uricosuric agents such as probenecid and sulfinpyrazone increase uric acid excretion (to reduce serum uric
acid concentration). These agents therefore will increase
the frequency of renal uric acid calculus disease.
This is also seen with unexpected agents which
have uricosuric properties such as losartan, atorvastatin, and fenofibrate.

There is a relationship between some urinary tract
pathogens and the formation of large casting (staghorn,
triple-phosphate) struvite renal calculi.
Renal calculi (Table 10-1) are seen as complications of
some drug therapies (e.g. antiretroviral HIV drugs such
as indinavir and atazanavir) and are also present in some
of the inherited forms of renal tubular acidosis.
Clinical presentation and investigations

The classical presentation for renal stones is loin pain and
hematuria.
The pain is described as severe, and radiates along the
upper urinary tract to the bladder.
Symptoms of lower urinary tract irritation, frequency
and dysuria may also be present.
The key to diagnosis is imaging (Table 10-2, overleaf),
ideally a CTKUB (CT scan of kidneys, ureters and
bladder).
Ultimately, the collection and analysis of the stone can
provide valuable information about the likely underlying metabolic abnormality.
Diagnosis
From a physicians perspective, identifying the causes of the
main metabolic derangements that lead to calculus formation
Table 10-1 Renal calculi
STONE TYPE
METABOLIC DERANGEMENT
POTENTIAL CAUSES
Calcium oxalate
Interstitial apatite plaque

Low urine volume
Increased urinary calcium excretion
Increased urinary oxalate (dietary)
Idiopathic hypercalciuria
Hypercalcemia (see Box-10-2)
Renal tubular acidosis (type 1)
Calcium phosphate
Inner medullary collecting duct plaque

Low urine volume
Increased urinary calcium excretion
Idiopathic hypercalciuria
Hypercalcemia (See Box 10-2)
Calcium carbonate
Hypercalciuria
Hypercarbonaturia
Ingestion of calcium carbonate as calcium

supplement (>2000 mg/day)
Cystine
Cystinuria
Defective transport of cysteine and di-basic
amino acids in kidney and intestine
Low urinary citrate
Autosomal recessive genetic disease (incidence

1/10,000)
Struvite
Magnesium, ammonium and phosphate; alkaline

urine
Infection with ammonia-producing

organisms: Proteus, Pseudomonas, Klebsiella,
Staphylococcus and Mycoplasma infections
High dietary magnesium
Uric acid
Hyperuricemia
Hyperuricemia
Renal tubular acidosis (types 1 and 2)
Drugs
Acyclovir, indinavir, atazanavir, triamterene
Antiviral treatment for herpes virus or HIV/AIDS;

diuretics to treat heart failure
AIDS, acquired immune deciency syndrome; HIV, human immunodeciency virus.
235
Table 10-2 Imaging modalities for renal calculus
IMAGING
MODALITY
STRENGTHS
WEAKNESSES
AXR , KUB
Good for calcium-containing stones; useful

when limited radiation dose is desirable, e.g. in
pregnancy
Frequent X-rays useful for stone clearance/
recurrence or growth assessment to reduce total
radiation dose
Misses uric acid stones or matrixcomponent stones (non-crystalline

mucoprotein), or antiretroviral-drug stones
(from indinavir, atazanavir)
Impaired quality in obese patients, poor
differentiation from vascular calcication
(phleboliths)
No information regarding obstruction
Ultrasound
Safe, non-invasive
High sensitivity for obstruction
Better for ureteropelvic junction and
ureterovesical junction stones
Operator-dependent; relies on acoustic

shadowing/twinkle artifact
Misses ureteric stones (<20% detected)
Non-contrast CT
Rapid, highly accurate, highly sensitive (91100%)

and specic (97100%) for ureteric and renal
stones
Accurate delineation of size and location;
obstruction
Able to identify non-calculus causes of ank
or abdominal pain; diagnoses retroperitoneal
disease
Signicant dose of radiation ~3 times the

dose of an IVP or AXR; high fetal doses
Low-dose protocols have been developed,
but with reduced sensitivity and specicity
CTKUB
Combination of above
MRI
Limited value; cannot identify calcications

Costly and time-consuming for ureteric and
renal stones
T2-weighted unenhanced MRI accurate for

degree and level of obstruction; gadolinium
improves calculus identication
IVP
Combines calcic stone detection with function

and anatomy (collecting system duplication,
calyceal diverticulae), degree and level of
obstruction
Useful for non-calculus causes of obstruction
(papillary necrosis, polyps, urothelial tumors)
Limited IVP can be used in pregnancy (lower
dose than a CT-based scan) when an ultrasound
is inconclusive
Exposure to ionizing radiation (especially

in pregnancy, and children), and contrast
allergy a contraindication
Study interference by overlying bowel gas
Takes at least 30 minutes
Surgicalretrograde
cystoscopy and
ureteroscopy
Imaging associated with surgical access to the

lower and upper urinary tract; diagnostic and
therapeutic
Requires surgical anesthesia
AXR, abdominal X-ray; CT, computed tomography; IVP, intravenous pyelogram; KUB, X-ray of kidneys, ureters, bladder; MRI, magnetic
resonance imaging.
is an important part of the diagnostic work-up. The most

common abnormalities are hypercalcemia and hyperuricemia. Hypercalcemia has numerous causes, as listed in
Box10-2; causes of hyperuricemia are listed in Box 10-3.
A 24-hour-urine collection for calcium, oxalate, uric
acid, citrate, phosphate, magnesium, sodium, cystine and
total volume, plus a random urinary pH, with a simultaneous collection of serum for calcium concentration, uric acid,
electrolytes, serum phosphate and magnesium should help
determine the likely metabolic derangement. Serum hypercalcemia should be investigated with a serum parathyroid
hormone (PTH) concentration.
236
Treatments and targets for kidney stones

If the stone does not pass spontaneously, the mainstay
of treatment for the acute calculus is to undergo stone
removal (usually cystoscopic), with or without extracorporeal shock wave lithotripsy.
The use of stents is important in patients with potential or proven obstruction and in patients undergoing
lithotripsy.
Tamsulosin (oral) has been shown to increase stone passage, and to reduce the duration of stone passage.
Box 10-2
Causes of hypercalcemia
Parathyroid gland structure-related

Primary hyperparathyroidism
Parathyroid adenoma
Parathyroid hyperplasia
Parathyroid carcinoma (may be part of multiple
endocrine neoplasia)
Hyperthyroidism
Pagets disease of bone
Parathyroid gland function-related

Lithium use
Calcium-sensing receptor-gene mutations causing
familial hypocalciuric hypercalcemia
Malignancy
Hematological malignancies
Multiple myeloma (bone turnover)
Osteolytic metastases: thyroid, breast, lung, renal,
adrenal, prostate (release of calcitriol, or PTHrP)
Non-small-cell lung cancer
Renal cell carcinoma
Pheochromocytoma
Vitamin D metabolic disorders

Excessive vitamin D intake
Sarcoidosis (elevated 1,25-dihydroxy-vitamin D)

Tertiary hyperparathyroidism
Aluminium intoxication
Increased bone turnover

Immobilization
Excessive vitamin A intake
Dietary
Milk-alkali syndrome
PTHrP, parathyroid-hormone-related peptide.
Box 10-3
Causes of hyperuricemia
Increased production
Solid-organ transplant
Tumor lysis syndrome
Rhabdomyolysis
LeschNyhan syndrome
Decreased excretion
Functionally normal kidneys
diuretics
salicylates
pyrazinamide and ethambutol
nicotinic acid
cyclosporine (ciclosporin)-reduced glomerular
ltration rate
Both production, and excretion

Ethanol lactic acid uric acid
Ethanol xanthine inhibits xanthine dehydrogenase
and accelerates adenosine degradation uric acid
Beer purines uric acid
Fructose (soft drinks) uric acid; competes with the
uric acid for transport protein in the kidney
Starvation
Ketones compete with uric acid for excretion
The preventative strategies for hypercalciuric stones include:

increasing the citrate content of the urine
control of urinary sodium content by dietary control;
increased dietary sodium concentration may increase
urinary calcium excretion
a high dietary magnesium intake can also assist with
stone prevention by inhibiting calcium oxalate and calcium phosphate crystal formation, particularly in those
relatively or definitively deficient in dietary magnesium
Associated with chronic kidney disease (CKD)

stages 25
preeclampsia
Increases conversion of purines to uric acid
vitamin B6 may be warranted in those who are deficient,

and this may decrease the formation of oxalate in those
with excessive excretion rates.
Preventative treatment via increased fluid intake, and protein and sodium restriction in addition to thiazide diuretics is effective in idiopathic calcium oxalate and calcium
phosphate stone-formers through decreasing the urine calcium concentration, as well as calcium oxalate and calcium
phosphate (CaP) supersaturation, and this may also decrease
237
plaque formation by increased proximal tubular calcium

reabsorption.
Citrate may be detrimental if urine pH rises, greatly
increasing CaP supersaturation.
The treatment for most stones includes treatment of the
underlying disease.
Treatment of uric acid calculi with allopurinol decreases
the conversion of purines (xanthine) to uric acid, and
thus decreases urinary uric acid content.
Hyperparathyroidism should be treated with definitive
treatment of the parathyroid lesion, usually by surgical
excision or alcohol ablation.
KIDNEY AND URINARY TRACT

INFECTION
Upper and lower urinary tract infections (UTIs) are an
important part of any complex or chronic medical condition.
They are a frequent, and important, complication of
most renal disease, and recurrent infection can lead to
further deterioration in renal function.
Thus, awareness of the risk of infection, screening
for infection, and appropriate control through treatment and prophylaxis can help with stabilizing or even
improving renal function in those at risk.
Escherichia coli is the infecting pathogen in 85% of cases,
and remaining infections are due to a range of organisms
including Staphylococcus saprophyticus (3%) and Proteus mirabilis. Infections can be associated with the development of
triple-phosphate (struvite) stones, as outlined above.
Risk factors
Lower tract infection/cystitis
The risk factors for lower tract infection are:
advancing age
dementia (it is a physical consequence of late-stage
dementia)
female, sexually active
post-menopausal state
persistent bacteriuria (asymptomatic)
diabetes mellitus
immunosuppression (e.g. post-transplantation, HIV/
AIDS)
abnormalities of the renal tract, including reflux disease
men over 50 years, due to benign prostatic hypertrophy
neurogenic bladder
sickle cell disease.
Upper tract infection/pyelonephritis
Risk factors here include:
pregnancy
sexual intercourse (females)
238
recent UTI
diabetes mellitus
urinary incontinence
new sexual partner in the previous year
recent spermicide use
UTI history in the patients mother
urinary tract stents or drainage procedures.

anddiagnosis
CLINICAL PEARL
The presentation of lower urinary tract infection is with
dysuria, urgency, stranguria, and suprapubic pain.
Upper tract ureteric infection is usually bilateral.

Pyelonephritis (parenchymal infection) is usually unilateral, and associated with marked flank pain and systemic
symptoms such as fever, sweats and rigors.
CLINICAL PEARL
10% of those with pyelonephritis develop septicemia,
and show signs of septic shock as a result and require
hospitalization.
The mainstay of immediate diagnosis is a urine dipstick test

suggestive of infection:
elevated urinary white cell count
elevated urinary nitrites
hematuria
occasionally a small amount of urine protein (+) will be
present in pyelonephritis during the acute phase only.
Treatment and targets for urinary tract

infection
Treatment for UTI (Box 10-4) is straightforward and dictated by the urine culture or blood culture result, in addition to directing antibiotic treatment at the likely or proven
offending organisms according to therapeutic guidelines.
Knowledge about local patterns of antibiotic resistance
will assist with the choice of empirical treatment of infections in the first 2448 hours.
INHERITED RENAL BASEMENT

MEMBRANE DISEASE
This is discovered on incidental urine testing, and can only
be definitively diagnosed by measuring the basement membrane thickness on an electron micrograph.
Box 10-4
Targets for urinary tract infection
Identify the offending organisms by culture of a

mid-stream urine sample
Identify the appropriate sensitivities of that organism to
antibiotics
Treat all symptoms
Demonstrate resolution via repeat urine culture
Screen for ongoing bacteriuria
Reduce the risk of recurrent infection by taking an
appropriate course of antibiotics, and by prophylactic
antibiotics in those at greatest risk:
very young children with reux disease and >1
proven infection
more than 2 infections per 6 months, or 3 per year
depending on the severity
read something like nephritic syndrome from focal necrotizing crescentic glomerulonephritis complicating systemic
lupus erythematosus (SLE), rather than lupus nephritis.
The pathological system has given us the most widely
accepted classification system for primary and secondary glomerular disease. This histological classification
system for glomerulonephritis, the predominantly
inflammatory condition, is best related to the predominant electron-microscopic features and the position of
immunological deposits.
These pathological diagnoses underpin a limited number of syndromal diagnoses which are in common use in
clinical practice.
In terms of treatment and prognosis, the etiological and
disease mechanism nomenclature is the most helpful.
CLINICAL PEARL
The presence of red cell casts is common to all forms
of inammatory glomerulonephritis.
CLINICAL PEARL
The most common cause of isolated hematuria in
the community is the benign familial condition of thin
basement membrane disease.
Alports disease
In some families, there is an X-linked mutation of the collagen genes which leads to a constellation of hearing loss, eye
lesions including posterior subcapsular cataract, and hematuria. The renal disease results from damage to the glomerular basement membrane. This can progress to end-stage
kidney disease requiring dialysis.
GLOMERULONEPHRITIS (GN)
Classication
To understand glomerular disease, the challenge is to align
four different classification systems in order to establish a
diagnosis and develop a management plan. The classification
systems are based on:
syndrome of presentationclinical classification
inflammatory versus sclerosing conditionsdisease
mechanism
whether the disease is primarily renal or part of a systemic diseaseetiological classification
the location of immunological deposits with respect to
the basement membrane in the glomeruluspathological classification.
Using the example of commonly known conditions, these
classification systems are attempting to define diseases such
as immunoglobulin A (IgA) disease, diabetic nephrosclerosis
or lupus nephritis, but require the use of at least three classification systems in just these examples. A more accurate
diagnosis which blends these classification systems would
This section will concentrate on a few common glomerular

diseases using elements from all four classification systems.
Primary glomerular inammatory

disease
Post-streptococcal glomerulonephritis (PSGN)
Mechanism of disease
Post-streptococcal glomerulonephritis is the most common glomerular disease globally. This tracks with poor
hygiene and poor living standards.
It is a manifestation of chronic infection, either of the
skin or the upper respiratory tract (the synpharyngitic
presentation).
Although once thought to be a one-off and reversible
disease, it is now clear that recurrence is common, and
that repeated post-streptococcal insult can lead to progressive renal disease in a small percentage of patients.
The mechanism is thought to be related to M and T
proteins in the walls of group A beta-hemolytic streptococci that elicit the nephritogenic response.
Significant advances have been made in terms of understanding the sequence of immunological events that lead
to this type of glomerular injury, with in situ immunological reactions including activation of complement
pathways and the capture in the membrane of circulating immune complexes.
CLINICAL PEARL
The usual presentation of post-streptococcal glomerulonephritis is as the nephritic syndrome with hematuria
and hypertension.
239
The presence of back pain and hematuria leading to oliguria or anuria has been recognized since the time of
Hippocrates.
A smaller group (<5%) present with acute azotemia and
edema. Any overlap with proteinuria confers a worse
long-term prognosis.
The serological or microbiological diagnosis of streptococcal infection is required to establish the diagnosis. This is most commonly achieved with an
anti-streptolysin O titer and/or an anti-DNAase test
that indicates acute streptococcal infection. A throat or
skin swab can also be undertaken and can assist with
bacterial diagnosis and antimicrobial sensitivity.
Non-specific tests include IgG concentrations in serum,
which are elevated in 44% of patients; and hypocomplementemia, which is not universal.
Examination of the urine reveals red cell casts (Figure
10-4), which are indicative of glomerular bleeding. The
characterization of red cells in the urine (fragmentation)
is an important indicator of passage across the filtration
barrier. The identification of casts requires the careful
handling of a fresh (<2 hours old) urine sample with
gentle spinning and immediate microscopy. Quantification of red cell casts is reported as red cell casts per
high-power (40) field; and proteinuria, by either a protein to urine creatinine ratio, or by 24-hour urine protein
quantification.
Alternatively, a renal biopsy can be performed and shows a
typical pattern.
The light microscopy change is one of proliferation
with polymorphonuclear leukocytes (PMNs) and other
inflammatory cell infiltrates, in a swollen and cellular
glomerulus.
Electron microscopy shows a lumpy bumpy collection

of immunocomplex deposits in the subepithelial position relative to the glomerular epithelium (foot processes), and adjacent to the basement membrane. This
position does not cause a basement membrane reaction,
but the deposits are electron-dense and large.
The immunofluorescent deposit pattern is also described
as lumpy bumpy along the capillary walls, and dense
deposits consist mostly of complement and IgG.
The mainstay of treatment in the acute setting is antibiotics (preferably penicillin) for the underlying streptococcal insult.
This may require longer-term antibiotics in the case
of skin infection, and attention to the early treatment of repeat infections.
Ultimately, attention to the socioeconomic determinants of poor health, and strategies that target the population at risk of post-streptococcal renal disease (low
socioeconomic status, crowded housing), will decrease
the incidence of this disease.
Immunoglobulin A (IgA) disease

Mechanisms
Immunoglobulin A disease is the most common
chronic glomerulonephritis seen in a population with
progressive renal disease, and a common cause of acute
nephritis.
The underlying inflammatory stimulus relates to the
deposition of IgA in the mesangial region of the glomerulus, and this is associated with glomerular infiltration
with inflammatory cells (proliferative change), and
eventual glomerular loss through sclerosis with tubulointerstitial scarring and fibrosis.
The male to female ratio is equal.
Much less commonly, secondary IgA disease is seen in
the context of elevated serum IgA levels due to reduced
hepatic clearance in conditions such as cirrhosis.
CLINICAL PEARL
Progression to end-stage disease occurs in 50% of
patients with immunoglobulin A nephropathy.

Figure 10-4 A red cell cast of urine. Red cell casts are
the deposition of red cells in TammHorsfall protein
excreted within renal tubules, and acting as a matrix
of urinary casts. These only occur in glomerular
inammation, and are quantitatively linked to severity
(number of casts per high-power eld)
From Zitelli BJ, McIntire S and Nowalk AJ, eds. Zitelli and Davis Atlas
of pediatric physical diagnosis, 6th ed. Philadelphia: Elsevier, 2012
240
Immunoglobulin A disease is suspected in asymptomatic patients with microscopic hematuria.

The more classic presentation is macroscopic hematuria and hypertension, especially after episodes of sore
throat.
The typical examination findings are of hypertension
and, perhaps, retinal vessel changes consistent with
severe hypertension (arterial changes, and retinal hemorrhages and infarcts).
The urine will have an increase in red cells, and red cell
casts may be present.
The presence of proteinuria is a poor prognostic sign in
IgA disease, and reflects irreversible glomerular damage.
The diagnosis can only be definitively established with
a renal biopsy and with direct glomerular examination
looking for typical mesangial IgA deposits and the resultant inflammatory lesions.
The light microscopy changes are typically increased
mesangial matrix and cellularity.
Electron microscopy shows electron-dense deposits
limited to the mesangial region.
Immunofluorescence indicates that these deposits are
IgA in nature.
The prognosis can be further clarified by the degree of
tubulo-interstitial scarring present on the initial biopsy.
In 5% of cases, a rapidly progressive (rapidly rising serum
creatinine, with glomerular crescents) form of GN can
occur, which requires intensive anti-inflammatory
therapy including cytotoxic agents and high-dose
corticosteroids.
The more usual treatments offered include control of
blood pressure, minimizing proteinuria, and control
of additional risk factors for deteriorating renal disease:
hyperlipidemia and hyperuricemia.
Fish oil supplements may help delay the onset of endstage renal disease.
Screening for other comorbidities which may contribute
to a more rapid deterioration in renal function includes
that for UTI, diabetes, and lower tract obstruction from
prostatism in older men.
Membranous nephropathy
Membranous nephropathy (membranous GN) is the second
most common cause of nephrotic syndrome (proteinuria,
hypoalbuminemia, hypercholesterolemia, edema) in the
30- to 50-year age group, with focal sclerosing glomerulosclerosis being more common. Secondary nephrotic syndrome
due to diabetes mellitus is rapidly increasing in prevalence.
The idiopathic forms of membranous nephropathy have
been associated with antibodies to M-type phospholipase A2 receptors, a highly expressed glomerular podocyte antigen.
This results in activation of complement and other
inflammatory pathways, leading to the characteristic
lesion in the membrane of the glomerulus.
The resultant proteinuria comes from destruction of the
integrity of the protein barrier.
Increased IgG excretion, HLA-DR3+/B8+, and Caucasian race have been linked to more severe disease.
Clinical presentation and investigation
This entity is clinically manifested by the gradual development of edema, malaise, foamy urine, poor appetite and
weight gain. Nocturia can be a feature. This contrasts with

the very rapid onset of nephrotic syndrome that is seen in
minimal change disease (see below).
Confirmation of the syndrome requires identification
of hypoalbuminemia, quantification of albuminuria/
proteinuria, quantification of hypercholesterolemia, and
measuring edema-related weight gain.
The identification of the type of hyperlipidemia is also
helpful in directing appropriate lipid-lowering therapy.
70% of cases are primary idiopathic.
The remaining secondary causes include drug-induced,
bee sting (rarely), lymphoma, solid tumors (lung and
colon), systemic lupus erythematosus (SLE) and other
autoimmune diseases, and infections (hepatitis B, syphilis, occasionally endocarditis).
The investigation of causes often needs to be exhaustive,
especially to exclude solid tumors as the cause in older
patients.
A standard battery of blood tests would include antinuclear antibodies (ANA), anti-double-stranded DNA
(anti-dsDNA) antibodies, hepatitis B serology, syphilis
serology, and complement levels at the onset to exclude
alternative diagnoses.
Diagnosis
Diagnosis is based on histological findings and progresses
through four stages based on the presence of membranous
glomerular deposits:
Stage 1intramembranous deposits; light microscopy
appears normal
Stage 2spikes grow out of the membrane
Stage 3spikes grow together on the epithelial side to form
a ladder pattern
Stage 4disarray and gross thickening of the membrane
with segmental or global glomerular sclerosis.
Treatment trials of long-term immunosuppression for
membranous nephropathy have been inconclusive. This
is largely due to the natural history of remission in onethird of cases.
It is possible that membranous nephropathy at stage 2 or
3 is more likely to respond to immunotherapy aimed at
reducing the risk of chronic disease and progression to
end-stage renal disease.
20% of patients progress to dialysis at some time between
2 and 20 years.
Immunosuppressive treatment may be indicated in
patients with an elevated creatinine at presentation, persistent nephrotic syndrome, thromboembolism, very
low serum albumin, male sex, and age over 50 years.
Immunosuppressive regimens under consideration at
present include corticosteroids, chlorambucil/cyclophosphamide, cyclosporine (ciclosporin), or mycophenolate mofetil. Rituximab can be used for severe or
refractory disease.
241
Treatment of secondary causes, e.g. with lamivudine for

hepatitis B, is essential.
Given the natural relapse rate, short-term studies with
immunosuppression need to be viewed with some caution regarding the potential long-term benefits compared with the high rate of toxicity and side-effects.
Box 10-5
Targets for membranous

nephropathy
Relieve nephrotic syndrome

Restore and preserve renal function
Control hypertension and hyperlipidemia
Prevent venous thrombosis and potential pulmonary
thromboembolism
Manage long-term with minimal or no corticosteroid
doses
Screen for or instigate prophylaxis against long-term
side-effects of corticosteroids (including osteoporosis,
hypertension and diabetes)
Screen for and instigate prophylaxis against
opportunistic or other infection (e.g. Pneumocystis
jirovecii pneumonia [PJP], tuberculosis, hepatitis C),
and treat accordingly
Screen for malignancy (including lung and colon
cancer and lymphoma)
Monitor for chronic kidney disease, and treat accordingly
A rapid decline in glomerular filtration rate (GFR) can

be been in some cases, and this is usually associated with
crescent formation within the glomerulus.
Investigation includes a screen for endocarditis, vasculitis, autoimmune diseases, sarcoidosis, malignancy,
hepatitis B and C, as well as lupus serology and baseline
renal function.
Renal biopsy is necessary to establish the type, to allow
consideration of treatment for secondary causes, and to
evaluate prognosis.
C3 nephritic factor is also useful in determining the
diagnosis.
Treatment of mesangio-capillary GN is generally
directed at the underlying cause.
Symptomatic treatment involves close control of elevated blood pressure, diuretic use for peripheral edema
and, in more aggressive cases, immunosuppression to
control rapidly deteriorating renal function. This will be
discussed in more detail in the sections on rapidly progressive and secondary GN.
Rapidly progressive glomerulonephritis

(RPGN)
Mechanism
CLINICAL PEARL
Mesangio-capillary glomerulonephritis
Mesangio-capillary glomerulonephritis (also known as
membranoproliferative GN) refers to a type of GN characterized by mesangial deposits and also deposits extending
around the capillary loop in either a subepithelial or a subendothelial position.
The basement membrane grows to restore its integrity
and causes the appearance of a double membrane on
light microscopy (double contour on silver staining).
These lesions are more commonly seen secondary to
significant and treatable conditions, such as hepatitis C
with cryoglobulinemia, and SLE.
There are subtle distinctions regarding the sites of the
immune deposits within the glomerulus, with regard to
the type of disease:
type I has glomerular subendothelial immune
deposits and duplication of the glomerular basement membrane
type II has dense homogeneous deposits in the subepithelial location which expand the lamina densa
of the basement membrane
type III has mesangio-capillary glomerulonephritis
with double contouring.
The presentation is most usually with the nephritic syndrome, although nephrotic syndrome has been described.
242
A rapid rise in serum creatinine concentration (evidence of acute kidney injury) in the setting of abnormal
urinary sediment (red cell casts, hematuria or proteinuria) denes a rapidly progressive glomerular disease.
The majority of cases are vasculitides, and the first consideration will be immunosuppressive treatment; however, it is important clinically to remember that subacute
and acute bacterial (infective) endocarditis can present
in this fashion.
Apart from that due to endocarditis, RPGN is more
common in males, other than type 3 and 4 lupus nephritis which are more common in females.
The diagnosis of RPGN is a clinical one, with rapid development of renal failure. However, often it is the non-renal
manifestations which bring the patient to hospital.
In the case of granulomatosis with polyangiitis (GPA),
the most common RPGN, it is pulmonary hemorrhage
that provides the clue. The diagnosis is confirmed by
typical pathological findings on the renal biopsy.
In PAN (polyarteritis nodosa), it is abdominal pain which
may present; in anti-GBM (glomerular basement membrane) disease, pulmonary hemorrhage; and in microscopic polyarteritis, a leukocytoclastic vasculitic rash,
although all may present as an acute nephritic syndrome
with a rapidly rising creatinine.
PAN can be a complication of hepatitis B infection.

Constitutional symptoms of fever, malaise, fatigue,
anorexia and weight loss are usual. Myalgias and
arthralgias or frank arthritis are occasionally present. Other inflammatory-associated conditions can
also include iritis or episcleritis.
The exclusion of endocarditis is essential prior to any
consideration of immunosuppression for vasculitides in
this scenario. This is achieved by appropriate echocardiography and blood cultures in the setting of clinical
signs of embolism (e.g. splinter hemorrhages, vasculitic
rash, splenomegaly, and a new cardiac murmur).
The remaining diagnoses are confirmed by an elevated
serological test (anti-neutrophil cytoplasmic autoantibody [ANCA] or anti-GBM-antibody test), supportive
tests such as an elevated erythrocyte sedimentation rate
(ESR), altered complement concentrations, and ultimately by characteristic changes in the glomerulus in a
renal biopsy sample.
Although this can be an idiopathic diagnosis, it is
important to exclude secondary causes such as ANCAassociated vasculitis, anti-GBM disease (Goodpastures),
polyarteritis nodosa (including hepatitis-B-related
PAN), infective (bacterial) endocarditis, and SLErelated GN by undertaking the appropriate blood cultures and serology.
Although preeclampsia and thrombotic thrombocytopenic purpura (TTP) can present with rapidly progressive renal failure, these diseases are not associated with
crescent formation (Figure 10-5) in the renal biopsy.
Treatment and targets for RPGN (general)

The indications for dialysis are the usual ones:
hyperkalemia, especially in the presence of cardiac
arrhythmia
acidosis
fluid overload in the presence of non-responding renal
deterioration (oliguria/anuria and rising creatinine
concentration)
uremic symptoms per se may be a contributory indication (including uremic pericarditis).
As below, the main focus of the treatment depends on treating the underlying disease process.
Treatment and targets for infective endocarditis
Acute kidney injury (AKI) occurs in 30% of patients
with infective endocarditis, and confers a poor prognosis.
Where renal injury has occurred, the contribution from
infective emboli is as important as the inflammatory
lesions.
Immune mechanisms include circulating immune
complexes and intra-glomerular formation of immune
complexes, leading to glomerular inflammation with
crescents.
Culture-positive endocarditis requires treatment with
predominantly bactericidal antibiotic regimens.
Consideration of timing and dose is important with
renal injury, particularly the timing and use of aminoglycosides to prevent nephrotoxicity (vancomycin toxicity can be synergistic with the aminoglycosides).
Calculation of estimated GFR is important in determining the dose and dose interval.
Antibiotic toxicity resulting in idiosyncratic acute interstitial nephritis needs to be considered if renal function
deteriorates after the commencement of treatment.
With appropriate long-term antibiotic therapy, the
renal vasculitic lesions are reversible. Renal infarction
and cortical necrosis are not.
Other renal arterial complications such as mycotic
aneurysm require specialist treatment and can potentially rupture, leading to massive blood loss and hemodynamic shock.
Treatment and targets for PAN
Polyarteritis nodosa is a condition of granulomatous
vasculitis involving any small to medium-sized blood
vessel. It can be a fatal condition if not treated aggressively at the first presentation. The mortality relates
to renal failure, cardiac and respiratory complications
such as pulmonary hemorrhage from microaneurysms
or capillaritis, and gastrointestinal complications such
as bowel infarction and perforation, cholecystitis, and
hepatic or pancreatic infarction.
The mainstays of treatment are corticosteroids and
alkylating agents (cytotoxic agents). This combination
of treatment has improved survival dramatically.
In hepatitis-B-related PAN, treatment will include
antiviral treatment, with corticosteroids, and daily
plasmapheresis for several weeks or until renal or acute
extrarenal symptoms and signs resolve.
Treatment and targets for GPA (Wegeners
granulomatosis)
Figure 10-5 Glomeruli showing segmental necrosis

with early crescent formation (arrows)
From Adkinson NF et al. (eds). Middletons Allergy: principles and
practice, 7th ed. Elsevier, 2009.
Whereas untreated granulomatosis with polyangiitis

confers a prognosis of 95% mortality in 6 months, treatment of active disease with corticosteroids and cytotoxic
chemotherapy has transformed the prognosis to 95%
survival.
243
The longer-term effects of malignancy and chronic

infection, including with opportunistic organisms, need
to be carefully considered.
About 50% of GPA patients have a relapse at some time
during the course of their illness.
Treatment doses and frequencies vary around the world.
The more common sequence is high-dose intravenous
corticosteroids for 5 days followed by high-dose oral
corticosteroids. The dose is tapered off over the ensuing months, with the option of increased dose pulses if
symptoms recur. It may take up to 34 months to taper
the dose, and ultimately a small dose or even a second
daily dose regimen is preferred.
Some regimens for cyclophosphamide include a lower
dose on a 2-weekly cycle, or a higher dose on a monthly
cycle for 6 months. This must be tailored to the individual patients circumstances.
Although a target of therapy is an optimal reduction
in serum creatinine (improvement in estimated GFR,
eGFR), the ANCA can sometimes be tracked as a
marker of active disease, and it would not be uncommon to re-biopsy the kidney to ensure that all crescents
and areas of focal necrosis are treated.
Alternatives to cyclophosphamide such as chlorambucil
have been explored over the years.
More recently, trials of steroid-sparing therapy with
methotrexate, mycophenolate or azathioprine are promising, and treatment during the acute phase with rituximab has been proposed (and recently FDA-approved in
the USA).
Box 10-6
Targets for granulomatosis with

polyangiitis
Relieve and improve pulmonary hemorrhage

Restore renal function
Abolish all glomerular crescents
Monitor ANCA titer as a marker of disease activity
Manage long-term with minimal or no corticosteroids
Screen for long-term side-effects of corticosteroids
(including osteoporosis, hypertension and diabetes)
Limit total cytotoxic dose (e.g. cyclophosphamide to
<12g)
Monitor for hemorrhagic cystitis and bone marrow
suppression in those treated with cyclophosphamide
Screen for and initiate prophylaxis against
opportunistic or other infection (e.g. PJP, tuberculosis),
Screen for future risk of malignancy (including
hematological and urological) after cytotoxic
treatment
ANCA, anti-neutrophil cytoplasmic autoantibody; PJP,

244
Treatment and targets for anti-GBM disease

Anti-glomerular basement membrane disease is an autoimmune disease in which antibodies specifically attack
the glomerular basement membrane, leading to aggressive
glomerulonephritis.
The mainstay of treatment for proven anti-GBM disease
is immunosuppression and plasmapheresis, with a target
of controlling the concentration of anti-GBM antibodies.
Although prognosis tracks with extent of renal failure
at the time of diagnosis, dialysis can often be required at
diagnosis, and may be temporary if immediate immunological response is achieved.
Box 10-7
Targets for anti-GBM disease
Relieve and improve pulmonary hemorrhage with

plasmapheresis
Restore renal function
Reduce anti-GBM titers to negligible
<12g)
treatment
anti-GBM, anti-glomerular-basement-membrane; PJP,

Treatment and targets for microscopic polyangiitis

This small-vessel vasculitis is associated with p-ANCA
positivity.
The glomerulus can show focal and segmental necrosis
and inflammation. Crescent formation is common.
Therefore, this condition requires early aggressive
immunosuppression to restore renal function, and to
prevent rapid progression to end-stage renal disease
(Box 10-8).
Minimal change disease (MCD)

Minimal change disease, a condition with no obvious
pathological changes on light microscopy but with electron microscopy changes of broad foot processes in the
epithelial cells, is the most common form of nephrotic
syndrome in children, but still accounts for 15% of
nephrotic syndrome in adults.
The name denotes the lesion with minimal change
on light microscopy, i.e. the exclusion of abnormal
findings on regular magnification and staining.
Box 10-8
Targets for microscopic polyangiitis
Restore and preserve renal function with appropriate

immunosuppression
Treat pulmonary hemorrhage
Reduce ANCA titer
<12g), and monitor side-effects
treatment
ANCA, anti-neutrophil cytoplasmic autoantibody; PJP,

While the exact cause is not known, the typical immediate and often dramatic response to steroids points to
an immunological cause.
There is a strong overlap with focal sclerosing glomerulosclerosis seen in adults.
It is thought to be a T-cell disorder, with cytokine
release disrupting glomerular epithelial foot processes.
This leads to a decreased synthesis of polyanions, which
thereby reduce the charge barrier to albumin, allowing
the leakage of albumin into urine.
Changes in protein synaptopodin and nephrin, as well as
interleukin-13, IL-18, and IL-12 have been implicated.
The appearance of ultra-structural lesions with IgM
deposits (especially in the mesangium), epithelial vacuolization, and glomerular hypertrophy are thought to
confer a higher risk of progression from minimal change
disease to focal sclerosing disease.
Although usually primary, there are some secondary
causes of minimal change disease such as bee sting, drugs
(e.g. non-steroidal anti-inflammatory drugs, NSAIDs),
and lymphoma.
The diagnosis is suggested by the classical presentation
of peripheral edema and proteinuria, with biochemical
evidence of hypoalbuminemia and hyperlipidemia.
The proteinuria can be extremely high (>3500
mg/1.73m2, >340 mg/mmol/L Cr)
The very acute onset in adults can lead to an acute and
profound hypovolemia, and there is a significant risk of
acute pre-renal failure. This can also occur if diuretics
are used to manage the peripheral edema in the acute
phase.
Late complications include hypertension in around 30%

of adults, with increasing rates in those over 60 years
old.
Profound hypoalbuminemia is associated with an
increase in prothrombotic risk. This is due in part to the
urinary loss of albumin-bound clotting factors, but also
to chronic hypovolemia.
This progressive deterioration in renal function is seen
in only those with the focal sclerosing end of the disease
spectrum.
The first-line treatment for MCD at any age is corticosteroids. Adult response rates are reported at 60%, and
remission can take up to 16 weeks.
Steroid-resistant disease can indicate lymphoma as a
cause, and remission of the MCD relates to treatment of
the underlying lymphoma.
Steroid-sparing treatment with other immunosuppressives is suggested in the long term in the presence of
relapsing disease, and in some circumstances when there
is progression to focal sclerosing glomerulosclerosis.
Box 10-9
Targets for minimal change disease
Reduce edema using immunomodulatory treatment

Reduce proteinuria using immunomodulatory
treatment and ACEIs
Monitor and treat long-term hypertension
Treat secondary hyperlipidemia
if relapse occurs
Screen for and treat long-term side-effects of
corticosteroids (including osteoporosis, hypertension
and diabetes)
Minimize side-effects of hypogammaglobulinemia
(antibiotics as required)
Minimize the risk of venous thrombosis
(anticoagulation, consider if serum albumin <25 g/L)
ACEI, angiotensin-converting enzyme inhibitor.
Secondary glomerular inammatory

disease
Lupus nephritis
CLINICAL PEARL
Systemic lupus erythematosus (SLE) nephritis is the
only glomerulonephritis that is more common in
females than males.
The renal manifestations of lupus glomerular disease

touch on the full spectrum of glomerular disease.
245
A basic understanding of the histological classification

system is necessary to link to complex presentation and
treatment options.
Renal involvement in lupus occurs in 50% of affected
individuals, and renal involvement confers a worse
prognosis, not only because of renal involvement but
also because of the impact of reduced renal function on
the treatment of the extrarenal manifestations.
The older World Health Organization classification of
nephritis into five classes has been updated (since 2004)
by the International Society of Nephrology (ISN) and
the Renal Pathology Society (hereafter the ISN classification) to allow for better comparison between studies
of prognosis, treatment and outcome (Table 10-3).
CLINICAL PEARL
Lupus nephritis can present in multiple ways: asymptomatic urinary abnormality, nephritic syndrome, nephrotic
syndrome, acute kidney injury, and chronic renal disease.
There is no clear correlation between nephritic syndrome, including AKI, and overall patient mortality;
but in general, persistent nephrotic syndrome is linked
with a worsening renal prognosis.
Investigation of suspected lupus nephritis depends on
the demonstration of acute glomerulonephritis through
the presence of red cell casts in the urine.
The ultimate diagnosis, class and prognosis are determined by histological examination of a renal biopsy.
Prognosis
The prognosis for both the patient and renal survival is
better for ISN class I and II GN than for those with ISN
classes III, IV and V.
The presence of nephrotic syndrome also influences

survival, and those in whom remission is achieved have
a better prognosis than those with persistent nephrotic
syndrome.
Improved survival for all patients with lupus is widely
thought to be due to better supportive care, and more
selective use of immunosuppressive therapy in patients
with milder forms of disease.
Patients with class I and II do not generally require any
specific renal immunotherapy.
The exception would be those with class I nephrotic
syndrome, in whom a short course of corticosteroids may be warranted intermittently to control
symptoms.
Optimal control of blood pressure, especially with the
use of ACEIs and ATRAs, or even spironolactone (aldosterone receptor antagonist) is warranted, especially in
those with proteinuria.
Treatment strategies which target the RAAS (renin
angiotensinaldosterone system) have been shown to
decrease intraglomerular pressure, lower systemic arterial pressure, reduce urinary protein excretion which is
in and of itself damaging, and delay the progression of
chronic renal disease to end-stage renal disease. There
may even be a benefit in reducing the inflammatory
component of lupus.
Patients with class III (focal) and IV (diffuse) endocapillary disease may or may not have a sclerosing component to their disease.
The most usual treatment here is an initial course of
high-dose corticosteroids (intravenously) and then
a high dose of oral corticosteroids tapering from
8weeks, used in conjunction with other immunosuppressive agents.
Table 10-3 The spectrum of clinical presentation and histological class in lupus nephritis
CLASS
TYPICAL CLINICAL
PRESENTATION
PATHOLOGICAL FINDINGS
Class I
Minimal or no proteinuria or rarely

nephrotic syndrome
Minimal mesangial glomerular deposits seen on IF or EM only
Class II
Nephritic syndrome
Mesangial glomerular deposits
Class III
Nephritic syndrome and AKI
Focal proliferation (<50% of glomeruli affected); mesangiocapillary pattern; mixed-site deposits
Class IV
Nephrotic syndrome and AKI
Diffuse proliferative (>50% of glomeruli affected)

Focal necrosis with crescents; mesangio-capillary pattern; mixedsite deposits
Class V
Nephrotic syndrome
Membranous deposits; diffuse thickening of the glomerular

capillary wall (LM) and subepithelial deposits (IF, EM)
Class VI
Advanced sclerosing lupus nephritis
>90% glomeruli sclerosed
AKI, acute kidney injury; EM, electron microscopy; IF, immunouorescence, LM, light microscopy.
246
Cyclophosphamide or mycophenolate mofetil are

the most commonly used and reliable treatments
for this induction phase. There is some debate
about oral versus intravenous (IV) therapy, but in
general the IV route for cyclophosphamide allows
a lower cumulative dose to be used, involves less
frequent cytopenias, and avoids problems of noncompliance with medication and safe home storage instructions.
Combined treatment with corticosteroids has
greater renal benefit but greater side-effects, including ischemic and valvular heart disease, avascular
necrosis, osteoporosis and premature menopause.
Major infection occurs in 45% of patients on the
combination of cyclophosphamide and corticosteroids.
While the higher-dose, monthly cyclophosphamide
regimen is favored, a half-dose given fortnightly in
association with corticosteroids has been shown to
be as efficacious, with equal long-term outcomes.
Mycophenolate is increasingly shown to be of benefit as a potential first-line agent in the initial phase
of treatment with corticosteroids. In some of the
original mycophenolate trials, there was an infection and mortality benefit from mycophenolate, but
this has not been borne out by larger studies, where
it is equal in effect to cyclophosphamide.
Azathioprine or mycophenolate can be used as a
maintenance agent.
Other steroid-sparing agents include methotrexate.
Rituximab (anti-CD20 monoclonal antibody) has
been considered as an adjuvant to the established
regimen of treatment, and has not been shown to
improve survival. It most likely has a role in those
who are refractory and relapse from usual treatment, to prevent flares and reduce the doses of other
immunosuppressives.
Similarly, tacrolimus (a calcineurin inhibitor) has
been trialed in the management of severe lupus
nephritis.
In shorter trials (up to 9 months) multi-target therapy (mycophenolate, tacrolimus and corticosteroids) has been shown to achieve high complete
remission rates (up to 80%) compared with any
alone. Also, adverse events were lower in the multitarget group. The longer-term benefit of these
therapies is unknown.
Class V membranous lupus requires aggressive initiation
therapy, as above, when it occurs in association with
diffuse or focal proliferation and mesangio-capillary
involvement. In isolation, the treatment of class V targets the reduction of nephrotic syndrome, as the renal
outcome is usually very good.
The treatment alternatives include cyclophosphamide (60% remission and few relapses), cyclosporine (ciclosporin) (83% remission but more
frequent relapses), and corticosteroid alone (27%
remission rate).
Mycophenolate has very similar rates of response
and remission to IV cyclophosphamide.
Combinations of tacrolimus, corticosteroids and

mycophenolate have been tried with good effect,
but show increased toxicity.
As with the initiation phase of treatment, there are
multiple and varied trials of appropriate agents in
the maintenance phase of lupus nephritis designed
to reduce relapses, maintain remission, and reduce
the progression to end-stage renal disease, while at
the same time reducing the net cumulative sideeffect burden of immunosuppressive treatment.
The most usual strategies involve low-dose continuous or second daily dose corticosteroids and,
potentially, azathioprine.
Ocrelizumab (a fully humanized anti-CD20 monoclonal antibody), abatacept (a T-cell co-stimulator
modulator) and belimumab (a soluble B-lymphocyte
stimulator binding monoclonal antibody) are being
trialed as add-on treatment for induction, or in
refractory disease.
Exogenous adrenocorticotropic hormone (ACTH)
is approved for refractory nephrotic syndrome and
SLE (in the USA), and laquinimod (a quinolone3-carboxamide derivative, mechanism unknown) is
also undergoing clinical trials.
Box 10-10
Targets for lupus nephritis
Relieve and improve life-threatening extrarenal

manifestations of disease (neurological, cardiac and
pulmonary)
Restore and preserve renal function
Reduce anti-dsDNA titer; improve C3/C4
Minimize deleterious long-term side-effects of
corticosteroids (including osteoporosis, hypertension
and diabetes)
Limit cumulative cytotoxic dose (e.g.
cyclophosphamide to <12g)
Optimize control of blood pressure
Screen for and actively treat urinary tract infection
Screen for and initiate prophylaxis against
treatment
anti-dsDNA, anti-double-stranded DNA; PJP, Pneumocystis

jirovecii pneumonia.
Hepatitis-C-related glomerulonephritis
Mechanism of viral-induced GN
Hepatitis C viral (HCV) infection can be associated
with a range of glomerular conditions.
247
The most common of these is mesangio-capillary glomerulonephritis. The mechanism is thought to be viralinduced cryglobulinemia.
Although immunohistochemistry has failed to reveal
HCV-related antigens in the kidney biopsy samples of
these patients, EM of renal tissues reveals virus-like particles in 50% and HCV RNA is often present in the
cryoprecipitates (66%) or renal tissue (22%).
The HCV-RNA positivity is linked to increased risk,
and viral-derived proteins such as NS3 are located along
the capillary wall and in the mesangium. Genotype 4 is
sequenced in up to 70% of cases.
Other forms of GN seen in the context of hepatitis C
are membranous GN, IgA nephropathy, and amyloid
nephropathy.
The clinical spectrum of HCV-related glomerular
injury includes microalbuminuria, nephritic syndrome,
and rapidly deteriorating AKI.
Treatment is directed at the more severe forms of renal
disease.
Renal biopsy is essential to confirm the nature of the
renal lesion, the site of deposits and extent of inflammatory reaction, and to determine prognosis.
Mesangio-capillary GN type III is associated with
demonstrable cryoglobulinemia.
Treatment of HCV-related GN focuses primarily
on treatment of the hepatitis C. This is usually with
pegylated alpha-interferon and ribavirin.
In those with nephrotic-range proteinuria or rapidly progressive renal failure, immunosuppression is
essential.
Rituximab and cyclophosphamide are the first-line
treatments, but caution needs to be taken with regard to
a viremic flare.
In the acute phase, plasmapheresis and pulsed high doses
of corticosteroids are warranted.
Blockade of the reninangiotensin system is useful for
control of blood pressure, renoprotection, and to reduce
proteinuria.
The eradication and control of viremia and cryglobulin
production are also targets of treatment.
SCLEROSING GLOMERULAR
DISEASE
Diabetes mellitus
Mechanisms of renal injury
Diabetes is a disease of enormous proportions in developing
and developed countries throughout the world.
248
The majority of these patients will have proteinuria,

either at a microalbuminuria level (<150 mg/day) or lowrange albuminuria (1501000 mg/day), or levels where
symptoms start to manifest themselves (>1000 mg/day, up to
nephrotic-range proteinuria and the nephrotic syndrome).
Eventually, in those susceptible, the duration and extent
of hyperglycemia, the associated hypertension, and endothelial dysfunction lead to basement membrane thickening,
tubular scarring and KimmelstielWilson nodules.

diagnosis of diabetic nephropathy
The earliest manifestation of renal disease in diabetes is
low-level (micro) albuminuria.
The presence of even minute quantities of albuminuria indicates a need for tighter blood pressure control
and tighter blood sugar control. The targets are well
proven in the clinical trial literature, but are very hard
to deliver in individual patients and in population-based
interventions.
Worldwide, there has been a steady increase in the percentage of patients on dialysis from diabetic nephropathy.
CLINICAL PEARL
40% of patients presenting with diabetes for the rst
time already have target-organ damage in the form
of retinopathy, nephropathy, diabetic neuropathy or
large-vessel atherosclerosis.
Treatment and targets for diabetic

nephropathy
Much work is being done to prevent type 2 diabetes by targeting the obesity epidemic in the broader
community.
Similarly, advertising campaigns are designed to
increase the early detection of diabetes and its targetorgan complications.
Treatment of early disease (Box 10-11) is focused on
reduction of proteinuria and preservation of renal
function.
Focal sclerosing glomerular

nephropathy (FSGN)
When focal (not global) and segmental (not diffuse)
areas of progressive scarring occur without significant
inflammatory change, the diagnosis of focal segmental
glomerulosclerosis (FSGS) is made.
This can be primary idiopathic or can progress from
minimal change disease.
It can also be secondary to drugs (e.g. NSAIDs or
bisphosphonates), viruses (e.g. hepatitis B, HIV, parvovirus), reduced renal mass (e.g. solitary kidney, transplanted kidney, reflux nephropathy), or malignancies
(e.g. lymphoma).
Box 10-11
Targets for diabetic nephropathy
Reduce microalbuminuria
Prepare for dialysis in progressive disease by referral to

an appropriate dialysis unit and specialist nephrological
care
Reduce frank proteinuria with ACEI or ATRA therapy
Provide renoprotection with blockade of the RAAS

(reninangiotensinaldosterone system)
Pre-pregnancy counseling for women to reduce risk of

superimposed preeclampsia
Tightly control hypertension to reduce progressive renal

damage
Appropriate treatment of lower-tract obstruction

(prostatomegaly) in older men

ACEI, angiotensin-converting enzyme inhibitor; ATRA, angiotensin II receptor antagonist; NSAID, non-steroidal anti-inammatory drug.
Figure 10-6 Light microscopy of structural changes in diabetic nephropathy: (A) normal glomerulus; (B) diffuse
glomerular lesion demonstrated by widespread mesangial expansion; (C) nodular lesion as well as mesangial
expansion, including a typical KimmelstielWilson nodule at the top of the glomerulus (arrow); (D) nodular
lesionmethenamine silver staining shows the marked nodular expansion of the mesangial matrix
From Johnson RJ, Feehally J and Floege J (eds). Comprehensive clinical nephrology, 5th ed. Philadelphia: Elsevier, 2015.
249
The relationship with reflux nephropathy may also

reflect a developmental abnormality.
The sclerosis eventually leads to global sclerosis (all of
the glomerulus) and diffuse spread (all glomeruli).
The typical sites within the glomerulus for scarring are:
glomerular tip (at the outer 25% of the tuft, near the
proximal tubule)
perihilar variant (perihilar sclerosis)
cellular variant (endocapillary hypercellularity)
collapsing (associated with reduced glomerular tuft size).
The amount of glomerular involvement and the extent

of tubulo-interstitial scarring are also helpful in looking
at likely response to aggressive immunotherapy.
The other complications of massive proteinuria, such
as increased thrombosis risk (deep venous or renal
vein thrombosis), need to be monitored, and considered whenever there is a sudden deterioration in renal
function. The loss of protein S and protein C with the
massive proteinuria is part of the explanation for this
increased risk. Complications and their management
are outlined in Table 10-4.

anddiagnosis
The most usual presentation is with proteinuria.

This typically leads to a refractory edema that is difficult
to manage.
The additional features of hypertension and progressive
renal disease are also typical.
Progression to end-stage renal disease can occur within
48 years, but both rapid and slower progression is also
encountered.
Pregnancy is known to accelerate the progression to
end-stage renal disease.
The prognosis is worse in those who have rapid progression, difficult or severe hypertension, massive proteinuria, and in some ethnic groups (e.g. African-American).
Markers of nephrotic syndrome form the basis of monitoring, as well as sequential renal function tests.
Ultimately the diagnosis is made on histopathological
grounds. The nature of the lesion is also defined by the
histological appearance, and can help define prognosis.
Treatment options for focal sclerosing disease have

focused on proteinuria reduction with ACEIs or ATRAs.
In some cases and on an individual basis, attempts are
made to decrease disease activity with immunosuppression.
There is no universal agreement that immunosuppression is warranted or effective, with reported response
rates of 30%. This low response rate is linked to the
amount of glomerular scarring but also to the extent of
tubulointerstitial scarring on the renal biopsy.
If considered worthy of a trial of treatment, prednisolone
(1 mg/kg orally once daily or 2 mg/kg orally every other
day for between 2 and 9 months) may be recommended
in those with nephrotic-range proteinuria (>3.5 g per
day) and who have rapidly deteriorating renal function.
A trial of immunosuppressive therapy is indicated in
idiopathic FSGS if proteinuria reaches the nephrotic
range or if any degree of renal dysfunction is present.
Table 10-4 Complications of FSGN
COMPLICATION
MANAGEMENT APPROACH
Edema
Symptomatic treatment with diuretics, monitoring of renal function and blood pressure
Thrombotic risk
Monitor proteins S and C; long-term anticoagulation if albumin <20 g/L, or at any time that
a documented thrombus occurs
Hyperlipidemia
Monitor and treat hypercholesterolemia and hypertriglyceridemia
Infection
Monitoring, vaccination and early aggressive treatment with antibiotics. Target: full
vaccination prole to prevent infection
Hypertension
Antihypertensive and uid management strategies. Target: BP <125/75 mmHg
Anemia
Erythropoietin replacement therapy. Targets: Hb to 110120 g/L; ensure adequate iron

stores and vitamin B12 and folate
Gastritis
Proton-pump inhibitor and other antacid treatment; target is reduced heartburn and nausea
Bone disorder
Calcium and vitamin D replacement. Targets: monitoring calcium concentration to within

the normal range; PTH to 1530 pmol/L
Hyperphosphatemia
Phosphate binders and appropriate dietary advice. Target: phosphate to <1.6 mmol/L
Fluid overload/hyperkalemia/
uremic symptoms/acidosis
Dialysis
BP, blood pressure; FSGN, focal sclerosing glomerular nephropathy; Hb, hemoglobin; PTH, parathyroid hormone.
250
Alternatives to corticosteroids in those who respond can

include cyclosporine (ciclosporin), or mycophenolate
mofetil.
VASCULAR RENAL DISEASE

Renal artery stenosis occurs in younger individuals
(usually females) when there is a fibromuscular hyperplasia along the renal artery and its branches. This is a
treatable form of refractory hypertension.
In older individuals, it is due to atherosclerosis of either
the aorta around the origins of the renal arteries or the
renal arteries themselves, especially at the ostia.
These are considered reversible forms of refractory
hypertension.
The clinical clues for renal vascular disease include:
past history of renovascular disease
new onset of hypertension before age 35 or after 55 years
of age
sudden deterioration in previously well-controlled
hypertension
any episode of malignant hypertension
a rise in serum creatinine (>30% from baseline) associated with use of ACEIs
discrepancy in renal size
hypertension and papilledema
hypertension and unexplained elevated serum creatinine
arterial bruits elsewhere (aorto-iliac, femoral vascular
disease, carotid disease, coronary artery disease)
flash pulmonary edema in the setting of uncontrolled
hypertension.
Investigations include screening for arterial narrowing or

differential renal function. A range of modalities is used
(Figure 10-7).
Screening tools available to detect renovascular disease
include duplex (Doppler), CT angiography, magnetic resonance angiography, renography, and renal vein renin concentrations or activity. Ultimately, confirmation is required
by renal angiography.

Considerable debate exists about the value of revascularization for atherosclerotic renovascular disease. In
general, the requirement for antihypertensive treatment
is not diminished by surgical intervention, and the effect
of revascularization on saving long-term renal function
is not yet known.
Surgery (stenting or repair) is absolutely indicated in the
case of renal artery aneurysms.
Prevention of re-stenosis requires attention to the risk
factors for disease, control of blood pressure and lipids, and tight glycemic control in diabetes. Antiplatelet agents can have a role in preventing re-stenosis after
treatment.
THROMBOTIC
THROMBOCYTOPENIC
PURPURA (TTP)/HEMOLYTIC
UREMIC SYNDROME (HUS)
This is an uncommon form of acute kidney injury which
occurs in the setting of microthrombi in the small vessel, and
endothelial injury. These conditions cause a constellation of
MRA
Duplex
CT angio
Clinical suspicion alone

Previous treated RAS
and clinical suspicion
of re-stenosis
0
10
20
30
40
50
60
70
80
90
100
PPV (%)
Figure 10-7 Positive predictive value (PPV) of investigations and of clinical suspicion in renal vascular disease.
CT angio, computed tomography angiography; MRA, magnetic resonance angiography; RAS, renal artery
stenosis; clinical suspicion refers to history of other macrovascular disease or detectable vascular bruit
From Paven G, Waugh R, Nicholson J et al. Screening tests for renal artery stenosis: a case-series from an Australian tertiary referral centre.
Nephrology 2006:11;6872.
251
microangiopathic hemolytic anemia, thrombocytopenia,

fever, and fluctuating neurological symptoms.
The renal involvement causes hematuria and proteinuria in the setting of hypertension, and a rapidly rising
serum creatinine.
The mechanism of disease is uncertain, but it occurs
either as a primary abnormality (related to alterations
in von Willebrand factor metabolism) or secondarily to
malignancy, some medication use, and HIV infection.
The HUS variant is more commonly seen in children and
is associated with exposure to the verotoxin (Shiga-like
toxin) from E. coli. It has a mortality of 510%, with some
children developing dialysis-dependent renal failure.
Hereditary forms of both HUS and TTP have been
described.
Secondary disease can occur in association with autoimmune disease, infection, cancer, drugs, bloody diarrhea, the post-partum period, and hematopoietic stem
cell transplantation.
ADAMTS13 is a metalloproteinase which is low in
patients with primary TTP.
The treatment consists of plasma exchange, and then
further immunosuppressive treatment in those who are
refractory.
MALIGNANT HYPERTENSION
Mechanisms of renal injury in
hypertension
A sudden and dramatic increase in blood pressure (BP)
to extraordinary levels (>180/110 mmHg) can cause a
dramatic vascular endothelial injury that is associated
with small vessel rupture, small vessel microthrombosis,
and microangiopathic hemolysis.
This conglomerate is much less common in populations
treated with modern, long-acting antihypertensives, and
where the RAAS is targeted in BP-controlling treatment.
The disease is more likely in those with a long history of
poorly controlled hypertension, including due to protracted non-adherence.

diagnosis
The presence of a rapidly rising serum creatinine concentration, severe hypertension (>180/110mmHg), and
hemolytic anemia with retinal hemorrhage would define
the most urgent and aggressive form of hypertension.
These symptoms could represent a number of the other
RPGNs; however, the urine does not have red cell casts.
Diagnosis is again made on renal biopsy, which shows
duplication of the elastic lamina in medium and small
vessels, marked endothelial injury, and vascular smooth
muscle hypertrophy, fibrinoid necrosis, and hyaline
degeneration.
252
The presence of proteinuria is not a feature of the acute

diagnosis, but may represent a longstanding chronic
hypertensive effect prior to the onset of the accelerated
hypertension syndrome.

The critical step in the management of malignant hypertension is to control the BP.
CLINICAL PEARL
Patients with renal failure as a result of malignant
hypertension may require dialysis for up to 6 months,
and with excellent blood pressure control can recover
sufficient renal function to come off dialysis.
SCLERODERMA KIDNEY
Mechanisms of scleroderma kidney
and renal crisis
Scleroderma is due to an accumulation of extracellular
matrix protein, leading to the widespread tissue fibrosis
that is the hallmark of the disease.
The accumulation is due to activation of fibroblasts by
growth factors and signaling molecules.

diagnosis
Vascular involvement of the kidney in progressive systemic sclerosis (SSc, scleroderma) can lead to an acute
deterioration in renal function, called scleroderma renal
crisis, or slower deterioration in renal function, and proteinuria leading to chronic kidney disease.
Scleroderma renal crisis occurs in 25% of patients with
SSc. This occurs more frequently in patients with the
diffuse cutaneous variety.
The crisis manifests by extremely elevated BP, oligo/
anuria, acute renal failure (AKI), and a high death rate
(5-year mortality of 35%).
Other associated features include microangiopathic
hemolytic anemia, thrombocytopenia, and hyperreninemia.
The mean age at onset is 4070 years and women are
more commonly affected, as with other autoimmune
diseases.
The definitive diagnosis of scleroderma kidney can
require a renal biopsy, but the fibrosing nature of the
lesion makes these patients particularly prone to bleeding after the biopsy. Biopsy should only be done where
there is clinical uncertainty and in a hospital large
enough to cope with the likely complication of massive
renal parenchymal hemorrhage.

There is no consensus for the prevention of renal crisis
in SSc.
The mainstay of treatment is increasing doses of ACEIs,
and addition of calcium-channel blockers if required.
Dialysis may well be necessary, and there are case reports
of renal recovery after a period of dialysis when BP control
and a period of treatment on ACEIs has been observed.
The target for treatment of SSc and of scleroderma renal
crisis is a BP below 120/75mmHg.
The potential for treatment with serotonin receptor 2B
inhibitors and other signal-controlling modifiers such as
PPAR-G inhibitors and DNA methyltransferase inhibitors is under investigation at present, and may offer new
treatments for the renal manifestations.
or by cystoscopy, revealing an open appearance of the

ureteric orifices in the trigone of the bladder.
Imaging can be used to determine the balance of renal
function between the left and right kidneys (DTPA
[diethylene triamine pentaacetic acid] renal scintogram
or captopril renal scan).

Ureteric surgery for congenital reflux disease remains controversial. There are some instances when surgery may assist
with reducing the frequency of infection, but surgery has not
been shown to prevent the progression to end-stage disease,
especially in those with scarring and glomerulosclerosis.
Box 10-12
Targets for reux nephropathy
REFLUX NEPHROPATHY
Vesico-ureteric reflux is the most common congenital
abnormality of the renal tract. This is thought to be
inherited in a dominant pattern involving mutations in
genes controlling the development pathway of the urinary tract.
Increasingly, this abnormality is detected by highquality intrauterine ultrasound, allowing strategies to be
put in place to monitor the infant for infection and loss
of renal function.
By the time those affected reach adulthood, the presentations are those of urinary tract infection, hypertension,
proteinuria due to focal sclerosing glomerulosclerosis,
and loss of renal function at an early age (mid-20s).
Reflux is also more likely wherever there is a urinary
tract abnormality such as horseshoe kidney, malrotations or ectopia of the kidneys, and ureteric duplication
or bifurcation.
Apart from the congenital variety, acquired reflux can
occur in the setting of bladder outlet obstruction from
enlarged prostate or bladder calculus disease.
Reflux is a very rare complication of ureter implantation
in renal transplant surgery, and is prevented by a meticulous urological approach to the surgery.

anddiagnosis
CLINICAL PEARL
Vesico-ureteric reux should be suspected in adults
with a history of childhood infections, particularly in
the rst 5 years of life.
The organisms involved in infection are typical.

The diagnosis is established either by a micturating
cystourethrogram, whereby the active reflux of contrastcontaining urine into the lower ureters is demonstrated,
Relieve UTIs
Improve the risk of recurrent UTIs by prophylactic
(daily) antibiotics and frequent urinary cultures
Control hypertension to reduce progressive renal
damage
Screen for and manage proteinuria with ACEI/ATRA
therapy
Prepare for dialysis in progressive disease
Pre-pregnancy counseling for women to reduce risk
of superimposed preeclampsia, or recurrent UTI
Appropriate treatment of lower-tract obstruction
(prostatomegaly) in older men
ACEI, angiotensin-converting enzyme inhibitor; ATRA,

angiotensin II receptor antagonist; NSAID, non-steroidal antiinammatory drug; UTI, urinary tract infection.
CHRONIC KIDNEY DISEASE

(CKD)
Definitions of acute and chronic renal failure have been
superseded by the terminology acute kidney injury (AKI)
and chronic kidney disease (CKD).
CKD is the result of loss of glomerular mass and thereby
filtration surface area, sustained over a period of at least
6 months.
CLINICAL PEARL
Chronic kidney disease can present relatively late in the
progression to end-stage disease if the underlying disease process is insidious. If this is the case, the kidneys
may be small and scarred at the time of presentation,
and an underlying diagnosis may never be made.
253
The calculation of an estimated glomerular filtration

rate (eGFR) is based on the principle that there is a nonlinear relationship between serum creatinine concentration and GFR.
The eGFR most commonly used is based on the MDRD
(Modification of Diet in Renal Disease Study) formula
which takes into account age, gender, and ethnicity in
some cases.
Formulas used to derive GFR become more unreliable at
the extremes of body size, extremes of age, especially very
low body mass index (BMI), high (dietary supplements)
or low (vegans or vegetarians) dietary intake of creatinine
or creatine, patients with muscle diseases such as atrophy
or amputation, and in particular ethnic groups.
The conversion of serum creatinine to eGFR has been
shown to be useful in targeted community screening
and identification of early kidney disease in those at risk
(e.g. diabetes).
A progressive serum creatinine concentration is used
when kidney disease is established to track possible disease progression (e.g. in renal transplant patients).
Early stages of CKD

Stage 1 kidney disease is defined as having no reduction
in glomerular filtration rate (eGFR) despite the presence
of urinary abnormalities or a diagnosis of renal disease.
An example would be a nephritic lupus patient with
2.2 g of proteinuria per day, known for 18 months,
with elevated serum markers of SLE, and a serum
creatinine concentration of 66 micromol/L (eGFR
149 mL/min/1.73 m2). This would be graded as
stage 1 CKD.
The presence of hypertension here would be diagnosed as secondary hypertension.
Stage 2 kidney disease is defined as a reduction in
eGFR to 6089 mL/min/1.73 m2 in the presence of
kidney damage.
Neuropathy
Poor nutritional status
Hb <110 g/L
Elevated BP
Tiredness scale
iPTH > 10 pmol/L
100
Percent (%)
80
60
40
20
0
0
30
60
eGFR (mL/min/m2)
90
Figure 10-8 Indicative rates for complications

of chronic kidney disease related to estimated
glomerular ltration rate (eGFR). BP, blood pressure;
Hb, hemoglobin; iPTH, intact parathyroid hormone
254
The presence of systemic tiredness can be a feature of

even very early chronic kidney disease. Other symptoms
of progressive chronic kidney disease include weakness,
muscle cramps, easy bruising, and hiccoughs.

Once the eGFR has fallen below 60 mL/min/1.73m2, the
early signs of chronic kidney disease are seen.
The earliest sign is hypertension.
The combined contribution of hypertension and the
deteriorating eGFR greatly increase the risk of cardiovascular events.
Hyperlipidemia should be identified and defined.
Phosphate, calcium and bone abnormalities begin to
manifest at this stage.
There are signs of poor nutritional status and weight
loss with changes in protein metabolism. This is exacerbated by proteinuria if present.
Patients are at risk of heart failure from either their
underlying vascular disease or from limited renal
reserves at a time of fluid challenge (e.g. postoperative
management).
The risk of infection and malignancy is increased and
should be screened for.
Neuropathy related to uremia can be identified at this
level of renal dysfunction.
The most usual presentation of this group is with rapidly
and dramatically deteriorating renal function, in the face of
additional pre-renal, renal or post-renal events.
As with earlier stages of kidney disease, observation
for urinary tract stones, infection or malignancy are
important in managing the risk of deteriorating renal
function.
Immunization for known infection risk and provision
of advice regarding medication use, especially over-thecounter medications, NSAIDs and drugs which alter
the RAAS, are important.
Clinical presentations of stages 4

and 5 CKD
Once the eGFR is below 30 mL/min/1.73m2, the patient is
at stage 4 CKD.
This is where symptoms of anemia occur, and contribute to marked tiredness and to worsening left ventricular failure if left untreated.
At this level of eGFR, there is a further reduction in oral
absorption of iron, so attention to parental iron administration, oral B12 and folate supplements, as well as starting erythropoietin replacement therapy (when Hb is
<100 g/L) is warranted.
Once the eGFR is below 15 mL/min/1.73 m2 (stage 5
CKD), the symptoms of uremia arise.
Nausea, vomiting, tiredness and lethargy are the most
common.
As with CKD stage 3, attention to calcium, phosphate,
anemia, blood pressure, and screening for events which

would worsen renal function such as infection or lower
tract obstruction is warranted.
Table 10-5 Targets in management of chronic kidney

disease
OPTIMAL TARGETS FOR

CKD STAGES 3 AND 4, AND
END-STAGE RENAL FAILURE
PATIENTS
End-stage renal disease (ESRD) and

renal replacement therapy
The controllable complications of ESRD include anemia, hypertension, calcium and bone disease (renal
osteodystrophy) and nutritional status.
They require frequent monitoring, and adjustment of
treatment strategies at the same time as the initiation
and maintenance of renal replacement therapy: dialysis
or transplantation.
Hemoglobin
110120g/L
Ca2+ phosphate
product
[Ca2+] normal; [Phos] <1.6 mmol/L
PTH
<23 times upper limit of normal
Blood pressure
<130139/90 mmHg, or 130/80

mmHg if proteinuria
Nutritional status
Dietary sodium <2.4 g/d (<100

mmol/d)
Maintain protein at 0.8 g/kg/d (10% of
calories); include sh protein
Maintain BMI at or below 25 kg/m2
Cease smoking
Absolute; use nicotine replacement

therapy
Immunization
Hepatitis B, inuenza,
Pneumococcus
Alcohol intake
Limited to uid restriction
Dialysis
Given time and cost constraints, more continuous or
in some cases overnight dialysis is favored, and options
available include peritoneal dialysis or hemodialysis
(Table 10-6, overleaf).
Ultimately, these therapies restore renal function
to 2045 mL/min/1.73 m2 averaged over the week,
depending on the modality chosen.
Improvement of GFR to 50 mL/min/1.73m2 requires a
well-functioning renal transplant graft.
Complications and care of the dialysis patient
The important aspects of care include each of the following:
monitor and maintain the access for dialysis
watch for and prevent cardiovascular complications
screen for infections and malignancy
reach targets for optimal outcomes for those with ESRD
(bone health, anemia, dietary management, and protection from chronic fluid overload).
There are several evidence-based guidelines to direct appropriate treatment and dialysis prescription (Table 10-7,
overleaf).
Concerns regarding adherence to diet and fluid restrictions occur when patients present with acute pulmonary
edema and recurrent hyperkalemia and hyperphosphatemia.
The net impact on quality of life is considerable, with a
requirement for very tight fluid restrictions in those who
are oligo/anuric.
The dietary restriction on potassium intake is essential
to prevent repeated and malignant hyperkalemia and
the risk of cardiac death. Ongoing dietary advice and
monitoring are required to ensure adequate attention to
dietary issues.
Given the extremely high rate of cardiovascular disease in this population, any episode of acute pulmonary
edema needs to draw attention to the risk of underlying
coronary artery disease and should be fully investigated.
Formations and prescription for dialysis require a multidisciplinary team with surgeons, vascular surgeons, interventional radiologists, interventional nephrologists, general
nephrologists, appropriately specialized nurse educators,
dietitians and family.
BMI, body mass index; CKD, chronic kidney disease; PTH,

parathyroid hormone.
Transplantation
The best alternative to restore the greatest renal functional
level is a renal transplant. A well-functioning, good-quality
transplant will return eGFR to close to 50%. The cost of
transplantation is also considerably lower than the annual
cost of dialysis treatment.
The following are considerations in any patient regarding transplantation:
underlying diagnosis, disease progression and likely
recurrence rates
suitability of the patient for major abdominal surgery
infective risks associated with immunosuppression
malignancy risks associated with immunosuppression
management of long-term medication side-effects,
especially from steroid treatment
management of long-term cardiovascular risk
chronic allograft nephropathy (return of CKD in a
transplanted kidney).
All patients on dialysis should be given consideration for
arenal transplant.
Preparation and access to the waiting list is achieved
by monthly tissue-typing, regular screening for crossreacting antibodies, viral screening for CMV, HIV and
hepatitis B and C, and control of regular anesthetic risk
factors.
255
Table 10-6 Advantages, disadvantages and dialysis prescription for end-stage renal disease
PERITONEAL DIALYSIS
HEMODIALYSIS
Access
Abdominal wall insertion of plastic catheter

into the peritoneum
Limitations: swimming and bathing can be
contraindicated. Previous abdominal surgery
can be a contraindication; rarely, a patent
pleuro-peritoneal canal exists
Arteriovenous stula, usually in the forearm
Timing
Daily exchanges, either every 6 hours

(CAPD), or attached to an overnight
(continuous) cycling machine (8 hours)
(CCPD); no non-dialysis days
57 hours every 2nd or 3rd day; in some

circumstances, daily or overnight hemodialysis
can be offered (e.g. pregnancy); some nondialysis days
Complications
Peritonitis (usually staphylococcal)

Poorer exchange rates over time
Peritoneal sclerosis in the long term
Bleeding from insertion sites

Fistula aneurysm formation
Recirculation or steal phenomenon
Poor ow rates and technical difficulties
Fistula thrombosis or infection
Progressive neurological disease
Compelling indications
Pregnancy
Congestive cardiac failure
Unstable coronary artery disease
Other considerations
Bulky home stores
Adequate space for machines at home

Adequate plumbing, good-quality water supply
2-year patient survival
77%
6080%
2-year technique survival
64%
6080%
CAPD, continuous ambulatory peritoneal dialysis; CCPD, continuous cycling peritoneal dialysis.
Table 10-7 Targets in management of the dialysis

patient
MANAGEMENT
OF:
TARGETS
Anemia
Hemoglobin 110120 g/L

In the setting of adequate iron
stores; uremia leads to poor
iron absorption, so parenteral
iron is often required
Hyperphosphatemia
Phosphate <1.6 mmol/L
Calcium and PTH
Calcium: high normal range

PTH: 1530 pmol/L
Cholesterol, LDL and

triglycerides
Total cholesterol: <4.5 mmol/L

LDL: <2.5 mmol/L
Triglcyerides: <2.0 mmol/L
Blood pressure
<140/90 mmHg
Access
Good-quality access with

aseptic approach to use
Dialysis adequacy
Reasonable urea concentrations

in between dialysis, controlled
potassium concentration, no
episodes of uid overload and,
ultimately, control of symptoms
LDL, low-density lipoprotein; PTH, parathyroid hormone.
256
Active malignancy is a contraindication to transplant, as

is any immediate anesthetic risk (e.g. recent myocardial
infarction, stroke).
Active infection is also a contraindication to the immunosuppression associated with transplantation. This
includes tuberculosis and other chronic infections which
should be excluded in the relevant risk groups.
In general, the most common transplant is now the living
related or non-related transplant. This has superseded the
cadaveric transplant, which has seen limited availability in
some countries due to lack of donation from affected families (beating-heart donation).
The acceptance of a living donor onto the transplant program is related to their underlying physical and mental
fitness for the donation, and the major surgery involved.
Tissue and cross-match compatibility directs the appropriateness of the donation, and the likely degree of
immunosuppression required.
The operation of kidney transplantation involves pelvic
placement of the donated kidney in the iliac blood supply
circle.
There is considerable bladder surgery to allow implantation of the ureter via a tunnel in the posterior bladder
wall.
Immediate immunosuppression is required, and is usually a multi-pronged approach with corticosteroids,
calcineurin inhibition, and an antimetabolite such as
mycophenolate mofetil. This blocks multiple pathways

in the immunological activation cascade, antigen recognition, cell multiplication, and inter-leukocyte signaling
to enhance T-cell responses.
On rare occasions, additional anti-T3 and other anticytokine therapy is indicated.
Considerable drug development is ensuring that new
treatments are constantly evolving.
The nonspecific effects of the current regimens, including calcineurin nephrotoxicity, limit their safety in the
longer term.
Transplant is best performed in highly active units with a
mutidisciplinary team approach.
Rejection
The immediate monitoring of a renal transplant is
designed to detect cellular rejection (mild interstitial and
tubular lymphocyte infiltration) and vascular (severe,
hemorrhagic) rejection at the earliest stages.
This is usually identified by the clinical signs of acute
renal failure in the immediate postoperative period.
This includes oliguria, a rising creatinine concentration
and, if severe, fever and graft tenderness.
It is usual to biopsy the transplant in this period to determine the severity and extent of rejection, and treat accordingly. Some institutions use protocol biopsies (timed
post-transplant biopsies whether creatinine is elevated or
not) to determine the need for rejection treatment.
The risk factors for acute rejection include:
prolonged ischemic period (for cadaveric grafts)
>40% panel-reactive active antibodies (sensitized recipient = 30% risk of rejection)
cadaveric transplantation
suboptimal immunosuppressive treatment.
Outcomes
The immediate prognosis for the transplant itself (graft
survival) is approaching 95% at 1 year.
Patient survival with a transplant in the first 5 years is
89%, which confers a significant survival advantage over
dialysis, even for those in the older age groups.
The intermediate to long-term outcomes for renal
transplantation depend in part on the progression of subsequent chronic renal damage due to chronic allograft
nephropathy (Box 10-13). This entity is characterized
by glomerular and tubulo-interstitial scarring, as well as
multilayering of the peritubular capillaries.
ACUTE RENAL FAILUREACUTE

KIDNEY INJURY (AKI)
The usual definition of acute renal failure has been replaced
by a system of determining acute kidney injury (AKI), which
can be due to de novo renal disease but is more usually a consequence of another major, often life-threatening illness.
Box 10-13
Risk factors for chronic allograft

nephropathy
Advanced donor age
Delayed graft function
Repeated acute rejection episodes
Vascular rejection episodes
Rejection that occurs late after transplantation
It is further contributed to by other cardiovascular
risk factors such as hypertension, hyperlipidemia and
prothrombotic tendency.
The RIFLE criteria classifies AKI according to urine

output and/or change in serum creatinine concentration.
The lowest level of injury is Risk and the highest is End-stage
renal disease:
R Riska 1.5-fold increase in serum creatinine and oliguria <0.5 mL/kg for 6 hours
I
Injurya 2-fold increase in serum creatinine and oliguria <0.5 mL/kg for 12 hours
F Failurea 3-fold increase in serum creatinine and oliguria (<0.3 mL/kg for 24 hours) or an absolute rise in
creatinine concentration to >355 micromol/L (reference range [RR] 6090 micromol/L)
L Lossif these insults persist for longer than 4 weeks
E End-stage renal diseaseif persisting for longer than
3months.
This classification system is helpful in terms of tracking
prognosis, i.e. length of stay in hospital, as well as hospital
and intensive care unit (ICU) mortality.
The decision to intervene with hemodialysis is determined by physiological consequences such as fluid
overload, hyperkalemia and acidosis, irrespective of
classification.
The mainstay of resuscitation, including judicious fluid
management, cardiac monitoring, and frequent electrolyte testing, inotropes if required, and treatment of fluid
overload with loop diuretics, prevents the need for dialysis in the majority of patients.
The association of renal injury with other serious disease confers a worse prognosis for discharge from the
ICU and for full recovery.
TUBULO-INTERSTITIAL
DISEASES
Acute tubular necrosis is a common consequence of protracted circulatory failure.
In hemodynamic shock, pre-renal failure is an early
manifestation of reduced renal perfusion, and when
corrected rapidly, restoration of renal function occurs.
If the pre-renal insult continues or is exacerbated by other
renal toxicity, then acute tubular necrosis can ensue.
257
Limited forms of acute tubular necrosis can take up to

6weeks to recover. Dialysis may be required during this
phase, and as the patient recovers renal function, dialysis
is withheld.
If renal cortical blood flow is fully compromised, bilateral
cortical necrosis occurs and there is no renal recovery.
Other acute tubular toxicity occurs with hypoperfusion, drug or contrast toxicities (e.g. aminoglycosides),
and rhabdomyolysis (see Table 10-8).
Rhabdomyolysis causes acute tubular injury by
accumulation of myoglobin in the renal tubules,
and direct toxicity to tubular epithelial cells.
The mechanism of injury is complex, involving prerenal insult by hypoperfusion, muscle damage and acidification of urine, and reduced filtrate volume leading to
myoglobin cast formation and release of heme from the
myoglobin. These lead to acute tubular necrosis, which
may or may not be reversible.
Reversibility of the decrease in renal function is best
achieved by restoration of blood pressure, restoration of
renal blood flow, and alkalinization of the urine.

Acute interstitial nephritis is an inflammation of the
interstitial intertubular region of the nephron, and it may
or may not be associated with a decline in renal function.
AIN has many causes, most commonly drug toxicity or
autoimmune disease such as Sjgrens syndrome and
systemic lupus erythematosus (SLE), or granulomatosis
with polyangiitis (GPA).
Interstitial infiltrates are seen in some forms of lymphoma, multiple myeloma, and transplant rejection.
AIN may occur in the context of drug hypersensitivity. This is associated with fever, rash, nausea and vomiting and, usually, a reduction in urine output with a
concurrent increase in serum creatinine concentration.
The diagnosis is suggested by eosinophils in the urine.
Table 10-8 Causes of rhabdomyolysis
CAUSE
PRESENTATION
Trauma
Crush
Blast injury
Fixed muscle position, such as with
alcohol or narcotic intoxication
Exertion
Extreme physical exercise (especially with

dehydration)
Prolonged seizures
Delirium tremens
Vascular
insufficiency
Arterial embolus or thrombosis
Drugs and
toxins
Statins
Malignant neuroleptic syndrome (e.g.
haloperidol, chlorpromazine)
Serotonin syndrome (selective serotonin
reuptake inhibitors, SSRIs)
258
Ultimately the diagnosis is confirmed by analysis of a

renal biopsy.
Treatment
The focus is on removing the toxin, or stopping the
agent that is the presumed cause.
In some cases, a short course of corticosteroids is warranted to reverse the inflammatory lesion.
In severe cases, dialysis may be required until some level
of renal function is restored.

Although there is a strong focus on the glomerular diagnosis of disease as outlined above, the progression to
end-stage kidney disease is conferred by the extent of
tubulo-interstitial scarring and tubular drop-out.
Tubulo-interstitial disease frequently results in electrolyte abnormalities.
Causes include analgesic nephropathy, chronic pyelonephritis, and some congenital diseases such as Fabrys
disease, an X-linked recessive sphingolipidosis.
Clinical presentation, investigation, diagnosis

and treatment of chronic interstitial nephritis
Chronic tubulo-interstitial disease is likely to present as
chronic kidney disease with a slow deterioration of the
GFR, and progressive proteinuria.
Progression toward dialysis is monitored and managed
accordingly, with appropriate and timely formation of
vascular access.
ELECTROLYTE DISORDERS
Hypernatremia
Hypernatremia is a concentration of sodium in the serum
that exceeds the upper limit of the normal range.
Hypernatremia is a problem of fluid volume, not salt.
It is almost universally seen in patients who are dehydrated and where the response to conserve sodium
(aldosterone) is stronger than the response to conserve
water (vasopressin).
In very rare cases it can occur from excessive salt ingestion, for example from drinking seawater.
Causes of dehydration include:
Excessive renal water loss
Diabetes insipidus
central decrease in vasopressin production
Diabetes mellitus, glycosuria
Osmotic diuretics
Psychogenic polydipsia
reduced urinary concentrating ability
Advanced age effect on renal urinary concentrating
ability
Hypovolemia from non-renal losses
decreased oral intake
extreme sweating/ burns

severe high-fluid-volume diarrhea
high-volume vomiting
Primary mineralocorticoid excess (extreme)

anddiagnosis
The clinical presentation of hypernatremia is predominantly that of dehydration: low BP with a significant
postural decrease, tachycardia with a postural increase,
dry mucous membranes, dry skin, and poor skin turgor.
The consequences of the hypernatremia per se relate to
muscle weakness, neuromuscular irritability, cerebral
irritability, seizure and coma.
Extreme hyponatremia is rarely seen and is almost
universally fatal.
The diagnosis of hypertnatremia is proven on routine biochemical testing. Pre-renal insult is suggested by:
the presence of high serum osmolality
low urinary sodium concentration (< 20 mmol/L)
high urine osmolality (> 500 mOsm/L)
high urine/plasma creatinine ratio (>40)
very low fractional excretion of sodium (<1%)
low fractional excretion of urea (<35%) .
Diabetes insipidus is diagnosed by:
dilute urine (osmolality < 300 mOsm/L) with a low
specific gravity
low urine sodium concentration
elevated serum osmolality (>290 mOsml/L).
When the diagnosis is unclear, a water deprivation test will
demonstrate a continued urine output of free water despite a
lack of intake, weight loss (water loss), hypernatremia, and a
trend to elevated serum osmolality. This is corrected with desmopressin in the second phase of the test in the case of hypothalamic causes, and not in the case of nephrogenic causes.

Treatment is largely by treating the underlying dehydrating illness.
Caution must be taken to give initially more water than
salt, but to monitor serum sodium concentration carefully so as not to cause a dilutional hyponatremia.
Rapid swings of serum sodium concentration are
thought to be causative of central pontine myelinolysis,
which is a devastating and irreversible complication of
rapid sodium concentration correction.
Hyponatremia
Hyponatremia is the most common electrolyte disturbance
seen both in the community and in hospital patients. This is
a serum concentration of sodium below the reference range.
It is associated with many chronic medical conditions,
medication use, and aging. It has significant physical
consequences, even in the milder ranges.
It is usually a problem of excess water relative to sodium

in any situation.
The situation arises when there is a vasopressin response,
either through excess or heightened vasopressin sensitivity, in comparison to the aldosterone response.

anddiagnosis
The easiest algorithm for hyponatremia is to confirm
whether the patient is wet, dry, or euvolemic (Table 10-9).
Table 10-9 Causes of hyponatremia
CAUSE
PRESENTATION
Hypovolemic
hyponatremia
(dry)
Vomiting/diarrhea
Diuretic use
Euvolemic
hyponatremia
SIADH (syndrome of inappropriate

secretion of antidiuretic hormone)
Pain and stress
Medication use
Hypervolemic
hyponatremia
(wet)

Chronic liver disease
The SIADH (syndrome of inappropriate secretion of

antidiuretic hormone) category includes a broad range of
causes which require excellent clinical skills, history, examination and basic biochemical investigations to sort out.
Causes include:
acute head injury and subarachnoid bleed
small cell cancer of the lung
pneumonia, lung abscess
brain abscess
meningitis
hypothyroidism
sarcoidosis
drugs (e.g. carbamazepine, selective serotonin reuptake
inhibitors [SSRIs]).

The initial management includes slow restoration of
serum sodium concentration by 1 mmol/L per hour, or
not more than 12 mmol/L every 24 hours. This is best
achieved by targeting the underlying abnormality: restoration of blood volume in dehydrated states, control of
fluid overload in hypervolemic states, and investigation
and control of pain in the euvolemic states.
CLINICAL PEARL
The caution with rapid reversal of hyponatremia, especially in those with extreme levels or where the comorbidity includes alcoholism, is to prevent central pontine
myelinolysis.
259
Rapid correction is often sought when the patient

has a decreased level of consciousness, and when fitting. The correction in these patients still needs to be
gradual, with appropriate supportive care and airway
protection.
Hyperkalemia
Serum potassium concentration is controlled within very
tight limits.
Hyperkalemia is a feature of very-late-stage CKD (endstage) and is one of the main indicators for dialysis. This
often occurs when the GFR is very reduced, but can
also occur at intermediate GFR reductions, especially
when ACEIs and ATRAs (particularly in combination)
are being used, and when there is tissue necrosis, gastroenterological hemorrhage, or an inflammatory collection.
Hyperkalemia is also seen in type 4 (distal) renal tubular acidosis (RTA) due to a functional decrease in aldosterone responsiveness. This is most commonly seen in
patients with diabetes mellitus.
Similarly, low mineralocorticoid concentration (seen
in Addisons disease) can lead to hyperkalemia. It also
occurs as a complication of various medications including cyclosporine A (ciclosporin A), ACEIs and ATRAs.
Hyperkalemia can be a transient phenomenon seen in
early acidosis, where the buffering of acid load means
that potassium is released from cells. This is corrected
with the treatment of the acidosis. This form of hyperkalemia/acidosis is seen in burns, tumor lysis, rhabdomyolysis and severe gastrointestinal bleeding.

and diagnosis
The usual presentation of extreme hyperkalemia for
those in whom this has developed slowly over time is
muscle weakness and cardiac rhythm disturbances.
A rapid rise in serum potassium in an acute setting can
cause cardiac death.
An electrocardiograph is required to determine PR
interval, bradycardia, widening of the QRS complex
and lengthening of the QT interval.

These are given in Box 10-14.
Hypokalemia
Hypokalaemia is the finding on biochemistry of a reduced
serum potassium concentration.
This is seen in states of fluid loss (diarrhea and vomiting,
renal losses), especially those associated with alkalosis.
It is especially important in the setting of hypertension,
as this may be a marker of secondary disease.
Secondary hypertension and hypokalemia can occur in:
primary aldosteronism
secondary aldosteronism
pheochromocytoma (sympathetic activation of renin)
260
Box 10-14
Treatment and targets for

hyperkalemia
Diagnose and correct mineralocorticoid deciency

Identify tubular acidosis, especially in diabetes
Reverse and correct any acute-on-chronic renal failure
Monitor blockade of the RAAS
Avoid ACEI and ATRA combination therapy; avoid
potassium-sparing diuretics and NSAIDs
Monitor for any intercurrent illness likely to increase
potassium in those with limited renal reserves (e.g.
pneumonia, myocardial infarction)
Rapidly deploy potassium into cells to protect the
cardiac rhythm (dextrose and insulin infusion, calcium
infusion)
Remove excess potassium from the body (oral
resonium, or dialysis)
ACEI, angiotensin-converting enzyme inhibitor; ATRA, angiotensin

II receptor antagonist; NSAID, non-steroidal anti-inammatory
drug; RAAS, reninangiotensinaldosterone system.
renal artery stenosis (secondary aldosteronism)

coarctation of the aorta (secondary aldosteronism).
The most common cause of hypokalemia is renal loss
due to diuretic use. This is particularly important in the
elderly.
Hypokalemia is seen in inherited and acquired renal
tubular acidosis (see below). It is also seen in rapid correction of acidosis (where hydrogen ions are removed
from cells and potassium rapidly returns).
Hypokalemia in the setting of anorexia nervosa is largely
dietary, but is contributed to by secondary aldosteronism.

and diagnosis
Presentation of hypokalemia is with muscle weakness
and cardiac arrhythmia (Figure 10-9).
Lower concentrations of potassium are associated with
supraventricular and ventricular ectopics, and tachyarrhythmias, as well as life-threatening torsades de
pointes and ventricular tachycardia.
CLINICAL PEARL
Electrocardiographic changes in hypokalemia are typically an increase in amplitude and depth of the P wave,
prolongation of the PR interval, T-wave attening and
ST depression, prominent U waves, and an apparent
long QT due to fusion of the T and U waves.

Treatment of hypokalemia depends on treatment of the
underlying condition.
These conditions are a form of pseudoaldosteronism.

In Liddles syndrome, there is hypertension, hypokalemia and alkalosis without demonstrable aldosterone
excess on repeated testing. This is due to a defect in the
epithelial sodium channel (ENaC), due to an autosomal dominant inheritance. It is treated by blocking the
sodium channel with a potassium-sparing diuretic (spironolactone), and control of sodium in the diet.
Similar presentations are seen in:
the syndrome of apparent mineralocorticoid excess
(autosomal recessive defect causing an increase in cortisone via 11-beta-hydroxysteroid dehydrogenase mutation, thus activating the mineralocorticoid receptor)
glucocorticoid-remediable aldosteronism (a chimerism of the 11-hydroxylase and aldosterone synthase
gene causing adrenocorticotrophic hormone [ACTH]sensitive rises in aldosterone)
other adrenal enzymatic disorders.
These are treated by a combination of ENaC blockade and
mineralocorticoid receptor inhibition. Glucocorticoid treatment suppresses the ACTH production, and is also effective.
With sodium wasting, there is normal blood pressure.
This occurs in Bartter syndrome (chloride channel defect)
and Gitelman syndrome (thiazide-sensitive sodium chloride
co-transporter [NCCT] in the distal convoluted tubule).
Figure 10-9 Electrocardiographic manifestations of

hypokalemia: the ST segment is prolonged, primarily
because of a U wave following the T wave, and the
T wave is attened
From Goldman L and Schafer AI. Goldmans Cecil medicine, 24th
Acute management requires rapid potassium replacement, with cardiac monitoring, in a hospital environment where cardiac support can be offered.
Where possible, particularly in chronic cases, oral potassium therapy is preferred.
INHERITED CHANNELOPATHIES
ASSOCIATED WITH HYPERTENSION OR HYPERKALEMIA
Hypokalemic alkalosis (with and
without hypertension)
This combination looks like mineralocorticoid excess,
when there is hypertension.
The renal tubular acidoses (RTAs; Table 10-10, overleaf) are

a set of electrolyte and acidbase disturbances that arise from
both congenital and acquired renal defects.
The more common acquired distal (type 4) RTA is seen
commonly in patients with diabetes mellitus, and features
prominently in routine biochemistry in these patients.
They are best understood by a classification system
related to location within the collecting system and the
presence of hyper- or hypokalemia. These are nonanion-gap acidoses, whereby the hyperchloremia and
metabolic acidosis are the defining features.
Type 1 RTA
This is the distal variety where the defect is in the cortical collecting duct of the distal nephron.
The principal defect is one of a failure of acid secretion
by the alpha-intercalated cells.
There is also an inability to reabsorb potassium, leading
to hypokalemia.
The main accompaniments of this RTA are:
urinary calculus formation due to hypercalciuria
low urinary citrate
alkaline nature of the urine; there is an inability to acidify the urine to a pH of <5.3
bone demineralization.
Acid challenge tests are used to establish the diagnosis in
milder cases.
261
Table 10-10 Renal tubular acidosis (RTA)
TYPE
CAUSE
LOCATION
PRESENTATION
POTASSIUM
STATUS
Type 1
Failure of H+ secretion
Distal tubular (cortical

collecting duct)
Osteomalacia
Renal stones
Nephrocalcinosis
Hypokalemia
Type 2
Bicarbonate wasting
Proximal tubular
Osteomalacia
Uric acid stones
Hypokalemia
Type 4
Hypoaldosteronism
Distal tubular
Reduced aldosterone
production or aldosterone
resistance
Hyperkalemia
Mixed*
Inherited carbonic
anhydrase II deciency or
early juvenile distal RTA with
proximal features and highsalt diet
Combined proximal and

distal
Cerebral calcication
Mental retardation
Osteopetrosis
* Mixed type RTA was formerly known as type 3.
Causes
Inherited
Acquired:
Sjgrens syndrome, SLE associations
chronic urinary infection
obstructive uropathy
sickle cell disease
Endocrine conditions such as:
hyperparathyroidism
hyperthyroidism
chronic active hepatitis
primary biliary cirrhosis
hereditary deafness
analgesic nephropathy
transplant rejection
renal medullary cystic disease
The disease is best understood by relating to the mechanisms of perturbed classical counter-exchange of potassium
and hydrogen ions at a cellular level.
The primary defect is either inability of the H+ pump
(proton pump) to work against the high H+ gradient, or
insufficient capacity due to tubular damage. There can
be back-diffusion of H+ due to damage (seen in amphotericin B nephrotoxicity).
Clinical presentation relates to the hypokalemia, and
subsequent muscle weakness and cardiac arrhythmias.
The inherited form in children manifests as growth
retardation if not treated.
The primary treatment is to correct the acidosis with
bicarbonate, and then correction of the hypokalemia, hypercalciuria, and salt depletion will follow.
Type 2 RTA
Type 2 is generally easier to understand because it reflects
a primary failure of main proximal tubular functions.
262
This leads to a loss of bicarbonate in the urine, and subsequent acidemia.

The other proximal tubular functions that may be
affected result in phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria.
This full-blown tubular loss is termed Fanconi
syndrome.
The bicarbonate loss can also be seen as an isolated defect.
Demineralization is also seen here due to phosphate
wasting.
THE KIDNEYS IN PREGNANCY

AND PREGNANCY-RELATED
DISEASES
Renal disease has important implications in pregnancy as the
normal adaptations to pregnancy have far-reaching effects,
not only on pregnancy events and outcomes per se, but also
on the progression of underlying renal disease to end-stage
kidney disease.

The sequence of physiological events in pregnancy starts
with a decrease in systemic vascular resistance such that
there is a dramatic and persistent decrease in BP.
This decrease in BP is resistant to the normal vascular
stressors which increase BP outside of pregnancy (e.g.
angiotensin II and epinephrine).
The decrease in BP manifests as a marked increase in
renal plasma flow, initiated by the decrease in renovascular resistance.
The increase in blood flow increases the GFR dramatically, up to 40% in the 1st trimester. This is important
to note, as it will lead to a dramatic decrease in the

value of the serum creatinine in pregnancy, due to
hyperfiltration.

The requirement in pregnancy for massive flow adaptation means that any underlying renal disease where renal
flow reserve is limited may manifest with complications in
pregnancy.
The most common of these is chronic hypertension. Of
those patients with chronic hypertension and also those
with renal disease, the risk of developing superimposed
preeclampsia is of the order of 30% and is largely conferred by the hypertension, particularly if BP control is
poor. Therefore, importance is placed on monitoring
for any decline in renal function and for the fetal and
maternal effects of hypertension in pregnancy.
The effect of the pregnancy per se on progression of renal
disease is hard to determine.
It is widely held that >3 pregnancies in women in
populations with higher rates of renal disease leads
to a more rapid progression to CKD and eventual
dialysis.
There are also some kidney diseases that are worse
than others in terms of progression, with FSGS
and reflux nephropathy being the most aggressive.
Rapid progression to end-stage kidney disease is
also described in many other renal diseases.
When the creatinine concentration is >140 mmol/L

(RR 6090 mmol/L), the chances of progression
within the pregnancy are greatly increased. Consideration should be given to early dialysis in these circumstances, with some published data suggesting
that a GFR <30 mL/min/1.73m2 should be considered for dialysis.
Management
Both hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) are options in pregnancy. The
mainstay of treatment is to maintain the serum urea to
<10.0 mmol/L (RR 38 mmol/L) in order to reduce the
fetal complication of polyhydramnios (which is associated with premature delivery).
Similarly, attempts to control BP are paramount to
managing the pregnancy and improving the likely pregnancy outcome.
Fertility is markedly reduced in women already established on dialysis. This is in part due to hyperprolactinemia, but is contributed to by the uremic milieu in
women with end-stage disease.
It is more likely that pregnancy will occur in the first
24months on dialysis. Management requires an increase
in the dialysis frequency, and targets for urea and BP
control should be carefully met.
Anemia should be carefully managed with appropriate
erythropoetin (EPO) replacement.
263
1
A 16-year-old is brought in by her sister due to a 9-day history of periorbital and ankle edema, both of which are worse
toward the end of the day. She has noticed foamy urine. She has had a sore throat in that time, but her medical history
is otherwise unremarkable and she takes no medications. Her birthweight was 2350g at 39 weeks of gestation (RR
normal >2500g) and she was born by normal vaginal delivery. Her mother consumed 1 glass of beer most days of the
pregnancy. She had menarche at 13 years and has a regular cycle. On physical examination, temperature is normal,
blood pressure is 160/90 mmHg, pulse rate is 60/min, and respiration rate is 12/min; body mass index is 24kg/m2.
Fundoscopic examination shows silver wiring of the retinal arterioles. There is bilateral pedal edema to just past the
knee. Urinalysis shows 4+ blood; no protein.
Laboratory studies show serum creatinine 70.7 micromol/L (RR 6090 micromol/L), urine proteincreatinine ratio
10 mg/mmol Cr. A kidney biopsy is performed. Light microscopy of the specimen reveals diffuse inammation
within the glomerular tufts. On electron microscopy, there are subepithelial lumpy immunoglobulin deposits.
Immunouorescence testing shows widespread granular deposits. Which of the following is the most appropriate
treatment for this patient?
A Cyclophosphamide
B Cyclosporine (ciclosporin)
C Penicillin
D Prednisone
A 35-year-old, otherwise well woman presented to the emergency department with 2 days of fever and macroscopic
hematuria. She had a prodrome of a sore throat for 2 days. On examination, blood pressure was 190/90mmHg, urine
heavily bloodstained and leucocyte-positive, protein
++. She has normal heart sounds and no stigmata
of bacterial endocarditis. She had had an uneventful
pregnancy 12 months previously, with no hypertension
or proteinuria. She is planning further children.
Laboratory investigations show creatinine initially
81 micromol/L (baseline 65micromol/L; RR 6090
micromol/L) and rising to 109 micromol/L. Urgent renal
ultrasound showed normal-sized kidneys. Urgent renal
biopsy was then performed (see Figure 10-10). Which
combination of treatment is most appropriate in this
clinical situation?
A Antihypertensive treatment with an angiotensinconverting enzyme (ACE) inhibitor and a course of
oral penicillin
B Antihypertensive treatment with a calcium-channel
blocker and consideration of high-dose prednisone
and cyclophosphamide
Figure 10-10 Renal biopsy results for patient in
C Combination antihypertensive therapy with an ACI
Question 2
inhibitor and an angiotensin II receptor antagonist
From Lim E, Loke YK and Thompson AM (eds). Medicine and
(ATRA) with a focus on her proteinuria
surgery: an integrated textbook. Elsevier, 2007.
D Antihypertensive treatment with high-dose diuretics
and a beta-blocker, with low-dose corticosteroids
A 29-year-old non-smoking male presents with marked

lethargy and recent increased creatinine discovered on blood testing. He had had an episode of hematuria at the age
of 3 years, and is known to have a duplex left ureter. A slightly elevated creatinine was noted 12 months earlier. He had
a renal biopsy at that time, and had refused any treatment with steroids due to the risk of diabetes. He now presents
12 months later. Laboratory investigations show creatinine 150 micromol/L (baseline 90 micromol/L; RR 6090
micromol/L) and rising to 553 micromol/L over the next 12months. A renal ultrasound performed at this presentation
shows small kidneys (9cm left and 8.8 cm right). A renal biopsy performed 12 months ago showed focal glomerular
sclerosis with a collapsing pattern and some mild cellular inltration. Which of the following management approaches
would be most appropriate in this situation?
A Monitor for anemia and serum phosphate, and control any blood pressure or lipid abnormalities.
B Commence dialysis immediately.
C Insist on a repeat renal biopsy to determine any new pattern of glomerular injury.
D Commence empirical treatment with steroids and cyclophosphamide.
264
ANSWERS
1
C.
This patient most likely has post-infectious/post-streptococcal glomerulonephritis (PSGN) in the setting of her recent sore
throat. A combination of hypertension, hematuria and positive serology for streptococcal infection in a younger patient
has a high positive predictive value for the disease. This disease is a common GN in communities of low socioeconomic
status and where crowding exists; there are concerns in some disadvantaged communities that renal mass is inuenced by
in utero factors such as alcohol consumption and prematurity or low birthweight. Renal biopsy is required to conrm the
diagnosis, although this is not essential in communities where PSGN is common. Empirical treatment should commence
immediately. Treatment in this situation would be appropriate with antibiotics for the streptococcal infection. Despite the
extent of the renal inammation there is no indication for immunosuppressive therapy, which is generally ineffective. In
those with recurrent disease and where there is progressive loss of renal function, monitoring renal function and treating
infections is the mainstay of treatment.
B.
The combination of crescentic GN in the setting of immunoglobulin A (IgA) disease (mesangial IgA deposits conrm the
diagnosis) is an uncommon but potentially kidney-threatening presentation of IgA disease. More commonly, IgA disease
has a classic presentation of nephritic syndrome with a chronic progressive pattern. The extent of renal damage is due to
the amount of progressive scarring. The presence of a crescent indicates that within 3 months all glomerular function will
be lost if there is not aggressive immunosuppressive treatment. The post-sore-throat presentation is again not uncommon
in IgA disease and would indicate that streptococcal disease should be excluded. Ultimately the renal biopsy is required
to differentiate IgA and post-streptococcal glomerulonephritis (PSGN). The presence of crescents requires a monthlong course of prednisone (1 mg/kg/day dosing) with slow tapering, and cyclophosphamide under the supervision of a
nephrologist. It is usual to follow up with a repeat renal biopsy to ensure that the inammatory component is completely
resolved. Refractory lesions will require ongoing maintenance support with steroid-sparing immunosuppressive treatment
(cyclosporine [ciclosporin], azathioprine or mycophenolate).
A.
He has demonstrated the rapid progression seen in about 15% of cases of focal segmental glomerulosclerosis (FSGS).
Up to 50% will require dialysis in the rst decade of the diagnosis. His current estimated glomerular ltration rate (eGFR)
is around 13 mL/min/1.73m2 and this is in the category when dialysis starts to be considered. The indications for urgent
dialysis are hyperkalemia uncontrolled by diet, acidosis, uremic pericarditis, uid overload, and symptoms of nausea and
vomiting. A recent study of the lifetime benet of commencing dialysis at 15 mL/min/1.73m2 vs 10 mL/min/1.73m2 did not
clearly demonstrate a survival advantage in starting early. The need for dialysis is determined by patient choice (peritoneal
dialysis vs hemodialysis) and the presence of symptoms. At the time, monitoring and treating erythropoietin-deciency
anemia, controlling hyperphosphatemia with diet and binders, and managing hypertension, hyperlipidemia and other
cardiovascular risk factors (smoking, weight reduction) are the important aspects of treatment.
265
CHAPTER 11
ENDOCRINOLOGY
Mark McLean and Sue Lynn Lau
Osteoporosis
Pagets disease (PD)
CHAPTER OUTLINE
SYSTEM OVERVIEW

Evaluating the function of hormonal systems
Pathogenic mechanisms of hormonal disorders
DISORDERS OF THE PITUITARY AND

HYPOTHALAMUS

Hypopituitarism
Surgery and radiotherapy for pituitary tumors
THYROID DISORDERS
Physiology and assessment of thyroid function

Thyroid imaging
Hyperthyroidism
Hypothyroidism
Thyroid cancer
DISORDERS OF BONE AND MINERAL

METABOLISM
Mineral homeostasis
Hypercalcemia
Hypocalcemia
ADRENAL DISORDERS
Physiology and assessment of adrenal function

Primary hyperaldosteronism (Conns syndrome)
Pheochromocytoma
(incidentaloma)
GROWTH AND PUBERTY

MALE REPRODUCTIVE ENDOCRINOLOGY
Testicular function
Male hypogonadism
Gynecomastia
FEMALE REPRODUCTIVE ENDOCRINOLOGY

Key points in the menstrual history
Laboratory tests
Female hypogonadism
267
NEUROENDOCRINE TUMORS (NETs)

Overview
Differential diagnosis of a hypoglycemic disorder
Treatment of malignant NETs
DISORDERS OF MULTIPLE ENDOCRINE

SYSTEMS
Other multiple endocrine tumor syndromes
Polyglandular autoimmunity (PGA) syndromes
SYSTEM OVERVIEW
A hormone is a chemical substance released from a secretory
cell that acts upon specific receptors present in another cell,
to effect a physiological change in the function of the target cell. Endocrine action occurs in a distant organ, usually
after transportation of the hormone through the circulatory
system. A paracrine action is upon a cell adjacent to the
secretory cell, and autocrine actions are upon receptors
expressed by the hormone-secreting cell itself.
Hormonal substances fall into a number of different
chemical categories:
small peptides such as the hypothalamic-releasing
factors, and glycopeptides such as thyroid-stimulating
hormone and the gonadotropins
large peptides such as insulin, glucagon and parathyroid
hormone
steroid hormones derived from cholesterol, including cortisol, aldosterone, estrogen, progesterone and
androgens
amino acid derivatives such as thyroid hormones and
catecholamines
vitamin derivatives such as the hydroxylated forms of
vitamin D.
The chemical nature of different hormones dictates their
sites of action and their chemical metabolism.
Thyroid hormones and steroid hormones are lipidsoluble and cross cell membranes readily. Therefore,
these classes of hormones are able to act on cytoplasmic
receptors within the target cell.
Peptide hormones are large and electrically charged
and unable to enter target cells. Therefore, they must
interact with cell surface membrane receptors and rely
upon intracellular second messenger systems to produce
target cell responses.
Many hormones bind with high affinity to binding proteins
in plasma. These include specific binding proteins such as
thyroid-hormone-binding globulin (TBG) and cortisolbinding globulin (CBG), but there is also a substantial
amount of nonspecific binding to more abundant proteins
such as albumin and pre-albumin. Protein binding has an
important effect on hormone function since it renders the
268
DIABETES AND METABOLISM

Hypoglycemia
Disorders of energy excessoverweight and
obesity
hormone molecule biologically inactive while in the bound
state, but also protects it from degradation. In this way,
protein binding creates a storage pool of inactive hormone,
which is in dynamic equilibrium with a smaller pool of free,
biologically active hormone.
Hormone action is determined as much by receptor factors as it is by the circulating hormone concentration. Abnormalities of receptor function or of downstream second
messenger systems can cause disturbance to endocrine systems, which
are not necessarily revealed by measurement of circulating hormone
concentrations.

Most endocrine systems regulate the secretion of hormones
through negative feedback. An example is the action of
the hypothalamus and pituitary in regulation of the thyroid,
adrenal cortex and gonads (Figure 11-1). The secretion of
HYPOTHALAMUS
CRH
ANTERIOR PITUITARY
ACTH
ADRENAL CORTEX
CORTISOL
TARGET ORGANS
Figure 11-1 An example of a classic endocrine

negative feedback loop. In this case, corticotropinreleasing hormone (CRH) from the hypothalamus
stimulates adrenocorticotropic hormone (ACTH)
release from the anterior pituitary, which in turn
stimulates cortisol production by the adrenal
gland. Cortisol provides negative feedback to the
hypothalamus and pituitary to regulate its own
production
Chapter 11 Endocrinology
thyroid hormones, cortisol and sex steroids is closely regulated by pituitary release of thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and
gonadotropins, respectively. These, in turn, are regulated
by hypothalamic releasing factors. The involvement of the
hypothalamus allows signal input from the central nervous
system (CNS) so that endocrine function can be responsive
to a wide variety of stimuli. Negative feedback action occurs
when thyroid hormones, cortisol or sex steroids act upon
the hypothalamus and anterior pituitary to inhibit production of stimulatory factors of each axis. This negative feedback regulation serves to stabilize the circulating hormone
concentrations, while allowing the system to be responsive
to external stimuli.
Hormonal systems not controlled by the pituitary also
demonstrate direct feedback regulation. Examples include
the regulation of parathyroid hormone secretion by serum
calcium, control of insulin and glucagon secretion by plasma
glucose concentration, and variation in antidiuretic hormone (vasopressin) in response to plasma osmolality.
Evaluating the function of hormonal

systems
An important function of most hormone systems is to maintain a stable metabolic and physiological environment. To
this end, the secretion of hormones often varies greatly in
response to external stimuli. For example, in order to maintain a fairly constant plasma glucose concentration, the
secretion of insulin can vary many-fold depending upon
whether the individual is in a fed or a fasted state.
Further variations in hormone concentrations occur
because of cyclical variation. For example, cortisol and
ACTH are regulated on a diurnal cycle; in menstruating
women the gonadotropins and sex steroids are regulated on
a monthly cycle; still other hormonal systems are regulated
upon lifetime cycles, such as those involved in the initiation
of puberty. Therefore, it is often difficult to define a normal hormone concentration.
CLINICAL PEARL
Always view the results of hormone measurements in
the light of the physiological context. It is often appropriate to perform dynamic tests of endocrine function
rather than rely on a static snapshot measurement of
a hormone concentration.
When excess of a hormone is suspected it is useful to

undertake a suppression test, or to create a physiological circumstance in which secretion of the hormone should normally be inhibited. Conversely, when a hormone deficiency
is suspected, a stimulation test will provide the most useful
diagnostic information. Specific examples will be considered throughout this chapter.
Hormone measurement
Almost all laboratory measurements of hormone concentrations use forms of immunoassay. These laboratory
techniques have high sensitivity and specificity and can be
applied to a very small volume of sample. However, laboratory artifacts may occur and produce inaccurate results.
The action of binding proteins is a very important
consideration. Most immunoassay techniques measure total
hormone concentration, which includes inactive, proteinbound hormone. In the case of cortisol or thyroid hormones,
less than 5% of the total hormone concentration is free and
biologically active. Variations in binding-hormone concentration (e.g. increased by pregnancy, decreased by nephrotic
syndrome) greatly affect the overall measured hormone concentration, although in some circumstances it is possible to
measure the free fraction of a circulating hormone (e.g. free
thyroxine) to circumvent this problem.
CLINICAL PEARL
When interpreting the results of endocrine testing, a
prudent physician considers the whole patient, and not
just the test result. If results appear discordant with the
patients clinical condition, always recheck the test and
consider potential sources of artifact.
Imaging in endocrinology
In the investigation of endocrine disorders it is important to
first determine whether a hormonal abnormality is present
before undertaking any imaging to identify a cause.
Modern medical imaging demonstrates that 510% of
healthy individuals harbor adenomas in the pituitary, adrenal or thyroid glands. The vast majority of these are benign
and hormonally inactive. Conversely, functionally significant
lesions causing, for example, hyperparathyroidism, Cushings
disease or insulinoma syndrome, may be impossible to locate
by imaging procedures. It is therefore important to demonstrate that a lesion is associated with a definite hormonal
abnormality before ascribing a functional diagnosis to it.
CLINICAL PEARL
Conrm the presence of a functional hormone disorder before undertaking imaging studies to locate its
source. Failure to do this can cause false assumptions
about the signicance of incidental lesions seen on
imaging studies.
Pathogenic mechanisms of hormonal

disorders
Hormone deciency
Endocrine hypofunction most commonly results from primary gland dysfunction acquired as a result of a variety
of pathological processes including autoimmunity, trauma,
surgery, irradiation, hemorrhage or infarction, infection or
an infiltrative process. Primary gland hypofunction can also
be due to congenital agenesis of a hormone-secreting gland
or a critical mutational change, which leads to reduced or
absent activity of the hormone or its receptor.
In the situation of primary hypofunction there is loss
of negative feedback, which may result in characteristic
269
and diagnostic elevations of stimulating factors to the failed

organ (e.g. elevated TSH secretion in response to primary
hypothyroidism).
Secondary gland hypofunction occurs when there
is loss of a normal physiological stimulator of glandular
function. The most common example of this is secondary
dysfunction of the thyroid, adrenal cortex or gonads as a
consequence of pituitary or hypothalamic disease. Secondary
hypofunction can be distinguished by the lack of compensatory elevation of stimulating factors and the presence of gland hypofunction.
A final mechanism of hormonal hypofunction is hormone resistance, which may be relative or absolute. Resistance to hormone action in the presence of an adequate
hormone concentration may be due to dysfunction of ahormone receptor or of downstream mediators of hormone
action. The most common example is insulin resistance,
which is a fundamental part of the pathogenesis of type 2
diabetes. Insulin resistance is usually a relative phenomenon, is multifactorial, and may be compensated by increased
insulin secretion by the pancreatic beta-cell. Rarer forms of
hormone resistance are associated with mutations of specific hormone receptors (e.g. thyroid hormone resistance,
pseudo-hypoparathyroidism).
Hormone excess
Primary hypersecretion of hormones is most commonly due to a benign neoplasm (adenoma) within a
hormone-secreting gland, which demonstrates autonomous
hyperfunction and loss of normal physiological feedback
inhibition. The molecular pathogenesis of most endocrine
adenomas is poorly understood.
A second mechanism of primary hormone hypersecretion is autoimmune stimulation. The classic example of this
is Graves disease in which a stimulating autoantibody to the
TSH receptor drives primary hyperthyroidism.
Gland hyperfunction may also rarely occur as a result of
an activating mutation in a tropic hormone receptor. For
example, an activating mutation of the LH receptor can
cause male precocious puberty due to inappropriate secretion of testosterone (testotoxicosis).
A final cause of hormone excess, mimicking primary
glandular hyperfunction, is iatrogenic administration of
supraphysiological amounts of hormones as therapy. This
is a particularly important consideration in the differential
diagnosis of hyperthyroidism and of adrenocortical excess.
DISORDERS OF THE PITUITARY

AND HYPOTHALAMUS
The pituitary gland is a composite of the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary),
which have separate embryological origins. The adenohypophysis originates from pharyngeal epithelium and migrates
into the cranial cavity in early fetal development, establishing
a vascular connection to the hypothalamus (hypothalamic
pituitary portal vessels). The neurohypophysis constitutes the
axonal projections of hypothalamic nerves. The important
anatomical relations of the pituitary are the optic chiasm superiorly, the sphenoid bone and sphenoid air sinus inferiorly,
and the structures of the venous cavernous sinuses laterally.
The cavernous sinus contains the carotid arteries, venous
plexus and the 3rd (oculomotor), 4th (troclear), 5th (trigeminal, ophthalmic and maxillary division) and 6th (abducens)
cranial nerves (Figure 11-2). Therefore, mass lesions arising
within the pituitary fossa may result in neurological symptoms from compression of these adjacent structures.
The anterior pituitary (adenohypophysis) secretes six
major hormones, as well as other hormone fragments
and intermediate products. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH),
luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH) and prolactin
(PRL) are each under the control of one or more hypothalamic factors (see Table 11-1). Hypothalamic control is predominantly stimulatory, with the exception of
prolactin which is predominantly regulated by inhibition. Therefore, disconnection of the anterior pituitary
from the hypothalamus results in a reduction in secretion of all hormones except prolactin.
The neurohypophysis secretes vasopressin (also known
as antidiuretic hormone, ADH) and oxytocin. Hormone
Pituitary
gland
Internal carotid
artery
Oculomotor
nerve
Trochlear
nerve
CLINICAL PEARL
Ophthalmic
nerve
A hallmark of all forms of primary endocrine hyperfunction is down-regulation of the physiological stimulators for that function.
Secondary hyperfunction of a hormone-secreting

gland occurs when there is excessive stimulation by a physiological regulator, for example adrenal cortical hyperfunction due to ACTH hypersecretion. Primary and secondary
hyperfunction will result in the same clinical syndrome but
can be distinguished from each other by the fact that secondary hyperfunction is not accompanied by negative feedback inhibition
of the stimulator.
270
Sympathetic
plexus
Abducens
nerve
Maxillary
nerve
Figure 11-2 A coronal section of the right cavernous

sinus showing the relationship between pituitary,
cavernous sinus, vessels and nerves
From Kline LB, Acker JD and Post MJD. Computed tomographic
evaluation of the cavernous sinus. Ophthalmology 1982;89:37485.
Table 11-1 Physiological regulators of pituitary hormone secretion
HORMONE
STIMULATOR
INHIBITOR
Adrenocorticotropic hormone
(ACTH)
Corticotrophin-releasing hormone
(CRH)
Thyroid-stimulating hormone (TSH)
Thyrotropin-releasing hormone (TRH)
Luteinizing hormone/folliclestimulating hormone [LH/FSH)
Gonadotropin-releasing hormone
(GnRH)
Prolactin
Growth hormone (GH)
Growth-hormone-releasing hormone
(GHRH)
Ghrelin
Somatostatin
Prolactin (PRL)
TRH
Dopamine
release occurs from nerve endings in the posterior pituitary but is controlled by the nerve bodies located in the
hypothalamus.

Adenomas are benign neoplasms arising from endocrine
cells of the anterior pituitary and are the most common
intracranial neoplasm. At autopsy, up to 20% of all adults
are found to harbor a small unsuspected adenoma, mostly
with no clinical significance.
Pituitary adenomas are usually sporadic and their pathogenesis is poorly understood. They are classified on the basis
of size into microadenomas (<10mm diameter) and macroadenomas (>10 mm) (Figure 11-3), and on the basis of hormonal evaluation as functioning or non-functioning. Adenomas
can arise from any of the pituitary cell types, but most do not
cause excess secretion of intact pituitary hormones (i.e. are
non-functioning). True pituitary carcinoma is an extremely
rare condition.
Other disease processes may produce a mass lesion in the
anterior pituitary, usually causing hypopituitarism:
A
non-adenomatous tumors (craniopharyngioma, germcell tumor)

autoimmune inflammation (hypophysitis)
other inflammatory disorders (sarcoidosis, histiocytosis)
cystic lesions (Rathkes cleft cyst, arachnoid cyst)
carotid artery aneurysm
metastatic neoplasms.
CLINICAL PEARL
Cardinal manifestations of pituitary disorders
Abnormalities of the anterior pituitary cause three clinical problems:
syndromes of pituitary hormone excess
effects of a space-occupying mass
hormone deciencies.
All three manifestations may be present in the same
patient and must be evaluated individually.
Figure 11-3 MRI images of (A) normal pituitary, (B) microadenoma, and (C) macroadenoma
From: (A) McMaster FP et al. Effect of antipsychotics on pituitary gland volume in treatment-nave rst-episode schizophrenia: a pilot study.
Schizphr Res 2007;92(13):20710. (B) Torigian DA, Li, G and Alavi A. The role of CT, MR imaging and ultrasonography in endocrinology. PET
Clinics 2007;2(3):395408. (C) Klatt EC. Robbins and Cotran Atlas of pathology, 2nd ed. Philadelphia: Elsevier, 2010.
271
Hypopituitarism
Deficiency of anterior pituitary hormone secretion results
in secondary failure of cortisol, thyroid hormone and sex
steroid production. The biochemical hallmark of secondary
failure is lack of a compensatory increase in pituitary hormone levels as the end organ fails (e.g. hypothyroidism without a rise in serum TSH). There is often a sequential loss of
hormone functionGH and gonadotropins first, followed
by TSH, and then ACTH.
Causes of anterior pituitary failure are:
pituitary mass lesions (as above)
infection (bacterial, fungal, tuberculosis)
irradiation (treatment of CNS or nasopharyngeal
tumors, total body irradiation)
trauma, surgery or vascular injury
congenital hypopituitarism (mutations of pituitary
transcription factors).
Function of the pituitaryadrenal axis and GH secretion

may require dynamic testing:
A 0900 plasma cortisol level <150 nmol/L (5.5 microg/
dL) indicates probable ACTH deficiency; >450 nmol/L (16.5 microg/dL) indicates sufficiency; intermediate
levels require clarification with a stimulation test (usually a hypoglycemia stress test).
GH secretion is pulsatile. Normal individuals can have
a GH level of 0 between pulses. Normal insulin-like
growth factor 1 (IGF-1) levels suggest probable GH
sufficiency. Definitive proof of GH deficiency requires
failure of GH response to a stimulation test (usually an
insulin tolerance test, ITT).
An ITT is performed by administering intravenous (IV)
insulin to provoke hypoglycemia <2.2 mmol/L (40mg/
dL), which provokes a prompt rise in plasma cortisol and GH in normal individuals. Peak cortisol <500
nmol/L (18 microg/dL) or GH < 9 mU/L (3 ng/mL) is
interpreted as a deficient response.
Clinical features
The clinical effects (Table 11-2) are similar to primary adrenal, thyroid or gonadal disease. Growth failure is an important additional manifestation in children.
Diagnosis
Basal concentrations of the anterior pituitary hormones
and of hormones produced by their respective target glands
should be measured. Most deficiencies can be determined
from a single plasma sample, best obtained in the morning.
CLINICAL PEARL
Posterior pituitary function is usually preserved in cases
of pituitary adenomaeven with large macroadenomas. When diabetes insipidus occurs with a pituitary
mass lesion, an alternative diagnosis (inammatory
cause, non-adenomatous tumor, metastasis) should
be suspected.
Table 11-2 Clinical effects of pituitary hormone deciencies

In panhypopituitarism, all are combined, although diabetes insipidus (ADH deciency) is often absent
HORMONE
ACTH
TSH
GH
Gonadotropins
Prolactin
Vasopressin (ADH)
CONTEXT
SYMPTOMS AND SIGNS
Acute
Fatigue, weakness, hypotension, weakness, vomiting
Chronic
As in Addisons disease, except lack of pigmentation, electrolyte disturbance

and hypovolemia
Hypoglycemia, weight loss
Children
Growth retardation
Adults
As for primary hypothyroidism, thyroid atrophy
Children
Growth retardation, increased adiposity
Adults
Exercise capacity, lean mass, fat mass, cardiovascular risk
Children
Failure of sexual maturation, lack of pubertal growth spurt
Men
As for primary hypogonadism, testicular atrophy, infertility
Women
Secondary amenorrhea, infertility, osteoporosis
Women
Failure of lactation
Polyuria, dilute urine, thirst, nocturia, hypernatremia
ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; GH, growth hormone, TSH, thyroid-stimulating hormone.
272
Pituitary hormone replacement

Hypopituitarism is usually permanent. Patients will therefore require lifelong hormone replacement therapy to replicate normal physiological hormone concentrations. With the
exception of GH and ADH treatment, replacement therapy is
achieved by administering target-organ hormones (glucocorticoids, thyroxine, sex steroids) rather than pituitary hormones.
The dosage and administration of these hormones is identical
to the treatment of primary hypoadrenalism, hypothyroidism
or gonadal failure, except for the following differences:
Treatment is monitored by measurements of the administered hormone (e.g. thyroxine), not the tropic hormone (TSH).
There is usually no need to administer mineralocorticoid replacement as adrenal secretion of aldosterone is
still regulated normally by the reninangiotensin axis.
To achieve fertility it is necessary to administer gonadotropins to stimulate ovulation or spermatogenesis.
CLINICAL PEARL
In treating pituitary failure, monitoring is of the administered hormone (e.g. thyroxine), not the pituitary hormone (TSH).
Hyperprolactinemia
Prolactin-secreting adenomas (prolactinomas) are the most
common functioning pituitary tumors. However, hyperprolactinemia can result from non-tumor causes because the
dominant control of prolactin secretion from the pituitary
is inhibitory, by dopamine release from the hypothalamus.
Any interruption of dopamine release, transport or action
will result in disinhibition of normal pituitary lactotropes,
and the plasma prolactin concentration can increase up to
sixfold above normal.
Mild levels of hyperprolactinemia (<2 times normal
range) are often transient and not related to any identifiable pathology.
Causes of significant hyperprolactinemia (>23 times
normal range) are:
prolactin-secreting pituitary adenoma (prolactinoma)
physiological stimulation (pregnancy, lactation,
nipple stimulation, stress)
dopamine antagonism (antipsychotic and antiemetic drugs)
pituitaryhypothalamic disconnection (stalk compression, trauma, surgery).
Clinical features
Prolactin inhibits the function of the pituitarygonadal axis at
the level of gonadotropin secretion and sex steroid synthesis.
In women:
abnormalities of the menstrual cycle due to anovulation or an abnormal luteal phase, presenting as
amenorrhea, irregular cycles or infertility
loss of libido
galactorrhea, but only if estrogen is also present
if due to a prolactinoma, the tumor is most often a

microadenoma.
In men:
impotence, infertility, hypogonadism
gynecomastia, but usually no galactorrhea
prolactinomas are often macroadenomas and present with mass-related symptoms.
Most microadenomas do not grow, or cause mass effects or
hypopituitarism.
Diagnosis
The cause of hyperprolactinemia can usually be determined by exclusion of drug-related or physiological causes,
and appropriate pituitary imaging. False positive results for
hyperprolactinemia can occur because of the presence of a
prolactin-binding antibody (macroprolactin), which can be
excluded by further laboratory analysis.
Treatment of prolactinoma
Prolactin-secreting pituitary adenomas are responsive to
pharmacological suppression by dopamine agonists (e.g.
bromocriptine, cabergoline, quinagolide). In >80% of cases
there will be suppression of prolactin levels to close to the
normal range, accompanied by reduction in tumor volume.
Such medical therapy is the mainstay of treatment in most
cases, and can be maintained for many years if needed.
In women desiring fertility, bromocriptine or cabergoline can be used to restore ovulatory cycles. Treatment can
be ceased at conception in women with microadenomas,
but should be continued in pregnancy to suppress pituitary
tumor growth in women with macroadenomas.
Pituitary surgery or radiotherapy are secondary treatments for prolactinomas which do not respond well to dopamine agonists.
Acromegaly
After prolactinomas, GH-secreting tumors are the next most
common functioning pituitary adenomas. In adults, the clinical expression of GH excess is subtle and slowly evolving.
Consequently, the GH excess syndrome, acromegaly, is often
very advanced at the time of diagnosis. The tumors are mostly
macroadenomas by the time of detection, and often present
to medical attention because of mass effect rather than symptoms of GH excess. Hypopituitarism is often also present.
Clinical features of GH excess
Facial change, jaw enlargement, frontal bone expansion
(Figure 11-4, overleaf)
Enlargement of hands and feet, carpal tunnel syndrome
Hypertrophic/degenerative spine or joint disease
Excessive sweating, oily skin, skin tags
Tongue enlargement, obstructive sleep apnea
Impaired glucose tolerance or diabetes
Congestive cardiac failure, hypertension, cardiomegaly
Diagnosis
GH excess cannot be reliably determined from measurement of GH levels alone, as the pulsatile release of GH in
273
Figure 11-4 Patient with typical signs of acromegaly;

note the change in the features in the photograph
on the right compared with that on the left when the
patient was younger
From Damjanov I. Pathology for the health-related professions,
2nded. Philadelphia: Elsevier, 2000.
normal individuals results in a highly variable normal

range.
Acromegaly is diagnosed on the basis of elevated IGF-1 levels
and/or failure of GH to suppress after glucose loading (oral glucose tolerance test), which completely suppresses GH secretion in
normal individuals.
Imaging should then be performed to visualize the pituitary adenoma, together with testing of other pituitary
hormone secretion.
Treatment
The goals of treatment of acromegaly are to control excessive GH secretion, reduce pituitary tumor mass, and preserve the normal secretion of other pituitary hormones. The
treatment options are:
Pituitary surgery, aiming to remove the adenoma. However, most tumors are macroadenomas at diagnosis and
complete surgical removal is possible in only 3040% of
these. Partial tumor reduction (debulking) may still be
beneficial.
Medical therapy with long-acting somatostatin analogues (octreotide, lanreotide, pasireotide). GH and
IGF-1 normalization can be achieved in 70% of cases
and some reduction in tumor volume is usual.
GH-receptor blockade using pegvisomant. Control of
IGF-1 levels can be achieved in most patients, but cost is
a major limiting factor. Tumor volume is not affected.
Radiotherapy, which has a good long-term cure rate
but may take many years to produce normalization of
GH levels. Hypopituitarism also usually occurs.
Surgery and radiotherapy for pituitary

tumors
Surgery for pituitary tumors is usually performed via the
trans-nasal, trans-sphenoidal route. A trans-cranial approach
274
may be needed for large suprasellar tumors, but is associated

with much higher morbidity and mortality. Successful control of hormone-secreting adenomas is highly dependent on
surgical experience and should be undertaken only in centers with considerable experience. Hormonal complications
of pituitary surgery include hypopituitarism and diabetes
insipidus; other occasional issues include cerebrospinal fluid
(CSF) leak and infection.
External beam radiotherapy has high efficacy for
control of hormone-secreting pituitary tumors. However,
the effect is extremely delayed. The average delay to normalization of GH and IGF-1 levels in acromegaly is about
5years, and to normalization of cortisol in Cushings disease
2 years. Medical therapy can be used in the interim. In nonfunctioning adenomas, radiotherapy is an effective adjunct
after debulking surgery and prevents tumor regrowth in
more than 80% of cases.
Conventional pituitary radiotherapy is delivered at a
total dose of 4500 to 5000 cGy in 25 fractional doses.
Stereotactic radiosurgery and gamma-knife (singledose) radiotherapy are newer techniques with practical
advantages, but currently no proof of greater efficacy
than conventional treatment.
Radiotherapy is damaging to normal pituitary tissue, and
virtually all patients receiving pituitary irradiation will
develop pituitary hormone deficiencies after a delay of 210
years.

These present as pituitary space-occupying masses or cause
hypopituitarism, and are usually diagnosed by magnetic
resonance imaging (MRI). Other features of the primary
disease, or occasionally biopsy, may assist in diagnosis:
craniopharynigomas and Rathkes cleft tumors
autoimmune hypophysitislymphocytic or granulomatous inflammation presenting as a pituitary mass and/
or hypopituitarism
systemic inflammatory disorders frequently involve
the pituitary and/or hypothalamus, causing hypopituitarism (sarcoidosis, vasculitis, Langerhans cell
histiocytosis)
tuberculosis, syphilis, fungal sinus disease or meningitis.

Diabetes insipidus is characterized by production of dilute
urine in excess of 3 L/day and inability to appropriately
concentrate the urine in response to dehydration. DI arises
through one of two mechanisms:
1 deficiency of ADH secretioncentral DI
2 deficiency of ADH action at the renal tubule (ADHreceptor or aquaporin defect)nephrogenic DI.
An important differential diagnosis is psychogenic polydipsia, in
which excessive water intake drives appropriate excretion of
a free water load.
Patients with DI are usually well and maintain normal
plasma osmolality and electrolytes, so long as they have a
normal thirst mechanism and can maintain sufficient water
intake to keep up with their urinary losses. Dehydration,

hyperosmolality and hypernatremia quickly develop if intake
of water is limited. This is the basis of the diagnostic use of a
water deprivation test, in which serum and urine sodium and
osmolality are measured while all fluid intake is withheld.
Treatment
Central DI is usually treated using a synthetic ADH
analogue, desmopressin. Desmopressin is administered
by intra-nasal or oral routes, twice daily.
Nephrogenic DI does not respond to desmopressin
treatment; partial control may be achieved using agents
that affect renal water handling (e.g. thiazides, nonsteroidal anti-inflammatory drugs [NSAIDs]).
Excessive desmopressin treatment can result in
hyponatremia.
THYROID DISORDERS
Physiology and assessment of thyroid
function
The thyroid hormones, thyroxine (T4) and liothyronine
(T3), are formed from iodination of the amino acid tyrosine. The thyroid gland extracts iodine from the circulation
through the sodiumiodide symporter. TSH, secreted by
the anterior pituitary, stimulates the formation, storage and
secretion of thyroid hormones, acting through a G-proteincoupled receptor.
The hypothalamicpituitarythyroid axis is a classic
negative-feedback endocrine system which maintains constant concentration of circulating thyroid hormones. The
relationship between TSH and thyroid hormone levels is
loglinear, such that decreases in thyroid hormone secretion
produce a logarithmic increase in serum TSH concentration, which is the hallmark of primary hypothyroidism.
T4 and T3 circulate in association with plasma binding
proteins (thyroxine-binding protein, transthyretin and albumin). Less than 0.05% of T4 and 0.5% of T3 is free from
protein binding and biologically active. The serum halflife of T4 is approximately 7 days, and of T3 approximately
1 day. Most (80%) of the circulating T3 is formed in the
plasma by peripheral conversion of T4 under the action of

deiodinase enzymes. Further T4 T3 conversion occurs
within target cells.
Thyroid hormones act by binding to nuclear thyroidhormone receptors. These complexes bind to specific DNA
sequences as heterodimers with retinoic acid X receptors
(RXRs), and in this form they inhibit or stimulate gene expression. Thyroid hormones are required for many physiological
processes in the body, including skeletal growth, regulation of
metabolism, organ maturation and augmentation of sympathetic nervous system responses in the cardiovascular system.
Thyroid function is traditionally tested by a measurement of circulating levels of T4, T3 and TSH. Assays for
free thyroid hormones (fT4 and fT3) have replaced the older
measurement of total circulating thyroid hormone levels. A
matrix for interpretation of thyroid hormone levels is shown
in Table 11-3. The logical approach to the evaluation of thyroid function is first to determine whether TSH is suppressed,
normal or elevated.
A normal TSH level effectively excludes a primary
abnormality of the thyroid gland (so long as pituitary
function can be assumed to be intact).
The finding of an abnormal TSH level should be followed by measurement of fT4 and fT3 concentrations to
confirm the diagnosis of hyperthyroidism (when TSH is
suppressed) or hypothyroidism (when TSH is elevated).
It is then appropriate to undertake tests to determine the
etiology of the thyroid dysfunction.
In the presence of significant systemic (non-thyroidal) illness, secondary alterations in thyroid hormone levels may
occur. This is known as sick euthyroid syndrome. The
characteristic pattern is of a low T3, due to inhibition of
deiodinase enzymes. Plasma T4 and TSH vary depending
upon the phase of the illness. Specific correction of the thyroid hormone abnormality is usually not required.
Thyroid imaging
Ultrasound
Most useful for assessing thyroid size and evaluating
nodules
No radiation exposure, can be used repeatedly for
follow-up
Table 11-3 Changes in thyroid hormone levels with disorders
THYROIDSTIMULATING
HORMONE (TSH)
DISORDER
fT4
fT3
Primary hyperthyroid
Primary hypothyroid
Hypopituitarism
Normal or
Secondary hyperthyroid (TSHoma)
Normal or
Thyroid hormone resistance
Normal or
275
Useful for differentiating solid and cystic nodules, and

guiding fine-needle aspiration
Does not assess function or exclude malignancy
Nuclear isotope scanning

Most useful for evaluating the cause of hyperthyroidism
Demonstrates function (e.g. hot versus cold nodules;
Figure 11-5)
Not accurate for assessing size of the thyroid or individual nodules
Computed tomography (CT) scanning

Most useful for demonstrating the anatomy of a large
goiter (e.g. retrosternal extension)
Identifies compression of the upper airway or esophagus
by an enlarged thyroid
Localization of nodal metastases in thyroid carcinoma
The use of iodine-containing contrast medium is inadvisable due to potential effects of iodine on an abnormal
thyroid gland.
Thyroid autoimmunity is the most common etiology of
thyroid function abnormalities.
It has a familial tendency, is more common in females,
and has an increased frequency in HLA (human leukocyte antigen) haplotypes B8 and DR3.
Patients may have antibodies to multiple thyroid proteins
(thyroid peroxidase, TSH-receptor, thyroglobulin).
Two primary syndromes are associated with similar
underlying autoimmune mechanisms:
Graves disease with hyperthyroidism
Hashimotos thyroiditis with euthyroidism or
hypothyroidism.
An individual patient may transition from one clinical
picture to another over time. The phenotypes differ
A
according to the predominant antibody type (e.g. stimulatory versus receptor-blocking versus destructive
immune responses).
Thyroid autoimmunity may be associated with other
organ-specific autoimmune syndromes (vitiligo, type1
diabetes, Addisons disease, pernicious anemia, myasthenia gravis, premature ovarian failure, autoimmune
hypophysitis).
CLINICAL PEARL
Although the presence of thyroid autoantibodies is a
hallmark of autoimmune thyroid disease, their pathogenic activity is still unclear, in that such antibodies may
persist for years without the patient developing a clinical disorder.
Hyperthyroidism
Clinical clues
Typical presentations
Heat intolerance, excessive sweating
Weight loss
Dyspnea (even without congestive cardiac failure)
Increase in frequency of bowel movements/diarrhea
Weak muscles
Emotional lability and nervousness/difficulty sleeping
Tachycardia and/or atrial fibrillation (especially in the
elderly)
Decreased menstrual flow
Atypical presentations
Unexplained atrial arrhythmias in the middle-aged
Severe proximal myopathy with normal creatine phosphokinase levels
Unexplained deterioration in cognition and functional
capacity in the elderly
Hypokalemic periodic paralysis (especially in Asian males)
Gynecomastia
Osteoporosis
Chronic diarrhea
Laboratory abnormalities
Low TSH is usually the first laboratory abnormality in
primary hyperthyroidism.
In overt hyperthyroidism there will be elevated fT4 or
fT3 levels (usually both).
Figure 11-5 Thyroid isotope uptake scans. (A) Normal
uptake in the thyroid lobes (seen as white on a black
background). (B) Irregular uptake (seen as black on
a white background) due to non-functioning cold
nodules (arrowed)
From: (A) Drakaki A, Habib M and Sweeney AT. Hypokalemic periodic
paralysis due to Graves disease. Am J Med 2009;122(12):e5e6.
(B) Katz D, Math K and Groskin S. Radiology secrets. Philadelphia:
Elsevier, 1998.
276
CLINICAL PEARL
In population screening studies, 25% of people have
low TSH levels with normal fT4 and fT3 (termed subclinical hyperthyroidism). This requires follow-up, but not
necessarily treatment. There is an increased long-term
risk of atrial brillation and osteoporotic fracture. About
half will normalize their TSH levels without treatment,
but 5% per year progress to overt hyperthyroidism.
Causes of hyperthyroidism
Autonomous hormone production
hot nodule (follicular adenoma)
toxic multinodular goiter
struma ovarii (rare)
Excess stimulation of thyroid
immunoglobulins in Graves disease (the most
common cause)
rarely, TSH-secreting pituitary adenomas
Excess release of thyroid hormone
painful subacute thyroiditis
silent lymphocytic thyroiditis
Exogenous thyroid hormone ingestion
Causes may be distinguished by the pattern of radionucleotide uptake (Box 11-1).
Iodine load
Iodine load may cause hyperthyroidism in the setting
of pre-existing autonomous functioning thyroid tissue
(hot nodule, toxic multinodular goiter). Iodine loading
does not cause hyperthyroidism in most people because
of suppression of iodine uptake by the thyroid (Wolff
Chaikoff effect).
Sources of iodine load:
drugsamiodarone, cough medicines
radiocontrast material
surgical exposure to povidone-iodine
dietary sources, e.g. seaweed.
In the setting of previous iodine deficiency, iodine loading causing hyperthyroidism is called the JodBasedow
phenomenon.
Graves disease
Characterized by thyroid-stimulating antibodies directed
against the TSH receptor.
The most common cause of hyperthyroidism. It is most
often seen in younger women, but can occur in both
sexes, and in the elderly.
Extra-thyroidal manifestations (pretibial myxedema, ophthalmopathy, clubbing) are immune-mediated, not thyroidhormone-related, and may be synchronous or at a different time
from the onset of hyperthyroidism.
Up to 50% of patients with hyperthyroidism due to
Graves disease may have normal thyroid size. When the
thyroid is enlarged, it is usually a diffuse goiter.
There is usually generalized increased tracer uptake on a
nuclear scan.
The condition may be characterized by spontaneous
remission and relapse.
Subacute thyroiditis
May occur after a viral illness, in the post-partum state,
or sporadically.
Involves excess release of stored thyroid hormone from
colloid.
There is a raised erythrocyte sedimentation rate (ESR),
and decreased/absent tracer uptake on a nuclear scan
(suppressed by inflammation and low TSH).
Manifests as tender enlarged thyroid, clinical thyrotoxicosis with fever, and raised ESR lasting for months.
Typically there is a phase of transient hypothyroidism on
recovery, then return to a euthyroid state.
Treatment of hyperthyroidism
CLINICAL PEARL
Effects of amiodarone on the thyroid
40% of the molecular weight of amiodarone is iodine.
Effects vary:
hyperthyroidism from the high iodine load, or from
thyroiditis
hypothyroidism from chronic thyroiditis
low plasma T3 levels because of impaired conversion of T4 to T3
nuclear thyroid scans will show no uptake of tracer
because of competition from the high iodine load.
The principles are:

block the effects of circulating thyroid hormones
inhibit synthesis of new hormone
consider thyroid ablation with radioactive iodine, or
thyroidectomy, in persistent cases.
Note that the TSH levels may remain low in the first few
months of treatment. Thyroid hormone levels should be
used to determine the efficacy of treatment.
Box 11-1
Differentiation of causes of hyperthyroidism according to pattern

of radionucleotide uptake
Reduced uptake
Thyroiditis
Exogenous thyroxine
Iodine loading
Ectopic thyroid hormone secretion
(struma ovarii)
Generalized increased uptake

Graves disease
Excess thyroid-stimulating hormone
stimulation
Focal increased uptake

Toxic multinodular goiter
Hyperfunctioning adenoma
277
Beta-blockade
The clinical manifestations of thyrotoxicosis are mainly
mediated by the sympathetic nervous system as a result of
increased adrenergic release and receptor expression. Betablockade with propranolol produces rapid improvement of
tachycardia, tremor, sweating and CNS effects.
Methimazole, carbimazole and propylthiouracil
Mechanism: decrease thyroid hormone synthesis by
decreasing the incorporation of iodide into thyroglobulin.
Propylthiouracil (PTU) also inhibits T4 to T3 conversion.
Remember that the half-life of thyroxine is 1 week, so
there will be a delay in effect until circulating hormone
is cleared.
Anti-thyroid drugs are given in high doses until a euthyroid state is achieved, and then in smaller maintenance
doses.
Side-effects: fever, rash, arthralgia, myalgia, leukopenia and agranulocytosis, hepatitis, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis
(PTU only).
The hyperthyroidism of Graves disease enters spontaneous
remission within a year in about 50% of patients. A trial of
withdrawal of treatment may then be attempted. If relapse
occurs, the patient can be re-treated, prior to definitive therapy with surgery or radioactive iodine.
Radioactive iodine (131I)
Administered as a single oral dose, after initial control of
hyperthyroidism with drug therapy. Cannot be used in
pregnancy or lactation.
Mechanism: beta-particle emitter preferentially taken
up by the thyroid, with minimal radiation effect on
other organs. Onset of cell death and thyroid hypofunction is within 68 weeks.
Side-effects: occasional acute thyrotoxicosis (710
days after treatment), late hypothyroidism (>50% at
10 years).
A large goiter or active Graves ophthalmopathy are relative contraindications.
Treatment with 131I is usually used after first relapse in Graves disease, but as primary treatment in toxic multinodular goiter or single
toxic adenoma.
Thyroidectomy
Best treatment for patients with a large goiter, ophthalmopathy or patients unsuitable for radioactive iodine.
Choice of total or partial thyroidectomy, depending on
the individual case.
Risks: hypothyroidism, hypoparathyroidism, recurrent
laryngeal nerve injury.
Hypothyroidism
Clinical clues
Weight gain
Constipation
278
Cold intolerance
Lethargy
Depression
Dementia
Hoarse voice
Menorrhagia
Dry skin, hair loss
Bradycardia
In childrengrowth retardation, delayed bone maturation, learning difficulty
Laboratory testing
TSH is always raised in primary hypothyroidism and is the
first laboratory abnormality.
Normal TSH excludes primary hypothyroidism (if
pituitary function is intact).
Elevated TSH in the presence of normal T4 and T3 levels (so-called subclinical hypothyroidism) is a common
finding (37% in population screening studies, women
> men).
Mildly elevated TSH levels often revert to normal without
treatment, and iodine supplementation may be indicated
in areas of deficiency. Commence thyroxine replacement
if TSH is >10 mU/L, patient is symptomatic, an antithyroid antibody test is strongly positive, or there is marked
hyperlipidemia.
Because of the established connection between elevated maternal
TSH during pregnancy and reduced IQ in offspring, any elevation
of TSH in a woman who is pregnant or planning pregnancy is justification for thyroxine supplementation.
Causes of hypothyroidism
1. Primary
Chronic autoimmune thyroiditis (Hashimotos
thyroiditis)
Idiopathic atrophy
Ablation (131I, prior neck irradiation, or surgery)
Thyroid agenesis
Drugs (lithium, amiodarone)
Iodine deficiency
Inborn errors of metabolism
2. Secondary
Pituitary or hypothalamic disease, with TSH deficiency
Hashimotos thyroiditis
A chronic inflammatory disease of the thyroid, often
associated with goiter.
Common in middle-aged women.
Associated with lymphocytic infiltration of the gland.
Usually occurs in association with positive antithyroglobulin antibodies, antithyroid peroxidase (anti-TPO)
antibodies (positive in 9598%), antimicrosomal antibodies (85%).

Has a recognized association with other autoimmune
diseases (pernicious anemia, vitiligo, celiac disease,
Addisons disease, type 1 diabetes).
Usually diagnosed by laboratory screening or because of
goiter or hypothyroid symptoms.
The patient may be diagnosed while still euthyroid,
but regular follow-up shows that frank hypothyroidism
develops in 80% of patients.
It is treated with thyroxine when associated with hypothyroidism. If a symptomatic goiter occurs, this may be
treated surgically.
6 Iodine deficiency (may be massive)

7 Goitrogens (substances which interfere with thyroidal
uptake of iodine and hormone synthesis), e.g. iodine,
lithium
8 Inborn errors of thyroid hormone synthesis
CLINICAL PEARL
The size of the thyroid gland does not indicate thyroid
function. Most people with thyroid enlargement have
normal thyroid function. Always assess thyroid structure and thyroid function as separate variables.
Management of goiter
CLINICAL PEARL
Subclinical hypothyroidism:
raised serum TSH but normal T4 level, seen in 38%
of the population
increases with age (20% of over-65-year-olds), and
in women (3:1)
among cases, 5% per year will go on to frank hypothyroidism
treat if symptomatic, pregnant, TSH >10 mU/L or
positive for anti-thyroid antibodies.
Thyroxine treatment
Hypothyroid patients usually require treatment for life.
The full replacement dose is typically 1.62 microg/kg
(100200 microg total) per day.
Commence with full dose unless the patient is elderly
or there is a history of cardiac disease (then commence
with half dose).
Administration of T3 is not needed; there is sufficient
conversion from exogenous T4.
Thyroxine has a half-life of 7 days, so wait 46 weeks
before reassessing thyroid function.
Titrate the dosage to achieve a TSH level in the normal
range.
Once-daily dosing is usual, but less frequent (e.g.
weekly) is also possible.
Failure to respond suggests poor adherence or, rarely,
malabsorption (celiac disease, co-ingestion of iron or
caffeine).
The structure of the thyroid is best assessed by ultrasound.

Nodules of >10mm diameter should be evaluated by fineneedle aspiration (FNA) cytology to exclude thyroid carcinoma. If there is clinical evidence of retrosternal extension
or thoracic inlet obstruction, this is best evaluated by CT
scanning.
Thyroidectomy is the best treatment in most cases where
thyroid enlargement is causing compressive or cosmetic
problems. TSH suppression with thyroxine has minimal
utility. Radioactive iodine may be used when surgery is
contraindicated, but size reduction is modest and large doses
may be required.
Thyroid nodules
Nodule formation is seen in up to 20% of all thyroid ultrasounds, increasing with age. Most are asymptomatic.
Nodules are not a single disease but occur as a result
of different processes including adenomas, carcinomas,
inflammation/scarring/regeneration, cyst formation and
focal accumulation of colloid.
Most nodules are hypofunctioning (cold on isotope
scanning), although thyroid function tests should be
performed to identify the minority (10%) that have
autonomous hyperfunction, causing thyrotoxicosis.
The main clinical issue is identification of the small proportion (<5%) of nodules that are thyroid malignancies.
A

Causes of diffuse goiter
1
2
3
4
5
Idiopathic
Puberty
Pregnancy
Graves disease
Thyroiditis
a Hashimotos thyroiditis
b Subacute thyroiditis (tender)
Figure 11-6 (A) Diffuse goiter; (B) multinodular goiter

From: (A) Shah JP, Patel S and Singh B. Jatin Shahs Head and neck
surgery and oncology, 4th ed. Philadelphia: Mosby, 2012. (B) Quick
CRG et al. Essential surgery: problems, diagnosis and management,
5th ed. Elsevier, 2014.
279
Ultrasound is the most useful imaging modality for nodules.

It has high sensitivity, accuracy in measurement, differentiates solid from cystic lesions, and may be used to guide FNA
biopsy. Ultrasound cannot reliably differentiate a benign thyroid nodule from a cancer. However, some ultrasonic features
of a nodule are associated with an increased risk of malignancy:
hypoechoic
microcalcifications
central vascularity
irregular margins
incomplete halo
documented enlargement on repeat scanning.
Risk of malignancy increases with increasing nodule size,
and all nodules >10mm diameter should be considered for
FNA cytology evaluation.
If FNA cytology shows atypia or suggests malignancy,
the patient should have a hemi- or total thyroidectomy.
Nodules with normal cytology can be observed with
repeat ultrasonography at 612 months, and if no further growth occurs the follow-up can be ceased.
CLINICAL PEARL
Investigation of a thyroid nodule should include:
thyroid function tests to detect hyperfunction
ultrasound to assess nodule size and structure
cytology assessment by ne-needle aspiration of
lesions >10mm diameter.
Thyroid cancer
Usually presents as a painless thyroid nodule, sometimes
associated with cervical lymphadenopathy, or as an incidental finding on ultrasound.
Highest incidence is ages 3060 years. The female to
male ratio is 3:1.
The most common forms are papillary (75%) and follicular (15%). Both are well differentiated, slow-growing
and take up 131I, which is therefore a valuable adjunctive
therapy to surgery. Hence these forms of thyroid cancer
have relatively good prognosis.
Less common is medullary cell cancer (35%), which
secretes calcitonin and may be familial. Anaplastic cancer (25%) and thyroid lymphoma (1%) are highly
malignant and radioiodine-resistant.
There is a causal association with prior external beam
radiotherapy to the neck (e.g. for childhood lymphoma).
The treatment of thyroid carcinoma is total thyroidectomy. More extensive neck dissection is performed for
nodal metastases.
In papillary or follicular carcinoma, adjuvant treatment
with 131I (in doses about 10-fold higher than for thyrotoxicosis) is effective, and serum thyroglobulin is a useful tumor marker.
123I whole-body scanning and neck ultrasound can be
used in follow-up to detect residual/recurrent disease
280
and to indicate potential for further treatment with

radioactive iodine.
Prognosis is relatively good in well-differentiated tumors,
even in the presence of nodal or distant metastases. Positron
emission tomography (PET) scanning (using 18F fludeoxyglucose) may detect poorly differentiated disease that is no
longer iodine-avid, and guide further surgical therapy.

Thyroid disease has a high prevalence in young women, so
it is relatively common in pregnancy. As maternal thyroid
disease can affect the unborn child, it requires prompt diagnosis and treatment. Evaluation of thyroid function during
pregnancy is made more complex by changes in maternal
physiology, particularly in regard to iodine handling and
thyroid hormone production.
Hypothyroidism in pregnancy
Thyroid hormone synthesis increases by 2050%
during normal gestation, with the increased hormone
requirement partly explained by increased production
of binding protein.
Therefore, borderline hypothyroidism may decompensate during pregnancy.
Maternal hypothyroidism impairs fetal neurological
development, and therefore women should be treated
with thyroxine to maintain TSH within pregnancyspecific reference ranges.
Thyroxine replacement doses usually increase with
advancing gestation, reflecting the known physiological
changes.
CLINICAL PEARL
Women on thyroxine replacement should increase
their dose by about 25% as soon as their pregnancy is
conrmed.
Hyperthyroidism in pregnancy
Placental human chorionic gonadotropin (hCG) has
homology to TSH and weak stimulatory activity at the
TSH receptor. This leads to a decrease in serum TSH
in the 1st trimester, which may occasionally be quite
pronounced, and is associated with elevations in T4 and
T3. This phenomenon, known as gestational hyperthyroidism, is a physiological process that does not require
treatment and resolves after the 1st trimester. However,
it may be difficult to distinguish from true primary
hyperthyroidism.
Primary hyperthyroidism in pregnancy has been associated with increased risk of maternal complications,
including miscarriage and pre-term birth. Graves disease, in particular, may affect the fetus due to transplacental passage of thyroid-stimulating antibodies that can
stimulate the fetal thyroid.
Anti-thyroid medications can be used in pregnancy, but
radioactive iodine is contraindicated.
DISORDERS OF BONE AND

MINERAL METABOLISM
Mineral homeostasis
The majority of calcium, phosphorus and magnesium ions
in the body are located in bone, where they are essential
for bone mineralization and strength. Powerful hormonal
mechanisms exist to control the interchange of ions between
the osseous and non-osseous compartments and to maintain
extracellular concentrations within a narrow range where
they are vital for cellular function throughout the body.
This involves a complex interplay between gut absorption,
renal excretion and bone sequestration (Figure 11-7), controlled by hormones such as parathyroid hormone (PTH),
calcitriol (activated vitamin D), calcitonin, PTH-related
peptide (PTHrP) and fibroblast growth factor 23 (FGF23).
Sex steroids, thyroid hormones, glucocorticoids, GH
and insulin may also affect bone and mineral homeostasis
CLINICAL PEARLS
Total calcium can be corrected for serum albumin
using the formula: corrected Ca (mmol/L) = measured Ca + 0.25 (40 albumin)/10.
In states of profound hypo- or hyperalbuminemia,
the correction is less accurate.
pH also affects Ca bindingacidosis reduces it,
alkalosis enhances it. Ionized Ca is a more useful
measure in such clinical situations.
Clinical features
Hypercalcemia
Table 11-5 (overleaf) gives the symptoms and signs of

hypercalcemia.
Background
45% of calcium is protein-bound, predominantly to
albumin; 45% is free/ionized; 10% is bound to small
anions (phosphate, citrate).
Solar UVB
Mild hypercalcemia (up to 3.0 mmol/L) may be

asymptomatic, or have nonspecific manifestations such
as fatigue and constipation.
Moderate hypercalcemia (3.03.5 mmol/L) is usually
symptomatic if acute, but may be unrecognized if developing insidiously and chronically.
Severe hypercalcemia (>3.5 mmol/L) is an emergency and may cause cardiac arrhythmia or severe
obtundation/coma.
7-dehydrocholesterol
Diagnosis and evaluation

Figure 11-8 (overleaf) gives a diagnostic algorithm for common causes of hypercalcemia.
GASTROINTESTINAL
TRACT
EPIDERMIS
Pre-vitamin D3
Other local effects

in target tissues
Dietary Ca
and PO4
absorption
Vitamin D3
Dietary
vitamin D
Calcitroic acid
25(OH)ase
25-hydroxyvitamin D3
NET EFFECT
PTH increases serum Ca
and decreases serum PO4
1,25(OH)2-vitD increases
serum Ca and PO4
in activation
24(OH)ase
D3-DBP
LIVER
TARGET TISSUES
TARGET TISSUES
1,25-dihydroxyvitamin D3
1(OH)ase
KIDNEY
urinary PO4
and Ca
excretion
1(OH)ase activity
urinary PO4 excretion
urinary Ca excretion
serum Ca
dietary Ca intake
serum 1,25(OH)2-vitD
Inhibits PTH
secretion
Parathyroid hormone
bone mineralization
osteoblast/osteoclast activity and
bone resorption (at high doses)
Regulates bone protein expression
BONE
osteoblast/osteoclast activity and
bone resorption (chronic high doses)
release of Ca & PO4
Low intermittent doses increase bone
formation
Chronic low Mg levels

Via Ca sensing
receptor
PARATHYROID GLANDS
Figure 11-7 Principal regulation of calcium (Ca) and phospate (PO4) homeostasis. The hormones 1,25(OH)2vitamin D and parathyroid hormone (PTH) have effects on bone, kidney and the gastrointestinal tract which
determine serum calcium and phosphate levels. 1,25(OH)2-vitamin D is the activated form of the vitamin
281
Table 11-4 Hormones involved in bone and mineral metabolism
HORMONE
FEATURES
Parathyroid hormone (PTH)
Produced by the parathyroid glands

Increases bone resorption, decreases urinary calcium (Ca) excretion, increases phospate
(PO4) excretion, stimulates activation of vitamin D
Net effect is to increase serum Ca and decrease PO4
Calcitriol
(1,25(OH)2-vitamin D)
Produced in the kidney by 1-alpha-hydroxylation of 25-hydroxyvitamin D

Increases gut absorption, decreases renal excretion of Ca and PO4
Inhibits PTH secretion
Net effect is to increase serum Ca and PO4
Calcitonin
Produced by the thyroid parafollicular C-cells in response to high Ca levels

Acts on osteoclasts to inhibit bone resorption
Promotes renal PO4 and Ca excretion
Net effect is lowering of serum calcium
Fibroblast growth factor

(FGF) 23
Growth factor secreted by osteocytes promotes renal PO4 wasting

Stimulated by hyperphosphatemia and calcitriol
PTH-related peptide (PTHrP)
Acts on shared PTH/PTHrP receptor; similar effects to PTH

Physiological secretion by placenta and local production in breast
Pathophysiological secretion by solid tumors (paraneoplastic)
Table 11-5 Symptoms and signs of hypercalcemia
GASTROINTESTINAL
NEUROLOGICAL/
NEUROMUSCULAR
RENAL
CARDIAC
Acute
Anorexia
Nausea, vomiting
Polyuria
Polydipsia
Dehydration
Confusion
Depression
Obtundation
Psychosis
Bradycardia
Heart block
Chronic
Pancreatitis
Dyspepsia
Constipation
Kidney stones
Nephrocalcinosis
Myopathy
Hypertension
Hypercalcemia
(normal renal function)
PTH
PO 4
PTHrP-mediated
Search for malignant source
1,250HD-mediated
Measure 1,250HD
Search for source
e.g. ACE level, chest
X-ray, microbiology,
autoantibodies
Suppressed
PO4
Normal or high
Urinary calcium:creatinine clearance ratio
High (>0.01)
Bone lysis/turnover
EPG/IEPG
Bone scan
TFT
ALP
Primary
hyperparathyroidism
Parathyroid
sestamibi/ultrasound
BMD
Review criteria for surgery
(exclude lithium use)
Low (<0.01)
Familial hypocalciuric
hypercalcemia
Family history
Consider gene testing
Figure 11-8 Common causes of hypercalcemia; a diagnostic algorithm. 1,25OHD, 1,25-dihydroxyvitamin D;

ACE, angiotensin-converting enzyme; ALP, alkaline phosphatase; BMD, bone mineral density; EPG/IEPG,
electrophoretogram/immunoelectrophoretogram; PTH, parathyroid hormone; PTHrP, PTH-related peptide;
TFT, thyroid function test
282
CLINICAL PEARL
90% of hypercalcemia is caused by primary hyperparathyroidism or malignancy.
Hyperparathyroidism is the common cause in the
community and usually presents with mild hypercalcemia.
Cancer is commonly the cause in hospital, and
hypercalcemia may be severe.
It is useful to distinguish PTH-dependent from

PTH-independent causes of hypercalcemia as a first step
(Box 11-2).
Primary hyperparathyroidism results from overproduction of PTH from one or more parathyroid glands,
resulting in release of calcium and phosphate from bone,
and urinary phosphate-wasting. If untreated, osteoporosis is a sequela.
Urine calcium excretion is high, predisposing
to nephrolithiasis. This distinguishes the condition from familial hypocalciuric hypercalcemiaa
benign hereditary condition not requiring treatment.
Production of PTHrP from a tumor may mimic hyperparathyroidism. Manifestations are often more acute
and severe, and PTH levels are suppressed.
The PTH level will also be suppressed where hypercalcemia is the result of excess vitamin D activity (from
overproduction of the vitamin-D-activating enzyme
1-alpha-hydroxylase) or direct calcium release from bone.
2 Bisphosphonates, if response to saline diuresis is

inadequate, to inhibit osteoclast bone resorption
e.g. pamidronate 6090mg IV. Onset of effect within
46 hours, full effect after 24 days, lasts 24 weeks.
3 Corticosteroids, to decrease gastrointestinal calcium
absorption and reduce 1-alpha-hydroxylase activity.
Used in high doses for granulomatous conditions,
malignancy, vitamin D intoxication.
4 Calcitonintransient response only.
5 Dialysis if acute, severe, life-threatening.
Primary hyperparathyroidism
1 Indications for surgery:
a moderate/severe (>0.25 mmol/L above upper
limit normal) or symptomatic hypercalcemia
b marked hypercalciuria (>10 mmol/day), nephrolithiasis, renal impairment
c osteoporosisfracture, bone mineral density
T-score <2.5, age <50 years.
2 Indications for imaging before surgerydistinguishing solitary adenoma from polyglandular hyperplasia, which may assist the surgical approach. Imaging
techniques may include ultrasound, dual-phase 99m
technetium/sestamibi nuclear scans.
3 Indications for medical therapy with cinacalcet (modulator of calcium-sensing receptor)severe hypercalcemia, unfit for surgery. Safety for use in children has
not been established with cinacalcet.
Management
Hypocalcemia
Acute symptomatic hypercalcemia

Acute symptomatic hypercalcemia requires urgent treatment:
1 Volume expansion and diuresisIV normal saline
(46 L), loop diuretics (furosemide 40 mg) if
hypervolemic.
Clinical features
The clinical features of hypocalcemia are listed in Box 11-3
(overleaf).
Box 11-2
Causes of hypercalcemia
PTH-dependent hypercalcemia
Primary hyperparathyroidismparathyroid adenoma
(81%), hyperplasia (15%), carcinoma (4%), multiple
endocrine neoplasia (MEN) I and IIa (<1%)
Tertiary hyperparathyroidismautonomous PTH
secretion in chronic kidney disease
Familial hypocalciuric hypercalcemiainactivating
mutation in calcium-sensing receptor
Lithium-associated hypercalcemia
PTH-independent hypercalcemia
Hypercalcemia of malignancy:
paraneoplastic secretion of PTHrP (e.g. squamous cell
carcinoma)
osteolytic bone metastases, multiple myeloma
Excess 1,25(OH)2-vitamin D:
drug ingestion
production in granulomatous tissue, e.g. sarcoid,
tuberculosis, granulomatosis with polyangiitis,
lymphoma
Drugsvitamin A intoxication, milk-alkali syndrome,
thiazide diuretics, theophylline
Otherthyrotoxicosis, adrenal insufficiency, renal failure,
prolonged immobility (especially with Pagets disease)
PTH, parathyroid hormone; PTHrP, PTH-related peptide.
283
Osteoporosis
Box 11-3
Clinical features of hypocalcemia

Acute
Delirium, anxiety,
depression
Tetany, muscle cramps,
carpal spasm
Hyper-reexia,
paresthesiae
Laryngospasm
Chronic
Lethargy, seizures, basal
ganglia calcication,
psychosis
Prolonged QT interval
on electrocardiogram
Dry skin, abnormal
dentition, cataracts
Diagnosis and evaluation

The most common causes of hypocalcemia are renal failure,
vitamin D deficiency, hypoparathyroidism (post-surgical,
less commonly immune), hypomagnesemia and pancreatitis. PTH, creatinine, phosphate and magnesium levels assist
diagnosis. A mild decrease in total calcium is often spurious;
in such cases, ionized calcium is normal.
Figure 11-9 provides a diagnostic algorithm for common
causes.
Features of osteoporosis include decreased bone mass and

microarchitecture, leading to increased fragility and fracture
risk.
Primary osteoporosis is related to the aging process and
the loss of estrogen-related bone protection after menopause.
A number of medical conditions and drugs can contribute
to low bone mass (secondary osteoporosis). Risk factors are
listed in Box 11-4.
Evaluation of osteoporosis
Historyheight loss, kyphosis, back pain, fractures
after fall from standing height, presence of risk factors.
Exclusion of medical causes of osteoporosis.
Ca, PO4, PTH, 25(OH)-vitamin D, TSH, electrophoretogram/immunoelectrophoretogram (EPG/IEPG),
celiac serology, 24-hour urine calcium.
X-ray of thoracolumbar spineloss of vertebral height.
Box 11-4
Risk factors for osteoporosis

Major
Age
Previous fragility
fracture
Family history of
osteoporosis
Menopause <45 years /
hypogonadism
Systemic
glucocorticoids
>3 months
Prolonged
immobilization
Medical disease
malabsorption,
hyperparathyroidism,
Cushings, chronic renal
failure
Management
Acute symptomatic hypocalcemia requires immediate
treatment:
IV calcium gluconate 12 ampoules (1g in 10mL) over
10 minutes, followed by continuous infusion of calcium
gluconate at a rate of 4g per 24 hours if necessary.
Aim to raise calcium to low normal range.
Cardiac monitoring is recommended. Infusion into a
large central vein is preferred.
It is important to correct coexisting magnesium deficiency, since this will inhibit the therapeutic response to
calcium.
Chronic/persistent hypocalcemia is treated with vitamin D analogues (e.g. calcitriol) and oral calcium to maintain calcium in low normal range, avoiding hypercalciuria
and soft-tissue calcium phospate (CaPO4) precipitation.
Minor
Smoking, excessive
caffeine or alcohol
intake
Low dietary calcium
Low bodyweight
Chronic anticonvulsant
therapy
Chronic heparin therapy
Medical disease
rheumatoid
arthritis, previous
hyperthyroidism
Hypocalcemia
PTH measurement
Low
Normal creatinine
Normal/high PO4
Hypoparathyroidism
Hypomagnesemia
Autoimmune
Surgical removal/damage
Irradiation, infiltration of glands
Familial
High
High/normal PO4
Pseudohypoparathyroidism
Renal disease
Rhabdomyolysis
Tumor lysis syndrome
Low/normal PO4
Vitamin D deficiency (in adequate

diet/sun or malabsorption)
Bisphosphonate use
Genetic mutations in vitamin D
signaling
Figure 11-9 Common causes of hypocalcemia; a diagnostic algorithm. PTH, parathyroid hormone
284
The diagnosis of osteoporosis is made by assessment of bone

mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) scanning at lumbar and femoral sites. Bone
density is a clinically useful tool for estimating fracture risk.
Osteoporosis definition: BMD T-score 2.5 or below
Osteopenia definition: BMD T-score between 1 and
2.5
CLINICAL PEARL
Bone mineral density test results:
T-score = the number of standard deviations below
the young adult peak
Z-score = the number of standard deviations below
the age-matched mean.
Treatment
All patients should have adequate calcium intake and
vitamin D repletion.
Alter modifiable risk factorsexercise, diet, smoking,
medication use.
Bisphosphonate agents have been the mainstay of osteoporosis therapy. They inhibit bone resorption and have
proven efficacy in fracture prevention in both vertebral
and non-vertebral sites.
Newer agents targeting different biological pathways
(including bone formation) are also now available.
Their optimum usage remains to be fully determined.
Table11-6 describes possible therapies.
Decisions to initiate therapy should be based on estimation of fracture risk, balanced with the cost/side-effect
profile of the treating agent. To assist in fracture-risk assessment, computerized algorithms are available, such as the
FRAX tool, providing a 10-year probability of hip or major
osteoporotic fracture based on patient clinical data. Caution
needs to be exercised, however, as estimates are imperfect
and may over- or underestimate risk.
CLINICAL PEARL
Bisphosphonates are the mainstay of osteoporosis
therapy, for their antiresorptive effect and proven fracture reduction in both vertebral and non-vertebral sites.
Administration can be by weekly or monthly oral dosing, or annual intravenous infusion.

Osteomalacia is a clinical syndrome caused by impaired
vitamin D activity due to deficiency or impaired action on
its receptor. Impaired mineralization of bone matrix is a key
feature. In children, the syndrome is referred to as rickets.
Osteomalacia affects only the bone, whereas rickets involves
the growth plate and cartilage, leading to characteristic
deformities.
Clinical features
Osteomalacia may be silent, or may present with bone
pain and fractures. Proximal myopathy is commonly
associated.
Rickets results in bowing of the long bones and widening of the cartilage of the growth plate and long bones.
This is confirmed on X-ray, which demonstrates a
pathognomic rosary appearance at the costochondral
rib junctions and wide transverse lucencies in bone
(pubic rami, medial proximal femur, scapulae), at rightangles to the bone cortex, known as Loosers zones.
Etiology
Causes include vitamin D deficiency, metabolic defects in
vitamin D signaling, or direct impairment of mineralization
due to inadequate supply of calcium/phosphate. Underlying
causes are given in Table 11-7 (overleaf).
Vitamin D deciency
Vitamin D is predominantly obtained from exposure to
sunlight, and to a lesser extent from natural or fortified
foods. Vitamin D deficiency is common in people with low
ultraviolet (UV) exposureinstitutionalized, elderly, veiled
or dark-skinned populations, and those living in temperate
climates during winter. Other risk factors for deficiency
include fat malabsorption and obesity.
Diagnosis
Vitamin D status is best assessed by measurement of
25-hydroxyvitamin D, 25(OH)D. The recommended
normal ranges for vitamin D are still under debate, but a
conservative approach defines deficiency as <25 nmol/L, insufficiency as 2550 nmol/L and sufficiency as >50 nmol/L. Levels
>75 nmol/L may be optimum.
Significant vitamin D deficiency is clearly related to
hypocalcemia, hypophosphatemia, rickets, osteomalacia,
Table 11-6 Osteoporosis therapies
AGENT
ADMINISTRATION
RESORPTION
Bisphosphonates
Oral/intravenous
Strontium ranelate
Oral
Teriparatide (parathyroid
hormone)
Subcutaneous daily
Denosumab
Subcutaneous every 6 months
Raloxifene
Oral
FORMATION
9
9
285
Table 11-7 Causes of osteomalacia
MECHANISM
CAUSES
Loss of 1-alpha-hydroxylase
Loss of renal function/mass

Vitamin-D-dependent rickets type 1
Renal tubular disorders (Fanconi syndrome)
Defects in vitamin-D receptor
Hereditary resistance to vitamin D
Hypophosphatemia
Familial X-linked hypophosphatemia

Oncogenic osteomalacia (excess FGF23 production)
Renal tubular disordersurinary phosphate-wasting
Antacids (decreased gut absorption)
Other mineralization defects
Hypophosphatasia (ALP gene mutation)

Fluoride, bisphosphonates, anticonvulsants
ALP, alkaline phosphatase; FGF23, broblast growth factor 23.
osteoporosis and muscle weakness. Newer evidence suggests, however, that vitamin D may have other widespread
effects throughout the body, and vitamin D has been linked
to disorders including malignancy, insulin resistance/betacell dysfunction, autoimmune diseases/allergy and neural
function. However, evidence for a definite pathological
role as opposed to a simple association, or for a beneficial
effect of supplementation on these conditions, remains
incomplete.
Treatment
Supplementation with cholecalciferol may be achieved with
oral or intramuscular dosing. As vitamin D is a prohormone,
requiring conversion to the active hormone, toxicity is rare;
high-dose cholecalciferol therapy (e.g. 50,000 IU single
dose) is well tolerated.
Patients with impaired 1-alpha-hydroxylation at the
level of the kidney require administration of the active hormone, 1,25(OH)2-vitamin D (calcitriol).
Asymptomatic elevation of serum alkaline phosphatase

(ALP), or incidental abnormality on a radiograph, are
probably the more common presentations.
Angioid streaks may be seen in the fundi.
High-output cardiac failure is a very rare complication.
Etiology
The cause of PD is unknown. A viral etiology has been
suspected, but never proven.
A minority of cases are familial, and associated with a
mutation of the SQSTM1 gene in around half of these
families. Sporadic mutations of this gene can also occur.
The incidence and severity of the disease seem to be
gradually decreasing in Western countries.
Affected bones show evidence of areas of rapid bone
turnover with bony lysis or sclerosis, and new bone
lacking the normal lamellar pattern.
Pagets disease (PD)
CLINICAL PEARL
Pagets disease of bone is a bone remodeling disease.

Increased osteoclastic resorption of bone is followed by
increased osteoblastic activity, with the result being the laying down of abnormal, enlarged sections of bone.
In a patient with suspected Pagets disease, look for

deafness, signs of basilar invagination and spinal cord
compression, bowing of the femur and tibia, and localized tender swelling (possible bone sarcoma).
Clinical features
When symptomatic, the usual presentation of PD
is with bone pain (typically older men). This is often
described as being worse at night.
Large bones are the usual site of disease: spine, pelvis,
skull, long bones.
Patients may notice deformity of their bone.
Compression neuropathy (e.g. deafness due to 8th nerve
palsy when the skull is involved, or nerve root entrapment due to spinal disease), osteoarthritis due to abnormal joint mechanics in joints controlled by abnormally
shaped bones, or pathological fractures may also be the
presentation.
286
Diagnosis
Elevated serum ALP is the most sensitive biomarker,
and can be used to monitor both disease activity and
response to treatment.
Plain X-ray generally reveals a characteristic pattern of
focal lytic lesions, bone enlargement, and loss of normal
trabecular pattern.
Bone scintigraphy can measure the extent of bony
involvement.
Treatment
Bisphosphonates are highly effective treatment for PD.

There is evidence that intravenous zoledronate is superior to oral bisphosphonates.
Patients need to be monitored long-term to detect
evidence of relapse, and the need for re-treatment.
There is an increased risk of osteosarcoma developing
in bones affected by PD, which although rare should be
borne in mind by the treating physician.
Primary destruction of the adrenal cortex results in deficiency of cortisol, aldosterone and adrenal androgens. Secondary failure of the adrenal cortex can occur if pituitary
or hypothalamic disease results in ACTH deficiency. In
that circumstance there is deficient secretion of cortisol and
androgens (which are ACTH-dependent), but not of aldosterone (which is predominantly stimulated by the renin
angiotensin axis).
Clinical clues
ADRENAL DISORDERS
Physiology and assessment of adrenal
function
The adrenal glands are composed of two separate organs
the adrenal cortex (secretes steroids) and the adrenal medulla
(secretes catecholamines). The cortex has three functional
zones, each secreting a steroid typezona glomerulosa
(aldosterone), zona fasciculata (cortisol) and zona reticularis
(androgens).
Adrenal production of cortisol and androgens is stimulated by ACTH.
Aldosterone production is principally regulated by the
reninangiotensin system, and catecholamine secretion
by neural stimulation.
All steroid hormones are derived from cholesterol,
through multiple enzyme-stimulated steps.
Physiological cortisol production is 1012 mg daily in
humans (equivalent to 1012mg hydrocortisone, 22.5mg
prednisone), but increases by as much as 10-fold in response
to stress. Diurnal variation in the activity of the hypothalamicpituitaryadrenal (HPA; Figure 11-10) axis drive
results in circadian variation of plasma cortisol from a peak
of 300500 nmol/L on wakening to <100 nmol/L overnight. This variability means that no single cut-off level can
define a normal plasma cortisol concentration for all circumstances. Figure11-10 summarizes the stimulation and
feedback control of cortisol production.
A plasma cortisol concentration of >500nmol/L in the
morning, or during illness/stress, reasonably excludes
deficiency of HPA axis function.
A level <150nmol/L in similar circumstances is highly
suggestive of cortisol deficiency.
Intermediate levels do not allow confirmation or
exclusion.
CLINICAL PEARL
It is often necessary to perform dynamic testing to
determine the function of the hypothalamicpituitary
adrenal axis. If cortisol excess is suspected, perform a
dexamethasone suppression test. If deciency is suspected, stimulate with tetracosactrin (short Synacthen
test) or insulin-induced hypoglycemia.
Cortisol deciency
Fatigue, weight loss
Anorexia, nausea, vomiting
Hypoglycemia, hypercalcemia
Increased ACTH secretion pigmentation
Aldosterone deciency
Hypotension
Hyponatremia, hyperkalemia, acidosis
Salt craving
Androgen deciency
(Only relevant in women; men still have gonadal androgens.)
Decreased axillary and pubic hair
Loss of libido and amenorrhea
Features of associated autoimmune disease
Vitiligo, other autoimmune endocrinopathies
Stress, fever, hypoglycemia,

hypoxia, circadian rhythm
+
Central nervous system
+
Hypothalamus
CRH
+
AVP
+
Anterior pituitary
Cortisol
ACTH
+
Adrenal cortex
Figure 11-10 The hypothalamicpituitaryadrenal

axis: stimulation and feedback control of cortisol
production ACTH, adrenocorticotropic hormone;
AVP, arginine vasopressin; CRH, corticotropinreleasing hormone
287
Causes of adrenal insufficiency
1. Primary
Autoimmune adrenal disease (80% of all cases in developed countries)
Infectiontuberculosis, histoplasmosis, meningococcal
septicemia (acute)
Metastatic malignancy
Lymphoma
Bilateral adrenal hemorrhageanticoagulation, spontaneous, trauma
adrenolytic drugsmetyrapone, ketoconazole,
mitotane
bilateral adrenalectomy
Congenital adrenal hyperplasia (synthetic enzyme defect)
or adrenal hypoplasia
2. Secondary
Pituitary or hypothalamic disease
Following long-term corticosteroid therapy
Diagnosis of adrenocortical failure

1 A morning plasma cortisol level >500nmol/L excludes
adrenal insufficiency, and a level <150nmol/L is highly
predictive of cortisol deficiency. At intermediate levels
a stimulation test is required.
2 Tetracosactrin (short Synacthen) test: 0.25mg of synthetic ACTH (tetracosactrin/Synacthen) is given intramuscularly or intravenously. A normal response is a rise
in plasma cortisol by >200 nmol/L (>7 mg/dL) and a
peak of >500nmol/L (>18mg/dL). A normal response
excludes primary adrenocortical failure but does not
exclude hypothalamicpituitary disease.
3 Insulin-induced hypoglycemia stress test: induction of
hypoglycemia (<2.2 mmol/L) by administration of IV
insulin results in a plasma cortisol level of >500nmol/L
(>18mg/dL) if the HPA axis is intact.
4 The ACTH level allows discrimination of adrenal from
hypothalamicpituitary disease. Elevated ACTH levels
are seen in primary adrenal insufficiency (e.g. Addisons
disease).
5 Unique clinical features of Addisons disease:
a hyperpigmentation (Figure 11-11)
b associated autoimmune disorders such as vitiligo,
autoimmune thyroid disease, pernicious anemia,
type 1 diabetes mellitus, celiac disease and hypoparathyroidism are common.
Laboratory abnormalities
Anti-adrenal antibodies (70%)
Antithyroid antibodies (80%)
Hyponatremia, hyperkalemia, hyperchloremic acidosis,
elevated urea
Lymphocytosis and eosinophilia may be present
288
Figure 11-11 Hyperpigmentation of the gums (A) and

face (B) in Addisons disease
From: (A) Gawkrodger DJ and Ardern-Jones MR. Dermatology:
an illustrated colour text, 5th ed. Churchill Livingstone, 2012. (B)
Bolognia JL, Jorizzo JL and Schaffer JV, eds. Dermatology, 3rd ed.
Philadelphia: Elsevier, 2012.
Treatment of primary adrenocortical failure

Chronic
Glucocorticoid replacementhydrocortisone (1030
mg/day in divided doses) or prednisone (45 mg each
morning).
Conventionally used replacement doses are in
excess of physiological production and patients
should be carefully monitored for clinical features
ofover-replacement.
In children, relate the cortisol replacement dose to
body surface area and monitor growth and bone
maturation carefully.
Mineralocorticoid replacementfludrocortisone (50
100 microg daily).
Acute
For minor illnesses or surgery in a patient with established Addisons disease, triple the dose of the usual
replacement glucocorticoid.
For severe illness or major surgery, give IV hydrocortisone 100mg every 6 hours.
For adrenal crisis, give intensive saline resuscitation, and
IV hydrocortisone 100mg every 6 hours.
An Addisonian crisis may be induced acutely by:
an acute pituitary or hypothalamic event
meningococcal septicemia
bilateral adrenalectomy
stressful situations or illness in a patient with chronic
hypoadrenalism
abrupt cessation of prolonged high-dose steroid therapy.
CLINICAL PEARL
Treatment with supraphysiological doses of glucocorticoids (>5mg prednisone daily) for a period in excess
of 4 weeks is likely to cause central suppression of
the hypothalamicpituitaryadrenal axis. Subsequent
abrupt withdrawal of steroid treatment may precipitate
an adrenal crisis. After chronic glucocorticoid therapy,
gradual steroid weaning is advisable.

Cushings syndrome describes the clinical manifestations of
excess glucocorticoid activity, regardless of the cause. Cushings disease is one specific cause of the syndrome, due to an
ACTH-secreting pituitary adenoma.
ectopic ACTH secretion (small-cell carcinoma of

the lung/pancreas, carcinoid tumors)
ACTH-independent causes (20%):
adrenal adenoma
macronodular adrenal hyperplasia (usually bilateral)
adrenal carcinoma (often causes virilization)
Diagnosis
The diagnosis of Cushings syndrome and determination of
the etiology occurs in three stages:
1 Confirm the presence of excess cortisol production, or
loss of normal diurnal regulation, or demonstrate failure
of physiological suppression of cortisol secretion.
2 Determine whether the hypercortisolism is secondary
to ACTH hypersecretion or to autonomous adrenal
cortical activity.
3 Identify the source of excess ACTH or independent
cortisol overproduction.
Figure 11-12 (overleaf) provides a diagnostic algorithm.
Stage 1
Clinical clues
Cushingoid appearancethin skin (dorsum of hands,
shins), easy bruising, moon-shaped face, facial plethora,
buffalo hump, central obesity, purple striae, supraclavicular fat pads
Weight gain
Acne, hirsutism (adrenal androgen effect)
Proximal muscle wasting and weakness
Osteoporosis, pathological fractures
Hypertension, edema, hypokalemia (mineralocorticoid
effect)
Hyperglycemia (new onset or worsening of diabetes
mellitus)
Mental changes (depression, psychosis)
Symptoms/signs of pituitary tumor (in Cushings disease)
Hyperpigmentation if excess ACTH is present
CLINICAL PEARL
The classical features of Cushings syndrome take
many months to develop. In cases of rapid onset of
hypercortisolism (ectopic ACTH syndrome, exogenous
steroid administration), these may be absent and the
predominant features are metabolic effects (hyperglycemia, hypokalemia, edema, hypertension) and psychiatric manifestations.
24-hour urinary free cortisol is elevated in the vast

majority of those with Cushings syndrome. However,
it can also be elevated in intercurrent illness/stress (poor
specificity in hospitalized patients), obesity, alcoholism
and depression, and after trauma and surgery.
Elevated midnight cortisol levels (demonstrates loss of
normal diurnal regulation).
Overnight dexamethasone suppression test: 1 mg of
dexamethasone is given at midnight and an 8 a.m.
plasma cortisol level is measured the next morning.
In normal individuals there will be suppression of
plasma cortisol to <140nmol/L (<5mg/dL).
Patients with Cushings syndrome usually have
values >280nmol/L (>10mg/dL).
Failure to suppress plasma cortisol can also be found
in obesity, alcoholism, depression, those taking
the oral contraceptive pill, and those on medications that hasten the metabolism of dexamethasone,
e.g. phenytoin and barbiturates.
An alternative version of this test is to administer
0.5mg dexamethasone four times a day orally and
assess plasma cortisol after 48 hours (same cut-off
values as above apply).
Causes of cortisol excess
Stage 2
Measurement of plasma ACTH. In the presence of hypercortisolism the secretion of ACTH should normally be
suppressed by negative feedback. Presence of a plasma
ACTH level in the normal range or higher demonstrates
ACTH-dependent hypercortisolism.
Excess administration of exogenous steroids

ACTH-dependent causes (80% of endogenous hypercortisolism):
ACTH-secreting pituitary adenoma (Cushings
disease)
Stage 3
Most often requires discrimination of ectopic ACTH secretion
(usually completely autonomous) from pituitary corticotroph
adenoma (retains some degree of physiological stimulation or
inhibition).
289
Elevated cortisol, lack of suppression

Suppressed
Not suppressed
Plasma ACTH
CRH test
High-dose dexamethasone suppression
Inferior petrosal sinus sampling
Pituitary MRI
Imaging of
adrenals
Suggestive of pituitary source?
Adrenal tumor
or hyperplasia
Yes
No
Cushings disease
Search for ectopic ACTH

Ectopic ACTH
syndrome
Figure 11-12 Investigation of Cushings syndrome; a diagnostic algorithm. ACTH, adrenocorticotropic

hormone; CRH, corticotropin-releasing hormone; MRI, magnetic resonance imaging
Perform stimulation of plasma cortisol with recombinant corticotropin-releasing hormone (CRH) (a
positive test equals a >20% rise in plasma cortisol), or
demonstrate partial inhibition (plasma cortisol to <50%
baseline) with high-dose dexamethasone (single dose
8mg overnight, or 2mg four times a day for 48 hours).
Either test, if positive, suggests a pituitary cause.
Pituitary (by MRI) or adrenal (by CT) imaging may
identify the causative lesion. Many cases (50% of
Cushings disease) have negative imaging.
Selective petrosal sinus venous sampling for measurement of ACTH concentrations may localize the source.
hypokalemia. Aldosterone hypersecretion continues despite

feedback inhibition of the reninangiotensin axis. Aldosterone levels are not suppressed by physiological maneuvers
that normally inhibit mineralocorticoid synthesis such as salt
loading or administration of fludrocortisone.
Treatment options
Causes
Definitive surgical removal of the causative lesion (transsphenoidal removal of pituitary adenoma, laparascopic
removal of adrenal adenoma, resection of ectopic source
of ACTH), when possible.
Inhibition of cortisol secretion using inhibitors of
steroidogenic enzymes (metyrapone, ketoconazole,
aminoglutethamide, mitotane).
Radiotherapy to the pituitary.
Bilateral adrenalectomy (may lead to Nelsons syndromepituitary adenoma growth becoming aggressive
after removal of inhibitory feedback from excess cortisol).
Aldosterone-producing adenoma
Idiopathic adrenal hyperplasia (may be bilateral or
unilateral)
Aldosterone-producing adrenocortical carcinoma (very
rare)
Glucocorticoid-remediable aldosteronism (GRA)
Some subtypes of congenital adrenal hyperplasia (e.g.
11-beta-hydroxylase deficiency)
Primary hyperaldosteronism (Conns

syndrome)
Primary hyperaldosteronism refers to autonomous overproduction of aldosterone from the adrenal cortex. It may occur
as a consequence of an adrenal tumor, or hyperplasia.
Aldosterone hypersecretion causes sodium and water
resorption at the distal renal tubule, together with potassium
and hydrogen ion loss to maintain electrical neutrality. This
leads to hypokalemia, metabolic alkalosis and hypertension.
High urinary potassium excretion is maintained despite the
290
Clinical clues
Hypertension (often refractory to treatment)

Persistent hypokalemia (in the absence of diuretic use)
Hypervolemia (without peripheral edema)
Metabolic alkalosis
Diagnosis
In a patient with suggestive clinical and biochemical features,
the best screening test is measurement of plasma aldosterone
and plasma renin, expressed as a ratio. An elevated aldosterone:renin ratio supports the diagnosis of primary hyperaldosteronism. Hypokalemia should be corrected before this
test is undertaken. Drugs affecting the reninangiotensin
aldosterone axis may also need to be stopped (beta-blockers
suppress renin secretion, diuretics increase aldosterone,
angiotensin-converting enzyme inhibitors [ACEIs] reduce
aldosterone and elevate renin).
Screen suspected hypertensive patients by measuring
the plasma aldosterone:renin ratio.
Measure 24-hour urinary aldosterone excretion.

Demonstrate lack of normal physiological suppression
of plasma aldosterone secretion after sodium loading (IV
normal saline, 3-day oral salt loading) or fludrocortisone
administration.
In patients with confirmed primary hyperaldosteronism,
CT scanning can usually differentiate unilateral disease
(adenoma or hyperplasia) from bilateral hyperplasia.
Adrenal vein sampling may be needed to definitively
distinguish unilateral from bilateral hypersecretion, to
ensure that any lesions demonstrated on CT scanning
are functionally active.
Glucocorticoid-remediable aldosteronism (GRA) is a rare
autosomal dominant inherited condition in which a hybrid
gene results in an ACTH-responsive aldosterone synthase
enzyme. Patients with GRA have ACTH-mediated hypersecretion of aldosterone. There is usually a strong family history of hypertension and hypokalemia. Aldosterone levels
are promptly suppressed by administration of dexamethasone, which suppresses ACTH release.
Treatment
Unilateral adrenal disease (adenoma or hyperplasia) can
be cured by adrenalectomy, usually by a laparoscopic
technique.
Bilateral hyperplasia is treated with medical therapy.
Mineralocorticoid receptor (MR) antagonists are the
mainstay.
Spironolactone is effective but causes side-effects
by also blocking androgen and progesterone receptors (gynecomastia and erectile dysfunction in men,
menstrual irregularity in women).
Eplerenone is a newer MR antagonist with fewer
side-effects but greater cost.
If blood pressure is inadequately controlled by MR
antagonists alone, addition of a potassium-sparing
diuretic (amiloride, triamterene) or a dihydropyridine
calcium-channel blocker is the most effective secondline treatment.
CLINICAL PEARL
Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are relatively ineffective antihypertensive agents in primary hyperaldosteronism
because the reninangiotensin axis is already suppressed by aldosterone excess.
Conditions mimicking hyperaldosteronism

As these are genetic conditions, diagnosis usually occurs in childhood.
Syndrome of apparent mineralocorticoid excess
(SAME). Cortisol is a natural agonist for MR but
its activity is normally prevented by the presence of a
cortisol-inactivating enzyme (11-beta-hydroxysteroid
dehydrogenase). Genetic mutational inactivation of this
enzyme allows physiological levels of cortisol to cause
excessive mineralocorticoid activity in the distal renal
tubule despite low plasma aldosterone levels.
Liddles syndrome. A gene mutation results in a

hyperfunctioning variant of the renal epithelial sodium
channel (ENaC). This results in a clinical syndrome
similar to hyperaldosteronism, but the plasma aldosterone level is normal or low.
Bartter syndrome, Gitelman syndrome. Involves
mutations in genes encoding epithelial ion-transport
proteins in the thick ascending limb of the nephron.
There is marked hypokalemia and hyperaldosteronism,
but hypertension is absent.
Pheochromocytoma
Pheochromocytoma is a rare catecholamine-secreting
tumor derived from chromaffin cells of the sympathetic
nervous system.
They most commonly (90%) arise in the adrenal
medulla, but may also occur at extra-adrenal sites
including sympathetic neural ganglia in the abdomen,
thorax or neck (also termed paraganglioma when occurring at these sites).
Most pheochromocytomas are sporadic, but some
(1015%) occur in association with familial syndromes
such as multiple endocrine neoplasia type 2 (MEN-2),
neurofibromatosis, von HippelLindau syndrome, and
mutations of succinate dehydrogenase.
Most pheochromocytomas behave as benign neoplasms
and the morbidity is associated with excess catecholamine secretion. A minority (1015%) may adopt a
malignant behavior and metastasize to distant sites
(more common when associated with a familial syndrome, or primary lesion at an extra-adrenal location).
Age of onset varies from childhood to old age.
Pheochromocytoma accounts for only about 0.2% of
hypertension cases.
Clinical clues
Hypertension50% suffer from paroxysmal hypertension, 40% have sustained elevated BP, 10% may not be
hypertensive
Classic triad or episodic symptoms: headache, palpitations /tachycardia, sweating
Tremor, anxiety (feeling of impending doom)
Chest or abdominal pain
Polyuria, dehydration, postural hypotension
Dilated cardiomyopathy
Hyperglycemia (especially if episodic and unexplained
by dietary causes)
CLINICAL PEARL
In suspected cases of pheochromocytoma it is important to rst determine whether catecholamine excess
exists, before undertaking imaging studies to localize a
source of catecholamine secretion.
291
Diagnosis
Mildly elevated catecholamine levels (less than double the
upper limit of the normal range) have fairly poor specificity and are commonly seen in stress and non-adrenal illness.
Catecholamine levels more than fourfold elevated above the
normal range are highly predictive of pheochromocytoma.
Confirm catecholamine excess:
24-hour urine collection for catecholamine excretion: usually free epinephrine (adrenaline), norepinephrine (noradrenaline), and their metabolites
metanephrine and normetanephrine.
Secretion may be intermittent. In patients with paroxysmal symptoms, have the patient commence
the collection immediately after the onset of typical
symptoms. Repeated collections may be necessary.
Measurement of plasma metanephrine and normetanephrine have high sensitivity and specificity, but
require careful observation of sampling conditions
(supine, fasting, at rest, pain-free collection).
The following drugs can cause false-positive urine
catecholamine tests and should be avoided at the
time of testing: beta-adrenergic blockers, tricyclic
antidepressants, monoamine oxidase inhibitors,
phenoxybenzamine, sympathomimetics, levodopa/
carbidopa.
Localization of a tumor:
Imaging options are to use anatomical localization
(CT or MRI) or functional imaging (123I-MIBG
scintigraphy). Meta-iodo-benzylguanidine (MIBG)
resembles norepinephrine and is taken up by chromaffin tissue, including the adrenal medulla. Imaging will identify about 95% of pheochromocytomas.
Treatment
Alpha-adrenergic blockade with phenoxybenzamine is
the mainstay of medical treatment.
Patients usually have significant plasma volume depletion
and may require gradual dose escalation and/or administration of IV fluids during initiation of treatment.
Beta-blockade is often also required for adequate blood
pressure, pulse and symptom control.
Effective pharmacological receptor blockade should be
achieved before attempting surgical removal of the tumor.
Surgery, often by laparoscopy, is the only means of
definitive cure.
Malignant pheochromocytoma
Approximately 10% of pheochromocytomas demonstrate
malignant behavior with evidence of metastases at the time
of diagnosis, or as a postoperative recurrence. Malignancy
is more common in extra-adrenal tumors, primary lesions
>5cm, and in patients with a succinate dehydrogenase complex sub-unit B (SHDB) gene mutation. The most common
sites of metastasis are liver, lung and bone. Treatment options
include (none are curative):
debulking surgery
131I-labeled MIBG therapy
292
systemic cytotoxic chemotherapy

external beam radiotherapy to localized metastases
(e.g. in long bones).
New biological agents (e.g. tyrosine kinase or mTOR
inhibitors) are under investigation.

All adrenal steroid hormones are synthesized from cholesterol by a multi-step pathway which requires the action
of a different catalyzing enzyme at each step. Mutations
in the genes coding for steroid synthetic enzymes result in
impaired steroid synthesis, most commonly of cortisol. The
low cortisol level causes increased ACTH drive, resulting in
bilateral adrenal hyperplasia. The hyperplastic adrenal glands
produce excessive quantities of steroid precursors at proximal stages of the synthesis pathway (Figure 11-13), which
may be shunted into alternative pathways (e.g. for androgen
synthesis).
The resulting clinical picture, with onset in prenatal life,
combines cortisol and/or aldosterone deficiency with androgen excess. In female infants this results in masculinization
of the external genitals (ambiguous genitalia). Milder forms,
with onset later in life, can also occur.
Each enzymatic step of steroid hormone synthesis from cholesterol can be disrupted by a genetic mutation of the relevant enzyme. The most common (95% of
cases) is cytochrome P450 21-hydroxylase. This enzyme
deficiency results in failure of synthesis of cortisol and
aldosterone, accumulation of the precursor 17-alphahydroxyprogesterone, and diversion of this precursor to
the androgen synthesis pathway.
Congenital adrenal hyperplasia syndromes are all inherited as autosomal recessive traits. The frequency is approximately 1:15000 live births.
Clinical clues
In females
Females with severe forms of CAH have ambiguous
genitalia at birth due to excess adrenal androgen production in utero. They also develop salt-wasting (aldosterone deficiency) and adrenal crises (cortisol deficiency)
in the neonatal period. This is termed classic CAH.
Mild forms of 21-hydroxylase deficiency manifest later
in childhood with precocious adrenarche (pubic hair),
accelerated linear growth and advanced skeletal maturation (eventual short stature) due to excess postnatal
exposure to adrenal androgens. This is called simple
virilizing CAH.
Milder deficiencies of 21-hydroxylase or 3-betahydroxysteroid dehydrogenase activity may present in
adolescence or adulthood with oligomenorrhea, hirsutism, acne, or infertility. This is termed non-classic
CAH.
In males
Classic CAH in males is generally not identified at birth
because the genitalia are not ambiguous. Presentation
Cholesterol
1
Mitochondria
6
Pregnenolone
17-hydroxpregnenolone
Dehydroepiandrosterone
2
6
Progesterone
2
6
17-hydroxprogesterone
3
3
11-deoxycorticosterone
Androstenedione
7
Testosterone
11-deoxycortisol
Corticosterone
Cortisol
8
Estradiol-17
1. Cytochrome P450 side chain cleavage
5. Aldosterone synthase
Aldosterone
2. 3-hydroxysteroid dehydrogenase
6. Cytochrome P450 17-hydroxylase/C17-20 lyase
3. Cytochrome P450 21-hydroxylase
7. 17-hydroxysteroid dehydrogenase
4. Cytochrome P450 11-hydroxylase
8. Cytochrome P450 aromatase
Figure 11-13 Adrenal steroid synthetic pathway
in the postnatal period is usually with failure to thrive,

recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock.
Males with less severe 21-hydroxylase deficiency present later in childhood with precocious puberty, accelerated growth and advanced skeletal maturation (eventual
short stature).
Diagnosis
In males and females
Treatment
In severe cases, in both genders skin hyperpigmentation

may result from excessive ACTH production.
Lifelong replacement therapy with glucocorticoid

mineralocorticoid therapy (as for other causes of adrenal
insufficiency)
Salt supplementation in classic CAH
Surgical correction of ambiguous genitalia in females
In post-pubertal females it may be necessary to give
androgen-blocking agents (e.g. cyproterone acetate) to
antagonize the action of excess androgens
CLINICAL PEARL
Prenatal diagnosis of congenital adrenal hyperplasia
may be attempted for babies who have an affected
older sibling, to prevent genital abnormalities for
females and life-threatening neonatal crises.
CAH in adulthood
In adulthood, even with appropriate treatment, CAH can
have ongoing morbidity. Adult women may have problems
such as infertility or gender dysphoria. Adult men with poor
compliance with steroid suppression may develop adrenal
rest tissue in their testes, presenting as a scrotal mass. Excess
adrenal androgen production in men can impair spermatogenesis and fertility. Careful adjustment of steroid suppressive therapy is required.
Elevated 17-hydroxyprogesterone levels

Low cortisol levels, elevated ACTH levels, elevated
adrenal androgens
Hyponatremia, hyperkalemia, hypoglycemia
Genetic mutation analysis

(incidentaloma)
Modern abdominal imaging techniques may identify adrenal lesions in 45% of asymptomatic individuals, increasing
to 10% in people aged >60 years. Most are 14cm diameter
and are cysts, myolipomas or non-functioning adenomas.
Two important clinical questions arise:
1 Is the lesion malignant?
a Diameter >4cm makes malignancy more likely,
> 6cm mandates surgical removal.
293
Figure 11-14 Adrenal computed tomography scans of: (A) normal adrenal glands, with the right gland seen as
an upside-down V and the left as an upside-down Y (enlarged in the lower image); (B) adrenal hyperplasia, with
diffuse thickening visible in the upper image and nodules (arrowheads) interspersed between normal adrenal
tissue (arrow) in the lower image; and (C) adrenal adenoma (arrow)
From: (A, B) Haaga JR et al, eds. CT and MRI of the whole body, 5th ed. Philadelphia: Mosby, 2009. (C) Tang YZ et al. The prevalence of
incidentally detected adrenal enlargement on CT. Clin Radiol 2014;69(1):e37e42. The Royal College of Radiologists. (D) Caolli EM et al.
Differentiating adrenal adenomas from nonadenomas using 18F-FDG PET/CT. Acad Radiol 2007;14(4):46875.
Benign adenomas usually have high lipid content,

low CT density, rapid contrast washout.
c Fine needle aspiration cytology is not reliable to
exclude adrenal carcinoma.
d The adrenal gland is a common site for metastatic
tumor deposits.
2 Is the lesion hormonally functioning?
a Assess clinically for cortisol, catecholamine, aldosterone or androgen excess.
b Measure catecholamine levels, cortisol suppressibility, plasma aldosterone:renin ratio.
Apparently non-functioning and benign lesions can simply
be observed by repeat scanning to assess subsequent growth.
The indications for adrenalectomy are hormonal hypersecretion, significant growth to > 4cm diameter, or radiological indications of a high risk of malignancy.
GROWTH AND PUBERTY

Longitudinal growth depends on genetic and environmental
factors. It requires constitutional good health and adequate
294
nutrition. The most important endocrine factors are the

GHIGF1 axis (growth hormoneinsulin-like growth factor axis), thyroid hormones, and gonadal steroids during
the peripubertal growth spurt. It is essential to consider
growth in terms of temporal development (plot progress on
growth charts), the individuals genetic potential (compare
with mid-parental height percentile), and the biological age
(assess bone age) rather than the chronological age.

Familial short stature
Constitutional delay of growth
Impaired nutrition:
malnutrition
malabsorption
eating disorders
Chronic diseases of childhood (especially chronic
inflammatory and infectious disorders, chronic heart
disease and renal failure)
Genetic causes:
Down syndrome (trisomy 21)
Williams syndrome
Turner syndrome
Impaired GH production/action:
hypopituitarism
isolated GH deficiency
Laron syndrome (IGF-1 deficiency)
Other endocrine causes:
hypothyroidism
cortisol excess
Bone/cartilage disorders:
achondroplasia (dwarfism)
rickets
CLINICAL PEARL
The most common causes of short stature in children
are familial short stature (calculate the parental height
percentages) and constitutional delay (consider radiological assessment of bone age). Worldwide, the most
frequent cause of growth failure is malnutrition.
Central (hypothalamicpituitary) causes

(Low or normal gonadotropins, low gonadal steroids.)
Constitutional delay/familial delay
Low bodyweight (female)
Kallmanns syndromegenetic isolated hypogonadotropic hypogonadism with anosmia
PraderWilli syndromedisorder arising from defective paternal chromosome 15, associated with obesity
and hyperphagia
Hypopituitarism
CNS tumors, infiltrative disorders, surgery or irradiation
Hyperprolactinemia
Chronic illness
Common causes of precocious puberty

Central (gonadotropin-dependent)
CNS tumors
Brain injuryinfection, surgery, trauma, radiation
Peripheral (gonadotropin-independent)
Puberty is characterized physically by the appearance of

secondary sex characteristics, changes in body composition and accelerated longitudinal growth. These changes
are produced by the action of gonadal steroids (estrogen or
testosterone) which are secreted as a result of activation of
the hypothalamicpituitarygonadal axis. The earliest signs
of puberty are augmentation of body fat and breast budding
in females, and testicular enlargement in males. Pubertal
development is classified according to the stages described
by Tanner (Figure 11-15, overleaf).
Sex-steroid-secreting tumor (in adrenals, ovaries, testes)

Congenital adrenal hyperplasia
Exposure to exogenous sex steroids
MALE REPRODUCTIVE
ENDOCRINOLOGY
Testicular function
Causes of delayed puberty

The most common cause is constitutional delay, for which
there is often a family history. A delayed bone age and
absence of a pathological cause are the clues to this. In
girls, low bodyweight commonly delays puberty. This may
be associated with eating disorders or excessive sporting
activity.
Primary gonadal causes
(Elevated serum gonadotropins and low gonadal steroids.)
Turner syndrome45 XO (female)
Kleinfelter syndrome47 XXY (male)
Gonadal agenesis
Cryptorchidism (male)
Bilateral testicular torsion, trauma, castration (male)
Gonadal irradiation (childhood malignancy)
Drugs (marijuana, alcohol, chemotherapeutic agents,
ketoconazole, glucocorticoids)
Autoimmune gonadal failure
Chronic systemic disease
The testis has two interdependent but different functions:

testosterone synthesis by Leydig cells
spermatogenesis by seminiferous tubules.
Leydig cell function is stimulated by LH, and testosterone
feeds back on the pituitary and hypothalamus to inhibit LH
secretion. Spermatogenesis requires stimulation by FSH as
well as a high local tissue concentration of testosterone from
neighboring Leydig cells. Sertoli cells are specialized supporting cells in the tubules which mediate these hormonal
signals, and also secrete inhibin which acts as a feedback regulator of FSH. The majority of testicular volume (90%) in
the adult testis is composed of seminiferous tubules. Increase
in testicular size is the first sign of onset of puberty in males.
The action of testosterone on many target cells involves
conversion to dihydrotestosterone (by 5-alpha-reductase)
to produce actions on androgen receptors, or conversion to
estradiol (by aromatase) to act on estrogen receptors. Circulating testosterone is predominantly (98%) protein-bound,
to sex-hormone-binding globulin (SHBG) and albumin,
with only the 2% free fraction being biologically active.
Tests of testicular function

Serum testosterone (total testosterone assays are more
reliable than those for free testosterone)
295
FEMALES
STAGE
BREASTS
ANNUAL HEIGHT
VELOCITY
PUBIC HAIR
OTHER
Prepubertal; elevation of nipple only
Villus hair only
5.06.0 cm
(2.02.4 in)
Adrenarche
Breast buds palpable, enlarged areola
Sparse, slightly pigmented
7.08.0 cm
(2.83.2 in)
Clitoral enlargement;
labial pigmentation
Mammary extends beyond edge of areola, no

separation of contours
Coarser, darker, curled
8.0 cm
(3.2 in)
Acne, underarm hair
Nipple mound forms secondary mound above

the level of the breast
Adult type, but not beyond

pubic area
< 7.0 cm
(< 2.8 in)
First menstruation
Adult-contour breast with integral nipple

mound
Adult type, spreading onto

inner thigh
Final height reached at

age 16
Adult genitals
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
MALES
STAGE
EXTERNAL GENITALS
PUBIC HAIR
ANNUAL HEIGHT VELOCITY
Prepubertal; no pubic hair, genitals

proportionally the same as in childhood
Villus hair only
5.06.0 cm
(2.02.4 in)
Enlargement of scotum and testes; scrotal skin

thins, reddens and changes in texture
Sparse growth of long, slightly

pigmented hair at base of penis
5.06.0 cm
(2.02.4 in)
Enlargement of penis (length at rst), further

growth of testes and scrotum
Darker, coarser and more curled

hair, spreading over junction of
pubes
7.08.0 cm
(2.83.2 in)
Increased penis size with growth in breadth

and development of glans; testes and scrotum
larger, scrotum skin darker
Adult type but covering smaller

area than in adults and not spread
to inner thighs
10.0 cm
(3.9 in)
Adult size and shape
Adult type and quantity, extending

to inner thighs
Final height reached at age 17
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Figure 11-15 Tanner pubertal stages for males and females

Diagrams from Phelps K and Hassad C. General practice: the integrative approach. Sydney: Churchill Livingstone, 2011; based on Tanner JM.
Growth at adolescence. Oxford: Blackwell Science, 1962.
296
Serum LH and FSH (distinguishes primary from

secondary causes of hypogonadism)
Testicular volume
Semen analysis (sperm number, motility, semen
volume)
hCG stimulation test (determines capacity to synthesize
testosterone)
Male hypogonadism
Clinical features of male hypogonadism
Hypogonadism with onset in infancy or childhood presents
as failure to enter puberty. Onset in adult life has variable
manifestations, listed below.
Symptoms
Decreased libido
Erectile dysfunction
Loss of energy and muscle strength
Hot sweats, flushing
Mood changes, depression
Infertility
Physical signs
Reduced growth of body and facial hair (a late sign,
indicates prolonged deficiency)
Gynecomastia (more common with primary than secondary hypogonadism)
Reduced muscle mass, increased subcutaneous fat, bone
loss
Reduced testicular volume
Soft facial skin with fine wrinkles
CLINICAL PEARL
Erectile dysfunction in older men is often a presentation of generalized atherosclerosis. Drug side-effects
and psychological factors are also important contributors. Endocrine causes are relatively uncommon but
should be excluded as they are readily treatable.
Causes of male hypogonadism

1. Primary hypogonadism
(Low testosterone, elevated LH, FSH.)
Gonadal dysgenesis, cryptorchidism, congenital anorchia
Kleinfelter syndrome (XXY karyotype)
Castration or trauma
Irradiation or chemotherapy for childhood cancer
Mumps orchitis
Infiltrative disorders of the testis (hemochromatosis,
amyloidosis, sarcoid)
Androgen synthetic enzyme defects
2. Secondary (hypogonadotropic) hypogonadism

(Low testosterone, normal or low LH, FSH.)
Pituitary or hypothalamic disease
Trauma or irradiation (may cause selective gonadotropin
deficiency with preservation of other pituitary hormones)
Kallmanns syndrome (congenital failure of GnRH
production in association with anosmia)
Hyperprolactinemia
Drugsnarcotics, prior anabolic steroid treatment,
GnRH agonists and antagonists
Obesity-associated syndromesPraderWilli syndrome, LaurenceMoonBiedl syndrome

Vascular causes (atherosclerosis, hypertension, trauma)
Psychological factors
Drug side-effects (beta-blockers, vasodilators, alcohol,
opiates, marijuana, antiandrogens, antidepressants, H2receptor blockers)
Neurogenic causes (stroke, spinal cord disorders,
peripheral neuropathy)
Hormonal causes (testosterone deficiency, prolactin
excess)
Age and systemic disease, especially diabetes (combination of above mechanisms)
Gynecomastia
CLINICAL PEARL
The anterior chest is a common site for fat deposition
in obese men. When there is apparent enlargement of
the breasts in a male it is important to distinguish by
palpation between true gynecomastia (mammary ductal hyperplasia) and simple adiposity.
True gynecomastia reflects local excess of stimulatory estrogen action relative to inhibitory testosterone at the mammary ductal epithelium.
Causes of gynecomastia are:
physiological (temporary increased estrogen)neonatal
period, puberty, old age
estrogen excess:
estrogen administration
increased aromatase activity (thyrotoxicosis)
increased hCG production (germ-cell tumors)
androgen deficiency (any cause above)
androgen blockade (spironolactone, lack of 5-alphareductase or androgen receptor)
hyperprolactinemia.
Medical treatment options for gynecomastia include androgens (testosterone, danazol), antiestrogens (clomiphene
citrate, tamoxifen) and aromatase inhibitors. Paradoxically,
administration of testosterone can exacerbate gynecomastia
297
because of local aromatization of androgen to estrogen in

the breast.
In severe or intractable gynecomastia, it may be necessary to perform surgical mastectomy.

The aim is to restore physiological levels of testosterone in
the systemic circulation and to maintain normal function of
androgen-responsive tissues.
Testosterone has very poor bioavailability if administered orally, due to extensive first-pass metabolism in
the liver.
The best routes of administration are depot injection or
transdermal preparations.
Testosterone esters in oil can be given as an intramuscular depot injection. Different preparations have dosing
frequency ranging from fortnightly to 3-monthly.
Skin patches (replaced daily) or transdermal gel (applied
daily) can achieve adequate serum testosterone levels.
Serum total testosterone concentrations should be monitored to assess adequacy of replacement.
Prostate cancer is a contraindication to testosterone
treatment, and care should be exercised to avoid supraphysiological testosterone levels in older men who might
have prostatic hyperplasia.
The hormonal changes accompanying the phases of the

menstrual cycle are illustrated in Figure 11-16.
Estrogen and progesterone have effects on target
reproductive organs, as well as other body systems (Box
11-5), and provide positive and negative feedback to the
hypothalamicpituitary axis.

Dysfunction in the reproductive axis may present as early
or delayed puberty, virilization, menstrual abnormalities
or altered fertility. Clinical assessment includes history and
examination of secondary sexual characteristics (see Tanner
staging, Figure 11-15), features of androgen excess, characterization of the menstrual cycle, and a sexual and reproductive history.
Key points in the menstrual history
Cycle length and regularity

Length of period, amount of bleeding
Age of menarche/menopause
Dysmenorrhea and other premenstrual syndromes
Pituitary
hormone
cycle
LH
FSH
FEMALE REPRODUCTIVE
ENDOCRINOLOGY
Ovarian cycle

The female reproductive system is controlled by the hypothalamicpituitaryovarian axis. Pulsatile secretion of
GnRH from the hypothalamus stimulates secretion of pituitary LH and FSH, which act in concert to control the ovary
in a cyclical fashion, the primary aim being development
and maturation of 1 follicle per month, ovulation, and subsequent fertilization and implantation, or menstruation. The
ovarian follicle is made up of the egg and the surrounding
theca and granulosa cells. LH stimulates androstenedione
production in theca cells, while FSH controls estrogen production from granulosa cells. Estrogen stimulates growth
of the endometrium, in preparation for pregnancy. After
ovulation, the remaining follicle (corpus luteum) produces
progesterone, which develops the secretory endometrium
required for implantation. If pregnancy does not occur, the
corpus luteum degenerates, estrogen and progesterone levels
fall, and endometrial shedding results in the appearance of
the menses.
The menstrual cycle

1 Early follicular phase: growth of recruited follicles
2 Late follicular phase: selection of a dominant follicle
3 Ovulatory phase: LH surge stimulates breakdown of
follicle and release of mature ovum
4 Luteal phase: follicle transforms into a corpus luteum.
298
Maturation
of follicle
Ovulation
Corpus luteum
E2
P
Endometrial cycle
M
2
10
Follicular phase
14
18
22
26
Luteal phase
Ovulatory phase
Figure 11-16 Menstrual cycle. Days of menstrual

bleeding are indicated by M. E2, estrogen; FSH,
follicle-stimulating hormone; LH, luteinizing
hormone; P, progesterone
Adapted from Rebar RW. Normal physiology of the reproductive
system. In Endocrinology and Metabolism Continuing Education
Program, American Association of Clinical Chemistry, November
1982. Copyright 1982 by the American Association for Clinical
Chemistry; reprinted with permission.
Box 11-5
Actions of estrogen and

progesterone
Estrogen actions
Maintains uterus,
endometrial
proliferation
Mammary glandductal
epithelial proliferation
Maintains vaginal wall
and lubrication
Reduces bone
resorption, increases
formation
Increases clotting
factors and platelet
adhesiveness
Increases HDLs and
triglycerides, decreases
LDLs
Increases hepatic
production of binding
proteins
Inuences female
body fat distribution
(increased
subcutaneous, reduced
visceral fat)
Progesterone actions
Converts endometrium
to secretory stage
Mammary gland
lobular alveolar
development
Thickens cervical
mucus
Inhibits lactation during
pregnancy
Decreases uterine
contractility
Relaxes smooth muscle
HDL, high-density lipoprotein; LDL, low-density lipoprotein
Laboratory tests
Measurement of estradiol, progesterone, LH and FSH
should be interpreted in relation to the timing of the
menstrual cycle, or prepubertal or postmenopausal state.
Progesterone secretion rises during the luteal phase
and indicates that ovulation has occurred during that
cycle. The luteal phase lasts exactly 14 days, while
the follicular phase may vary from 7 to 21days. This
is useful in determining the time of ovulation and
interpreting a serum progesterone result.
CLINICAL PEARL
The timing of a serum progesterone test in relation to
the menstrual cycle is crucial for its interpretation. In
retrospect, a sample must have been taken 47 days
before the next menstrual period to be able to interpret
whether ovulation occurred.
Testosterone and estradiol circulate in the bloodstream,

predominantly bound to SHBG and albumin. Only the
albumin-bound and the unbound (free) fractions are
biologically active, and total testosterone and estradiol
levels should therefore be interpreted in the context of
the SHBG levels. SHBG is lowered in the setting of
insulin resistance (e.g. polycystic ovarian syndrome,
diabetes) and hypothyroidism, and this may contribute

to increased free androgen activity.
There is poor standardization of testosterone assays.
Depending on the method used, levels in normal
women may be at the lower end of the assay detection
range and potentially unreliable. Calculated free androgen index from testosterone and SHBG is the most clinically sensitive marker of androgen excess in women.

The definition of excess hair growth is subjective and varies
greatly between races, as well as having variable tolerability
and acceptability among women.
It is important to exclude drug causes (anticonvulsants,
ciclosporin/cyclosporine, danazol).
It is also important to distinguish simple hirsutism from
virilizationthe latter indicating excess androgen levels
rather than increased local action.
Simple hirsutism is often confined to the face, and drug
treatment is not always necessary. Local measures and
reassurance may satisfy the patient. If medical therapy is
required, benefits only occur after >3 months, as this is the
duration of a complete hair cycle.
Excessive androgen production is derived from
the ovary (commonly polycystic ovary syndrome; rarely
virilizing tumors) or the adrenal gland (CAH, functioning adenomas). Characteristic features of virilization are a
male pattern growth of androgen-dependent terminal body
hair (back, chest, abdomen, face), temporal balding, clitoral enlargement, deepening of the voice, and acne. If there
is a tumoral cause of androgen excess, it should be surgically removed. Alternatively, estrogen (increases SHBG and
androgen binding) or an anti-androgenic drug (spironolactone, cyproterone) might be beneficial.

Polycystic ovary syndrome affects 1020% of the female
population. The exact etiology is unclear, but genetic predisposition in combination with lifestyle factors leads to
hormonal changes of hyperandrogenism, hyperinsulinemia
and their resulting clinical features. Obesity contributes to
the hormonal changes, but lean PCOS phenotypes are also
observed, particularly in high-risk ethnic groups.
Clinical features
Onset often age 1535 years, but manifestations continue throughout life
Hirsutism and acne
Menstrual disturbance (usually oligomenorrhea), subfertility, polycystic ovaries on ultrasound
Features of insulin resistance, e.g. acanthosis nigricans,
glucose intolerance or type 2 diabetes
Features of metabolic syndrome (hypertension, dyslipidemia, abdominal adiposity) and increased cardiovascular risk
Psychosocial implicationsmood disturbance, impaired
quality of life
299
CLINICAL PEARL
Diagnosis of polycystic ovary syndrome is based on the
Rotterdam criteria, requiring two of three key features:
oligo- or anovulation
clinical and/or biochemical hyperandrogenism
polycystic ovaries on ultrasound.
Despite its name, the appearance of polycystic ovaries
on ultrasound is therefore not an obligatory requirement for diagnosis of the syndrome.
Management
Recommendations for a healthy lifestyle are key. Prevention of weight gain across the lifespan and weight
reduction in the already overweight are first-line
strategies.
The clinical phenotype is diverse; other management is
targeted toward specific clinical presentations.
Hirsutismcosmetic approaches (laser, bleaching,
eflornithine cream), oral contraceptive (increases
SHBG, thereby blocking androgens), anti-androgen
agents (spironolactone, cyproterone).
Infertilityearly family initiation, weight loss, clomiphene citrate, metformin (insulin sensitizer),
gonadotropins, in-vitro fertilization.
Menstrual disturbanceoral contraceptive pill,
cyclical progesterone, metformin.
Screen and manage other cardiovascular risk factorsincluding hypertension, dyslipidemia, glucose intolerance, smoking.
Attention to psychosocial aspects.
Female hypogonadism
Abnormal function of the hypothalamicpituitaryovarian
axis resulting in impaired estrogen production leads to
impaired sexual development (in pubertal age group), menstrual disturbance and/or symptoms of estrogen deficiency
(flushing, dry vagina, osteoporosis).
Premature ovarian failure:
Menopause before the age of 40 years
Characterized by high FSH/LH and low estradiol
concentrations
Causesidiopathic, genetic (Turner syndrome,
galactosemia), autoimmune oophoritis, surgery,
chemotherapy and irradiation.
Hypothalamic amenorrhea:
Abnormalities of GnRH pulse generation in the
hypothalamus lead to low FSH/LH levels and
hypoestrogenemia
Causes:
functionalexercise, weight loss (anorexia nervosa), low BMI, stress
organichypothalamic
lesions,
genetic
GnRH deficiency (Kallmanns syndrome).
Pituitary disease.
300
Several hormonal axes are altered during pregnancy.
Thyroid: increased requirement for thyroid hormone
production because of increased thyroid-hormone
binding protein (induced by estrogen). Impaired thyroid
reserve may be unmasked during pregnancy. Beta-hCG
has a stimulatory effect on TSH receptors, in some cases
resulting in gestational hyperthyroidism. TSH levels are
therefore lower in the 1st trimester when hCG levels
are highest. Thyroid function tests in pregnancy should
be interpreted according to trimester-specific reference
ranges if available.
Hypothalamicpituitaryadrenal axis: there is
hyperactivity of this axis during pregnancy, related
to corticotropin production from the placenta and an
estrogen-induced increase in cortisol-binding proteins.
Cortisol levels may be 23 times the normal reference
range, although pregnancy-specific reference ranges are
poorly defined.
Prolactin: increases 10- to 20-fold during pregnancy
and lactation, in response to lactotrope expansion by
estrogen. Lactotrope hypertrophy results in increased
pituitary size during pregnancy.
Calcium: increased renal 1-alpha-hydroxylase activity results in calcitriol production, facilitating intestinal
calcium absorption and provisioning of calcium to the
developing fetus. Placentally derived PTHrP may be
involved in increasing calcium availability and transplacental passage.
Growth hormone/Insulin-like growth factor 1:
placental GH rises during pregnancy and replaces pituitary GH as the prime regulator of maternal IGFs.
Glucose regulation: insulin resistance increases during
pregnancy, particularly late in the 2nd trimester. This is
under the influence of placental hormones and adipokines,
including placental GH, cortisol and tumor necrosis factor alpha (TNF-alpha). A compensatory increase in insulin secretion normally maintains glucose tolerance. In
510% of women, the combination of increased insulin
resistance and a failure of beta-cells to meet the demands
for insulin production results in development of gestational diabetes. Testing for glucose intolerance is ideally
performed around 2428 weeks of gestation.
NEUROENDOCRINE TUMORS
(NETs)
Overview
In addition to the classical organ-based endocrine system,
there is a diffuse network of hormone-secreting cells spread
throughout the body. Sites include:
gastrointestinal tractsignaling gut motility, acid and
fluid secretion, insulin release
respiratory tractsignaling inflammation, toxic
exposure
skinMerkel cells signaling physical and chemical

exposure.
Neuroendocrine tumors arising from these cells are capable
of secreting a variety of peptide hormones and vasoactive
amines. They most commonly arise in the foregut or bronchi, and are slow-growing but have malignant potential.
Histologically they are characterized by neurosecretory
granules. Proteins associated with secretory vesicle function
(e.g. chromogranin A) can often be used as tumor markers. Many NETs express receptors for somatostatin. Consequently, radiolabeled somatostatin is useful for diagnostic
imaging, and long-acting somatostatin analogues can be
effective in suppressing excessive hormone secretion.
Carcinoid syndrome
A clinical syndrome produced by excessive production
of NET-derived vasoactive amines (serotonin, histamine, kallikrein, prostaglandins).
Episodic symptomsflushing, sweating, diarrhea,
bronchospasm.
Serotonin excess can induce fibrosis and scarring of
right-sided cardiac valves.
Diagnosis is by measurement of plasma serotonin,
or urinary excretion of a serotonin metabolite,
5-hydroxyindoleacetic acid (5-HIAA).
Glucagonoma
Causes insulin resistance and secondary diabetes mellitus.
Characteristic skin rash (necrolytic migratory erythema;
Figure 11-17).
High incidence of thromboembolism.
Diagnosis is by measurement of plasma glucagon and
tumor imaging.
Most glucagonomas are located in the pancreas.
VIPoma
Vasoactive intestinal polypeptide (VIP) stimulates intestinal secretion of water, potassium and bicarbonate and
inhibition of gastric acid secretion.
VIPoma causes a syndrome of profuse watery diarrhea,
hypokalemia and achlorhydria.
Diagnosis is by measurement of plasma VIP and tumor
imaging (most are found in the pancreas or upper gastrointestinal tract).
It is treated by surgical excision when possible, or with
somatostatin analogues.
Insulinoma
A rare NET causing hyperinsulinemia and subsequent
hypoglycemia.
The cornerstone of diagnosis is deliberate provocation
of hypoglycemia by a prolonged supervised fast of 4872
hours.
In cases of insulinoma (beta-cell tumor) or nesidioblastosis (islet-cell hyperplasia), most patients develop
hypoglycemia within 18 hours of fasting.
Figure 11-17 Necrolytic migratory erythema.

From Compton NL and Chien AL. A rare but revealing sign:
necrolytic migratory erythema. Am J Med 2013;126(5):3879.
If hypoglycemia is provoked, samples should be obtained

for measurement of plasma insulin and C-peptide while
the patient is hypoglycemic.
Imaging studies may then be undertaken to localize the
source of insulin hypersecretion.
CLINICAL PEARL
Levels of C-peptide, which is co-released with insulin
from pancreatic beta-cells, can be used to distinguish
endogenous hyperinsulinemia (C-peptide high) from
exogenous insulin administration (C-peptide low).
Insulinoma characteristics:
insulinomas present with recurrent episodes of spontaneous hypoglycemia
10% are associated with multiple endocrine neoplasia
type 1 (MEN-1), and up to 10% are malignant
they are most commonly located in the pancreas.
Most insulinomas are very small (<2 cm) and difficult to
localize by standard imaging with CT, ultrasound or MRI.
Endoscopic/intraoperative ultrasound and portal vein sampling for insulin may be used to localize the lesion
Surgery is curative in >75% of cases of localized insulinoma. Medical therapy with diazoxide or somatostatin
analogues may be used.
301
Differential diagnosis of a
hypoglycemic disorder
Excessive endogenous insulin secretion/action:
insulinoma
nesidioblastosis
non-islet-cell tumors (secreting insulin-like growth
factors)
reactive hypoglycemia, alimentary hypoglycemia
Drugs:
sulfonylureas (high C-peptide and insulin levels,
drug detectable in urine and plasma)
insulin (including surreptitious use, will have high
insulin levels but low C-peptide)
ethanol
beta-blockers
salicylates, ACEIs, lithium
Impaired hepatic gluconeogenesis:
chronic liver disease
congenital enzyme deficiencies
Deficient counter-regulatory hormones:
hypoadrenalism (cortisol)
hypopituitarism (ACTH and growth hormone)
pancreatic insufficiency (glucagon deficiency plus
carbohydrate malabsorption)
Autoimmune hypoglycemia (insulin antibodies, activating insulin-receptor antibodies)
CLINICAL PEARL
The classic features of a hypoglycemic disorder are
termed Whipples triad:
episodes of symptoms consistent with hypoglycemia
demonstration of low blood glucose during symptoms
rapid amelioration of symptoms by administration
of glucose.
Treatment of malignant NETS

NETs are slow-growing but may metastasize to regional
lymph nodes and the liver. Many patients do not present with
hormone-related symptoms until there is a substantial tumor
burden, so metastases are often present at the time of diagnosis.
If curative surgery is not possible, the following options
may be beneficial in palliative management. Treatment choices
are individualized, and often combined with somatostatin
analogue therapy to suppress hormone secretion. Long-term
survival is often possible, even with metastatic disease.
Cytotoxic therapy with streptozotocin, doxorubicin or
fluorouracil.
Surgical debulking with partial hepatectomy, or liver
transplantation.
Ablation of liver metastases using chemo-embolization,
radioactive sphere embolization or radiofrequency
probe ablation.
Systemic radiopharmaceutical treatment with radiolabeled somatostatin analogues.
302
DISORDERS OF MULTIPLE
ENDOCRINE SYSTEMS
There are a number of rare disorders which produce endocrine dysfunction affecting multiple organs. These are predominantly familial syndromes and may be detected by
screening in an asymptomatic individual with a relevant
family history. The proband case in a family is usually someone diagnosed with a primary endocrine complaint who
subsequently develops a second disorder.

There are three MEN syndromes, all inherited as autosomal
dominant traits, which produce functioning endocrine neoplasms in multiple organs.
MEN-1
Caused by a mutation of the MEN1 gene (11q13) which
codes for a tumor suppressor protein, menin
Most common manifestation is hyperparathyroidism (multi-gland hyperplasia), usually manifest by age
25years
Benign skin lesions (angiofibromas) are very common
Pancreatic/duodenal endocrine tumors may secrete gastrin (most common), insulin, glucagon or vasoactive
intestinal peptide (VIP)
Pituitary adenoma (any type, but prolactinoma or nonfunctioning most common)
Diagnosis by MEN1 gene analysis
Treatment for each tumor is similar to sporadic cases:
hyperparathyroidism by surgery
pancreatic tumors by surgery or somatostatin
analogues
pituitary adenoma by surgery, dopamine agonist
(for prolactinomas) or radiotherapy
Other rare associations are extra-pancreatic carcinoid
tumors and adrenocortical tumors
CLINICAL PEARL
MEN-1 is characterized by the 3 Pstumors/hyperplasia of:
parathyroids
pancreas
pituitary.
MEN-2
Caused by a gain of function mutation of the RET

proto-oncogene (10q11) which codes for a receptor
tyrosine kinase (RTK)
Two clinical syndromes (MEN-2a and MEN-2b) differ
slightly in phenotypic expression
Earliest manifestation is usually hyperplasia of the
(calcitonin-secreting) C-cells of the thyroid, with later
development of medullary thyroid carcinoma (MTC)
Pheochromocytoma (usually occurs later than the

MTC)
Parathyroid hyperplasia and adenoma formation (only
in MEN-2a)
Mucosal neuromas of lips, eyelids, tongue and Marfanoid body habitus (only in MEN-2b)
Diagnosis is by RET gene analysis
Familial MCT without the other features of MEN-2
can be seen (also have RET mutation)
Families should be screened, and total thyroidectomy is
advised in childhood to prevent MTC
Tumors are treated similarly to sporadic cases
Other multiple endocrine tumor

syndromes
Box 11-6
Polyglandular autoimmunity (PGA)

syndromes
PGA type 1
Mucocutaneous
candidiasis
Hypoparathyroidism
Addisons disease
Celiac disease
Vitiligo
Type 1 diabetes mellitus
Hypogonadism
Autoimmune hepatitis
Carney complex
Autosomal dominant inheritance
Associated with mutations in the PRKAR1A gene
which codes for a tumor-suppressor protein
Presents with spotty skin pigmentation and lentigines,
myxomas (cardiac, skin and breast)
There is adrenocortical hyperplasia and hyperfunction,
most often causing ACTH-independent Cushings
syndrome.
McCuneAlbright syndrome
Caused by a somatic activating mutation in the gene
that codes for the alpha sub-unit of the stimulatory G
protein (Gs-alpha). G proteins are involved in intracellular signaling from cell-surface hormone receptors,
such as the receptors for ACTH, PTH, gonadotropins,
melanocyte-stimulating hormone and TSH.
Constitutive overstimulation of cells bearing the mutation results in clinical manifestations such as precocious
puberty, skin pigmentation, fibrous dysplasia, hyperthyroidism, Cushings syndrome, hypophosphatemia
and acromegaly/gigantism.
Polyglandular autoimmunity (PGA)

syndromes
In some individuals the occurrence of multiple endocrineorgan failure reflects an underlying disorder of immune
regulation. Two syndromes are recognized, containing
clusters of endocrinopathies together with some associated
non-endocrine autoimmune disorders (Box 11-6). In both
syndromes the development of endocrine organ involvement is sequential and the diagnosis is usually not realized
until at least two organs are involved. The evidence for an
autoimmune etiology is the presence of chronic inflammatory (lymphocytic) infiltrates in the affected organs, and the
presence of autoantibodies to specific antigens expressed in
the target tissues. The three main classes of self-antigens to
which autoantibodies are produced in PGA syndromes are:
organ-specific surface receptor molecules (e.g. TSH
receptor)
PGA type 2 (Schmidt

syndrome)
Addisons disease
Autoimmune thyroid
disease
Pernicious anemia
Vitiligo and alopecia
Hypophysitis
Myasthenia gravis
Chronic biliary cirrhosis
Immune
thrombocytopenia
intracellular enzymes (e.g. thyroid peroxidase, adrenal

21-hydroxylase, pancreatic glutamic acid decarboxylase)
secreted proteins (e.g. insulin).
In PGA type 1 (PGA-1) the endocrinopathies are invariably associated with coexisting mucocutaneous candidiasis.
PGA type 2 is considerably more common than PGA-1
and is not associated with fungal infection. Both syndromes
have a strong familial basis, and a monogenic mutation of
the AIRE gene (autoimmune regulator) has been strongly
linked to PGA-1. The genetic basis of PGA-2 has not yet
been identified.
Diagnosis is based on association of multiple disorders
and positive autoantibodies.
In individuals with Addisons disease or type 1 diabetes mellitus, it is cost-effective to screen for other
endocrinopathies.
Treatment is the same as for each individual disorder.
Modulation of the underlying immune disorder is not
currently possible.
CLINICAL PEARL
In a patient with type 1 diabetes mellitus, the presence
of a polyglandular autoimmune syndrome is often
revealed by development of recurrent hypoglycemia
due to coexisting cortisol deciency.
DIABETES AND METABOLISM

Metabolism refers to the chemical reactions that occur
inside a living cell and result in production of energy and
the synthesis of new organic material to support cell growth,
reproduction and survival. It consists of two processes, catabolism and anabolism. Catabolism provides the energy and the
components required for anabolism (Figure 11-18, overleaf).
303
ANABOLISM: Small simple

molecules
Large complex
molecules
Energy usage
CATABOLISM: Large complex

molecules
Energy release
Small simple
molecules
Figure 11-18 Metabolism involves the

complementary processes of anabolism and
catabolism
The structural components of all living things are composed of three main classes of molecule: amino acids, carbohydrates and lipids. Catabolism of these molecules in
our food provides the energy required to make new molecules for cells (biosynthesis), and carry out mechanical work
and molecular transport. The energy extracted from food
depends on the relative composition of molecules within
that food, with fat having twice the energy density of carbohydrates and protein.
An individuals energy requirements cover the needs
of basal metabolism, physical activity, and the metabolic
response to food. During certain stages of the lifecycle, further energy may also be required for growth, pregnancy and
lactation.
An average person consumes 20002400 kilocalories
(830010,000 kJ) per day to meet energy requirements,
although this is influenced by multiple factors such as age,
weight, muscle mass, physical activity levels and ambient
temperature. Conditions such as systemic illness, fever and
endocrine disturbance can also significantly alter energy
requirements. When the energy from food exceeds the
bodys requirements, the excess energy is stored as fat, from
where it can be re-accessed at times when the daily requirement exceeds intake.
The following sections cover disturbances of the metabolic system, in particular the derangement of carbohydrate
metabolism (diabetes mellitus and its complications), the

consequences of long-term energy excess (overweight and
obesity) and the constellation of obesity, diabetes, dyslipidemia and hypertension known as the metabolic syndrome.

Ingested carbohydrates are broken down into monosaccharides (e.g. glucose, fructose, galactose) in the small intestine
and absorbed into the bloodstream. Glucose is the most
important carbohydrate in animal metabolism, being used
as the primary source of cellular energy.
Glucose levels are normally maintained within a tight
optimum range. They both control and are controlled by
the central metabolic hormone insulin (Figure 11-19]. Pancreatic islet cells secrete insulin in response to food intake
and rising blood glucose concentrations, resulting in glucose
uptake into cells for storage and energy production. The
insulin response to food is mediated by incretin hormones
produced by the intestine. Insulin controls lipid and amino
acid metabolism, promoting anabolism. It signals to cells in
the brain and bone, which further contribute to metabolism
at a whole-body level.
Diabetes: denition, diagnosis and

classication
Diabetes mellitus is the impairment of carbohydrate metabolism characterized by inadequate insulin secretion or action,
resulting in hyperglycemia. Although the pathological consequences of sustained hyperglycemia are evident, there is no
specific biological marker by which diabetes is clearly defined.
Blood glucose levels (BGLs) have been used for diagnosis,
but the cut-point at which non-diabetes becomes diabetes
remains unclear. Current definitions (Table 11-8) have been
reached by consensus opinion based on the BGLs at which
the risk of complications appear to increase, and the characteristics of the BGL distribution curve in populations.
L hepatic
glucose
production
K blood
glucose
levels
ulin
Pancreas
Liver
Ins
Insulin
Insulin secretion
K cellular
glucose
uptake
Ins
ulin
Muscle
K intestinal
glucose
levels
Fat
L lipolysis
Figure 11-19 Glucose homeostasis. In response to intestinal glucose absorption and rising blood glucose levels,
insulin secreted by islet cells acts on liver, muscle and fat to reduce glucose output, increase glucose uptake
and prevent fat breakdown
304
Table 11-8 WHO criteria for diagnosis of diabetes and intermediate hyperglycemia*
DIAGNOSIS
FASTING BGL AND/OR 2-HOUR LEVEL ON GTT
Normal
<6.1 mmol/L and <7.8 mmol/L

(110 mg/dL and 140 mg/dL)
Impaired fasting glycemia
6.16.9 mmol/L and <7.8 mmol/L

(110125 mg/dL and 140 mg/dL)
Impaired glucose tolerance
<7.0 mmol/L and 7.811.0 mmol/L

(126 mg/dL and 140199 mg/dL)
Diabetes
>7.0 mmol/L or >11.1 mmol/L

(126 mg/dL or 200 mg/dL)
* Note that the American Diabetes Association (ADA) criteria use 5.6 rather than 6.1 mmol/L as the cut-off for impaired fasting glycemia.
The ADA now also endorses HbA1c v 6.5% as diagnostic of diabetes.
GTT, glucose tolerance test; WHO, World Health Organization.
Normal levels of fasting plasma glucose are below

6.1mmol/L (110 mg/dL).
Fasting levels between 6.1 and 7.0 mmol/L (110125
mg/dL) are borderline; termed impaired fasting glycemia (IFG).
Fasting levels repeatedly at or above 7.0 mmol/L (126
mg/dL) are defined as diagnostic of diabetes.
When BGL is measured in a non-fasting state, a level
above 11.1 mmol/L (200 mg/dL) represents likely diabetes and levels between 7.8 and 11.0 warrant further assessment with a fasting measurement or glucose tolerance test
(GTT).
In a GTT, a 75g oral glucose load is administered to a
fasting patient. The BGL after 2 hours should be below
7.8 mmol/L (140 mg/dL).
Levels between 7.8 and 11.1 mmol/L (140200 mg/dL)
indicate impaired glucose tolerance (IGT).
Glucose levels above 11.1 mmol/L (200 mg/dL) at
2hours confirm a diagnosis of diabetes.
The categories of intermediate hyperglycemia known as
impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have been used to define a state at which the risk
of complications and the risk of progression to frank diabetes is increased. The pathophysiological processes associated
with diabetes are already evident, but reversion to normoglycemia is not uncommon on subsequent testing.
The underlying pathophysiology assists diabetes
classification.
Type 1A diabetes mellitus is an autoimmune condition
in which inflammation of islet cells leads to destruction and subsequent deficiency of insulin secretion. It
is responsible for the vast majority of cases of type 1
diabetes.
Type 1B diabetes is characterized by a lack of evidence
of autoimmune etiology, and a fluctuating need for
insulin; diabetic ketoacidosis can still occur.
Type 2 diabetes mellitus is characterized by resistance
to the actions of insulin and by failure of islet cells to
compensate for the increased secretory demand.
Gestational diabetes is temporary carbohydrate intolerance precipitated by the hormonal changes of pregnancy.
Diabetes may develop secondary to other disease states or
medications that either impair insulin secretion or action,
or both (Box 11-7). Additionally, while both type 1 and
type 2 diabetes mellitus are polygenic disorders with environmental influences, rare forms of diabetes result from
directly inherited gene mutations that affect insulin secretion or action.
Box 11-7
Causes of secondary diabetes

(or contributors to worsening
glucose tolerance)
Pancreaticinsulin insufficiency
Cystic brosis
Pancreatectomy
Fibrocalculous pancreatopathy
Pancreaticmixed insulin insufficiency and/or
impaired action
Hemochromatosis
Pancreatic cancer
Hormonal disordersimpaired action
Pheochromocytoma
Cushings syndrome
Glucagonoma
Acromegaly
Hyperthyroidism
Somatostatinoma
Hyperaldosteronism
Medicationsinsulin insufficiency or impaired action
Antipsychotics
Immunosuppressives, including corticosteroids
Antiretroviral drugs
Pentamidine
(Beta-blockers, thiazide diuretics, oral contraceptives)
305

Epidemiology
See Table 11-9.
The prevalence and incidence of type 1A diabetes varies
significantly with ethnicity and geography, being highest in
white populations in Europe. The incidence is increasing at
a rate of 34% per year, particularly in those younger than
5years, probably due to environmental influences.
Onset of disease may occur at any age, although it occurs
predominantly in childhood or adolescence; hence the old
term juvenile-onset diabetes. In older age groups a more
insidious variant known as latent autoimmune diabetes in
adults (LADA) may occur.
Pathogenesis
Cell-mediated autoimmune destruction of beta-cells
leading to insulin deficiency.
Autoantibodies (usually multiple) against islet-cell antigens (insulin, ICA512 [IA-2], GAD65) are present in
8590% of children at diagnosis.
There is good evidence of genetic predisposition to
T1DM. Concordance rates for monozygotic twins are
3050% compared with 610% in dizygotic twins.
More than 90% of cases have high-risk human leukocyte antigen (HLA) haplotypes.
Environmental factors act as initiators of beta-cell autoimmunity. Possible factors include viruses (coxsackievirus B, mumps, cytomegalovirus, rubella), early
exposure to cows milk protein or reduced exposure to
the potential protective effects of breastfeeding.
A small proportion of cases of T1DM have no evidence
of autoimmunity, islet-cell inflammation or high-risk
HLA haplotypes.
Table 11-9 Epidemiology of Type 1A diabetes mellitus
Prevalence
<1% to 3%, depending on population
Incidence
1/100,000 per year in Japan to

45/100,000 per year in Finland
Seasonal predominance in winter
Clinical features
Autoimmune destruction and progressive loss of beta-cell
function precedes diagnosis, often by years. Symptoms
(Box 11-8) do not develop until there is inadequate insulin
to maintain normoglycemia. Patients with severe insulin
deficiency may present with symptoms of ketoacidosis.
The history may be brief, especially in young children
with rapidly progressive beta-cell destruction. Adults with
LADA have a more insidious onset that may resemble type
2 diabetes mellitus.
Management
Insulin therapy
Management centers around replacement of the deficient
hormone, insulin, in ways that most closely resemble normal
physiology. In healthy individuals, basal levels of insulin are
secreted to regulate glucose production from the liver and
suppress lipolysis. This occurs 24 hours a day in the absence
of food intake. During meals, a more rapid burst (bolus) of
insulin is secreted in response to the glucose load from food.
Modern insulins are manufactured with recombinant DNA
technology using the human insulin gene. Alterations in the
natural insulin molecule are performed to make insulin analogues, changing the pharmacokinetic properties.
The key properties of a manufactured insulin are its onset,
peak and duration of action. Knowledge of an insulins pharmacokinetics (Table 11-10) allows insulin delivery to mimic
physiological patterns and be tailored to a persons diet and
lifestyle. Insulin is usually administered by subcutaneous
injection in the abdominal wall, using an injecting pen device.
The most physiological method of subcutaneous multidose insulin administration is basalbolus therapy:
rapid- or short-acting insulin is used at mealtimes
and the dose matched to carbohydrate intake
intermediate or long-acting insulin is administered
once or twice daily to provide basal requirements
and control fasting glucose.
Box 11-8
Symptoms of hyperglycemia
Thirst, polyuria
Age of onset
Peak onset in puberty, but may occur

at any age throughout the lifespan
Gender ratio
Equal in childhood and adolescence.

Male:female ratio 1.5:1 after age 25
Weight loss
Blurred vision, headache
Supercial infections, especially Candida
Table 11-10 Pharmacokinetic properties of different types of insulin
INSULIN TYPE
ONSET
PEAK
DURATION
EXAMPLES
Rapid-acting
15 min
3090 min
34 h
Lispro, Aspart, Glulisine
Short-acting
3060 min
23 h
36 h
Regular
Intermediate-acting
12 h
414 h
Up to 24 h
NPH (isophane)
Long-acting
12 h
Minimal
Up to 24 h
Detemir, Glargine
306
Insulin pump therapy provides an alternative to multiple

daily injections. Short-acting insulin is delivered continuously via a subcutaneously placed catheter, at prespecified rates that can be varied according to time of
day (basal rate).
The pump also administers bolus insulin at mealtimes according to food intake, programmed by the
patient.
Pumps may improve quality of life and reduce
hypoglycemia, but are expensive.
Efficacy in achieving glycemic control is highly userdependent.
Other issues
Insulin requirements are significantly affected by lifestylediet choices, physical activity, illness, stress, alcohol and drugs.
Education about correct insulin administration techniques, management of hypoglycemia and sick-day
management is essential.
Specific education and management plans include
those for commercial vehicle drivers, shift-workers and
women planning pregnancy.
The aim is to tailor management to allow maintenance
of usual lifestyle.
Monitoring outcomes
Efficacy of treatment is assessed by:
home capillary (fingerprick) BGL monitoring
the glycosylated hemoglobin (HbA1c) concentration.
HbA1c reflects average BGLs over the preceding 3
months and is closely correlated with the risk of endorgan complications.
Treatment targets are tailored to the individuals age, comorbidities and lifestyle. As a general rule, BGLs are maintained
as close to normal as possible without incurring hypoglycemia. Appropriate HbA1c targets are proposed in specific
situations (Table 11-11).
Management also focuses on minimization of cardiovascular risk by optimizing blood pressure and lipids, diet and
exercise, and smoking cessation. Screening for complications
of diabetes is performed regularly. T1DM is a chronic disease requiring intensive lifelong management. Depression
and altered body image are significant comorbidities that
warrant specific attention.
CLINICAL PEARL
Principles of type 1 diabetes mellitus management:
insulin therapy that mimics physiological insulin
secretion
diet, exercise and lifestyle management
knowledge and understanding of diabetes
home blood glucose level (BGL) monitoring, appropriate HbA1c and BGL targets
minimize risk and severity of hypoglycemia
screening for complications
minimizing cardiovascular risk
managing psychosocial aspects of the disease.
Transplantation
Transplantation of islet cells or whole pancreas from healthy
donors offers a theoretical cure, but is not yet a viable solution for most patients. In addition to the issue of reduced
donor availability, the requirement for ongoing immunosuppression and its side-effects currently outweigh the benefit in most individuals.
Whole pancreas transplants are performed in patients
with severe diabetes complications already undergoing
renal transplantation.
Islet cell transplantation is reserved for patients with severe
recurrent hypoglycemia and hypoglycemic unawareness.

Type 2 is differentiated from type 1 diabetes mellitus according to Table 11-12 (overleaf).
Epidemiology
CLINICAL SITUATION*
HbA1c TARGET
General target
f7.0%
See Table 11-13, overleaf.

Type 2 diabetes mellitus accounts for approximately
90% of cases of diabetes. Its prevalence is increasing
dramatically worldwide.
Aging populations, increasing obesity and urbanization
are key factors. There is strong ethnic predisposition.
It is a disease of affluence in developing countries but
is associated with socioeconomic disadvantage in developed countries.
There is a concerning trend for increasing diagnosis in
childhood and adolescence.
Pregnancy or planning pregnancy
f7.0% (f6.0%
desirable)
Pathogenesis
Recurrent severe hypoglycemia or

hypoglycemic unawareness
f8.0%
Table 11-11 Suggested HbA1c targets for adults with

type 1 diabetes
* Consider individual patient factors.

Adapted from Cheung NW et al. Position statement of the
Australian Diabetes Society: individualisation of glycated
haemoglobin targets for adults with diabetes mellitus. Med J Aust
2009;191:33944.
Insulin resistance plays a major role in pathogenesis, predating the development of the disease by 1020 years. To
maintain normoglycemia, islet cells compensate for impaired
insulin action by increasing insulin secretion. In genetically
predisposed individuals, beta-cell reserves are insufficient
to keep up with this demand for hyperinsulinemia, insulin
levels cannot be sustained and progression through IGT to
frank diabetes occurs.
307
Table 11-12 Differentiating type 1 and 2 diabetes mellitus
TYPE 1
TYPE 2
Ethnic predisposition
White European
Non-white, non-European
Typical age of onset
Childhood/adolescence
Adulthood (but childhood increasing)
Typical phenotype
Lean
Normal, overweight or obese
Other features
Autoimmunity
Metabolic syndrome, polycystic ovary

syndrome, fatty liver
Pathophysiology
Insulin deciency
Insulin resistance with beta-cell exhaustion
Treatment
Insulin essential
Diet, lifestyle, oral hypoglycemics, insulin
Diabetic ketoacidosis
Complication of insulin deciency
Rarely develops, usually late in disease

course
Laboratory tests
Positive antibodies, susceptible human

leukocyte antigen (HLA) groups
Negative antibodies
Table 11-13 Epidemiology of type 2 diabetes mellitus

Prevalence
6.4% of adults worldwide (3.8% in Africa, 10.2% in the Western Pacic)

Projected to increase to 7.8% of the worlds adults by 2030
Age
From childhood to old age. Typically middle to old age, but average age of diagnosis is
decreasing
High-risk ethnic groups
Native Americans (especially Pima Indians), South Pacic Islanders (especially from Nauru),
Indigenous Australians, minority or migrant populations in Western countries (Hispanic/
African Americans in USA, Asian/Afro-Caribbeans in UK)
Impaired insulin action occurs in multiple tissues, resulting in reduced glucose uptake into muscle, increased hepatic
glucose production, and elevated free fatty acids. The causes
of insulin resistance are multifactorial, including genetics,
obesity and environmental factors such as hormones, aging,
lifestyle and nutrient availability (Box 11-9). Inadequate
beta-cell reserve is largely genetically determined.
Clinical features
Insidious onset; T2DM may be present for many years
before diagnosis.
Box 11-9
Risk factors for type 2 diabetes mellitus
308
Age
Obesity, especially abdominal (central) distribution
Sedentary lifestyle
Family history and ethnicity
Hypertension, dyslipidemia
Personal history of gestational diabetes or intermediate
hyperglycemia
Personal history of polycystic ovary syndrome,
acanthosis nigricans
Low birthweight, child of a diabetic pregnancy
Diagnosis is commonly made in asymptomatic individuals on routine health screening.

Symptoms of hyperglycemia may be present.
Delayed presentation may be with a diabetes-associated
complication.
Occasionally presents with severe hyperglycemia, dehydration t mental obtundation, known as hyperosmolar
hyperglycemic state.
Management
CLINICAL PEARL
In selecting from the large variety of available therapies for type 2 diabetes mellitus, consideration should
be given to medications with complementary mechanisms of action, favorable side-effect proles, longterm safety and efficacy, and suitability to the individuals lifestyle. Medications are used to achieve an HbA1c
target individualized to the patient.
Lifestyle
While age, race and genetics are unmodifiable, weight
loss, increased physical activity and healthy diet target the
underlying pathogenesis of the condition, assist in maintenance of glycemic control and potentially slow progression
of the disease. Weight loss improves insulin sensitivity and

beta-cell capacity. Reduction in body fat (particularly central adiposity) is more important than weight loss, and is
better assessed with measurements of waist circumference
than body mass index.
Independent of weight loss, physical activity itself
improves insulin sensitivity and lowers BGLs. 150 minutes
per week of moderate-intensity exercise or 90 minutes of
vigorous exercise, spread over at least 3 days of the week,
is recommended. Dietary counseling advises foods with a
low glycemic index and low in saturated fat, with modest
carbohydrate intake in proportion and temporal relation to
medication use.
Oral hypoglycemic agents
Medical therapy is required in the majority of patients. It
can be instituted in conjunction with diet and exercise,
rather than awaiting the failure of a lifestyle program.
Metformin is the mainstay of T2DM treatment, targeting the underlying pathology (Figure 11-20).
Metformin monotherapy is the usual starting point
for therapy but may be inadequate if beta-cell failure
is already well progressed, or may become inadequate
after some years of treatment. 5570% of patients who
initially achieve target HbA1c levels (Table 11-14) with
metformin monotherapy have progressive deterioration
in the next 23 years.
Oral hypoglycemic agents (OHGs) with complementary
actions may be used in combination to achieve HbA1c
targets. Agent selection (Table 11-15, overleaf) is based
on the known mode of action and glucose-lowering
efficacy, patient tolerability, known side-effect profile,
and issues of cost and availability specific to the country
of use.
CLINICAL PEARL
In older patients, or those with multiple comorbidities
limiting life expectancy, the primary aim of diabetes
management may be to avoid symptoms of hyperglycemia or hypoglycemia rather than treat to a specic
HbA1c target.
Insulin therapy
Insulin may be initiated early after diagnosis, or after failure
of OHGs to maintain targets. In the case of secondary oral
failure, it may be used as add-on therapy with continuation
of the OHGs. A common scenario is the addition of oncedaily basal insulin to combined OHG therapy (so-called
basal-plus), to lower overnight and fasting BGLs.
Alternatively, insulin therapy may replace OHGs. Basal
bolus regimens, as for T1DM, offer the greatest flexibility and
glycemic control. For convenience, insulin mixtures combine rapid- or short-acting insulin with intermediate-acting
insulin in fixed proportions. These require only twice-daily
injection, but provide less physiological insulin delivery and
require careful adherence to dietary content andtiming.
Other injectable therapies
Incretins are gut hormones that enhance glucose-stimulated
insulin secretion from beta-cells. The most important in
humans are GLP-1 (glucagon-like peptide 1) and GIP (gastric
inhibitory peptide), which are secreted from the gastrointestinal tract in response to nutrient intake. They also slow gastric
Table 11-14 HbA1c targets in type 2 diabetes mellitus
CLINICAL SITUATION
HbA1c
f7.0%
General target
Diabetes of short duration, no clinical
cardiovascular disease:
requiring lifestyle modication t
metformin
requiring any antidiabetic agents other
than metformin or insulin
requiring insulin
f6.0%
f6.5%
f7.0%
Pregnancy or planning pregnancy
f6.0%
Diabetes of longer duration or clinical

cardiovascular disease
f7.0%
Recurrent severe hypoglycemia or

hypoglycemic unawareness
f8.0%
Adapted from Cheung NW et al. Position statement of the Australian

Diabetes Society: individualisation of glycated haemoglobin targets
for adults with diabetes mellitus. Med J Aust 2009;191:33944.
L hepatic
glucose
production
L glucose
absorption
Insulin secretion
K cellular
glucose
uptake
Figure 11-20 Mechanisms of action of metformin. Metformin reduces hepatic glucose production and
stimulates glucose uptake into muscle, as well as reducing enteric glucose absorption
309
Table 11-15 Actions of oral hypoglycemic agents
PROS
CONS
Metformin
Low risk of hypoglycemia

Improves lipids and brinolysis
Weight neutral or mild weight loss
Long-term experience and safety
Potential benets for CVD and cancer
Contraindicated in renal failure

Risk of lactic acidosis (rare)
Gastrointestinal side-effects
Sulfonylureas
Insulin secretagogueeffective glucose

lowering
Late postprandial hypoglycemia

Weight gain
Thiazolidinediones
p insulin sensitivity
p safe lipid storage in peripheral fat
r triglycerides, p HDL
Weight gain, uid retention

p incidence of cardiac failure
1.52.5w p fracture risk
Uncertain effect on cardiovascular risk
Alpha-glucosidase
inhibitors
Inhibit oligosaccharide breakdown at intestinal

brush border
r postprandial glucose rise from complex
carbohydrates
Low efficacy in diets already low in complex
carbohydrates
DPP-4 inhibitors
(gliptins)
p GLP-1 (incretin) levelsstimulate glucosedependent insulin secretion, r glucagon

No weight gain
CVD, cardiovascular disease; DPP-4 inhibitors, dipeptidyl-4 inhibitors; GLP-1, glucagon-like peptide 1; HDL, high-density lipoprotein
emptying, reduce glucagon secretion and signal to the CNS

to inhibit appetite. GLP-1 analogues effectively lower glucose
levels with low risk of hypoglycemia and promote weight loss,
but may cause nausea. Exenatide and liraglutide are synthetic
GLP-1 analogues administered by subcutaneous injection.
Amylin (islet amyloid polypeptide, IAPP) is co-secreted
with insulin by beta-cells, slowing gastric emptying and
decreasing glucagon production. Pramlintide is a synthetic
amylin analogue used to control postprandial glucose excursion when administered subcutaneously with insulin.
The major end-organ complications of diabetes are listed in
Box 11-10.
Hyperglycemia is the primary cause of tissue damage.
The process is modified by individuals genetic susceptibility and independent accelerating factors such as hypertension and insulin resistance. Cells which are unable to
down-regulate glucose transport are vulnerable to hyperglycemic damage. These include capillary endothelial cells of
the retina, mesangial cells in the glomerulus, neurons and
Schwann cells, and vascular endothelium.
Diabetic eye disease triad

1 Microaneurysm formation and microhemorrhages (dot
and blot hemorrhages).
2 Exudates.
3 New vessel proliferation. Hemorrhage or edema in the
macula region can lead to blindness.
With regular eye screening, proliferative retinopathy and
clinically significant macular edema can be identified early
310
Box 11-10
Micro- and macrovascular

complications of diabetes
Microvascular
Retinopathy
Macrovascular
Ischemic heart disease
Nephropathy
Cerebrovascular disease
Peripheral vascular disease
Autonomic
neuropathy
and treated with laser photocoagulation before visual loss

ensues. Diabetes also increases the risk of other eye disease
such as cataract and glaucoma.
Diabetic kidney disease

Diabetic nephropathy (Table 11-16) is the most common
cause of end-stage renal disease (ESRD) in many countries.
Nephropathy is associated with a 2040 times increase in
mortality, mostly from cardiovascular disease. Urine albumin excretion reflects the stages of nephropathy. For screening
and monitoring, a morning spot urine albumin:creatinine ratio is an
acceptable surrogate for albumin excretion rate.
The primary management aim is to prevent the progression from normoalbuminuria to microalbuminuria
and macroalbuminuria, as cardiovascular risk and risk of
ESRD increases with each stage. Optimized glycemic control, BP control (<130/80 mmHg, or <125/75 mmHg if
Table 11-16 Stages of diabetic nephropathy
Box 11-11
Cardiovascular management of the

asymptomatic patient with diabetes
URINE ALBUMIN
EXCRETION
STAGE
1. Glomerular
hyperltration, increased
kidney size
<20 microg/min or
30 mg/day
2. Early glomerular lesions
<20 microg/min or
30 mg/day
3. Microalbuminuria
20200microg/min or
30300 mg/day
4. Overt nephropathy/
macroalbuminuria
>200microg/min or
>300 mg/day
5. End-stage renal disease

(ESRD)
overt nephropathy) and blockade of the reninangiotensin

aldosterone system are key factors.
Autonomic neuropathy
Diabetic autonomic neuropathy may manifest in multiple
organ systems (Table 11-17) and significantly impairs quality of life. It is a strong predictor of mortality.
Cardiovascular disease
Hyperglycemia, along with other common diabetes-related
conditionshypertension, dyslipidemia, obesity, endothelial dysfunctioncontribute to a three- to four fold risk of
cardiovascular disease in people with diabetes. Patients with
diabetes may have atypical presentations of cardiac ischemia
(e.g. silent infarcts), and have greater risk of re-occlusion
after coronary revascularization. Additionally, autonomic
neuropathy (poor rhythm control) and diabetic cardiomyopathy contribute to poor outcome. Modifiable cardiac risk
factors should be optimized (Box 11-11).
Diabetic foot disease

The combination of peripheral neuropathy, autonomic
neuropathy, vascular disease and predisposition to infection places the diabetic foot at high risk of disease. Clinical
Table 11-17 Manifestations of diabetic autonomic
neuropathy in different organ systems
Cardiovascular
Tachycardia, orthostatic hypotension,

loss of heart rate variability
Neurovascular
Anhidrosis or hyperhidrosis, altered

skin blood ow
Gastrointestinal
Constipation, gastroparesis, diarrhea

and incontinence
Genitourinary
Erectile dysfunction, retrograde

ejaculation, neurogenic bladder
Metabolic
Hypoglycemic unawareness
Risk factor modication

Cholesterol: target LDLs <2 2.5 mmol/L, HDLs
>1.0 mmol/L
Blood pressure: target <130/80 mmHg
Weight reduction if overweight/obese, diet and
lifestyle advice, smoking cessation
Consideration of anti-platelet agents, renin
angiotensinaldosterone system blockade, if multiple
risk factors
Consider screening for cardiac ischemia if evidence of
other vascular disease elsewhere
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
manifestations include ulcers, osteomyelitis or Charcots

neuroarthropathy. Diabetes is the leading cause of lower
limb amputation in developed nations.
In addition to glycemic control and minimizing vascular
risk factors, regular foot care and clinical testing for peripheral neuropathy is advised.
Hypoglycemia
Normal blood glucose is maintained during fasting by the
mobilization of glucose from glycogen stores (predominantly
from the liver), and by activation of gluconeogenesis from various substrates including glycerol (derived from adipose stores
of triglyceride) and amino acids. Gluconeogenesis is activated
in the liver by the action of glucagon, and requires reduced
insulin signaling. Catecholamines, cortisol and growth hormone are also potent stimulators of hepatic glucose synthesis.
The release of these hormones, termed glucose counter-regulatory
hormones, is stimulated in response to hypoglycemia.
Hypoglycemic symptoms are related to:
activation of the sympathetic nervous system and
appetite center
sweating, tachycardia, tremulousness, anxiety,
hunger
brain dysfunction secondary to decreased levels of glucose
confusion, impaired concentration, altered level
of consciousness
focal impairments (e.g. hemiplegia)
seizures, coma and death
generalized glycopenia to metabolizing tissues
weakness and fatigue.
Adrenergic symptoms usually precede the neuroglycopenic
symptoms and provide an early warning of hypoglycemia to
the patient.
The primary stimulus for the release of catecholamines is
the absolute level of plasma glucose; the rate of decrease
is less important.
The blood glucose threshold for onset of hypoglycemic symptoms is variable, but most people experience
symptoms at <3.0mmol/L (55 mg/dL). This threshold
decreases with repeated episodes of hypoglycemia, and
311
some patients with repeated events can have almost no

symptoms until unconsciousness ensues (hypoglycemic
unawareness).
Hypoglycemic unawareness is associated with increased
mortality, especially in the setting of cardiovascular
disease.
In the context of diabetes, hypoglycemia is commonly
precipitated by:
reduced dietary carbohydrate intake
increased physical activity
inappropriate timing of drug administration in relation
to food intake
erratic absorption of insulin due to incorrect injection
technique
impaired renal elimination of insulin/other drugs.
Diabetic emergencies
The diabetic emergencies diabetic ketoacidosis and hyperosmolar hyperglycemic state have the features given in
Table11-18. Common precipitants are listed in Box 11-12.
Diabetic ketoacidosis (DKA)
Diabetic ketoacidosis is a complication of severe insulin
deficiency, resulting in hyperglycemia and generation of
ketoacids. In the absence of insulin, there is a lack of glucose
entry to cells. Lipolysis provides fatty acids as a substrate for
production of ketones in the liver, an alternative fuel source
for energy, but also leads to the formation of ketone bodies
which are toxic and acidic.
Precipitants should be sought. Management is with
fluid resuscitation, insulin infusion and correction of
electrolytes.
The cardinal manifestations of DKA are:
hyperglycemia
ketonemia, ketonuria, acetone breath
metabolic acidosis (with anion gap), Kussmaul
respiration
marked dehydration secondary to polyuria, vomiting
potassium depletion, but plasma potassium may be
initially high due to acidosis.
Box 11-12
Common precipitants of diabetic

ketoacidosis or hyperosmolar
hyperglycemic state
Sepsis
Acute myocardial infarction
Stroke
Glucose-raising medications, e.g. corticosteroids
Alcohol abuse
Stopping/reducing insulin (e.g. if unwell, vomiting)
Hyperosmolar hyperglycemic state (HHS)

Hyperosmolar hyperglycemic state is a complication of
insulin deficiency, occurring in people with T2DM. Insulin
secretion is adequate to suppress ketone formation, but as
a result a more insidious progression to severe hyperglycemia, hyperosmolarity and dehydration occurs. Metabolic
acidosis may be present due to lactate formation, but not
ketoacidosis.

The hormonal changes of pregnancy contribute to a state of
increased insulin resistance, for which beta-cells normally
compensate in order to maintain normoglycemia. Reduced
beta-cell reserves predispose to glucose intolerance, particularly from the late 2nd trimester onwards. New onset
of hyperglycemia or glucose intolerance first recognized
during pregnancy is termed gestational diabetes.
Diabetes in pregnancy has clinical consequences for
both mother (risk of preeclampsia, obstructed labor, assisted
delivery) and fetus (large for gestational age, prematurity,
growth retardation, shoulder dystocia). Intensive BGL
control and monitoring of fetal wellbeing reduce the risk.
GDM is a strong risk factor for future T2DM in the mother
and may predispose the child to later obesity and glucose
intolerance.
Table 11-18 Diabetic emergencies
DIABETIC KETOACIDOSIS
HYPEROSMOLAR HYPERGLYCEMIC STATE
BGL usually >14 mmol/L
BGL usually >33 mmol/L
Acidotic, pH <7.3, ketonemia
No ketonemia, may have mild ketonuria
Mortality <5%
Mortality 15%
Acute onset
Insidious onset over days
Abdominal pain, vomiting, weight loss
Extreme dehydration, high serum osmolality >320 mOsm/kg H2O

Mental obtundation, renal failure, thrombosis
BGL, blood glucose level.
312
Disorders of energy excess

overweight and obesity
Overweight/obesity is a complex chronic disease, influenced by many social, cultural, behavioral, physical and
genetic factors.
Denition
The prevalence of overweight/obesity is assessed using
body mass index (BMI; Table 11-19), although these
are arbitrarily defined cut-points and the risks of disease
increase progressively with increasing BMI.
Abdominal fat is an independent predictor of risk; measurement of waist circumference (men >102 cm/40 in,
women >88cm/35in) assists further risk stratification.
Note that different BMI cut-offs may apply to some ethnic
groups (e.g. lower cut-offs for people of Asian ancestry).
to promoting healthy diet and physical activity, management of comorbidities, and specific interventions to promote weight loss in individuals (Box 11-13).
Pharmacotherapy is an adjunct to a low calorie diet,
physical activity and behavioral therapy in patients who fail
to lose weight by those measures alone and for whom the
risk of obesity-related complications is high. Medications
work by altering neurotransmitters to suppress appetite
(phentermine) or by blocking fat absorption (orlistat).
The aim of bariatric surgery is to manipulate the gastrointestinal tract to reduce net food intake. Substantial
and sustained weight loss is possible compared with other
therapies. Procedures include gastric banding, sleeve gastrectomy and gastric bypass. Operative risks must be balanced with potential benefits. Long-term follow-up is
required, with monitoring for nutritional deficiencies and
other complications.
Epidemiology
More than 1 billion adults are overweight worldwide, and
prevalence is increasing. Rates of obesity in childhood and
adolescence are of particular concern. This epidemic is
occurring in both developed and developing nations and
contributes substantially to healthcare costs.
Health consequences
Overweight/obesity increases the risk of hypertension, dyslipidemia and insulin resistance, which together contribute to the risk of coronary heart disease and stroke. It has
a pathogenic role in conditions such as obstructive sleep
apnea, obesity-hypoventilation, gallbladder disease, osteoarthritis and infertility. Obesity is a risk factor for breast,
endometrial, prostate and colon cancer.
All-cause mortality increases with increasing BMI.
Reduced mobility, inability to work, stigmatization and
discrimination in certain cultural contexts adds to the social
cost.
Management
The metabolic syndrome is a cluster of modifiable factors

occurring in an individual that stem from insulin resistance
and increase cardiovascular risk (Box 11-14, overleaf). Also
known as the insulin resistance syndrome, the criteria were
defined by the World Health Organization in 1998 and have
since been revised by numerous organizations. All definitions share the common features of abdominal obesity, dyslipidemia, hyperglycemia and hypertension.
Depending on the criteria and the population, individuals meeting the definition of the metabolic syndrome
have a two- to threefold increased risk of cardiovascular
morbidity and mortality.
Box 11-13
Management of the overweight/

obese patient
Combating the problem of obesity includes strategies such

as prevention and education, population-based approaches
Table 11-19 World Health Organization classication

of overweight and obesity
CLASSIFICATION
BODY MASS
INDEX
(kg/m2)
Underweight
<18.5
Normal weight
18.524.9
Overweight
25.029.9
Obese
Class I
30.034.9
Class II
35.039.9
Class III
v40
Goal-setting: initially, 10% reduction from baseline

over 6 months, followed by weight maintenance, or a
further attempt at weight loss after reassessment
Dietary advice: individualized plan to create 500
1000 kcal/day (20004000 kJ/day) decit by reducing
total/saturated fat and carbohydrates
Physical activity: most helpful in maintenance of
weight loss in conjunction with caloric restriction. Aim
for 30 minutes of moderate-intensity activity most
days of the week
Behavioral therapy: methods to improve
complianceself-monitoring, stress management,
cognitive strategies, social support
Pharmacotherapy: part of a comprehensive program,
with diet and activity, for body mass index (BMI)
v 30 with no obesity-related comorbidities, or v27
if comorbidities are present
Bariatric surgery: selected adults with clinically severe
obesity (BMI v40, or v35 kg/m2 with comorbidities)
when less-invasive methods have failed and morbidity/
mortality risk is high
313
Box 11-14
NCEP ATP III criteria for the

metabolic syndrome
Any 3 or more risk factors
Obesity: waist circumference v102cm (40in) for
men, v88cm (36in) for women
Triglycerides: v1.7 mmol/L (150 mg/dL), or drug
treatment for elevated levels
HDL cholesterol: <1.03 mmol/L (40mg/dL) in
men, <1.29 mmol/L (50mg/dL) in women, or drug
treatment for low levels
Blood pressure: v130mmHg systolic or v85mmHg
diastolic, or drug treatment for hypertension
Fasting glucose: v5.6 mmol/L (100mg/dL), or drug
treatment for diabetes
The International Diabetes Federation (IDF) criteria (2006)
are similar, but use ethnic-specic cut-offs for waist
circumference + 2 or more risk factors.
ATP, Adult Treatment Panel; HDL, high-density lipoprotein; NCEP,
National Cholesterol Education Program.
The syndrome is also associated with other conditions that are pathologically linked to insulin resistancefatty liver disease, polycystic ovarian syndrome,
hyperuricemia.
Pathogenesis
Patients with this cluster of risk factors have a proinflammatory and prothrombotic state. Adipose tissue, particularly
visceral, is metabolically active, producing free fatty acids
and inflammatory cytokines that result in impaired insulin
signaling, oxidative stress, hepatic production of atherogenic
lipoproteins, and endothelial dysfunction. Together, these
contribute toward the genesis and progression of cardiovascular disease.
Management
Diet and lifestyle management to achieve weight loss, similar to that recommended for T2DM, is essential. Pharmacological management focuses on treating the individual
components (Table 11-20). Addressing other cardiovascular risk factors such as smoking and low-density lipoprotein
(LDL) cholesterol is also key.
Data from the National Institutes of Health, National Heart, Lung,

and Blood Institute www.nhlbi.nih.gov/les/docs/resources/
heart/atp3full.pdf
Table 11-20 Pharmacological management of metabolic syndrome components

Dyslipidemia
Aim to lower triglycerides and LDLs and increase HDL cholesterol

Agents: statins, brates; alone or in combination
Blood pressure
Introduce therapy if BP v140/90 mmHg, or v130/80 mmHg if established

diabetes
No denitive best antihypertensive agent. Drugs targeting reninangiotensin
aldosterone system often used
Insulin resistance
Possible agents that prevent or delay progression from pre-diabetes to

diabetesmetformin, thiazolidinediones, acarbose, orlistat
BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
314
1 Which of the following hormones is not regulated by the hypothalamicpituitary axis?
A Cortisol
B Parathyroid hormone
C Thyroxine
D Estrogen
E Insulin-like growth factor (IGF-1)
2 Which condition of hormonal excess is most likely to be caused by overstimulation by the pituitary tropic hormone
rather than excess peripheral production?
A Hyperthyroidism
B Cushings syndrome
C Conns syndrome
D Hyperprolactinemia
E Acromegaly
3 In a patient with a toxic multinodular goiter, which of the following laboratory ndings would be expected?
A Increased levels of thyroid-stimulating hormone (TSH) receptor and microsomal antibodies
B Increased TSH
C Decreased serum calcium
D Low plasma free T3 and T4
E Increased plasma free T3 and T4
4 A 78-year-old woman from a nursing home presents with features of hyperthyroidism. What is the least likely cause?
A Recent computed tomography scan with intravenous contrast
B Recent viral infection
C Medication error
D Papillary thyroid cancer
E Multinodular goiter
5 Which of the following hormonal conditions is not associated with osteoporosis?
A Prolactinoma
B Precocious puberty
C Hyperthyroidism
D Cushings disease
E Hyperparathyroidism
6 In a patient with hypercalcemia, which of the following ndings is consistent with a diagnosis of primary
hyperparathyroidism?
A Low serum phosphate and an elevated urinary calcium excretion
B High serum phosphate and low urinary calcium excretion
C Soft-tissue calcication and elevated serum calcium/phosphate product
D Low serum vitamin D levels
E Elevated bone mineral density
7 Which investigations are the most appropriate for exclusion of Cushings syndrome?
A 8a.m. serum adrenocorticotropic hormone (ACTH) and cortisol measurements
B 24-hour urinary cortisol excretion and low-dose dexamethasone suppression test
C Serum cortisol and computed tomography scan of the adrenals
D Serum cortisol and magnetic resonance imaging scan of the pituitary
E Short Synacthen (tetracosactide) test
8 Which of the following statements regarding cortisol is true?
A Cortisol circulates in blood bound to albumin as well as a specic cortisol-binding globulin.
B Cortisol acts on target cells by binding to a specic cell-membrane receptor.
C Most of the cortisol released by the adrenals is subsequently excreted unchanged in the urine.
D A signicant amount of cortisol secretion occurs independent of adrenocorticotropic hormone (ACTH) stimulation.
E Cortisol and aldosterone are both made by adrenal cortical cells and are therefore co-secreted under the inuence
of ACTH.
9 In a male with Addisons disease, what forms of treatment are most appropriate?
A Hydrocortisone and salt tablets
B Hydrocortisone and udrocortisone
C Hydrocortisone and spironolactone
D Hydrocortisone and testosterone
E Hydrocortisone and potassium supplements
315
10 Which of these endocrine conditions cannot arise from autoimmune mechanisms?

A Hypothyroidism
B Adrenal insufficiency
C Hypopituitarism
D Type 1 diabetes mellitus
E Insulinoma
11 A 58-year-old man with longstanding type 2 diabetes mellitus has poorly controlled hypertension despite taking
multiple hypertensives. Which of these features would not be suggestive of a non-diabetes-related endocrine cause of
hypertension?
A Signicant proteinuria
B Low serum potassium
C Episodes of sweating and palpitations
D Pigmented striae
E A history of hypercalcemia
12 A 40-year-old man complains of severe fatigue, low libido and loss of muscle strength. The most appropriate
investigations include:
A Serum gonadotropins, early morning testosterone and cortisol, thyroid-stimulating hormone (TSH)
B Early-morning luteinizing hormone (LH) and follicle-stimulating hormone (FSH), adrenocorticotropic hormone
(ACTH), TSH, testicular ultrasound
C Random testosterone, prolactin, dexamethasone suppression test, free T3
D 24-hour urine cortisol, pituitary magnetic resonance imaging, early-morning LH/FSH and growth hormone
E Glucose tolerance test, 24-hour urine testosterone, short Synacthen (tetracosactide) test, prolactin
13 Which of the following is not a cause of amenorrhea/oligomenorrhea?
A Polycystic ovarian syndrome
B Congenital adrenal hyperplasia
C XXY karyotype
D Hashimotos thyroiditis
E Prolactinoma
14 Which of the following are characteristic of polycystic ovarian syndrome?
A Hirsutism, insulin resistance, onset in late adulthood
B Hyperandrogenism, insulin resistance, anovulation
C Virilization, increased risk of type 1 diabetes mellitus, appearance of multiple peripheral ovarian cysts on ultrasound
D Hyperandrogenism, increased risk of gestational diabetes, earlier age at menopause
E Acne, increased risk of type 1 diabetes mellitus, anovulation
15 In which of these conditions would you expect to nd low C-peptide levels?
A Polycystic ovarian syndrome
B Newly diagnosed type 2 diabetes mellitus
C Insulinoma
D Sulfonylurea overdose
E Exogenous insulin overdose
16 A 28-year-old woman has persistent polyuria and thirst. A random laboratory blood glucose measurement is
12.2 mmol/L, and on a second occasion is 14.1 mmol/L. Which test should be done to conrm the diagnosis of diabetes
mellitus?
A Fasting blood glucose
B Glucose tolerance test
C Insulin tolerance test
D Islet cell autoantibodies
E No further tests necessarythe results are already diagnostic.
17 What is the most sensitive investigation for detecting diabetic nephropathy?
A Creatinine clearance rate
B Urine microscopy
C Urinary microalbumin excretion
D Urinary protein electrophoresis
E Serum creatinine
18 Which statement is true regarding type 1 diabetes mellitus?
A Early in the disease, patients may be treated with oral hypoglycemic drugs.
B In the absence of visual symptoms, diabetic retinopathy is unlikely to be present.
C Women with type 1 diabetes mellitus should be advised against undertaking pregnancy.
D Autoimmune destruction of beta-cells precedes onset of hyperglycemia by a period of months to years.
E All patients should aim for a target HbA1c of <7%, to minimize the risk of complications.
316
19 Which of the following conditions is not associated with insulin resistance?

A Pheochromocytoma
B Diabetes insipidus
C Cushings syndrome
D Acromegaly
E Polycystic ovarian syndrome
20 Regarding obesity, which of the following statements is true?
A Bariatric surgery is rarely recommended in severe obesity due to the increased anesthetic risk.
B Obese diabetic patients should receive insulin therapy as rst-line, as they are unlikely to respond to oral
hypoglycemic agents and strict glycemic control is essential.
C Obesity increases the risk of comorbid conditions such as cancer, osteoarthritis and cardiovascular disease.
D The most common cause of severe obesity is an endocrinological condition such as Cushings disease,
hypothyroidism or polycystic ovarian syndrome.
ANSWERS
1 B.
Parathyroid hormone secretion is regulated by serum calcium levels acting at the calcium-sensing receptor on the surface
of parathyroid cells.
2 E.
The high insulin-like growth factor (IGF-1) levels of acromegaly typically result from excess growth hormone secretion
from a pituitary tumor.
3 E.
Autonomously secreting nodules within a toxic multinodular goiter secrete excess amounts of T3 and T4, which are not
regulated by negative feedback from the pituitary.
4 D.
Most thyroid cancers are non-functional and do not secrete thyroid hormone. Exposure to excess iodine and viral
infections can both result in thyroiditis and an excessive release of thyroid hormone from the thyroid gland.
5 B.
An early puberty advances bone age. Bone density is increased, appropriate for bone age. High prolactin levels increase
the risk of osteoporosis by suppressing the gonadotropinsex steroid axis. High levels of thyroid hormone, cortisol and
parathyroid hormone all increase bone resorption.
6 A.
Parathyroid hormone decreases phosphate reabsorption in the proximal tubule. Although parathyroid hormone stimulates
renal calcium reabsorption, the net effect of high serum calcium levels is increased urinary excretion.
7 B.
A single random cortisol measurement is generally not useful in the evaluation of excess cortisol secretion. Both 24-hour
urine free cortisol and dexamethasone suppression tests are used as screening tests for Cushings syndrome. Earlymorning cortisol levels and short Synacthen test are used to evaluate adrenal insufficiency rather than excess.
8 A.
Cortisol secretion from the zona fasciculata of the adrenal cortex is stimulated by ACTH, while aldosterone secretion
from the zona glomerulosa is under the control of the reninangiotensin system. Cortisol is protein-bound in serum, but
excreted as the free hormone in urine. Being a steroid hormone, it acts on intranuclear receptors.
9 B.
Addisons disease results in autoimmune destruction of the adrenal cortex. Hydrocortisone and udrocortisone are the
respective pharmacological equivalents of cortisol and aldosterone. Adrenal androgen replacement is unnecessary in
males, due to testicular production of androgens (testosterone).
10 E.
Antibodies toward thyroid, adrenal, pituitary or islet cells may result in clinical deciencies of those endocrine organs.
Insulinomas are islet-cell derived tumors, unrelated to autoimmunity.
317
11 A.
Proteinuria may be a feature of longstanding hypertension of any cause and is a typical nding in diabetic nephropathy.
Low potassium may suggest hyperaldosteronism; sweating and palpitations are associated with pheochromocytoma; and
pigmented striae suggest Cushings syndrome. Hypercalcemia has been linked to hypertension.
12 A.
Androgen deciency is best assessed by measurement of an early-morning testosterone. Gonadotropins will be elevated
if there is a primary testicular defect. Cushings syndrome and hyperthyroidism can also produce symptoms of weakness
and fatigue.
13 C.
Individuals affected by Kleinfelter syndrome have an XXY karyotype and a male phenotype.
14 B.
Features of polycystic ovarian syndrome may include clinical and/or biochemical hyperandrogenism, ovulatory
disturbance and insulin resistance, with increased risk of type 2 and gestational diabetes. It typically manifests in early
adulthood.
15 E.
C-peptide is enzymatically cleaved from the pro-insulin molecule and co-secreted with insulin from beta cells. C-peptide
is therefore elevated in conditions of high insulin secretion such as insulin resistance, insulinoma or exogenous stimulation
by sulfonylureas. As exogenous insulin suppresses endogenous insulin production, C-peptide levels will be low.
16 E.
Two random blood glucose readings above 11.1 mmol/L and the presence of typical symptoms are sufficient for the
diagnosis of diabetes, and a glucose tolerance test is not required for conrmation. Islet cell autoantibodies may assist in
classication of the type of diabetes, but are not used for diagnosis.
17 C.
The earliest clinical evidence of diabetic nephropathy is the presence of an abnormal level of albumin in the urine.
Changes in creatinine occur late.
18 D.
Ongoing autoimmune destruction of beta cells ultimately results in inadequate secretion of insulin to maintain glucose
homeostasis. Target levels of glucose control should be individualized, according to clinical need. Pregnancy outcomes
are good if tight glycemic control can be achieved during gestation.
19 B.
Diabetes insipidus is a disorder of water balance, unrelated to mechanisms of glucose homeostasis.
20 C.
Obesity is associated with increased risk of malignancies, including colorectal, endometrial, esophageal, pancreatic,
renal and postmenopausal breast cancer. Excess weight increases mechanical stress on joints. It increases cardiovascular
risk both directly and indirectly through contributing toward hypertension, dyslipidemia and insulin resistance/glucose
intolerance.
318
CHAPTER 12
GASTROENTEROLOGY
Magnus Halland, Vimalan Ambikaipaker, Kara De Felice and Nicholas J Talley
CHAPTER OUTLINE
ESOPHAGUS
Dysphagia
Motor disorders
Esophagitis due to causes other than acid reux
STOMACH

Tumors
Gastroparesis
SMALL BOWEL
Celiac disease
Diarrhea
Malabsorption
Microscopic colitis
Tropical sprue
Small-intestinal bacterial overgrowth (SIBO)
Chronic idiopathic intestinal pseudo-obstruction
(CIIP)
NUTRITIONAL DEFICIENCY
Nutritional assessment in end-stage liver disease
LARGE BOWEL

Constipation
Colon polyps
BOWEL CANCER SCREENING

surveillance
GASTROINTESTINAL BLEEDING
Upper
Lower
Obscure GI bleeding
PANCREAS
Acute pancreatitis
Pancreatic cysts
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ESOPHAGUS
CLINICAL PEARL
Dysphagia
Difficulty swallowing is termed dysphagia. Patients usually
report the sensation of incomplete passage or a sensation of
hold-up of the swallowed bolus. Dysphagia can occur with
both solids and liquids, and symptom patterns are helpful
in differentiating between oropharyngeal and esophageal
causes.
CLINICAL PEARL
Prominent coughing, choking and aspiration points
toward oropharyngeal causes, while retrosternal pain
and hold-up indicates esophageal disease.
Stroke is the most common cause of oropharyngeal dysphagia, but other neurological disorders such as Parkinsons
disease and motor neuron disease, and inclusion body myositis should be considered.
It is also useful to consider whether the disease is structural
or a motility disorder.
If dysphagia is for solids and progressing, structural
causes are likely. Structural causes of esophageal dysphagia include:
strictures (benign and malignant)
rings and webs
eosinophilic esophagitis (Figure 12-1)
Zenkers diverticulum (an acquired pouch in
the upper esophagus due to cricopharyngeal
hypertrophy).
If dysphagia is for both solids and liquids, a motor disorder should be considered. True motor disorders of the
esophagus are rare, with achalasia and pseudoachalasia
the most prevalent.
Generally, a narrowing in the esophagus to less than

13 mm can cause symptoms. Most endoscopes are
9 mm and can therefore miss strictures. An esophagram, preferably with administration of a 13 mm barium
tablet, can be helpful.
The presence of pain on swallowing, odynophagia, generally

means that esophagitis or ulcerated mucosa is present. An
infectious cause or pill esophagitis is often identified in this
circumstance.
Investigation
Although history and physical examination are very helpful
in establishing the differential diagnosis for dysphagia and/
or odynophagia, further investigation is always warranted.
The initial test of choice is usually a barium swallow,
as proceeding directly to endoscopy is risky due to the
possibility of a Zenkers diverticulum which can perforate during endoscopy.
Video-fluoroscopy and nasopharyngeal laryngoscopy
are also particularly helpful in patients with oropharyngeal dysphagia.
Esophageal manometry is used when endoscopy fails to
show a cause, and can differentiate between motor disorders. The characteristic finding of failure of relaxation
of the lower esophageal sphincter and no esophageal
peristalsis is found in achalasia.
Endoscopy is indicated in nearly all patients with dysphagia. It has the capacity to obtain tissue biopsies as
well as to increase the luminal diameter by dilatation if
required.
CLINICAL PEARL
A rare but under-recognized cause of dysphagia is
lichen planus with esophageal involvement. Examine
the oral cavity of every patient with dysphagia, and ask
female patients about dyspareunia as this is often present and supports the diagnosis.
Motor disorders
Achalasia
Figure 12-1 (A) Ringed esophagus in eosinophilic

esophagatis. (B) Tear post dilatation (same case)
From Flint PW et al. Cummings Otolaryngology, 5th ed. Philadelphia:
Elsevier, 2010.
320
Achalasia is a rare esophageal motor disorder caused by

myenteric plexus nerve degeneration. The underlying etiology remains unknown.
The hallmarks of this disorder are failure of the lower
esophageal sphincter to relax during swallowing, and
absent peristalsis in the esophageal body.
Patients often present with dysphagia, which typically
includes difficulty with swallowing liquids as well as
solids. Symptom progression is usually slow, and weight
loss is common.
Typical age at diagnosis is between 25 and 60 years, and
both genders are equally affected.
Chapter 12 Gastroenterology
No single test is diagnostic and patients should undergo

triple testing as outlined below.
CLINICAL PEARLS
Difficulties with belching and nocturnal regurgitation of ingested food in the setting of dysphagia are
highly suggestive of achalasia.
Due to the slowly progressive nature of achalasia, patients learn to adapt. Ask patients if they walk
around during meals and raise their arms to facilitate
passage.
The diagnosis is most commonly made in patients who

undertake esophageal manometry as part of a diagnostic work-up for non-cardiac chest pain or dysphagia. The
pathogenesis and natural history of DES are poorly understood, but treating gastroesophageal reflux disease improves
symptoms in a proportion of patients. Patients should avoid
cold liquids, as this is a precipitant.
Medical therapy with calcium-channel antagonists, tricyclic antidepressants, or sildenafil improves symptoms in
some patients. Botulinum toxin injection can also provide
temporary relief for patients with DES.

Investigation
Triple testing should be performed:
1 Barium swallowA barium study will often reveal a
bird-beak-like narrowing distally with hold-up of barium above. The degree of dilatation of the esophagus is
most accurately appreciated with this test.
2 Endoscopyclassical findings on endoscopy include a
dilated esophagus with pooled saliva or food residue.
3 Esophageal manometrycommon manometric findings
are lack of peristalsis along with a lower esophageal
sphincter (LES) that fails to relax with swallowing.
Treatment
Treatment aims at relieving the LES pressure, which can
be achieved through pneumatic endoscopic dilatation or
laparoscopic Hellers myotomy. Newer endoscopic techniques, in which an a endoscopic myotomy is performed,
are emerging as possible alternatives to surgery.
Medical therapy with calcium-channel blockers is generally ineffective, but can be trialed in patients who are unwilling or have comorbidities that prevent surgery or dilatation.
Botulinum toxin injection is short-lived (6 months)
and wears off, so is reserved for high-risk patients (e.g. very
elderly or with severe medical comorbidities) or can be of
use if the diagnosis is unclear. Repeated botulinum toxin
injections should be avoided in patients who are surgical
candidates as this may negatively affect surgical outcomes.
Conditions that can mimic achalasia include tumors at
the gastroesophageal junction (pseudoachalasia), which is
why endoscopy is a crucial part of the diagnostic work-up.
Rarely, paraneoplastic syndromes can cause a similar picture. Rapid progression of symptoms, profound weight loss
and late onset (> age 60) are all red flags for possible esophageal cancer.
Rarely, an infection with the protozoan Trypanosoma cruzi
can mimic achalasia. This should be thought of in patients
from South America or if cardiomyopathy and megacolon
are also present.
Diffuse esophageal spasm (DES)

This rare condition is an esophageal motility disorder characterized by simultaneous, non-peristaltic contractions
of the esophagus. Barium swallow may show a corkscrew
esophagus.
Gastroesophageal reflux disease is present when the esophagus is exposed to acidic stomach contents, which may or
may not lead to symptoms. Symptomatic patients notice
heartburn, regurgitation or chest pain. Extra-esophageal
manifestations can include:
chronic cough
vocal cord dysfunction
hoarseness
asthma.
Pathophysiologically, reflux occurs when the intraabdominal pressure exceeds the resting LES pressure, or
when inappropriate relaxations of the LES occur. Obesity
is a factor.
Triggers for LES relaxation include:
alcohol
pregnancy
smoking
caffeine
fatty foods and large meal size.
A diagnosis of GERD can be made on clinical grounds and
confirmed by endoscopic evidence of reflux esophagitis.
Endoscopy can also identify complications of GERD such as
strictures or Barretts metaplasia. Endoscopy is often completely normal (>70%), allowing a diagnosis of non-erosive
reflux disease (NERD) to be made.
CLINICAL PEARL
Reux symptoms in young patients who respond to
therapy in the absence of alarm features do not routinely require endoscopy.
Ambulatory reflux monitoring is useful when endoscopy is normal and the diagnosis is unclear. This should be
considered in patients without typical reflux symptoms,
and possible extra-esophageal symptoms such as hoarseness
and throat discomfort. Newer techniques allow endoscopic
placement of pH electrodes, avoiding the need for a nasogastric catheter. Correlation between symptoms and reflux
events is crucial for determining the likely success of antireflux surgery in those in whom proton-pump inhibitors
(PPIs) fail to improve symptoms.
321
Treatment
Treatment depends on the severity of symptoms and evidence of complications.
On-demand antacids and histamine-2 receptor antagonists are appropriate for patients with mild symptoms,
in conjunction with addressing lifestyle factors such as
meal size reduction, avoidance of dietary triggers, and
reduction in weight.
Regular PPI therapy is required to control symptoms
in most patients, and is generally effective. Patients
with moderate to severe esophagitis need long-term
therapy.
A minority of patients have persistent symptoms on
maximal medical therapy, and anti-reflux surgery
should be considered in carefully selected patients
after appropriate lifestyle modification has taken place.
Esophageal manometry should be performed prior to
surgery to rule out achalasia and to assess preoperative
peristalsis.
CLINICAL PEARL
Anti-reux surgery works best in patients with gastroesophageal reux disease who do not respond to
proton-pump inhibitor therapy.
Barretts esophagus
The hallmark of this condition is the metaplasia of squamous
esophageal epithelium into specialized intestinal columnar
type epithelium. This is a pre-malignant condition, although
the progression to adenocarcinoma is low in absolute terms
(0.20.5% per year). The greatest risk is observed in Caucasian males, obese patients, and those with longer segments
of disease. Screening is generally not recommended, but
can be considered in white males over 50 with longstanding
(>10 years) reflux symptoms who are at highest risk. Other
risk factors include smoking, abdominal adiposity and diabetes mellitus. Regular surveillance is recommended to
identify patients with dysplasia or early malignancy.
Non-dysplastic Barretts requires 5-yearly endoscopy
with biopsies taken at 2 cm intervals in the diseased segment. Targeted biopsies should be taken from any nodular or inflamed area of Barretts. The detection of dysplasia
alters management:
Low-grade dysplasia is more closely followed (6 months
rather than annually if no progression of dysplasia
occurs).
High-grade dysplasia requires treatment to prevent progression to cancer. Traditionally esophagectomy was
the preferred treatment, but newer modalities such as
radiofrequency ablation and other endoscopic therapies
are now recommended as first-line invasive alternatives
for high-grade dysplasia in selected patients.
No convincing evidence for ablation of low-grade dysplasia or non-dysplastic Barretts currently exists.
322
Esophagitis due to causes other than

acid reux
Eosinophilic esophagitis (EoE)
CLINICAL PEARL
Consider eosinophilic esophagitis in young patients
with repeated episodes of food bolus obstruction.
Eosinophilic esophagitis is characterized by intense eosinophilic infiltration of the esophagus, leading to inflammation and submucosal fibrosis. An esophageal biopsy with an
eosinophil count v15 eosinophils per high-power field (eos/
hpf) is generally accepted as diagnostic.
The pathogenesis is incompletely understood, although
chemokine eotaxin-3 is involved. The incidence is rising.
The general concept is that EoE is an allergic disorder,
which can respond to immune suppression or careful dietary
modification to identify the offending food.
The disorder affects children and adults, and the most
common symptoms are dysphagia or food impaction. In
particular, a history of intermittent dysphagia or recurrent
food bolus obstruction, rather than progressive symptoms,
should raise suspicion. Many patients with EoE have a history of atopy and asthma. Characteristic endoscopic findings
include concentric rings and longitudinal fissures, although
these are present in only a minority of cases.
Treatment
A trial of high-dose PPIs for 8 weeks is recommended
as first-line therapy, as reflux can also lead to esophageal
eosinophilia and some patients with true eosinophilic
esophagitis respond to PPIs alone.
Swallowed topical steroids are standard therapy when
response to PPIs is inadequate. Many clinicians use a
12-week course of fluticasone (440 microg twice a day)
with oral prednisone for refractory patients.
Recurrence frequently occurs after cessation of therapy.
Despite medical therapy some patients require esophageal
dilatation to manage their symptoms, which carries a higher
than usual risk of perforation.
Esophageal infections
Bacteria, viruses and parasites all have the ability to cause
esophagitis, but viral esophagitis is most commonly encountered in clinical practice. The major risk factor is immunosuppression, although herpes simplex virus type 1 can
occasionally infect immunocompetent persons.
Common to most esophageal infections is the presence
of chest pain, odynophagia and dysphagia. Systemic symptoms and signs of infection are often present and include
fever, malaise, chills and fatigue. Peripheral blood examination often shows leukocytosis. Endoscopic findings vary
from discrete small ulcers to severe esophagitis with giant,
confluent ulcers. The diagnosis is confirmed by demonstrating inclusion bodies on esophageal biopsies.
Therapy is directed at the underlying viral cause (if

known), and is supportive when oral intake is compromised.
The most common viral causes are:
1 herpes simplex virus types 1 and 2
2 cytomegalovirus
3 varicella zoster
4 human immunodeficiency virus.
Fungal infections other than Candida infection are rare and
usually occur in the setting of severe immunosuppression,
or among those who are using topical steroid therapy in
the upper aerodigestive tract. This should be considered
inpatients on chemotherapy who develop dysphagia.
Pill esophagitis
Many medications have the potential to cause inflammation
in the esophagus if lodged there. Often another condition
is present that leads to pill retention, such as achalasia or a
stricture.
Oral bisphosphonates are commonly the offending
agent. Other high-risk tablets include:
tetracycline antibiotics and non-steroidal antiinflammatory agents including aspirin
oral potassium supplementation as well as prednisone
tablets.
Correction of an underlying esophageal disorder, choice of
an alternative pharmacotherapy, and medication administration advice such as ingesting tablets in the upright position
with generous amounts of water can help to minimize risk.
radiation dose and concomitant therapy with radiosensitizing medications. The most common symptom is odynophagia, and topical treatment (viscous lidocaine or opiates) or
systemic analgesics are usually required. Development of significant strictures often occurs and dilatation is very difficult.
STOMACH
Normal gastric physiology includes the ability to produce
hydrochloric acid and other digestive secretions. While acid
is useful in nutrient processing and absorption, the potential
for inducing or potentiating gastric mucosal injury is always
present.
Gastric acid secretion is closely regulated, with a small
basal rate of excretion which follows a circadian pattern
as well as an on-demand system stimulated by a variety
offactors. The main stimuli for the increased production of
hydrochloric acid are summarized in Table 12-1.
The secretory activity of the parietal cell, which is
responsible for hydrochloric acid production, is tightly regulated by neural and chemical messengers. The main drivers
behind acid production are gastrin and histamine.
Preventing stimulation of the parietal cell is the aim of
many acid-suppressing medications. PPIs directly inhibit
the proton pump, while histamine antagonists reduce acid
secretion by attaching to the histamine receptor and thereby
CLINICAL PEARL
Ask about how patients take their tablets! Many patients
admit to taking tablets with little or no water and while
supine. This often causes pill retention in the esophagus and can lead to esophagitis if the tablet has erosive
potential.
A rare cause of esophagitis is injury due to accidental or

intentional ingestion of corrosive material. Patients who do
not succumb to immediate complications such as bleeding and perforation usually develop long strictures that are
difficult to dilate. Surgery may be required if endoscopic
therapyfails.
Radiation
Another cause of esophagitis is radiation therapy, which
is usually evident from the history. Severity is related to
Figure 12-2 Gastric acid secretion. CCK,

cholecystokinin; ECL, enterochromaffin-like cell; G,
gastrin; SST, somatostatin
Table 12-1 Stimuli for gastric acid production
PHASE
RESPONSE
Cephalic
The thought, sight or smell of food increases acid production via vagal stimulation
Gastric
Distension of the stomach leads to G-cell stimulation and gastrin release. Food matter also directly
leads to G-cell stimulation and gastrin release
Intestinal
Nutrient entry into the proximal small bowel also stimulates acid production. The exact mediators
remain unknown
323
blunting the response of gastrin and acetylcholine on the

parietal cells.

Although no consensus definition of dyspepsia exists, this
usually refers to patients who suffer pain or discomfort
located in the upper abdomen.
Meal-related symptoms, such as increased discomfort after eating and the inability to tolerate a normalsized meal, are suggestive of functional (non-ulcer)
dyspepsia.
No physical cause for symptoms can be identified in
the majority of patients. In those with an organic cause,
reflux esophagitis, peptic ulcer disease and malignancy
are the most common explanations.
If alarm symptoms are present, prompt investigation is
required. These include:
age of onset >55 years
unintentional weight loss
dysphagia or odynophagia
anemia or iron deficiency
jaundice
previous gastric surgery
palpable abdominal mass or lymphadenopathy.
If the patient is taking aspirin or non-steroidal antiinflammatory drugs (NSAIDs), the indication should be
reviewed and alternatives sought. Screening and eradication of Helicobacter pylori should be performed in all patients.
Celiac disease needs to be excluded.
For most patients an organic cause cannot be identified
(functional dyspepsia), and reassurance and symptom management is important. PPIs, motility agents and tricyclic
antidepressants can be trialed.
Helicobacter pylori
H. pylori infection is usually acquired in childhood, and
the prevalence is falling in developing nations. All infected
patients have biological gastritis. For those infected, the risk
of peptic ulcers, gastric cancer and B-cell (MALT) lymphoma is increased.
Testing for H. pylori is well established in the following
circumstances:
all patients with current or a previous history of peptic
ulcer disease (PUD)
MALT (mucosa-associated lymphoid tissue) lymphoma
patients with dyspepsia (test and treat if age <55 years).
It is also considered appropriate in patients with:
functional (non-ulcer) dyspepsia
a family history of gastric adenocarcinoma
the requirement for long-term non-steroidal antiinflammatory treatment, to help prevent peptic ulcers
unexplained iron-deficiency anemia.
324
How to test for H. pylori

The method of testing for H. pylori depends on whether the
patient requires endoscopy or not.
CLINICAL PEARL
Endoscopy for the sole purpose of testing for Helicobacter pylori is not cost-effective and a noninvasive
method should be chosen.
Invasive tests (endoscopy)

Rapid urease tests
A piece of gastric mucosa is placed in agar containing urea and a pH reagent. The presence of urease, an enzyme produced by H. pylori, leads to urea
breakdown and a change in pH which is detected by
a change in color.
False-positive tests are rare, but false-negative
results can occur when patients are acid-suppressed.
False-negative results also occur during gastrointestinal (GI) bleeding.
Histology
This is the gold-standard test for H. pylori, but is
more expensive than rapid urease testing and not
routinely performed. It is appropriate if the patient
is on PPI therapy at the time of endoscopy.
Culture
This is rarely performed. Its main role lies in determining bacterial resistance patterns in patients who
fail standard eradication regimens.
Noninvasive
Urea breath testing (UBT) is a simple and reliable test
provided that antacid therapy has ceased 1 week prior to
the test. It can also be used to confirm eradication.
Fecal antigen testing is a highly accurate test for detecting the presence and absence of H. pylori and is not
affected by PPI therapy. It is most often used to confirm
successful eradication.
Serological testing is widely available and inexpensive,
but cannot distinguish between current and past infection, and is less accurate than other tests.
CLINICAL PEARL
Urea breath testing is affected by the use of
proton-pump inhibitors (PPIs), and a negative test for a
patient on PPIs needs conrmation.
Treatment
All patients should initially receive triple therapy (protonpump inhibitors and two antibiotics). See Table 12-2 for
treatment options.
Table 12-2 Options for therapy for Helicobacter pylori infection
REGIMEN
DRUGS
DURATION
ERADICATION
RATES
Triple therapy
Proton-pump inhibitor (PPI) twice daily

Amoxicillin 1g twice daily
Clarithromycin 500 mg twice daily
714 days
7085%
Quadruple
therapy
PPI twice daily

Bismuth subcitrate 525 mg four times a day
Metronidazole 250 mg four times a day
Tetracycline 500 mg four times a day
1014 days
7590%
Sequential therapy
PPI and amoxicillin 1g twice daily for 5 days

followed by:
PPI (twice daily) plus clarithromycin (500 mg twice daily)
and tinidazole (500 mg twice daily) for 5 days
10 days
>80%
Testing for eradication after therapy

Current guidelines recommend confirmation of eradication
in specific groups of patients:
peptic ulcers caused by H. pylori
persistent dyspepsia after treatment
patients with MALT lymphoma
patients with early gastric cancer.
Testing for eradication is best done with UBT or fecal antigen testing, but must occur at least 4 weeks after H. pylori
therapy and preferably with the patient off PPI therapy.
Patients who are persistently infected after two courses of
therapy should be reviewed by a specialist.

Gastritis is not a clinical diagnosis, but is made by endoscopic and microscopic examination of gastric tissue. The
hallmark of this disorder is the presence of inflammatory
cells in the gastric mucosa. Causes include:
infectionsH. pylori, human immunodeficiency virus
(HIV)
autoimmunepernicious anemia
drug-inducednon-steroidal anti-inflammatory agents
and antibiotics
physiological stresssepsis, admission to intensive care.
Chronic atrophic gastritis is characterized by metaplasia.
Infections and autoimmune processes can lead to metaplastic
changes, which are associated with increased risk of gastric
adenocarcinoma. Rates of progression are too low to recommend screening.
Gastropathy is present when gastric epithelial cells are
damaged without the presence of inflammatory cells. It is
most commonly caused by direct irritation by NSAIDs,
alcohol or portal hypertension.

Peptic ulcer disease occurs most commonly in the elderly
and those with comorbidities. Duodenal and gastric ulcers
now occur with similar frequency. The most common cause

remains infection with H. pylori, and those treated have a very
low risk of becoming re-infected and suffering further ulcers.
The second most common cause is NSAIDs. The ulcer
risk is decreased with cyclo-oxygenase-2 (COX-2) inhibitors, but if they are combined with low-dose aspirin the risk
is identical to any NSAID!
CLINICAL PEARL
Most peptic ulcers are due to Helicobacter pylori or
non-steroidal anti-inammatory drugs.
Rarer causes for PUD include acid-overproduction

states, most commonly due to gastrinoma (Zollinger
Ellison syndrome). Also remember that Crohns disease
can ulcerate mucosa anywhere in the GI tract, including the
stomach and duodenum.
The diagnosis of PUD is often only made once complications are present (bleeding, perforation or stenosis).
Asymptomatic ulcers are often found at endoscopy, and
the symptoms (e.g. abdominal pain) are a poor indicator of
ulcer presence. Endoscopy is the diagnostic test of choice,
and is often therapeutic when complications are present by
the means of epinephrine (adrenaline) injections followed by
gold probe diathermy, or placement of a hemostatic clip.
CLINICAL PEARL
Remember peptic ulcer in the differential diagnosis
of patients with severe abdominal pain or tenderness.
Perforation is possible, and an erect abdominal X-ray
examining for free intraperitoneal air should be undertaken promptly. Endoscopy is contraindicated when
evidence of perforation is present.
Healing of the ulcer is successful in most cases when acid

suppression is coupled with removal of the offending agent,
be it infectious or medication-related. Gastric ulcers usually warrant re-endoscopy and repeat biopsy to make sure an
early malignant lesion has not been missed.
325
Tumors
Gastrinomas/ZollingerEllison syndrome (ZES)
Acid hypersecretion due to a gastrinoma causing peptic
ulcers and diarrhea is termed ZollingerEllison syndrome.
It accounts for less than 1% of duodenal ulcers, and the most
common presenting complaint is diarrhea and/or steatorrhea. The tumor is usually found distant to the ulcer, with
most being located within an anatomical triangle bounded
by the porta hepatis, mid-duodenum and head of the pancreas. Patients with ZES should be screened for multiple
endocrine neoplasia (MEN) type 1 syndrome, which is
present in up to 20%.
The diagnosis is often considered where there are atypical ulcers due to excessive acid despite PPI therapy or when
ulcer disease is coupled with chronic diarrhea.
Most patients who are being worked up for possible ZES
are already on PPI therapy. This makes interpreting serum
gastrin levels difficult, as acid suppression from PPIs commonly causes hypergastrinemia, but an elevated level in a
patient off PPIs is concerning. Many physicians still do a
level while the patient is on PPI therapy, and if this is normal
consider the diagnosis excluded. Differential diagnoses are
given in Box 12-1.
Box 12-1
Differential diagnosis of elevated

serum gastrin levels
Apart from proton-pump inhibitors and histaminereceptor antagonists, differential diagnosis for an elevated
serum gastrin level includes:
renal failure
chronic atrophic gastritis
tumors (ovarian, pheochromocytoma).
gastrin. Only 1:200 of gastric tumors is due to carcinoid.

Episodic flushing, often spontaneous, is common with gastric carcinoid (Figure 12-3). Most patients remain asymptomatic and the metastatic potential is low.
Gastrointestinal stromal tumors (GISTs)

Gastrointestinal stromal tumors arise from mesenchymal
cells. They are often an incidental finding but can also
cause bleeding. Autopsy studies as well as data from capsule
endoscopy indicate that small, benign GISTs are relatively
common. As they are submucosal, biopsies are often normal
and fine-needle aspiration (FNA) using endoscopic ultrasound is often needed to make the diagnosis.
Some GISTs behave in an aggressive manner, leading
to local invasion and metastasis. Despite this, most (80%)
GISTs have mutations in the KIT proto-oncogene which
make tyrosine kinase inhibitors an effective therapy for
many patients. Prognosis is therefore better than most other
metastatic malignancies in terms of survival.
Partial gastrectomy is now rarely performed, and can lead to
complications depending on the size of the gastric remnant
and the integrity of innervation. Many patients experience
dumping syndrome:
sweating
tachycardia
nausea and
diarrhea
if large meals or food containing refined carbohydrates are
consumed.
Dietary changes (frequent small meals, restriction of glucose and lactose) are all that are required for most patients.
CLINICAL PEARL
To diagnose ZollingerEllison syndrome (ZES), a fasting serum gastrin level of >300 pg/mL in a patient off
proton-pump inhibitors is suggestive, while >1000 pg/
mL makes ZES likely.
Cross-sectional imaging, endoscopic ultrasound and

somatostatin receptor imaging is undertaken in most
patients prior to considering resection.
Treatment consists of resection of the tumor in selected
patients, essentially those who are fit and have no evident
metastases. Unresectable gastrinomas are treated with highdose PPIs lifelong.
Carcinoid
Gastric carcinoids usually occur in the setting of a chronically elevated serum gastrin level due to ZES or autoimmune gastritis. The precursor cell is nearly always the
enterochromaffin-like cell (ECL), which is stimulated by
326
Figure 12-3 Marked facial ushing in a patient with

the carcinoid syndrome
From Jayasena CN and Dhillo WS. Carcinoid syndrome and
neuroendocrine tumours. Medicine 2013;41(10):5669.
Long-term vitamin B12 deficiency can arise due to lack

of absorption because of absent intrinsic factor, which is
produced by parietal cells in the stomach.
Bacterial overgrowth causing fat and B12 malabsorption
may occur in a blind loop, and achlorhydria due to loss
of acid-producing cells is a contributing factor.
Gastroparesis
Gastroparesis is the clinical syndrome that occurs due to
impaired gastric emptying. Clinical clues to gastroparesis
include nausea and vomiting which is usually postprandial.
Early satiety and weight loss are commonly seen, along with
abdominal pain. Occasionally gastroparesis is the symptom that leads to the diagnosis of diabetes mellitus. Insidious onset is common, while rapidly progressive nausea and
vomiting is rarely a feature of a gastric motor disorder.
Causes of gastroparesis relate to failure of the nerves
or muscles that control gastric emptying. Diabetic gastroparesis is an important cause, but rarely infiltrative processes
such as amyloidosis or scleroderma produce gastroparesis. In
many patients no cause is found and the disorder is labeled
idiopathic.
The diagnostic work-up consists of endoscopy to rule out
gastric outlet obstruction or other mucosal lesions. Agastric
emptying study (usually a radioisotope-labeled meal) confirms the diagnosis. Small-bowel obstruction needs to be
excluded by appropriate imaging.
Treatment
Treatment should both address the underlying cause (if
identified) and the symptoms.
Tight diabetic control is essential in halting disease progression. Dietary management (small, frequent meals,
split solids and liquids, low in fat, low in fiber) helps.
Pro-motility agents and anti-nausea agents combined
are the mainstay of treatment.
Erythromycin can often help in the acute inpatient
setting, but long-term efficacy is disappointing.
Gastric electrical pacing (surgically placed) helps vomiting in refractory cases.
Currently, patients who fail medical therapy require placement of a percutaneous endoscopic gastrostomy (PEG) or
jejunostomy tube to feed them.
will have one of these alleles but will not necessarily have
celiac disease.
The immune response triggered by gluten leads to
mucosal damage in the small bowel (villous atrophy, crypt
hyperplasia, epithelial lymphocytosis), and malabsorption.
The disease should be expected in patients with:
unexplained iron deficiency
multiple vitamin deficiencies (vitamin D, folate, B12)
abnormal liver function tests
weight loss
diarrhea or steatorrhea
a positive family history
a small bowel biopsy showing subtotal villous atrophy or
epithelial lymphocytosis
growth-delayed children.
Patients with celiac disease often have no symptoms or relatively unimpressive GI symptoms (symptoms like those of
irritable bowel syndrome), dental or skeletal problems (osteoporosis or arthralgia), or infertility. The presence of dermatitis herpetiformis should raise suspicion. Celiac disease
is called the great mimicker for good reason!
CLINICAL PEARL
Many patients with celiac disease are relatively asymptomatic and are found by screening for a positive family history, but their risk of long-term complications is
similar to symptomatic cases, including small-bowel
lymphoma and vitamin deciencies.
Diagnosis
The gold standard diagnosis is demonstration of villous
atrophy on duodenal biopsies (Figure 12-4). The disease can
be patchy in the duodenum, so multiple biopsies are recommended. Some patients may have intact villous architecture
with only intraepithelial lymphocytosis, although this finding is less specific than villous atrophy.
SMALL BOWEL
Celiac disease
Celiac disease is one of the most common autoimmune
diseases, with 1% of the population affected in many populations (northern Europeans have the highest incidence).
Women are more often affected than men. The immune
response is directed toward gluten, which is found in
wheat, barley and rye. Patients who carry HLA DQ2 or
DQ8 alleles are susceptible (so those testing negative to
HLA DQ2 and DQ8 can be ruled out as having celiac disease), although a substantial proportion of the population
Figure 12-4 Subtotal villous atrophy

From Lo A et al. Classication of villous atrophy with enhanced
magnication endoscopy in patients with celiac disease and tropical
sprue. Gastrointestinal Endoscopy 2007;66(2):377-82.
327
Serological markers are useful and sensitive, but due to

imperfect specificity the decision for a lifelong gluten-free
diet should be made on biopsies. Blood tests for celiac disease
are a good first step in patients with consistent symptoms or
when clinical suspicion is present. The best serological tests
are either tissue transglutaminase (tTG) or anti-endomysial
antibodies (not anti-gliadin!).
CLINICAL PEARL
If the tissue transglutaminase (tTG) test is negative,
check the total serum immunoglobulin A (IgA) level, as
the tTG test measures IgA antibodies against tTG and
will be negative in the 12% of the population with IgA
deciency.
Both biopsies and antibody testing are optimal if the

patient is eating gluten. Making the diagnosis after a patient
has commenced a gluten-free diet can be very difficult.
CLINICAL PEARL
HLA DQ2 and DQ8 testing are useful for ruling celiac
disease out, owing to the high negative predictive
value. (A positive test simply means at risk, but in no
way conrms the diagnosis.)
Long-term complications
Patients with untreated celiac disease can develop long-term
complications.
Malabsorption/metabolic:
iron-deficiency anemia
metabolic bone disease
vitamin deficiency
cirrhosis/chronic liver disease
Immunological:
functional asplenia (pathogenesis unknown, pneumococcal vaccine recommended)
Malignancy:
small bowel lymphoma
Neuropsychiatric symptoms.
Capsule endoscopy (small intestinal capsule) is useful in difficult cases to investigate anemia, weight loss or bleeding to
exclude a malignancy.
Box 12-2
Causes of subtotal villous atrophy

Celiac disease
Tropical sprue
Giardia
Bacterial overgrowth
Microsporidiosis
Viral infection
Hypogammaglobulinemia
Lymphoma
ZollingerEllison syndrome
Drugs, e.g. colchicine and neomycin
Radiation and ischemia
particular, are possible causes. Tropical sprue often responds

to 36 months of tetracycline and folic acid. A travel history
is important for the diagnosis of tropical sprue.
CLINICAL PEARL
If there is no response to a gluten-free diet in celiac
disease:
rst consider poor diet adherence or inadvertent
gluten exposure
check the diagnosis (rule out lymphoma, diffuse
ulceration, or collagenous sprue)
consider other concurrent diseases, including lactose intolerance or pancreatic insufficiency, and
treat accordingly.
Diarrhea
It is useful to categorize diarrhea into colonic and small-bowel
diarrhea (Box 12-3). The duration of the diarrheal illness is
important in determining the diagnosis.
Acute diarrhea
Acute diarrhea is defined as increased stool frequency
(>3loose bowel movements daily) or volume (>200g daily)
for less than 14 days.
Box 12-3
CLINICAL PEARL
Patients with celiac disease may be functionally
asplenic, so be aware of the increased risk of sepsis.
Differential diagnosis of subtotal villous

atrophy
Not all flat biopsies are due to sprue (celiac disease)
(Box 12-2). Tropical sprue and bacterial overgrowth, in
328
Characteristics of colonic and

small bowel diarrhea
Colonic diarrhea
Typically presents
with blood, mucus,
tenesmus, urgency
Frequent, smallvolume stools
Small bowel diarrhea

No blood, no mucus, no
tenesmus or urgency
Stools are large in volume,
with modest increase in stool
volume
The common causes are bacterial or viral infection,

medications, and systemic illness.
Viral infection is the most common cause, with norovirus being the most common pathogen. Bacteria are
responsible for more severe acute diarrhea.
The method of transmission most commonly implicated
is fecaloral transmission. Most cases are transmitted
through contaminated water, food or direct person-toperson contact.
Diarrhea may be classified as non-inflammatory or inflammatory (Box 12-4).
The clinical history gives valuable clues to the likely
causative agent in acute diarrhea (Table 12-3).
Vomiting-predominant illness with non-bloody stools
is likely to be related to viral-induced or toxin-induced
food poisoning.
Rotavirus is a common cause of acute diarrhea in
daycare centers and nurseries.
Norovirus is common on cruise ships, in nursing homes, schools and hospitals, and shellfishassociated outbreaks.
If watery diarrhea is predominant, it is more likely to be
due to bacterial infection with or without enterotoxin
production, Escherichia coli, enteropathogenic E. coli,
Vibrio cholerae, V. parahaemolyticus, Campylobacter jejuni,

Salmonella spp., Clostridium difficile, Yersinia enterocolitica,
Plesiomonas spp. or Aeromonas spp. (patients usually present with fever and bloody diarrhea).
Protozoal infections are less common but are associated
with chronic symptoms; causes include Giardia, Cryptosporidium, Isospora belli and Cyclospora. Bloody diarrhea
occurs with Entamoeba histolytica, but also in Campylobacter and Shigella infection.
G. lamblia is often associated with daycare centers,
travellers, and swimming pools.
E. histolytica should be considered in those who have
traveled to endemic areas for more than a month,
and men who have sex with men.
Fever suggests invasive bacteria (e.g. Salmonella, Shigella
or Campylobacter), enteric viruses or cytotoxic organisms
such as C. difficile or E. histolytica.
Systemic features of infectious diarrhea may include
fever, myalgia, malaise, nausea, vomiting and anorexia.
These symptoms do not help distinguish the different
types of infection.
Women who are pregnant have a 20-fold increased risk
of developing listeriosis from meat products or unpasteurized dairy products.
Box 12-4
Common causes of acute and chronic non-inammatory and inammatory diarrhea

Inammatory diarrhea
Bacterial disease:
Shigella
Salmonella
Campylobacter
Yersinia
Vibrio cholerae
Clostridium difficile
Enteropathogenic Escherichia coli
Toxin-mediatedenterohemorrhagic E. coli (057)
Protozoal disease:
Entamoeba histolytica
Strongyloides stercoralis
Mesenteric ischemia
Radiation colitis
Non-inammatory diarrhea
Viral disease:
norovirus
rotavirus
Bacterial disease (toxin-mediated):
Bacillus cereus
Clostridium perfringens
Protozoal disease:
Giardia lamblia
Medication-induced diarrhea:
antacid (containing magnesium)
colchicine
Irritable bowel syndrome
Dietary intolerance
Disaccharidase deciency, e.g. lactase
Table 12-3 Clinical clues to the causative agent involved in acute diarrhea
ORGANISM
INCUBATION PERIOD
FOOD
Staphylococus aureus
16 hours
Salads, meat and dairy foods
Bacillus cereus
16 hours
Rice and meat
Clostridium perfringens
816 hours
Meat and poultry
Escherichia coli (enteropathogenic)
13 days
Fecal contamination of food and water
Campylobacter spp.
25 days
Poultry, unpasteurized milk and water
329
In AIDS, diarrhea of high volume suggests small-bowel

disease. A CD4 count <200/mm3 suggests that infection is likely. If there is fever, consider cytomegalovirus
(CMV), Histoplasma, Cryptococcus and Mycobacterium.
Hepatitis A may occur through fecal contamination of
food and water, and men who have sex with men are at
higher risk.
Diagnosis
Stool culture and microscopy are helpful for making the
diagnosis.
Special culture techniques (e.g. cold enrichment for
Yersinia, sorbitol MacConkey agar for E. coli 0157:H7)
may be needed, and ask for C. difficile toxin if you suspect C. difficile.
About 2040% of acute infective diarrhea cases will
elude diagnosis even with appropriate cultures.
Ova, cyst and parasite identification should be sought if
travelers diarrhea is suspected, or patients are immunocompromised, have persistent diarrhea, or have traveled
to Nepal, Russia or mountainous regions, or there is
persistent diarrhea with exposure to infants in daycare
centers.
In patients in whom bloody diarrhea does not respond to
antibiotics, consideration should be given to sigmoidoscopy
or colonoscopy with random biopsy to investigate the possibility of inflammatory bowel disease (IBD). Crypt abscesses
are found in both infection and IDB, but crypt architectural
distortion only in IBD.
Treatment
The first aim of treatment is to replace fluids and electrolytes.
Most of the time this can be done using oral rehydration
solutions.
In patients incapable of retaining fluids, fluids should
consist of glucose-based solutions as glucose facilitates
the absorption of sodium and water in the face of secretory processes.
If intravenous (IV) hydration is required, normal saline
should be used. If tolerated, the normal diet should be
continued, as this helps to reduce intestinal permeability induced by infection. Some patients develop lactose
intolerance due to loss of brush-border enzymes. This
can last up to several weeks, and these patients need lactose restrictions.
Medications:
The combination of loperamide and antibiotics is more
effective than antibiotics alone in travelers diarrhea.
However, this is not true for inflammatory diarrhea.
Antimotility agents should not be used for the treatment
of patients with acute diarrhea with fever or bloody
stools, as this may enhance the severity of illness due to
toxin retention.
It is important to note that treatment with antibiotics
for non-typhoidal Salmonella may actually prolong shedding of the organism. Thus, treatment is rarely required
unless the host is immunocompromised or at risk for
sepsis.
330
The treatment of E. coli O157:H7 with antibiotics may

induce hemolytic uremic syndrome (HUS). If E. coli
0157:H7 is confirmed, antibiotics are contraindicated.
Campylobacter resistance to quinolones is high; an alternative is erythromycin or azithromycin as first-line
treatment. If empirical therapy is warranted, treatment
with fluoroquinolone for 35 days in the absence of
enterohemorrhagic E. coli or Campylobacter infection can
be considered.
Antibiotic therapy may shorten the course of Shigella
infection and should be considered in severe cases.
Chronic diarrhea
Chronic diarrhea is defined as the frequent passage of stools
(>3/day) or loose stools >25% of the time, or more than
200250g/day lasting more than 1 month. At a fundamental level, the diarrhea is due to excess water in the stools
because absorption of fluid from the lumen is reduced and/
or secretion of fluid is increased.
Irritable bowel syndrome should be distinguished from
chronic diarrhea by its clinical characteristics based on the
Rome III criteria (Box 12-5).
CLINICAL PEARLS
High-volume diarrhea associated with persistent
fasting is indicative of secretory diarrhea.
The presence of abdominal pain and diarrhea without alarm features raises the possibility of irritable
bowel syndrome.
Diarrhea with the presence of hyperpigmentation
raises the possibility of Addisons disease.
Box 12-5
Rome III diagnostic criteria* for

irritable bowel syndrome
Recurrent abdominal pain or discomfort# at least 3 days
per month in the past 3 months associated with 2 or
more of the following:
1 Improvement with defecation
2 Onset associated with a change in frequency of stool
3 Onset associated with a change in form (appearance)
of stool
* Criteria fullled for the past 3 months with symptom onset at
least 6 months prior to diagnosis.
#
Discomfort means an uncomfortable sensation not described
as pain.
From Drossman DA et al. Rome III. The functional gastrointestinal
disorders: diagnosis, pathophysiology and treatment, 3rd ed.
McLean, VA: Degnon Associates, 2006.
Chronic diarrhea can be categorized into the following

subtypes:
watery diarrhea, which is further divided into secretory
and osmotic diarrhea (Table 12-4).
inflammatory diarrhea
fatty diarrhea.
Watery diarrhea
In normal stool, the number of cations [Na+] plus [K+] is
equal to the number of anions [Cl] plus [HCO3] plus other
absorbable anions (e.g. short-chain fatty acids).
Normal stool osmolality is calculated as follows:
Causes of chronic diarrhea

Common causes of chronic diarrhea are listed in Box 12-7.
2 w ([Na+] + [K+]) = 290 mOsm/L
Common causes of chronic diarrhea

by typical stool characteristics
In secretory diarrhea there is no osmotic gap, i.e.

stool osmolality is normal, i.e. 2 w ([Na+] + [K+]) =
290mOsm/L.
In osmotic diarrhea there is a gap because of unmeasured/
osmotically active molecules, i.e. 2 w ([Na+] + [K+])
< 290 mOsm/L .
If stool osmolality is greater than serum osmolality, the stool
collection is faulty.
Non-watery diarrhea
Forms of non-watery diarrhea are described in Box 12-6.
Box 12-7
Osmotic diarrhea
Magnesium, PO4, SO4 ingestion
Carbohydrate malabsorption
Fatty diarrhea
Small bowel overgrowth
Pancreatic exocrine insufficiency
Post-resection diarrhea
Mesenteric ischemia
Severe small bowel mucosal disease (e.g. celiac
disease)
Box 12-6
Forms of non-watery diarrhea

Inammatory diarrhea
Increased white blood cells in the stool
Stool pH is <5.6
Fatty diarrhea
Fecal fat testing:
stool fat excretion >14g/24h suggests
malabsorption or maldigestion
a stool fat concentration of >8% strongly suggests
pancreatic insufficiency
Protein-losing enteropathy
Should be considered in the presence of
hypoalbuminemia but no nephritic syndrome or
hepatic dysfunction. Conrmation via fecal clearance
of alpha-1 antitrypsin (A1A)
Elevated A1A clearance suggests excessive
gastrointestinal protein loss (the positive predictive
value of the test has been found to be 98% and the
negative predictive value is 75%)
Patients with protein-losing enteropathies generally
have A1A clearance values >50 mL/24 h and A1A stool
concentrations
Inammatory diarrhea
Ulcerative colitis
Crohns disease
Pseudomembranous colitis
Infective colitis
Ischemic colitis
Radiation colitis
Colorectal cancer and lymphoma
Secretory diarrhea
Laxative abuse
Bacterial toxins
Ileal bile acid malabsorption
Villous adenoma
Ulcerative colitis and Crohns disease
Microscopic colitis
Vasculitis
Diabetic autonomic neuropathy
Hyperthyroidism
Neuroendocrine tumors, e.g. VIPoma
Malignancy
Drug and poisons
Table 12-4 Secretory vs osmotic diarrhea
SECRETORY DIARRHEA
OSMOTIC DIARRHEA
High volume (>1L/day)
<1 L/day
Stool osmolality is normal, i.e. 2 w ([Na+] + [K+]) = 290

mOsm/L
No osmotic gap, i.e. <50mOsm/kg difference
Stool osmolality is below normal, i.e. 2 w ([Na+] + [K+]) <290

mOsm/L
Osmotic gap >50, often 125mOsm/kg
Persists with fasting
Disappears with fasting
Watery diarrhea; no pus, blood or steatorrhea
Watery diarrhea
331
Clinical clues for making the diagnosis

In the history:
Celiac diseasehistory of gluten intolerance, family history of celiac disease or other autoimmune
disorders
Inflammatory bowel diseaserectal bleeding,
abdominal pain, mucus, tenesmus, family history of
inflammatory bowel disease and other autoimmune
disorders
Pancreatic insufficiencyhistory of foul-smelling
stool, fat-soluble vitamin deficiency, and cystic
fibrosis, or chronic pancreatitis and weight loss
Post-surgeryblind loops leading to small-bowel
bacterial overgrowth, short bowel syndrome,
dumping syndrome
ZollingerEllison syndromerecurrent peptic
ulcer disease and diarrhea
Drugslaxatives, magnesium, antacids, antibiotics, colchicine
Frequent infectionimmunoglobulin deficiency
Milk intolerancelactose intolerance.
In the physical examination:
Marked weight lossconsider thyrotoxicosis, cancer, malabsorption and inflammatory bowel disease
Arthritis with hyperpigmentationWhipples
disease
HyperpigmentationAddisons disease, CronkhiteCanada syndrome (a rare syndrome which
presents with multiple polyps in the digestive
tract, chronic diarrhea, protein-losing enteropathy, alopecia, abnormal atrophy of nails and skin
pigmentation)
Chronic lung diseasecystic fibrosis
Postural hypotensionautonomic dysfunction in
diabetes, Addisons disease
Neuropathydiabetes, amyloidosis
OnycholysisCronkhiteCanada syndrome.
Treatment
Treatment of chronic diarrhea ultimately depends on the
underlying condition. Therapy with anti-diarrhea drugs
(e.g. loperamide) can provide symptomatic relief.
Giardia lamblia infection

Giardia lamblia is a protozoal parasite. It has been associated
with epidemic and sporadic diarrheal illness (noninvasive
disease).
It is an important cause of food- or water-borne disease.
Its incubation period is 714 days. The common route
of transmission between individuals is fecaloral (swimming in infected bodies of water, daycare workers or
parents with young children in diapers).
High-risk individuals include children, international
travelers, immunocompromised individuals, and patients
with hypochlorhydria or cystic fibrosis.
There are two morphological forms: cysts and trophozoites.
Cysts are infectious. Once ingested, they migrate to the
small bowel and trophozoites are released from the cyst.
These cause malabsorption and hypersecretion.
332
Trophozoites that do not adhere in the small bowel

migrate to the large bowel. Here they revert back to cyst
form. Once excreted in the feces, they have the potential to infect again.
About half of those infected clear the infection in the absence
of clinical symptoms. 3045% of individuals present with
symptomatic infection.
Common clinical presentations include diarrhea, malaise, abdominal cramps, bloating, vomiting, weight
loss and fatty stools. Symptoms usually last 24 weeks.
However, chronic symptoms can develop in 50% of
individuals and in the absence of acute illness.
Malabsorption can result in significant weight loss, with
malabsorption of fats, sugars, carbohydrates, vitamin A,
vitamin B12 and folate. Acquired lactose intolerance can
occur in 40% of patients. Stool microscopy should be
done to confirm the diagnosis.
The mainstay of treatment is oral metronidazole for 57
days. Alternatively, albendazole orally daily for 5 days or
single-dose tinidazole can be used.
Entamoeba histolytica
The protozoan Entamoeba histolytica causes amebiasis, and is
transmitted by the fecaloral route (Figure 12-5). It has two
forms: a cyst stage which is infective, and a trophozoite stage
which is invasive. High-risk persons are from poor socioeconomic groups, travelers and migrants.
E. histolytica can cause both intestinal and extraintestinal
complications.
Intestinal complications:
Amebic dysentery/colitistreatment with oral
metronidazole 500750 mg three times a day for
710 days, followed by a luminal agent, paromomycin, or iodoquinol
Extraintestinal complications:
Pulmonaryempyema, often secondary to liver
abscess via development of an effusion, or rupture
of liver abscess into the chest cavity or hematogenous spread. Factors associated with development
of this complication include malnutrition, chronic
alcoholism and atrial septal defect with left-to-right
shunt
Cardiacpericarditis, secondary to rupture of liver
abscess from left lobe of liver
Brainabscess secondary from hematogenous
spread
Spleenabscess
Amebic liver abscess.
Amebic liver abscess

These patients present with fever and right upper quadrant pain with concurrent diarrhea in one-third of
patients. Median incubation is about 12 weeks.
Occasional patients can present with chronic symptoms
of fever, weight loss and abdominal pain. These patients
often present with anemia and hepatomegaly.
Blood tests usually reveal leukocytosis (>10,000/mm3)
without eosinophilia.
Ingestion of fecally contaminated

water or food containing
Entamoeba histolytica cysts
Brain
Invasive disease
10% of cases
Pleural and
pericardial effusions
Self-limiting,
asymptomatic infection
Mucin
layer
Extraintestinal
disease
90% of cases
<1% of cases
Liver
abscess
Mucin
layer
Hematogenous
dissemination
Colon
Excystation
in lumen of
small intestine
Multiplication
of trophozoites
by binary
fission
Colonic
epithelium
Invasion of
colon by
trophozoites
Colitis
In general:
metronidazole, tinidazole, emetine, and dehydroemetine are active in invaded tissues
chloroquine is active only in the liver
tetracycline acts on the bowel wall
paromomycin (10 days), and iodoquinol (20 days) are
luminal agents only.
The use of oral metronidazole 500750 mg three times a
day for 710days has a cure rate of 90%.
IV treatment has no significant advantage, due to metronidazole being well absorbed in the gut.
Percutaneous drainage is not indicated for treatment, as
it does not shorten recovery time.
Asymptomatic patients with E. histolytica should be
treated with an intraluminal agent alone.
Factitious diarrhea
Invasion of mucosa
and submucosa
by trophozoites
CLINICAL PEARL
Colonization
Amebic
cytotoxicity
Neutrophilinduced
damage
Think of factitious diarrhea when there is an increased

fecal osmolar gap (suggesting osmotic laxatives). Urine
analysis is helpful in making the diagnosis.
Encystation
Excretion
of cyst
Gal/GalNAc-specific
lectin
Neutrophils
Figure 12-5 Lifecycle of Entamoeba histolytica.

From Haque R, Huston CD, Hughes M et al. Amebiasis. N Engl
J Med 2003;348(16):156573.
Liver function tests show elevation of alkaline phosphatase in 80% of cases, and hepatic transaminases may also
be raised.
Stool examination is positive in 75% of patients.
Ultrasound, computed tomography (CT) or magnetic
resonance imaging (MRI) can aid in the diagnosis of
amebic liver abscess.
Serological testing to detect antibodies is positive in
9297% at the time of presentation, although it may be
negative in the first 7 days. Indirect hemagglutination is
the most sensitive method for detecting the antibodies.
In some endemic areas, up to 25% of uninfected individuals have anti-amebic antibodies.
Treatment involves a tissue agent followed by a luminal
agent, even if stool culture is negative.
Use tissue amebicides to eradicate the invasive trophozoite forms in the liver.
After completion of treatment with tissue amebicides,
administer luminal amebicides for eradication of the
asymptomatic colonization state.
Failure to use luminal agents can lead to relapse of infection in approximately 10% of patients.
The most common cause is related to surreptitious laxative

abuse. 90% of patients with factitious diarrhea are women.
These patients often seek care from many physicians and
have multiple admissions.
The key clinical features include chronic watery diarrhea that is high in frequency and volume. About 50% of
patients complain of nocturnal bowel movements. This
presentation is not common in patients with irritable bowel
syndrome. Other symptoms include cramping abdominal
pain, weight loss and, in severe cases, cachexia. In addition,
concurrent nausea and vomiting may be present in patients
with anorexia and bulimia.
The diagnosis is confirmed by the following methods:
Stool analysismeasurement of stool osmolality.
Increase in fecal osmolar gap (> 50mOsm/kg), indicating the presence of unmeasured solute which can
be due to laxatives containing magnesium, sorbitol, lactose, lactulose or polyethylene glycol as active
ingredients.
Measured fecal osmolality is helpful in factitious
diarrhea resulting from the addition of water in the
stool; this diagnosis is suspected if the measured
stool osmolality is lower than of plasma, since the
colon cannot dilute stool to an osmolality which is
less that of plasma
It is important to note that if stool osmolality is
higher than that of plasma, consider contamination with concentrated urine (particularly if there is
a high sodium concentration, urea and creatinine),
or stool that was not processed in a timely manner, leading to fermentation and thus an increase in
osmotically active substances.
High stool magnesium levels indicate potential abuse of
magnesium-containing laxatives.
333
Urine analysistesting the urine may reveal evidence

of some stimulant laxatives such as bisacodyl, but will
not detect senna.
Endoscopic appearancemelanosis coli (dark-brown
discoloration of the colon with lymph follicles shining
through as pale patches) occurs with anthraquinonecontaining laxatives; this is not seen with osmotic or
diphenolic agents. It develops within 4 months of the
onset of laxative ingestion and disappears in the same
timeframe when laxatives are discontinued.
Rarely, dilatation of the colon can occur as a consequence
of prolonged stimulant laxative abuse, and this is termed a
cathartic colon.
The mainstay of treatment involves stopping the medication and obtaining a psychiatric evaluation to help maintain abstinence from these agents.
Clostridium difficile infection (CDI)

Diarrhea associated with C. difficile occurs in patients
infected with toxin-producing (exotoxin A and B) C. difficile bacteria. Toxin B is more potent.
The term pseudomembranous colitis refers to the
endoscopic appearance of scattered white-yellow mucosal
plaques which appear in the colon (Figure 12-6). However,
the presence of C. difficile in the colon does not always infer
active infection. Asymptomatic carriage has been reported
in 14% of hospitalized patients receiving antibiotics and up
to 70% of healthy infants.
CLINICAL PEARLS
Clostridium difficile infection is usually associated
with antibiotic exposure, PPI use or hospitalization, although community-acquired infection (without recent hospitalization or antibiotic exposure) is
being increasingly recognized.
Patients with inammatory bowel disease are at risk
of C. difficile infection. It is important to rule this out
prior to starting immunosuppressive agents.
The risk factors associated with the development of CDI

include current or recurrent use of antibiotics, advanced age,
hospitalization and comorbid illness. Inflammatory bowel
disease is also a risk factor.
The key clinical features include the following:
frequent semi-formed or watery non-bloody diarrhea
patients with severe fulminant disease may develop
ileus, peritoneal signs or shock
peripheral edema or ascites has been observed
due to secondary protein-losing enteropathy and
hypoalbuminemia
other clinical signs that are nonspecific include low-grade
fever, diffuse abdominal tenderness and dehydration.
The diagnosis is usually made by detection of C. difficile genes on a polymerase chain reaction (PCR) assay in a
patient with appropriate symptoms. Enzyme immunoassay
(EIA) for toxins A and B in the stool can also be used. It is
important to note that some strains only produce exotoxinA
334
Figure 12-6 Endoscopic appearance of Clostridium

difficile-associated pseudomembranous colitis.
Plaquelike, cream-coloured pseudomembranes
overlie erythematous mucosa and have become
conuent in the foreground
From Weidner N et al. Modern surgical pathology, 2nd ed.
or exotoxin B. The EIA test is close to 100% specific, but

sensitivity is limited by the fact that the EIA does not detect
small concentrations of toxins. Endoscopic findings show
pseudomembranes with patchy, simple erythema, and friability with confluent ulcers, but these are found in only a
small subset of patients.
Treatment
The treatment of CDI involves four main tenets, once the
diagnosis is confirmed:
1 All causative antibiotics should be stopped unless absolutely required for patient care.
2 Initiate appropriate antibiotics for the treatment of
CDI.
3 Monitor for signs of complications.
4 Initiate infection-control measures.
Management of C. difficile infection is as follows:
1 First infective episode
a Mild to moderate infectionoral metronidazole
500mg three times daily for 1014days.
b Severe infectionoral vancomycin 125mg four
times daily for 1014 days (remember that this
does not work IV).
c Fulminant colitisoral/nasogastric/rectal vancomycin 500mg four times daily and IV metronidazole 500mg three times daily. If patient is unable
to have oral intake, consider nasogastric feeding
or total parenteral nutrition.
2 First recurrence
a Non-severe infectionretreatment with oral
metronidazole 500 mg three times daily for
1014days.
b Severe infectionoral vancomycin 125mg four
times daily for 1014days.
3 Recurrent episodes
a Initially oral vancomycin 125mg four times daily
for 14 days, then taper off over a month. Many
clinicians use 125 mg three times daily for 1week,

followed by twice daily, then daily for 1 week,
and finally 125 mg every second or third day prior
to stopping.
b Alternatively, oral vancomycin 125mg four times
daily for 14 days followed by rifaximin 400 mg
twice a day for 14 days.
Most patients (>90%) will respond to treatment for 7 days
with metronidazole or vancomycin after initial uncomplicated CDI. However, up to 30% will develop at least one
recurrence and at least half of those will proceed to further
relapses.
Fecal transplantation has been employed in selected
patients who have failed three or more treatment attempts
with conventional modalities. A stool suspension from a
screened donor (usually a family member) is administered
to the colon via an enema or during a colonoscopy. The
treatment is highly efficacious. The aim is to restore normal
fecal microbiota.
Malabsorption
Overview
Malabsorption is pathological interference with the normal
physiological sequence of the digestion (intraluminal process), absorption (mucosal process) and transport (post-mucosal
events) of nutrients. Mechanisms of intestinal malabsorption
include:
infective agents
structural defects
mucosal abnormality
enzyme deficiencies
systemic disease affecting the GI tract.
The most common causes of malabsorption are celiac
disease, chronic pancreatitis, post-gastrectomy, Crohns
disease and a lactase deficiency. It is important in the medical history to ask the patient if they have diarrhea. If the
patient admits to frequent stooling and has characteristics of
steatorrhea, intestinal malabsorption is the most likely cause
of weight loss.
Screening
Patients should be screened for:
low albumin, iron and calcium levels
low carotene and cholesterol levels, and
a prolonged prothrombin time (PT) or international
normalized ratio (INR).
If screening tests are abnormal, specific tests will be required
to unravel the etiology.
CLINICAL PEARL
Whipples disease is fatal if missed. Consider Whipples
in the setting of malabsorption, pigmentation, weight
loss, seronegative arthritis and fever of unknown origin.
Whipples disease
This is a rare cause of malabsorption. Tropheryma whipplei is a
Gram-positive actinomycete, most commonly causing infection in the 4th or 6th decade with a male predominance. It is
more common in people involved in farm-related trades.
The clinical features include:
diarrhea and steatorrhea, commonly
associated abdominal bloating, cramps, anorexia and
weight loss
arthritis, which is a common extraintestinal symptom
and usually precedes the diagnosis
neurological symptoms, also commonly, with dementia, paralysis of gaze and myoclonus.
Other features include pigmentation, low-grade fever,
fatigue and generalized weakness.
On clinical examination, hyperpigmentation and peripheral lymphadenopathy are the most common features. Other
findings include fever, peripheral arthritis, heart murmurs,
pleural or pericardial friction rub, ocular abnormalities and
cranial nerve involvement.
If Whipples disease is suspected, biopsy is essential. GI features
and arthritis occur early in the disease course, whereas central nervous system (CNS) symptoms are late.
Diagnosis
Small-intestinal mucosal biopsy is diagnostic.
Findings of infiltration of the lamina propria of the small
intestine by periodic acidShiff (PAS)-positive macrophages containing Gram-positive, acid-fast-negative
bacilli accompanied by lymphatic dilatation is specific
and diagnostic of Whipples disease. PCR testing confirms the diagnosis.
Differential diagnosis is lymphoma, Mycobacterium avium
complex, and celiac disease.
There are key differences from celiac disease:
Whipples is caused by a pathogen and associated with
occupational exposure (farm trades)
there is no family history associated with this disorder
malabsorption is due to obstruction of lymphatics rather
than villous atrophy
negative anti-gliadin and anti-tTG antibody
small-bowel histology does not improve with a glutenfree diet
small-bowel histology does improve with antibiotic
treatment.
Treatment
Treatment is trimethoprim 160mg + sulfamethoxazole
800mg (TMP-SMX) given twice daily for 1 year. Initial
parenteral penicillin G and streptomycin for 1014days
may be of additional benefit, resulting in a lower relapse
rate.
For patients allergic to TMP-SMX, parenteral penicillin
and streptomycin for 1014days followed by oral penicillin V potassium or ampicillin for 1 year isreasonable.
335
Repeat small-bowel biopsy following treatment is

required to ensure eradication.
Relapses are common; positive bacilli on electron microscopy suggest inadequate treatment. Repeated courses of
antibiotics are needed in that circumstance.
Microscopic colitis
CLINICAL PEARL
Consider microscopic colitis in a middle-aged patient
with chronic diarrhea without bleeding.
Symptoms of microscopic colitis include chronic watery

diarrhea with abdominal pain. Some patients might present
with mild weight loss or fecal incontinence. Colonoscopy is
normal, but biopsies are diagnostic with increased intraepithelial lymphocytosis (>1020 lymphocytes per 100 epithelial cells; normal is <5).
There are two subtypes:
collagenous colitis is similar with respect to clinical and
histological features, but with thickened subepithelial
collagen band
lymphocytic colitis has a normal collagen band.
There is an association with autoimmune conditions, e.g.
celiac disease; however, there is no cancer risk associated
with this condition.
Treatment
Antidiarrheal agents (loperamide or diphenoxylate) are
useful in mild cases. Bismuth subsalicylate, mesalamine
or cholestyramine may be beneficial.
If refractory, corticosteroids (budesonide) could be tried.
Disease can either be self-limiting, or follow a waxing
and waning course requiring maintenance treatment.
Tropical sprue
Tropical sprue is an acquired disease of unknown etiology
mainly related to tropical areas (a zone centered on the
equator and limited in latitude by the tropic of Cancer in
the Northern Hemisphere and the tropic of Capricorn
in the Southern Hemisphere).
It may be caused by an infection, but no organism has
been identified.
The clue to diagnosis is chronic diarrhea with recent
prolonged (> 6 weeks) travel to the tropics.
The clinical features include diarrhea, steatorrhea,
abdominal pain, weight loss, fatigue, glossitis, nutritional deficiencies and anorexia. Patients often present
with megaloblastic anemia (due to folate deficiency).
The diagnosis is one of exclusion, especially of protozoa.
Tropical sprue differs from celiac disease in that:
it is probably caused by an infective pathogen and is not
immune-mediated
there is no family history
no gender predilection is present
336
the disease is mainly related to tropical areas

anti-gliadin and anti-tTG are negative
the small-bowel histology is similar to celiac disease, but
affects both proximal and distal regions (celiac disease is
more proximal)
severe folate deficiency is more common in tropical
sprue, while iron-deficiency anemia is more common
in celiac disease
histology does not improve with a gluten-free diet
histology improves with antibiotic treatment.
Treatment involves broad-spectrum antibiotics and folic
acid. Tetracycline is the antibiotic of choice, for 36 months.
Alternatively, sulfamethoxazole/trimethoprim may be used
for a similar duration. Clinical response is rapid, within
weeks, and complete. Relapse is common if the patient
returns to or remains in the same tropical environment.
Small intestinal bacterial overgrowth

(SIBO)
This is defined traditionally by the quantitative culture of
aspirated juice from the proximal jejunum, or noninvasively
by a lactulose breath test or C14-glycocholate breath test.
More than 105 colony-forming units of bacteria per milliliter of aspirate (CFU/mL) is diagnostic by culture.
The normal gut flora is maintained by five major mechanisms: gastric acid secretion, pancreatic enzyme secretion,
small-intestinal motility, structural integrity of the GI tract,
and an intact gut immune system.
SIBO is usually a byproduct of structural abnormalities involving the GI tract or alteration in gut motor, secretory or immunological function. A clue to the presence
of bacterial overgrowth is the finding of low serum vitamin B12 levels and high serum folate levels (from bacterial
production).
Clinical features
Diarrhea, abdominal bloating, distension and florid
malabsorption
Nutritional deficiencies (vitamin B12 and fat-soluble
vitamins). Megaloblastic anemia, follicular hyperkeratosis (vitamin A deficiency), and peripheral neuropathy
may occur as a consequence. Serum levels of folate and
vitamin K are usually normal or elevated, due to bacterial synthesis
Diarrhea is multifactorial, with contributions from malabsorption, maldigestion, bile acid deconjugation and
protein-losing enteropathy
Treatment
Antibiotics are given to acutely decontaminate the small
bowel.
Antibiotics should be active against aerobic and
anaerobic enteric bacteria.
Amoxicillin and clavulanic acid, ciprofloxacin, norfloxacin, metronidazole, neomycin or doxycycline
for 714 days are options. Rifaximin is also effective, but costly.
If patients have recurrent bouts of SIBO, then rotating courses of antibiotics every 46 weeks is effective.
A low-carbohydrate, high-fat diet may minimize
the available substrate for bacterial metabolism and is
recommended.

This is a rare eosinophilic disease that can affect any part of
the gut. It is subdivided into primary and secondary EGE.
Causes of secondary eosinophilic gastroenteritis are
hypereosinophilic syndrome, celiac disease, Crohns
disease, vasculitis (eosinophilc granulomatosis with
polyangiitis, polyarteritis nodosa and scleroderma),
parasites and drug hypersensitivity.
Primary eosinophilic gastroenteritis is diagnosed if
histopathology demonstrates predominant eosinophilic
infiltration (>20eos/hpf) with absence of other causes of
eosinophilia and no eosinophilic involvement of organs
outside the GI tract. The clinical presentation is dependent on the layer of involvement (Table 12-5).
The mainstay of treatment is corticosteroids. It is important
to rule out Strongyloides before starting corticosteroids.
Relapse is common. Maintenance with dietary modification (in the form of an elemental diet) may help in difficult
cases.
Chronic idiopathic intestinal

pseudo-obstruction (CIIP)
examples being degenerative neuropathies, paraneoplastic phenomenona and genetic abnormalities. Small-bowel
or colonic transit studies are the tests of choice, as specialized small-bowel or colonic manometry is not readily available. Full-thickness biopsies obtained at surgery often show
abnormalities in the enteric nervous system and with the
interstitial cells of Cajal.
Treatment focuses on nutritional supplementation,
with cautious use of pro-motility agents. Surgery and total
parenteral nutrition is often employed in severe cases. Overall prognosis is poor.

CLINICAL PEARL
The presence or absence of an intact colon has a
major impact on whether gut failure due to small
bowel resection occurs.
Short bowel syndrome results when an inadequate length

of intestine is available for nutrient absorption. In adults the
most common cause is surgical resection of diseased bowel,
but in children congenital abnormalities and resection following necrotizing enterocolitis predominate.
CLINICAL PEARL
The most common cause for small bowel syndrome in
adults is resection due to Crohns disease, followed by
resection due to bowel obstruction with strangulation
or mesenteric infarction.
CLINICAL PEARL
Suspect the diagnosis of chronic idiopathic intestinal
pseudo-obstruction in a young person with persistently
dilated small or large bowel, and symptoms of bowel
obstruction without an identiable anatomical cause.
This rare syndrome is characterized by recurrent and progressive symptoms of intestinal obstruction without an identifiable anatomical cause. Affected parts of the small bowel
or colon appear dilated on radiographical studies.
Causes are related to disorders of the enteric nervous
system (neuropathy) or smooth muscle (myopathy), with
Whether short bowel syndrome develops depends on

several factors:
length of the remaining small bowel
mucosal integrity of the remaining small bowel
presence or absence of the colon.
As a general rule, 100 cm of small bowel is sufficient to
avoid short bowel syndrome if the colon is intact. Without a colon, persons with 200 cm of remaining small bowel
can manage after a long period of adaptation. Total parental
nutrition (TPN) is required if intestinal failure (inability to
absorb sufficient nutrients) has occurred.
Table 12-5 Clinical presentation of eosinophilic gastroenteritis
LAYER OF INVOLVEMENT
DISTRIBUTION
CLINICAL FEATURES
Mucosal
Most common
Associated with food allergy (15%)
60%
Nausea, vomiting, abdominal pain, diarrhea

Gastrointestinal hemorrhage
Anemia
Malabsorption
Protein-losing enteropathy
Failure to thrive
Muscularis propria
30%
Symptoms of bowel obstruction
Serosal
10%
Ascites
High peripheral eosinophilia
337
Remember: the length of remaining gut is a crude predictor of whether intestinal failure will occur. Measurement
of plasma citrulline concentrations is a more sensitive measure of absorptive capacity and can help predict the likelihood of resuming an oral diet.
CLINICAL PEARL
Adaptation to a short gut takes yearsmany patients
can avoid long-term parenteral nutrition if carefully
managed and followed up.
Patients with short bowel syndrome need to consume

frequent small meals, which should be nutrient-dense. Isotonic fluids that also contain carbohydrates are often useful,
and supplemental nocturnal feeding (via nasogastric or gastrostomy tube) can help some patients avoid TPN.
It is important to know the main complications of longterm TPN:
sepsis (bacterial and fungal) associated with IV catheters
vascular thrombosis
hepatic dysfunction
small-bowel bacterial overgrowth due to stasis.
Small-bowel transplantation is evolving and is a therapeutic
option in highly selected patients.
NUTRITIONAL DEFICIENCY
Vitamins are categorized as water-soluble or fat-soluble:
fat-soluble vitamins include vitamins A, D, E and K
water-soluble vitamins include vitamins B and C.
Clues to identifying vitamin deficiency are outlined in
Table12-6, along with treatment options.

Clinical assessment of the severity of malnutrition:
biochemical parameters such as low albumin or prealbumin are important clues
malnutrition is present when bodyweight is <70% of
ideal or there is weight loss of >20% over 6 months
body fat and lean muscle are estimated using anthropometric measurements
a low triceps skinfold thickness is indicative of
malnutrition
a weak hand grip strength during physical examination
can indicate malnutrition.
Table 12-6 Clinical clues in identifying vitamin deciency
CLINICAL FEATURES
CAUSES AND DIAGNOSIS
TREATMENT AND NOTES
Vitamin A deciency
Can take years to be symptomatic
Xerophthalmia causing night blindness
and Bitots spots is the earliest sign
Poor bone growth
Follicular hyperkeratosis
Impaired immune system
Conjunctival xerosis
Keratomalacia
Low dietary intake (preformed

vitamin A is from animals;
provitamin A is found in plants)
Diagnosis is made by measuring
serum retinol levels
Vitamin A supplementation
Daily requirement (RDA) for adult males
is 3000IU and for females is 2300IU
Vitamin A toxicity is related to chronic
ingestion (25,000IU/d); serum retinol
levels are not helpful as vitamin A is
stored in the liver
Low dietary intake

Pernicious anemia
Terminal ileum disease
Vitamin B12 supplementation

If both folate and vitamin B12 deciency
are present, you must replace vitamin
B12 rst to avoid subacute combined
degeneration of the spinal cord
Mainly secondary to drugs, e.g.

isoniazid, cyloserine, penicillamine,
phenobarbitol
Can measure serum levels of
pridoxal-phosphate
Vitamin supplementation
Large doses can cause both impaired
position and vibratory sense
Vitamin B12 deciency

Can take several years to show symptoms
Macrocytic anemia
Smooth tongue
In severe deciencysubacute combined
degeneration of the spinal cord
Peripheral sensory neuropathy affecting
large and small bers
Dementia
Vitamin B6 (pyridoxine) deciency
Can take weeks to be symptomatic
Glossitis
Cheilosis
Vomiting
Seizures
Scrotal dermatitis
338
CLINICAL FEATURES
TREATMENT AND NOTES
Vitamin B2 (riboavin) deciency

Normochromic normocytic anemia
Sore throat and magenta tongue
Glossitis
Cheilosis
Seborrheic dermatitis in perianal area, nose
Associated with phenothiazine and

tricyclic antidepressants
Vitamin supplementation
Low dietary intake

Alcoholic patients, chronic dialysis
patients
IV glucose can precipitate WE: give
thiamine before glucose.
Can directly measure thiamine
levels in serum
Thiamine supplementation
Low dietary intake
Vitamin C supplementation
Large doses can cause oxalate renal
stones and impaired absorption of
vitamin B12
Low dietary intake

Drug and alcohol abusers
Improve dietary intake
Low dietary intake; tryptophan is

used in the body to make niacin
Carcinoid syndrome (tryptophan is
used up)
Isoniazid (increased excretion of
tryptophanpyroxidine supplement
must be used concurrently to
prevent this)
Hartnup disease
Replacement treatment
Low dietary intake
Zinc supplementation
Vitamin B1 (thiamine) deciency

Wet beriberiheart failure secondary to
cardiomyopathy
Dry beriberi
Wernicke encephalopathy (WE)
nystagmus, ophthalmoplegia and ataxia
Korsakoff syndrome
Vitamin C deciency (scurvy)
First symptoms are petechial hemorrhage
and ecchymoses
Bleeding, swollen gums (see Figure 12-7A)
Hyperkeratotic papules
Hemorrhagic into joints, nail beds
Loosening of teeth
Periosteal hemorrhages
Coiled hairs
Impaired wound healing
Weak bones
Sjgrens syndrome
Iodine deciency
Hypothyroidism
Niacin deciency (pellagra)
The 3 Ds:
dermatitis (sun-exposed areas)
diarrhea
altered mental statedepression to
dementia to psychosis
Hyperpigmentation (see Figure 12-7B)
Glossitis
Stomatitis
Zinc deciency
Rash (face, body: pustular, bullous,
vesicular, seborrheic, acneiform; see Figure
12-7C), skin ulcers, alopecia, dysgeusia
Impaired immunity
Night blindness
Decreased spermatogenesis
Diarrhea
continues
339
Table 12-6 Clinical clues in identifying vitamin deciency continued
CLINICAL FEATURES
TREATMENT AND NOTES
Vitamin E deciency
Peripheral sensory and motor neuropathy
Hemolytic anemia
Retinal degeneration
Dry skin
Vitamin E supplementation
Large doses can potentiate the effects
of oral anticoagulation
Vitamin K deciency
Bleeding tendency
Easy bruisability
Low dietary intake

Systemic diseases that cause
fat-soluble vitamin malabsorption
Can detect by checking
coagulation prole (INR and PT)
Vitamin K supplementation
Decreased exposure to the sun

Decreased intestinal absorption
from the intestine
Renal disease
Systemic diseases that cause fat
malabsorption
Can be directly measured by
checking for serum 25(OH)D
Increase casual exposure to sunlight

Vitamin D supplementation:
25(OH)D (Ostelin 1000)
activated vitamin D (calcitriol; this
form should be used in renal disease)
The RDA for vitamin D is 600IU for
adults
Treatment of osteoporosis for adults
older than 71 years is 800IU daily
The upper limit of normal of vitamin D
is 4000IU/d in adults
Avoid excessive doses, as toxicity
can cause hypercalcemia, confusion,
polyuria, polydipsia, anorexia, vomiting
and muscle weakness
Long-term toxicity results in bone
demineralization and pain
Vitamin D deciency
The major source of vitamin D is from sun
exposure. Secondary sources are from
dietary means or intestinal absorption
In the liver, vitamin D undergoes
hydroxylation by 25-hydroxylase to
25-hydroxyvitamin D, 25 (OH)D. Further
hydroxylation takes place in the kidneys to
activated vitamin D (1,25-dihydroxyvitamin
D). Activated vitamin D is important in
bone mineralization
Vitamin D deciency leads to:
rickets in children
osteomalacia in adults
hypocalcemia
secondary hyperparathyroidism which
leads to phosphaturia
INR, international normalized ratio; RDA, recommended dietary allowance; PT, prothrombin time.
Figure 12-7 Signs of (A) scurvy, (B) pellagra and (C) zinc deciency
From: (A) Li R, Byers K and Walvekar RR. Gingival hypertrophy: a solitary manifestation of scurvy. Am J Otolaryngol 2008;29(6):4268.
(B) Piqu-Duran E et al. Pellagra: a clinical, histopathological, and epidemiological study of 7 cases [in Spanish]. Actas Dermosiliogr
2012;103(1):518. (C) Marks JG and Miller JJ. Lookingbill and Marks Principles of dermatology, 5th ed. Elsevier, 2013.
340
Nutritional assessment in end-stage

liver disease
Protein energy malnutrition in end-stage liver disease is
multifactorial:
poor oral intake
restrictive diets (overzealous sodium-restricted diets)
altered taste sensation
early satiety (gastric compression from ascites)
portal hypertension associated with malabsorption
insulin resistance (hyperinsulinemia and glucose
intolerance)
reduced glycogen capacity.
Weight is a poor indicator in end-stage liver disease due to
the presence of ascites and /or peripheral edema. Malnutrition in cirrhotic patients is associated with an increased risk
of complications. It is an independent predictor of mortality
in cirrhosis.
Malnutrition should be assessed as shown in Table
12-7. Anthropometrical measurements of mid-arm circumference, triceps skinfold thickness and mid-arm muscle
circumference should be performed.
Grip strength is a good reflection of protein status in
these patients. Poor grip strength is associated with development of ascites, hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, and a longer stay
in intensive care post-transplant as well as increased risk of
infection post-transplant.
Table 12-7 Assessment of malnutrition
Weight
Weight lost in the last 6 months
Dietary intake
Adequate or not
Presence of
gastrointestinal
symptoms
Nausea, vomiting, diarrhea,

anorexia
Functional capacity
Metabolic demand
Signs of micronutrient
deciencies
HarrisBenedict equation
(HBE): estimation of resting
energy expenditure
Indirect calorimetry
Vitamin deciency, e.g. vitamin
D, vitamin A, zinc

Enteral nutrition is generally the preferred route where
possible because it sustains the digestive, absorptive and
immunological barrier functions of the GI tract.
Patients who are malnourished or at risk of malnutrition
and have a non-functioning or inaccessible GI tract will
need TPN.
Total parental nutrition (TPN)

The components in TPN include:
essential and non-essential amino acids
glucose
fats
electrolytes
micronutrients.
These are given in an iso-osmotic liquid emulsion to provide
an energy-rich solution.
TPN is used when required for patients in whom all avenues of
oral feeding have been exhausted. Clinical scenarios where this
may arise include:
postoperative (bowel surgery, protracted recovery)
severe acute pancreatitis
severe inflammatory bowel disease
selected patients with severe acute radiation enteritis or
chemotherapy enteritis preventing meaningful enteral
nutrition
enterocutaneous fistula involving the small bowel
short gut syndrome
preoperative (severely malnourished patients only).
Complications
Access/catheter-related complications
Pneumothorax/hemothorax from line insertion

Cardiac arrhythmias
Cardiac tamponade
Venous thrombosis and pulmonary embolus
Air embolus
Infection (staphylococcal, enterococcal, Candida, Klebsiella pneumoniae and Pseudomonas aeruginosa. If catheter is
in long-term, the patient is at risk of coagulase-negative
Staphylococcus)
Subacute bacterial endocarditis
Chylothorax
Thrombophlebitis
Systemic complications
Early complications:
Hypophosphatemia (refeeding syndrome)
Hypokalemia
Hypomagnesemia
Thiamine deficiency
Volume overload and cardiac failure
Hyperchloremic acidosis
Hypoglycemia and hyperglycemia
Late complications:
Azotemia and hyperosmolarity
Liver dysfunction (hepatocellular or cholestatic and fatty
liver)
341
Acalculous cholecystitis
Cholelithiasis with gallstone and gallbladder sludging
(long-term treatment)
Vitamin or mineral deficiency (rare)
TPN-related nephropathy
Metabolic bone disease (rare)
Trace-mineral deficiency
Essential fatty acid deficiency
Refeeding syndrome
Patients who have been malnourished for extended periods
of time are at risk of refeeding syndrome when re-institution
of nutrition occurs via either enteral nutrition or TPN.
When oral nutrition is re-introduced, close monitoring of
fluid and electrolyte status is mandatory.
In the starvation phase, intracellular electrolyte stores
and phosphate stores are depleted. The key energy source
during starvation is from fat. Upon refeeding, the bodys
metabolism is switched to carbohydrate as the main source
of energy. The basal metabolic rate increases with increased
production of insulin and further intracellular uptake of
phosphate, potassium, magnesium, glucose and thiamine,
causing significant deficiencies. Multi-organ involvement
occurs as a consequence in refeeding syndrome.
The risk of developing refeeding syndrome is directly
related to the amount of weight loss that has occurred and
the rapidity of the weight restoration process.
High-risk groups
Patients with eating disorders (anorexia nervosa/
bulimia)
Chronic malnutrition
A prolonged fasting period
Prolonged IV hydration therapy
Complications of refeeding syndrome
Electrolyte disturbance
Rhabdomyolysis, muscle weakness and tetany
Cardiac failure and volume overload
Cardiac arrhythmias (bradycardia) and labile blood
pressure
Respiratory failure due to muscle weakness from
hypophosphatemia
Seizures
Coma and death
LARGE BOWEL
Irritable bowel syndrome is common, with more women
than men affected. Currently no diagnostic test is useful
apart from excluding other causes for symptoms. The diagnosis is based on taking the history (Rome III criteriasee
Box 12-5).
Patients with IBS all have abdominal pain and suffer
predominantly from either constipation or diarrhea,
although the mixed type is also common. Symptoms are
commonly made worse by eating and emotional stress,
while defecation often gives relief.
CLINICAL PEARL
Irritable bowel syndrome does not cause anemia,
weight loss or malnutrition.
The discomfort can be felt anywhere in the abdomen

and is often associated with bloating.
Young patients with classical features and no alarm features
require few if any tests, but a full blood count, thyroidstimulating hormone and celiac serology at baseline are
often done. Onset of symptoms after the age of 50 years or
abnormal baseline testing (elevated C-reactive protein, low
serum albumin) is highly suggestive of alternative pathology. Patients with anemia, fever, significant weight loss, or
rectal bleeding always require further evaluation.
CLINICAL PEARL
Patients presenting with new-onset altered bowel
habit after the age of 50 need colonoscopy to exclude
bowel cancer or other pathology. Patients rarely present with new-onset IBS after the age of 50.
The pathogenesis of IBS is poorly understood, but current hypotheses revolve around visceral hypersensitivity
and abnormal gut microbiota, coupled with genetic and
environmental triggers. Post-infectious irritable bowel can
occur after an episode of gastroenteritis, and diarrhea is often
the predominant symptom.
Treatment
Treatment aims at relieving the predominant symptoms
(Box 12-8).
Box 12-8
Treatment of irritable bowel syndrome

Relieving constipation
Bulking agent (psyllium)
Laxatives
Linaclotide or lubiprostore
342
Relieving diarrhea
Antidiarrheal (loperamide,
cholestyramine)
Bulking agent
Bile-salt binder
Relieving pain
Spasmolytics such as
anticholinergics, peppermint oil or
mebeverine
Whenever possible, non-pharmacological approaches

should be trialed. The following treatments have robust
evidence to support efficacy for improving global IBS
symptoms:
structured patient education
moderate exercise
adherence to a low FODMAP diet (fermentable
oligosaccherides, disaccharides, monosaccharides and
polyols)
hypnotherapy and cognitive behavioral therapy.
Avoiding exacerbating foods is recommended. Gut-specific
antibiotics (such as rifaximin) have shown some promise in
improving symptoms in diarrhea-predominant IBS.
Constipation
Constipation is common, and the great majority of patients
affected are female. Constipation is a symptom, not a
diagnosis.
Common symptoms:
decreased frequency of stool (<3/week)
excessive straining to open bowels
hard stools
feeling of incomplete evacuation.
Conditions causing constipation can be classified as shown
in Table 12-8.
Investigations
Basic blood tests to exclude hypothyroidism, diabetes
mellitus and hypercalcemia
History and physical examination detect most cases, but

a plain abdominal X-ray is often useful, particularly if
the patient cannot give a reliable history (dementia, psychiatric disease, children)
CLINICAL PEARL
In the setting of constipation, rectal examination is
mandatoryfecal impaction, ssures, pelvic-oor dysfunction and rectal prolapse can readily be detected at
the bedside.
More advanced testing is reserved for patients where a simple reversible cause has not been established and where there
has been no response to basic therapy (as described below).
Colonic transit studyexamines transit time by means
of a radio-opaque marker.
Balloon expulsion testthe ability to expel a waterfilled balloon is tested. If unable, or it takes more than
2minutes, this is suggestive of dyssynergic defecation.
Anorectal manometry and balloon expulsion testing are
useful tests for pelvic-floor dysfunction.
Defecography (barium or MRI)defines anatomy in
difficult cases.
Treatment
Initially, most patients should be trialed on a basic treatment
consisting of:
increased dietary intake of fiber (>30 g/daily is required)
laxatives (preferably osmotic, e.g. polyethylene glycol)
(Table 12-9).
Table 12-8 Classication of conditions causing constipation
CLASSIFICATION
EXAMPLE CONDITION/CAUSE
No structural abnormality
Inadequate ber intake

Constipation-predominant irritable bowel syndrome
Idiopathic slow-transit constipation
Pelvic-oor dysfunction
Structural abnormality
Anal ssure or stenosis

Colon cancer or stricture
Aganglionosis (Hirschprung, Chagas)
Abnormal colonic muscle (myopathy, muscular dystrophy)
Idiopathic megarectum and/or megacolon
Neurological causes
Diabetic autonomic neuropathy

Spinal cord damage or disease, e.g. multiple sclerosis
Parkinsons disease
Endocrine or metabolic causes
Hypothyroidism
Hypercalcemia
Pregnancy
Drug side-effects
Opiates
Antidepressants
Adapted from Talley NJ. Clinical gastroenterology: a practical problem-based approach. Sydney: Churchill Livingstone, 2011.
343
Table 12-9 Types of laxative
LAXATIVE TYPE
EXAMPLE
NOTES
Dietary ber (bulking)
Psyllium, bran, methylcellulose
Safe, cheap, effective
Osmotic
Lactulose, polyethylene glycol, sorbitol
Safe, can be used long-term
Stimulant
Senna, bisacodyl
Effective, but can cause cramps and

fail to relieve
Stool-softener
Docusate, poloxalkol
Safe, but less effective than osmotic

laxatives
Those not responding should undergo further investigation.

If pelvic-floor dysfunction is present, biofeedback is useful
in selected and motivated patients. If IBS is present, specific
treatments for this condition should be trialed (see above).
For many patients constipation is a lifelong condition,
and regular daily therapy is required for most.
In addition to laxatives, newer drugs are now available,
but should be prescribed only when a trial of osmotic laxatives has failed and an evacuation disorder has been excluded.
Newer drugs include:
Prucalopride
5HT4-receptor agonist (prokinetic)
Involves direct stimulation of enterokinetic activity
Nausea is the main limiting side-effect, and this
drug is contraindicated in those with severe colonic
inflammation (such as Crohns disease or ulcerative
colitis) or obstruction
Lubiprostone
Chloride-channel activator
Increases intraluminal water contents
Headaches and nausea are common side-effects,
and this drug is contraindicated in those with partial
or complete colonic obstruction, and in pregnancy
Linaclotide
Chloride-channel activatorlocally active
Diarrhea is the main side-effect.
A variety of enemas are available, mainly useful if colonic
transit is normal but anorectal function is impaired (pelvicfloor dysfunction).
Constipation is a common symptom and underlying disorders must be sought. In many patients an easily reversible
cause is not found, and a sensible management plan including lifestyle alteration and careful use of laxatives should be
developed.
Diverticular disease and diverticulitis
A diverticulum is a sac-like protrusion of the colonic wall
which can become inflamed or infected, causing diverticulitis. The incidence is rising and the condition is more
common in the elderly. It is thought to be the result of inadequate fiber intake, but this is now controversial.
Although most patients remain asymptomatic, complications can arise and include bleeding and infection.
344
Episodes of diverticulitis are often due to microperforations, and lead to fever and pain.
Most patients will have left iliac fossa pain and tenderness.
Systemic signs of infection are often present (fever, elevated white cell count)
Treatment is conservative, with antibiotics (cover of both
aerobic and anaerobic Gram-negative bacteria is needed).
In mild disease, ambulatory treatment with ciprofloxacin and metronidazole is often sufficient.
In more severe disease, hospitalization and broadspectrum antibiotics such as ticarcillin/clavulanate or
meropenem are often used.
Abscesses are often drained radiologically, and surgical
resection of diseased bowel is indicated if conservative treatment fails.
A convalescent colonoscopic examination should be
done 12 months after resolution to exclude bowel cancer.
CLINICAL PEARL
Colonoscopy is contraindicated during an episode
of diverticulitis. The air introduced at the time of the
examination can turn a microperforation into a major
perforation, resulting in peritonitis.

Inflammatory bowel disease (IBD) is a chronic idiopathic
inflammatory disorder that can be subdivided into Crohns
disease (CD) and ulcerative colitis (UC). In up to 1015% of
patients no subtype can be defined, and these are considered
indeterminate colitis.
CLINICAL PEARLS
Crohns diseaseasymmetric, transmural, and sometimes granulomatous chronic inammation that can
occur anywhere from mouth to anus.
Ulcerative colitismucosal inammation limited
to the colon that occurs in a contiguous fashion
from the rectum and extends proximally.
Clinical symptoms
Symptoms of IBD vary and may be a consequence of disease
location, behavior and complications (Box 12-9).
Box 12-9
Complications in ulcerative colitis

(UC) and Crohns disease (CD)
Acute/subacute
Gastrointestinal bleeding (UC >> CD)
Toxic megacolon (UC >> CD)
Toxic fulminant colitis (UC >> CD)
Perforation (CD >> UC)
Small-bowel and colonic obstruction secondary to
inammation or strictures (CD)
Abscessesintra-abdominal, perianal (CD)
Long-term
Colorectal cancer (UC > CD)
Fistulasenteroenteric, enterovesical, enterovaginal,
perianal (CD)
Fibrostenotic stricturessmall bowel and colon (CD)
Cholelithiasisimpaired bile acid reabsorption in the
diseased terminal ileum (CD)
Nephrolithiasisimpaired oxalate absorption (CD)
Iron deciency (CD and UC)
Vitamin B12 deciency (CD)
Figure 12-8 Pyoderma gangrenosum with

partial response to treatment. There is persistent
inammation and evidence of healing ulcerations
with residual cribiform scarring
From Paller AS and Mancini AJ. Hurwitz Clinical pediatric
dermatology, 4th ed. Elsevier, 2011.
Table 12-10 Differential diagnosis of inammatory

bowel disease
Inammatory
Collagenous colitis
Lymphocytic colitis
Appendicitis
Celiac disease
Infections
Bacteria: Salmonella, Shigella,

Escherichia coli, Yersinia,
Campylobacter, Mycobacterium,
Viruses: cytomegalovirus, herpes
simplex virus
Parasites: amebiasis (Entamoeba
histolytica)
Medication
Non-steroidal anti-inammatory
drugs and chemotherapy drugs
Radiation
Radiation colitis
Vascular
Ischemic colitis
Posttransplantation
Graft-versus-host disease
Diagnosis
Eosinophilia
Eosinophilic colitis
The diagnosis of CD and UC is based on a combination

of clinical symptoms, endoscopy, imaging and histology. It
should be differentiated from other causes of inflammation
affecting the colon and/or small bowel (Table 12-10).
Neoplasia
Lymphoma
Carcinoid
Extraintestinal
Skinerythema nodosum, pyoderma gangrenosum
(Figure 12-8)
Oral ulcers
Ocularepiscleritis, scleritis, uveitis
Primary sclerosing cholangitis
Cholangiocarcinoma (rare)
Anemia
Prothrombotic state
Musculoskeletalsacroiliitis, ankylosing spondylitis,
peripheral (oligoarticular or polyarticular) arthritis,
osteopenia, osteoporosis
Crohns disease (CD)

Crohns disease is a chronic idiopathic inflammatory bowel
disorder that leads to focal, asymmetric, transmural, and
sometimes granulomatous inflammation anywhere in the
GI tract. It can occur at any age, with the highest peak incidence in the 2nd and 3rd decade and a smaller peak in the 5th
to 7th decades of life. There is a slight female predominance.
Risk factors for CD include smoking, family history,

genetic loci (NOD2/CARD 15), and geographical locations (colder climates). CD is becoming more common in
underdeveloped countries, suggesting that Westernization
of lifestyle and industrialization are possible environmental
triggers for developing the disease.
CD can be classified with regard to location: ileal (~30%),
colonic (~20%), ileocolonic (~40%), and upper gastrointestinal
(<5%). Disease behavior can be classified into inflammatory
345
(luminal), stricturing, and fistulizing (enteroenteral, enterovesical, enterovaginal, perianal). Symptoms of CD depend
on the disease location, behavior (inflammatory, stricturing, and penetrating/fistulizing disease), and complications
(fistulas and abscesses).
Diagnosis
Diagnosis of CD is a combination of clinical symptoms,
endoscopy, imaging and histology. Infection should always be
ruled out by checking stool studies for common bacterial pathogens
and Clostridium difficile.
General symptoms
Chronic diarrhea
Abdominal pain
Fever
Weight loss
Specific symptoms
Hematochezia points toward colonic CD.
Perianal pain, drainage, and fevers are characteristic
of perianal fistulas with or without abscesses.
Dysphagia, odynophagia, chest pain, and gastroesophageal reflux disease suggest esophageal CD.
Gastric and duodenal CD is marked by epigastric
pain, nausea, vomiting, or gastric outlet obstruction.
Obstructive symptoms can be seen in stricturing
disease that can affect the upper and lower GI tracts.
Laboratory function
Raised inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein).
Fecal calprotectin identifies active disease.
Autoantibody testing in the form of pANCA (antineutrophil cytoplasmic autoantibodies, perinuclear
pattern) and ASCA (anti-Saccharomyces cerevisiae
antibodies) has poor sensitivity and specificity and
is not used routinely.
Endoscopy
Colonoscopy
abnormalities are patchy or skip, with focal
inflammation adjacent to areas of normalappearing mucosa along with polypoid mucosal changes giving a cobblestone appearance
ulcerations (aphthous ulcers or deep transmural ulcers)
strictures and fistula
Video-capsule endoscopy:
evaluates small-bowel CD that cannot be
reached with upper or lower endoscopy
is contraindicated in stricturing CD (as the
capsule can become stuck and require surgical
removal)
Histologyendoscopic biopsies
Early CD: acute inflammatory infiltrate and crypt
abscesses are seen
Late CD: chronic inflammation, crypt distortion,
crypt abscesses, and in some subjects non-caseating
granulomas are seen
Imaging
CT or MR enterography
small-bowel CD: inflammation, extent of disease, and complications
346
inflammation: segmental mural hyperenhancement, bowel-wall thickening, and

stratification
fistulous tracts (enteroenteral, enterocutaneous, enterovaginal, enterovesical)
perianal fistulas and/or abscesses (better seen
on MRI of the pelvis)
intra-abdominal abscesses
Upper GI series (barium swallow)
to assess esophageal, stomach, and duodenal
CD
reveals strictures and fistulas
Treatment
CD is a multisystem and complex disease that is not medically or surgically curable. The aim of treatment is induction
and maintenance of clinical remission, with the ultimate goal
of mucosal healing. The choice of medical (Table 12-11)
and/or surgical treatment depends on the disease severity,
location, behavior and complications.
Surgical resections, stricturoplasty, or drainage of
abscesses is indicated to treat medically refractory disease or
complications. Fistulizing and perianal CD is often treated
with a combination of surgery and medical therapy.
In general:
Inflammatory CD
Mild-to-moderate disease
induction: budesonide (terminal ileum and/or
right colon) or corticosteroids
maintenance: immunomodulators and/or biologicals
Moderate-to-severe disease
induction: budesonide (terminal ileum and/or
right colon) or corticosteroids or biologicals
maintenance: immunomodulators and/or biologicals
Stricturing CD
Fibrostenotic stricture with proximal bowel
dilationsurgery
Stricture without proximal bowel dilatation, possibly inflammatory stricturetrial of corticosteroids or biologicals. If no response, surgery should
be considered
Fistulizing CD
Internal fistulous tractsbiologicals and/or surgery
Perianal fistulizing diseasesurgery, antibiotics,
biologicals
Note that:
NSAIDs can cause IBD flares and should be avoided in
patients with CD.
Smoking cessation is essential in all patients with CD, as
smoking is associated with flares, more aggressive disease and an increased need for surgery.
Ulcerative colitis (UC)

Ulcerative colitis involves the colonic mucosa extending
proximally from the rectum in a contiguous fashion to
involve all or part of the entire colon. There is a bimodal
age distribution (20s to 30s, and 50s to 60s) of disease onset,
Table 12-11 Medical therapy used in Crohns disease (CD)
DRUG
RELEASE SITE
TREATMENT OF CD
SIDE-EFFECTS
Oral mesalamine for the treatment

of CD is minimally effective
compared with placebo, and
less effective than budesonide or
corticosteroids
Sulfasalazine has only modest
efficacy for inducing remission in
mild-to-moderate ileocolonic and
colonic CD compared with placebo
Rash, alopecia, and

hypersensitivity reaction
resulting in worsening
diarrhea can occur
Severe adverse events
such as interstitial nephritis,
pancreatitis and pneumonitis
can rarely occur
Oral 5-aminosalicylates
Sulfasalazine
Colon
Mesalamine (mesalazine)
Distal ileum, colon
(controlled-release)
Duodenum,
jejunum, ileum,
colon
Olsalazine
Colon
Balsalazide
Colon
Topical 5-aminosalicylates
enema
Rectum, sigmoid
suppository
Rectum
Topical mesalamine should only

be used for distal colonic CD as
adjunctive therapy to systemic
therapy
Antibiotics
Ciprooxacin
Metronidazole
Amoxicillin/clavulanic acid
Rifaximin
Systemic
Antibiotics are not used for the

treatment of CD except for perianal
CD
Ciprooxacin: tendonitis and

rupture
Metronidazole: neuropathy
Amoxicillin/clavulanic acid:
hepatitis
Budesonide (Entocort)
Small intestine,
right colon
Induction of remission in mild-tomoderate CD involving the distal

ileum and/or right colon
Not used for maintenance
High rst-pass metabolism

More favorable side-effect
prole than prednisone
Prednisone
Systemic
Induction of remission in mild-tomoderate CD

Not effective for maintenance of
remission
Infection, diabetes mellitus,

osteoporosis, osteonecrosis,
cataracts, glaucoma, and
myopathy
Increased risk of mortality
Methylprednisolone
Systemic
Induction of remission in severe CD

Not used for maintenance
As for prednisone
Effective for maintaining a steroidinduced remission of CD

Not used for induction
Allergic reactions,
pancreatitis,
myelosuppression, nausea,
infections, hepatotoxicity,
and malignancy, in particular
lymphoma
Effective at maintaining steroidinduced remission in moderate-tosevere CD

Not used for induction
Rash, nausea, diarrhea,

myelosuppression,
hepatic brosis, and rarely
hypersensitivity pneumonitis
Corticosteroids
Immunomodulators
6-Mercaptopurine
Systemic
Azathioprine
Systemic
Methotrexate
Systemic
continues
347
Table 12-11 Medical therapy used in Crohns disease (CD) continued
DRUG
RELEASE SITE
TREATMENT OF CD
SIDE-EFFECTS
Have been approved for the

induction and maintenance of
moderate-to-severe CD
Also used for stulizing and perianal
disease
Combination therapy with
immunomodulators is superior to
monotherapy
Infections (tuberculosis,
fungal infections),
autoantibody formation,
psoriasis, drug-induced lupus
Infusion reactions
(iniximab), injection-site
reaction (adalimumab and
certolizumab), delayed
(iniximab)
Lymphoma (higher in
combination therapy with
immunomodulator)
Biologicals
Iniximab
Systemic
Adalimumab
Systemic
Certolizumab pegol
Systemic
Natalizumab
Systemic
Effective in the induction and

maintenance of remission in
Second-line to other biologicals
due to possibly causing progressive
multifocal leukoencephalopathy
(PML)
Infusion reaction,
hepatotoxicity, infections,
and autoantibody formation
Vedolizumab
Systemic

Headache, infections,
abdominal pain, infusion
reactions
but the disease can present at any age. Male and females are
equally affected. Family history and smoking cessation
arerisk factors. NSAIDs increase UC flares.
UC can be classified into three different phenotypes:
1 Proctitis (one-third)
2 Left-sided colitisup to the splenic flexure (one-third)
3 Extensive colitispast the splenic flexure (one-third).
Diagnosis
Diagnosis of UC is based on a combination of clinical symptoms, imaging, endoscopy and histology. Infection should
always be ruled out by checking stool studies for common bacterial
pathogens and Clostridium difficile.
Clinical symptoms
Diarrhea
Hematochezia
Urgency
Tenesmus
Severe and fulminant UC flares require hospitalization for
resuscitation, IV steroids, possible rescue therapy (infliximab or cyclosporine), and a consideration of surgery.
Severe UC:
>6 bloody stools daily
Systemic symptoms: fever and tachycardia
Anemia
Elevated ESR
348
Fulminant disease:
>10 bowel movements daily
Persistent GI bleeding
Systemic toxicity
Abdominal tenderness and distension
Blood transfusion requirement
Colonic dilatation on abdominal plain films
Laboratory function:
Raised inflammatory markers (ESR, CRP)
Fecal calprotectin identifies active disease
Autoantibody testingpANCA and ASCA have
poor sensitivity and specificity and are not used
routinely
Endoscopycolonoscopy
Erythema, granularity, loss of vascular pattern,
friability, and ulceration
Changes involve the distal rectum and proceed
proximally in a symmetric, continuous and circumferential pattern to involve all or part of the colon
Histologyendoscopic biopsies show chronic inflammation with crypt distortion and crypt abscesses
ImagingCT or MR enterography
Used to assess for small bowel disease and rule out
Crohns disease
Reveals colonic bowel-wall thickening
Thiopurines (azathioprine and 6-mercaptopurine)

are used for maintenance of remission in steroiddependent, steroid-refractory or steroid-induced
disease.
Infliximab, adalimumab and golimumab can be
used to induce and maintain remission in moderateto-severe colitis that is steroid-refractory or not
responding to thiopurines.
Vedolizumab has also been shown to induce and
maintain remission in patients with moderate-tosevere UC.
Severe colitis
Patients with systemic symptoms should be
hospitalized.
IV methylprednisone at doses of 4060 mg daily
should be started.
Infectious colitis should be ruled outespecially
that due to C. difficile, CMV and common bacterial pathogens.
Flexible sigmoidoscopy with biopsies should be
performed within 48 hours of admission.
If there is no improvement on IV steroids within
35 days, either colectomy or rescue therapy with
IV cyclosporine (ciclosporin) or IV infliximab is
indicated.
If responding to IV steroids, the patient could be
switched to a tapering dose of oral corticosteroids
and thiopurine or biologicals.
Treatment
The goal of treatment is to induce and maintain clinical
remission, with the ultimate goal of mucosal healing. Medical (Table 12-12) or surgical therapy depends on the severity
of the disease and the location.
Distal colitisproctosigmoiditis
Oral aminosalicylates, topical mesalamine or topical
steroids can be used to induce and maintain remission in mild-to-moderate distal colitis.
Topical mesalamine agents (enemas or suppositories) are superior to topical steroids or oral aminosalicylates. Suppositories should be used for proctitis
and enemas for proctosigmoiditis.
Combination oral and topical aminosalicylates are
more effective than either alone.
If refractory to the above regimens at maximum
doses, budesonide extended-release or prednisone
should be used for induction of remission. This is
followed by thiopurines or biologicals for the maintenance of remission.
Left-sided ulcerative colitis and extensive colitis
Induction, followed by maintenance, of mildto-moderate extensive colitis should start with
aminosalicylates in combination with topical
aminosalicylates.
If aminosalicylates fail, oral prednisone or
budesonide extended-release can be used to induce
remission. This is followed by thiopurines or biologicals for maintenance.
Table 12-12 Medical therapy used in ulcerative colitis (UC)
DRUG
RELEASE SITE
TREATMENT OF UC
SIDE-EFFECTS
Oral 5-aminosalicylates
Sulfasalazine
Colon
Distal ileum, colon
(controlled-release)
Duodenum, jejunum,
ileum, colon
Olsalazine
Colon
Balsalazide
Colon
Induce and maintain remission in

mild-to-moderate UC
Use in combination with topical
mesalamine for distal colitis
Rash, alopecia, and

resulting in worsening
diarrhea can occur
Severe adverse events
such as interstitial
nephritis, pancreatitis and
pneumonitis can rarely
occur
Topical 5-aminosalicylates
enema
Rectum, sigmoid
suppository
Rectum
Induce and maintain remission in

mild-to-moderate distal disease
Combination therapy with oral
aminosalicylates are superior to
monotherapy
Antibiotics
Ciprooxacin
Metronidazole
Amoxicillin/clavulanic
acid
Rifaximin
Systemic
Antibiotics are not used for the

treatment of UC but are used for
pouchitis
Ciprooxacin: tendonitis
and rupture
Metronidazole: neuropathy
Amoxicillin/clavulanic acid:
hepatitis
continues
349
Table 12-12 Medical therapy used in ulcerative colitis (UC) continued
DRUG
RELEASE SITE
TREATMENT OF UC
SIDE-EFFECTS
Corticosteroids
Budesonide extendedrelease
Colon
Induce remission in mild-tomoderate UC

Should not be used for
maintenance
High rst-pass metabolism

More favorable side-effect
prole than prednisone
Prednisone
Systemic
Induce remission in mild-tomoderate and some moderate-tosevere UC ares

Not used for maintenance therapy
Infection, diabetes mellitus,

osteoporosis, osteonecrosis,
cataracts, glaucoma, and
myopathy. Increase risk of
mortality
Methylprednisolone
Systemic
Induce remission in severe UC
As for prednisone
6-Mercaptopurine
Systemic
Azathioprine
Systemic
Maintain remission in steroiddependent, steroid-refractory, or

steroid-induced-remission UC
Not used to induce remission
Allergic reactions,
pancreatitis,
myelosuppression, nausea,
infections, hepatotoxicity,
and malignancy, in particular
lymphoma
Cyclosporine
Systemic
Rescue therapy to induce remission

in severe UC not responding to IV
methylprednisolone
Infections, hypertension,
renal insufficiency, tremor,
headache, hepatotoxicity
Iniximab
Systemic
Adalimumab
Systemic
Golimumab
Systemic
Can be used to induce and maintain

moderate-to-severe UC and are
steroid-sparing
Iniximab is also used as a rescue
therapy to induce remission in
severe UC not responding to IV
methylprednisolone
Infections (tuberculosis,
fungal infections),
autoantibody formation,
psoriasis, drug-induced
lupus
Infusion reactions
(iniximab), injection-site
reaction (adalimumab
and golimumab), delayed
(iniximab)
Lymphoma (higher in
combination therapy)
Vedolizumab
Systemic

moderate-to-severe UC
Headache, infections,
abdominal pain, infusion
reactions
Immunomodulators
Biologicals
Indications for surgery in UC

Severe colitis not responding to IV steroids or rescue
therapy (cyclosporine or infliximab)
Fulminant colitis with or without toxic megacolon
Exsanguinating hemorrhage
Perforation
Patient unable to tolerate medication side-effects
High-grade dysplasia (some low-grade dysplasia)
Cancer
350
The most common surgery performed for UC is:

a total colectomy with formation of an ileostomy in an
urgent/emergency situation
a total proctocolectomy with ileal-pouch anal anastomosis (IPAA) in an elective setting.
Pouchitis
Patients with an IPAA are at risk of developing acute (lasting
<4 weeks) or chronic (lasting >4 weeks) pouchitis. Diagnosis
is made based on clinical symptoms, endoscopic appearance,
and histology.
Clinical symptomsincrease in stool frequency

(>810 per day), urgency, incontinence, increase in
night-time seepage, and perianal/abdominal pain.
Pouchoscopyerythema, edema, granularity, friability, loss of vascular pattern, mucous exudates, and
ulcerations.
Histologychronic inflammation with crypt distortion and crypt abscesses.
Stool culturesrule out C. difficile, CMV and
common bacterial pathogens.
Treatment
Primary prophylaxisVSL#3 (a probiotic) daily.
Acute pouchitis:
antibiotics for 14 days (ciprofloxacin, metronidazole, or amoxicillin/clavulanic acid)
VSL#3 in mild cases.
Secondary prophylaxisVSL#3 daily.
Chronic pouchitis:
antibiotic-dependentrotating antibiotics + VSL#3
antibiotic-resistant4-week course of combination
antibiotics (ciprofloxacin + metronidazole, ciprofloxacin + rifaximin).
Colon cancer screening

Patients with UC have a higher risk of colon cancer compared with patients with CD and the general population.
Risk factors for colorectal cancer in UC are:
duration of colitis
primary sclerosing cholangitis
extensive colitis
backwash ileitis
severe inflammation, pseudopolyps
family history of colorectal cancer
dysplasia.
The recommended screening is:
810 years after diagnosis of extensive colitis in UC or
>30% colitis in CD
15 years after left-sided colitis
at diagnosis of primary sclerosing cholangitis (PSC) and
then every 12 years thereafter.
The results of screening determine the course of action.
Flat lesions with:
low-grade dysplasiaconsider colectomy or close
surveillance
high-grade dysplasiacolectomy
Polypoid lesionscomplete removal and vigilant
follow-up
Unresectable/carpet lesionssurgery
Vaccines in IBD
All IBD patients should be vaccinated if possible, according
to usual guidelines, preferably at diagnosis before they are
immunosuppressed. The definition of immunosuppression
in IBD is:
treatment with corticosteroids (prednisone >20mg/day

for 2 weeks or more and within 3 months of stopping)
treatment with azathioprine/6-mercaptopurine or discontinuation within the previous 3 months
treatment with methotrexate or discontinuation within
the previous 3 months
treatment with anti-TNF (tumor necrosis factor) agents
or discontinuation within the previous 3 months
significant proteincalorie malnutrition.
General rules
1 Live-attenuated vaccines should be avoided for at least
3 months after finishing immunosuppressive therapy.
2 Immunosuppressive therapy should be withheld for at
least 3 weeks (412 weeks) after a live vaccine injection.
3 It is best to vaccinate at diagnosis, before starting
immunomodulator therapy.
Pregnancy in IBD
Fertility in women with IBD without previous pelvic
surgery is similar to that in the general population.
The goal is to achieve and maintain remission at conception and during pregnancy to have favorable pregnancy outcomes.
Smoking (for CD), discontinuation of medications, and
active disease during pregnancy are risk factors for IBD
flares.
Most medications used to treat IBD are low-risk during
pregnancy except for methotrexate (Table 12-13).
Most IBD medications are safe during lactation with
the exception of methotrexate, metronidazole, and cyclosporine (ciclosporin) (Table 12-13).
The riskbenefit ratio between maintaining disease
remission and possible medication side-effects should
be discussed on a case-by-case basis.
Colon polyps
CLINICAL PEARLS
Detection and removal of these polyps through
effective screening is important.
Colonoscopy is the diagnostic test of choice in
detecting colorectal cancer.
Risk factors for colon cancer include age and a history of

adenomatous colon polyps (but not hyperplastic polyps).
Colonic polyps may be:
Adenomassubdivided into tubular, villous and tubulovillous. Those of large size (>1 cm), with high-grade
dysplasia and/or tubulovillous morphology typically
comprise advance adenomas which are closely related
to colorectal cancer.
Macroscopically flat or depressed lesions, which account
for 10% of adenomas, appear to have a high malignancy
potential.
351
Table 12-13 Inammatory bowel disease medications in pregnancy and breastfeeding
DRUG
FERTILITY
BREASTFEEDING
PREGNANCY
COMMENTS
Antibiotics
Metronidazole
Ciprooxacin
Amoxicillin/
clavulanate
Rifaximin
(9)
(9)
Probiotics
Mesalamine
(mesalazine)
Mesalamine
(mesalazine)
(Asacol, Asacol HD)
(9)
(9)
Teratogenic in animal studies
Sulfasalazine
Give with folic acid 2mg daily

Affects fertility in men
Olsalazine
Limited data available
Prednisone
Budesonide
Azathioprine/
6-mercaptopurine
Methotrexate
Cyclosporine
(ciclosporin)
Tacrolimus
Iniximab
Adalimumab
Certolizumab
Golimumab
(9)
(9)
Natalizumab
(9)
(9)
Vedolizumab
No available data
Wait 1224 hours before

breastfeeding
Aminosalicylates
Corticosteroids
Immunomodulators
Teratogenic
Biologicals
(9) limited data, caution

9 relatively safe to use based on limited data
X do not use
352
Genetic alterations on DCC, K-ras, p53 and COX-2 genes,

and expression of mismatch repair (MMR) proteins appear
to be inducible in colorectal neoplasia.
BOWEL CANCER SCREENING

surveillance
Average risk
Persons aged between 50 and 75 years who have no symptoms of bowel cancer and no special risk factors have an average risk of bowel cancer. Those aged 50 and above should be
counseled to engage in a screening program:
There is a 1533% reduction in mortality from bowel
cancer using fecal occult blood testing (FOBT). It can
miss a third of advanced cancers.
Colonoscopy 10-yearly from age 50 is the screening
procedure of choice, although many countries use a
fecal test as the initial screening test for asymptomatic
persons. Alternatives include flexible sigmoidoscopy
and barium enema, or CT colography.
Above-average risk
Most patients who have curative surgery for bowel cancer or
removal of advanced colorectal adenomatous polyps should
enter an endoscopic surveillance program.
In general, colonoscopy is recommended every
35years.
After polyps are found, surveillance depends on the size,
number and family history.
Patients with >10 adenomas should have repeat colonoscopy every 3 years. It is important to consider
the possibility of an underlying familial syndrome.
Patients with sessile adenomas that are removed
piecemeal require repeat colonoscopy in 26months
to confirm complete excision.

There are two main types of test:
guaiac testbased on the pseudoperoxidase activity of hemoglobin
immunochemical testutilizes the antibody to
human hemoglobin, and is more accurate and thus
preferred for population screening.
Three stools should be sampled annually and test cards
should be used at home. A single FOBT test has poor
sensitivity, but this is increased by repeat testing (hence
the three samples).
Dietary restriction is highly desirable for the guaiac test
(no beef or lamb). If dietary restrictions are followed,
false-positive results are uncommon (12%). One
advantage of the immunochemical test is that dietary
restriction is unnecessary.
A person who has a positive FOBT has a 3045%
chance of having adenoma and a 35% chance of having
cancer.
FOBT is negative in up to 66% of patients

withcolon cancer.
Positive tests should be followed up with
colonoscopy.
Fecal DNA testing may replace FOBT in the future.
Carcinoembryonic antigen (CEA) testing is only useful
for checking for recurrence of colon cancer, and only if
the levels were elevated before surgery and reduce after
surgery. Other causes of CEA rise include smoking,
benign biliary disease, sclerosing cholangitis and inflammatory bowel disease.

Important factors to be taken in consideration for surveillance are:
size of polyps
number of polyps
histopathology.
Table 12-14 describes the malignant potential and surveillance requirements for different types of polyp.
Family history of bowel cancer without

genetic basis
Recommendations
One first-degree relative with bowel cancer at age 55 or
oldercolonoscopy from age 50.
One first-degree relative with bowel cancer diagnosed
under age 55, or two or more first-degree relatives on
the same side of the family with bowel cancercolonoscopy every 5 years starting at age 50 or 10 years
younger than the age of the earliest diagnosis of colorectal cancer (CRC).
Family history of bowel cancer with known

genetic basis
Familial adenomatosis polyposis (FAP)
This is characterized by hundreds to thousands of colorectal adenomas that usually develop in adolescence.
One in five FAP patients has new-onset mutations (no
known family history of FAP). Risk of colonic cancer is
100% if not treated.
Unless total protocolectomy is performed CRC universally develops, with mean age at diagnosis of approximately 40 years. Extracolonic features include duodenal
adenomas and cancer, gastric fundic gland hyperplasia,
mandibular osteomas and supernumerary teeth.
Following colectomy, patients are at risk of developing
duodenal cancer.
Attenuated FAP is associated with fewer colorectal
adenomas (<100) and later onset of CRC (mean age
approximately 55 years).
353
Table 12-14 Malignant potential and surveillance of colonic polyps
POLYP TYPE
MALIGNANT POTENTIAL/
SURVEILLANCE REQUIREMENTS
MORPHOLOGY
Tubular adenoma
Branched tubules
<1cm: 1%
12cm: 10%
>2cm: 34%
Surveillance every 35years (12 small polyps
with low-grade dysplasia after polypectomy)
Villous adenoma
Frond-like pattern
<1cm: 4%
12cm: 20%
>2cm: >50%
Surveillance every 3 years (310 adenomas
or 1 adenoma >1cm or any adenoma with
villous features or high-grade dysplasia after
polypectomy)
Tubulovillous adenoma
Mixed pattern
<1cm: 4%
12cm: 9%
>2cm: 45%
Surveillance every 3 years
Classic hyperplastic polyp
Increased glandular cells

Reduced cytoplasm
Nuclear atypia, stratication and
hyperchromatism is absent
Small and distally located

Do not appear to be associated with increased
risk of colorectal cancer
Hyperplastic polyposis
syndrome
1cm or more, 30 or more polyps, and

mixed adenomatous features have
increased risk of colorectal cancer
Surveillance 1-yearly
Serrated polyps
1. Classic hyperplastic
polyps
2. Sessile serrated polyp

without dysplasia
3. Traditional serrated
adenoma with dysplasia
4. Mixed: sessile serrated

and tubular adenoma
5. Serrated
adenocarcinoma
Referral for surgery
Recommendations
Refer for genetic counseling.
Offer screening in the teenage years.
These patients need to be considered for protocolectomy by age 20.
Individuals who test positive for the APC gene mutation, or
all at-risk first-degree relatives where no APC gene mutation has been characterized, should have annual or biennial
sigmoidoscopy from 1215 years (the exact age depending on the maturity) to 3035 years, and less frequently to
55years of age.
354
Gardner syndrome
This is a variant of FAP. There may be fewer colonic polyps
than FAP, but it presents with extraintestinal manifestations
(osteomas, epidermal cysts, fibromas, dental abnormality,
desmoids, tumors, etc.).
Hereditary non-polyposis colon cancer (HNPCC) or
Lynch syndrome
This is the most common form of inherited colon cancer.
It is an autosomal dominant disorder and caused by germline mutations (mismatch repair genes, MMR) in MLH1,
MSH2, PMS1, PMS2 or MSH6. The most common mutations are in MLH1 and MSH2.
The median age for CRC diagnosis is 46.
The polyps tends to be located in the more proximal
colon.
It is associated with other cancers (uterine, ovarian,
genitourinary, small bowel and hepatobiliary).
Tissue should be tested for microsatellite instability by
immunohistochemistry and/or by PCR.
The Amsterdam criteria are used to help identify families
likely to have Lynch syndrome:
1 At least 3 relatives with histologically confirmed colon
cancer (or endometrial cancer or small-intestine cancer)
2 At least 2 successive generations
3 At least 1 colon cancer diagnosed before age 50
4 One relative should be a first-degree relative of the
other two.
Recommendations
Colonoscopy from age 25, or 5 years younger than the
age of the earliest cancer in the family (whichever comes
first).
HNPCC-testing for microsatellite instability (MSI)
and/or immunohistochemistry of the mismatch repair
gene product.
Annual screening in known mutation carriers, and biennial screening for at-risk first-degree relatives in families where the mutation is not characterized.
Annual gynecological screening, with transvaginal
ultrasound for ovarian screening and endometrial sampling, is recommended for pre-menopausal female gene
carriers and at-risk women with family members where
no mutation has been found.
For postmenopausal women, transvaginal ultrasound
to evaluate endometrial thickness, and ovarian pathology and cancer-associated antigen 125 (CA-125) is
recommended.
Figure 12-9 PeutzJeghers mucosal pigmentations

From Weston WL, Lane AT and Morelli JG. Color textbook of
pediatric dermatology, 4th ed. Elsevier, 2007.
GASTROINTESTINAL BLEEDING
Upper
PeutzJeghers (PJ) syndrome
The most common causes of upper GI bleeding are:

bleeding peptic ulcers
esophago-gastric varices
ulcerative esophagitis
MalloryWeiss tears (physical mucosal tears due to
vomiting)
bleeding from GI vascular lesions:
gastric antral vascular ectasia (GAVE)
Dieulafoy lesion (an aberrant submucosal vessel that
has eroded into the epithelial layer)
hereditary hemorrhagic telangiectasia (Osler
WeberRendu syndrome: an autosomal dominant
vascular disorder where epistaxis, GI bleeding and
cerebral arteriovenous malformations are common;
Figure 12-10)
arteriovenous malformations and angiodysplasia.
The most common symptoms of upper GI hemorrhage are
hemetemesis and melena, but some patients simply present
with collapse and shock.
In this syndrome, multiple hamartomatous polyps are

present in the GI tract associated with distinctive mucocutaneous pigmentationslips and buccal mucosa,
nose, perianal area, genitals and rarely in the GI tract
(Figure 12-9).
PJ syndrome is an autosomal dominant disorder, with
male and females equally affected.
The PJ gene is located on chromosome 19p13.3.
PJ syndrome is associated with an increased risk of malignancy, both GI and non-GI (gynecologicalovarian or cervical tumors; malesSertoli cell testicular tumors), with an
average age of developing malignancy of 42 years. The most
common sites for cancers are colon/rectum and pancreas,
and breast for non-GI cases.
Figure 12-10 OslerWeberRendu syndrome

From Feldman MD, Friedman LS and Brandt LJ (eds). Sleisenger and
Fordtrans Gastrointestinal and liver disease, 9th ed. Philadelphia:
Elsevier, 2010.
355
CLINICAL PEARL
Peptic ulcer bleeding is common in the elderly with
comorbidities and use of anticoagulants. Stigmata of
chronic liver disease should raise suspicion of variceal
hemorrhage.
Management
Initial management is focused on management of the
airway and hemodynamic resuscitation.
The presence of tachycardia, hypotension or hematochezia indicates rapid, large-volume blood loss, and
early endoscopy is indicated.
CLINICAL PEARL
Despite a normal supine blood pressure, hypovolemia
can exist: checking for a postural drop in blood pressure is mandatory in all such patients.
Intravenous PPI therapy should be commenced prior to

endoscopy and continued depending on the pathology
found.
Placement of a nasogastric tube prior to endoscopy
when upper GI hemorrhage is suspected has not been
shown to improve outcomes.
If the patient has known varices or variceal hemorrhage
is suspected, vasoactive peptides (octreotide or terlipressin) should be given IV.
All patients with suspected or confirmed variceal bleeding should receive prophylactic antibiotics. 50% of such
patients have bacterial sepsis at the time of presentation,
and many more develop sepsis during admission.
Peptic ulcer bleeding
In peptic ulcer bleeding, endoscopy is important for risk
stratification. Larger ulcers, with visible vessels or overlying
clots, are the highest risk for re-bleeding, while clean-based
ulcers rarely re-bleed.
High-dose PPI therapy helps to prevent early rebleeding after endoscopic therapy. Few patients (2%)
require surgery; the main indications are:
bleeding that cannot be controlled endoscopically
perforated ulcers
refractory ulcers
bleeding secondary to cancers.
Appropriate investigation for and eradication of Helicobacter pylori should be done in all patients with peptic
ulcer bleeding.
CLINICAL PEARL
Active bleeding may lead to gastric biopsy tests being
falsely negative for Helicobacter pylori.
356
Variceal bleeding
Control of bleeding is often obtained with endoscopic
banding devices or injection of sclerosing agents.
Compression of gastric or esophageal varices with a
balloon catheter (SengstakenBlakemore or Linton
tube) is used if hemostasis cannot be achieved with
other means.
Insertion of a transjugular intrahepatic portosystemic
shunt reverses portal hypertension and can be used to
manage acute bleeding and also prevent re-bleeding.
Bleeding from gastrointestinal vascular lesions
Upper GI hemorrhage due to abnormal vascular lesions is
not uncommon. Often the offending lesion responds well to
treatment with argon plasma coagulation, which ablates the
vessel. Repeated treatments are often required.
Lower
Lower GI bleeding generally includes bleeding sources
below the ligament of Treitz.
Most commonly, bleeding per rectum is the presenting
symptom, and the causes depend on the age of the patient
and the clinical scenario. Common anorectal causes are:
hemorrhoids
anal fissure
proctitis.
Colonic bleeding
Colonic bleeds are not uncommon, and the most commonly
encountered pathologies are:
diverticular bleeds
angiodysplasia
ischemic colitis (see below)
cancers.
Intestinal ischemia
Inadequate blood supply to the intestines has many causes,
but four distinct clinical scenarios are recognized:
1 acute mesenteric ischemia
2 chronic mesenteric ischemia
3 colonic ischemia
4 mesenteric venous thrombosis.
Acute mesenteric ischemia
Acute mesenteric ischemia is a life-threatening event. Unless
revascularization (radiologically) or, more commonly, resection of the affected bowel occurs promptly, survival is poor.
Embolic occlusion due to atrial fibrillation is the most common cause. It is important to recognize that prothrombotic
disorders and hypercoagulability due to cancer can present
like this.
CLINICAL PEARL
CLINICAL PEARL
The presentation of acute mesenteric ischemia is

nonspecic, with description of severe abdominal
pain out of keeping with relatively minor abdominal tenderness on examination. The serum lactate is
often high.
Postprandial pain occurring in a patient with vascular

risk factors or established vascular disease should raise
suspicion of intestinal angina.
Clues on imaging such as pneumatosis intestinalis,

thumbprinting (Figure 12-11) and bowel-wall edema are
useful, but unfortunately are late signs of disease.
Chronic mesenteric ischemia
Chronic mesenteric ischemia is angina of the gut.
It occurs due to atherosclerotic occlusion of the main
mesenteric vessels (celiac, superior or inferior mesenteric arteries).
Significant occlusion of at least two of the three main
vessels is required for symptoms.
Weight loss is common, and occasionally abdominal
bruits may be heard.
Investigation should be with mesenteric ultrasound
Doppler and/or an angiogram.
Endoluminal treatment is often possible, but formal
bypass procedures are sometimes required.
Any vascular risk factors need to be optimized.
Mesenteric venous thrombosis

In mesenteric venous thrombosis the outflow of blood is
occluded, usually due to local swelling, infection or masses,
or prothrombotic states. Anticoagulation and bowel rest
form standard therapy, although case reports of thrombolysis or thrombectomy exist.
Ischemic colitis
Ischemic colitis is more common than the conditions
described above. It leads to colonic bleeding due to sloughing of necrosed mucosa. This mainly occurs from watershed areas of the colon which are prone to hypoperfusion
during low flow states such as dehydration or reduced cardiac output. Unlike acute mesenteric ischemia, colonic
ischemia is rarely due to embolic disease.
Most patients recover without complications, but those
who develop colonic gangrene and perforation have high
mortality.
Risk factors for ischemic colitis include:
advanced age
hemodialysis
diabetes mellitus
hypoalbuminemia.
Passing maroon stools after sudden-onset abdominal pain
(most often in the left lower quadrant) is common. Colonoscopic examination with biopsies is appropriate if peritonitis
is not present, and shows friable, ischemic mucosa within a
distinct segment of colon. A colonoscopic examination also
helps to exclude inflammatory bowel disease or infectious
causes.
Other causes of colonic bleeding are discussed below.
Diverticular bleeding
Diverticular bleeding is often impressive in terms of
blood loss, but commonly stops spontaneously and can
recur days, months or years later.
Manifestations of bleeding include bright rectal bleeding, but also red blood mixed with stool (hematochezia)
or darker maroon stools.
A technetium-labeled red-cell scan is often helpful for
localization, and if brisk bleeding is present a CT angiogram is often diagnostic.
Bleeding that does not cease spontaneously often
requires surgery.
Angiodysplasia
Figure 12-11 Thumbprinting of the bowel in acute
mesenteric ischemia on plain abdominal X-ray
From Talley NJ. Clinical gastroenterology, 3rd ed. Sydney; Elsevier
Australia, 2011.
Angiodysplasias are fragile, superficial blood vessels in the

colon that easily bleed. They are commonly found in
the cecum but can occur anywhere. Impressive bleeding
can occur, particularly in the setting of anticoagulation.
357
The treatment is endoscopic ablation, and repeated

treatments are often required.
Rarer causes of overt colonic bleeding include bleeding
from colonic malignancies and Meckels diverticulae.
Obscure GI bleeding
Obscure GI bleeding is a challenging clinical scenario.
Often, repeat investigation of the upper or lower GI tract
will reveal a cause missed by previous investigation.
Imaging modalities such as CT angiogram and isotopelabeled red-cell scans can be helpful, but require active
bleeding to be present at the time of investigation to give
a positive yield.
With the advent of video-capsule endoscopy the small
bowel can now be safely investigated in most patients.
The video-capsule device is ingested and takes plentiful images of the GI tract. It can often identify bleeding
lesions in the small bowel such as:
angiodysplasia
tumors
ulceration
stenosis.
The main risk of video-capsule endoscopy is capsule
retention, which occurs in 1% of patients. It can be
asymptomatic or cause bowel obstruction.
CLINICAL PEARL
If it gets stuck, the small-bowel video-capsule is usually retained at a site of signicant pathology (stenosis,
tumor), and both the retained capsule and the offending lesions can be addressed surgically.
Lesions identified by capsule endoscopy in the small

bowel are often amenable to endoscopic therapy using
antegrade or retrograde double-balloon enteroscopy.
Occasionally, aorto-enteric fistulas (usually post abdominal aortic aneurysm repair) or bleeding into the biliary
tract (hemobilia) will cause obscure GI bleeding.
infection (mumps, infectious mononucleosis)

duct obstruction (carcinoma, roundworm)
metabolichypercalcemia (and MEN 1), hyperlipidemia
uremia, porphyria, pregnancy
vascular
drugsthiazides, steroids, contraceptive pill, tetracycline, sulfonamides, valproic acid, azathioprine
pancreas divisum
idiopathic.
Acute pancreatitis is a spectrum of disease.
The milder form presents as interstitial pancreatitis
with mild edema of the pancreas, with inflammation
of the fat in the peripancreatic area and development of
afluid collection around the pancreas. Extra-pancreatic
fluid collections can develop into a pseudocyst.
In the more severe form, the disease is characterized
by pancreatic necrosis with fat necrosis (necrotizing
pancreatitis).
Mortality is dependent on the severity of the acute pancreatitis. Patients with necrotizing pancreatitis have a 1030%
mortality and a 70% risk of developing complications,
whereas interstitial pancreatitis has less than 1% mortality.
Clinical features include severe abdominal pain lasting
many hours. The location of the pain is frequently in the
epigastric area and left upper quadrant, with radiation to the
back. The character of the pain can be fluctuating and associated with nausea and vomiting.
Clinical examination
Cullens and Turners signs (caused by extravasated pancreatic exudates) should be examined for. It is important to note
that these signs are not pathognomonic of acute pancreatitis.
Cullens sign is a faint blue discoloration around the
umbilicus, indicating hemoperitoneum (Figure 12-12).

Sometimes GI bleeding presents as iron-deficiency anemia
without overt bleeding symptoms. Iron-deficiency anemia
always warrants further investigation unless severe comorbidities lead to an unfavorable riskbenefit ratio.
Investigation of the upper and lower GI tract should be
undertaken, with further investigation reserved for patients
where no cause is found or the iron deficiency returns after
adequate replacement.
PANCREAS
Acute pancreatitis
Alcohol and gallstones account for 6075% of acute pancreatitis. Other causes include:
traumaafter endoscopic retrograde cholangiopancreatography (ERCP), penetrating peptic ulcer or trauma
358
Figure 12-12 Cullens sign

From Chauhan S et al. Cullens and Turners signs associated with
portal hypertension. Lancet 2008;372(9632):54.
Turners sign is a bluish-reddish-purple or greenish brown discoloration of the flanks, resulting from
retroperitoneal blood dissecting along the tissue planes
(Figure 12-13).
The differential diagnosis for both is any other cause of
retroperitoneal hemorrhage.
The basic investigations that aid in the diagnosis of acute
pancreatitis include pancreatic enzymes (serum amylase and
lipase).
A serum amylase level >3 times normal is indicative of
a possible diagnosis of acute pancreatitis (Box 12-10).
Serum amylase is elevated initially compared with
lipase, and falls after 23 days. (Serum lipase remains
elevated for longer: 714 days.)
Elevated serum or urine amylase, >900U/L and >6000
U/L, respectively, is sensitive for acute pancreatitis (97%), but specificity is low (5070%). If elevated
amylase persists for >10 days after acute pancreatitis,
consider the possibility of leakage from a pseudocyst or,

with large fluid collection, a disrupted pancreatic duct.
It is important to note that high triglyceride levels
can cause a spuriously normal amylase level. Levels
of triglyceride >1000mg/dL (11.3 mmol/L) can cause
pancreatitis. An abdominal CT is helpful in confirming the diagnosis of acute pancreatitis (Table 12-15,
overleaf).
Management
The management of high-risk patients and those with mild
pancreatitis differs. The key is to determine the risk of
complications and identify factors that affect morbidity and
mortality.
There are a number of scoring systems used (e.g.
Ranson criteriaTable 12-16 (overleaf), APACHE II).
A limitation of the Ranson criteria is that this is
only valid up to 48 hours after the onset of symptoms. The sensitivity is 73% and the criteria are
77% specific to predict mortality.
The systemic inflammatory response syndrome (SIRS)
score (based on temperature, respiratory rate, heart rate
and white cell count; Box 12-11) is favored as it is simple, cheap, readily available and as accurate as any of the
complex scoring systems.
However, no single score is completely accurate. Clinical assessment of severity is important and should not be
replaced by these scoring systems.
Amylase is not a prognostic indicator.
Other risk factors for severity at admission include older
age, comorbidity and obesity.
Complications of acute pancreatitis

Figure 12-13 Turners sign
From Chauhan S et al. Cullens and Turners signs associated with
portal hypertension. Lancet 2008;372(9632):54.
Necrotizing pancreatitis
50% of patients with necrotizing necrosis will have organ
failure. The remainder will have resolution of necrotizing
pancreatitis as it evolves into walled-off pancreatic necrosis.
Box 12-10
Box 12-11
Differential diagnosis of
hyperamylasemia
Dening features of systemic

inammatory response syndrome
(SIRS)
Pancreatic disease
Chronic
pancreatitis
Pancreatic
pseudocyst
Pancreatic
abscess
Pancreatic cancer
Trauma to the
pancreas
Non-pancreatic disease
Renal failure
Parotitis
Intestinal perforation
Intestinal obstruction
Intestinal infarction
Ruptured ectopic pregnancy
Drugs, e.g. morphine
Diabetic ketoacidosis
Burns
Solid tumors, e.g. esophagus,
lung, ovary
Two or more of the following conditions:
Temperature >38.5C or <35.0C

Heart rate of >90 beats/min
Respiratory rate of >20 breaths/min or a PACO2 of
<32 mmHg
WBC count of >12,000 cells/mL, <4000 cells/mL, or
>10% immature (band) forms
PACO2, alveolar partial pressure of carbon dioxide; WBC, white

blood cell.
Data from: Annane D, Bellissant E and Cavaillon JM. Septic
shock. Lancet 2005;365:63.
359
Table 12-15 CT ndings and grading of acute pancreatitis (CT severity index)
GRADING BASED UPON FINDINGS ON UNENHANCED CT

GRADE
FINDINGS
SCORE
Normal pancreasnormal size, sharply dened, smooth contour, homogenous

enhancement, retroperitoneal peripancreatic fat without enhancement
Focal or diffuse enlargement of the pancreas; contour may show irregularity

Enhancement may be inhomogeneous, but there is no peripancreatic
inammation
Peripancreatic inammation with intrinsic pancreatic abnormalities
Intrapancreatic or extrapancreatic uid collections
Two or more large collections of gas in the pancreas or retroperitoneum
NECROSIS SCORE BASED ON CONTRAST-ENHANCED CT

NECROSIS (%)
SCORE
<33
3350
50
CT SEVERITY INDEX (CTSI)

CTSI equals unenhanced CT score plus necrosis score
Maximum = 10; 6 = severe disease
CT, computed tomography.
Adapted from Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CF in establishing prognosis. Radiology
1990;174(2):3316.
The clinical features include intractable pain, nausea and

vomiting, inability to maintain adequate weight,
andlow-grade fever.
Abdominal pain is due to raised intra-parenchymal
pressures within the walled-off pancreatic necrosis.
As soon as the diagnosis of necrotizing pancreatitis is
made, IV antibiotics are recommended if systemic signs
of sepsis are present.
Sterile and infected acute necrotizing pancreatitis can be difficult to distinguish clinically, as both
present with fever, leukocytosis and severe abdominal pain. CT-guided FNA is a safe and accurate way
to confirm that infection is present.
Treatment modalities include:
1 Surgical (cystogastrectomy or Roux-en-Y cystojejunostomy with finger dissection of necrotic tissue).
2 Endoscopic technique using transgastric and transduodenal drainage catheters.
3 Less commonly, radiological percutaneous placement
of a catheter to facilitate debridement.
360
Pancreatic abscess
This usually occurs 46 weeks after an acute pancreatitis attack. It can present with fever and shock. CT-guided
biopsy with bacterial smear and culture helps with diagnosis.
Treatment involves immediate surgical debridement
and drainage, and antibiotics. (Timing is important when
the process has evolved into a walled-off necrosis.) Treatment of sterile necrosis is generally non-surgical.
Pancreatic pseudocyst
This develops in 1015% of patients in the 24 weeks following an acute pancreatitis attack. Some are asymptomatic,
while others can present with abdominal pain and have the
potential to become infected. If the size is >5cm and it has
lasted more than 6 months, this indicates that it will not
resolve spontaneously.
Treatment modalities include:
1 Surgicalcystogastrostomy or Roux-en-Y cystojejunostomy.
2 Endoscopicendoscopic cystogastrostomy.
3 Radiologicalpercutaneous catheter drainage.
Table 12-16 Ranson criteria to predict severity of

acute pancreatitis
MEASURE
CRITERION
0 hours
Age
>55
White blood cell count
>16,000/mm3
Blood glucose
>200 mg/dL (11.1 mmol/L)
Lactate dehydrogenase
>350 U/L
Aspartate aminotransferase
(AST)
>250 U/L
48 hours
Hematocrit
Fall by 10%
Blood urea nitrogen
Increase by 5 mg/dL
(1.8 mmol/L) despite uids
Serum calcium
<8 mg/dL (2 mmol/L)
pO2 (partial oxygen

pressure)
<60 mmHg
Base decit
>4 MEq/L
Fluid sequestration
>6000 mL
The presence of 13 criteria represents mild pancreatitis;

the mortality rate rises signicantly with 4 or more criteria.
Adapted from Ranson JHC, Rifkind KM, Roses DF, et al.
Prognostic signs and the role of operative management in acute
pancreatitis. Surg Gynecol Obstet 1974;139:6981.
CLINICAL PEARL
The classic triad of chronic pancreatitis is recurrent
abdominal pain, diabetes and steatorrhea from pancreatic exocrine and endocrine dysfunction. This form of
diabetes does not cause retinopathy or nephropathy.
Chronic pancreatitis is a syndrome of progressive, irreversible and destructive inflammatory changes in the pancreas,
resulting in permanent structural damage and leading to
impairment of the exocrine and endocrine functions.
Unlike acute pancreatitis, serum amylase and lipase
levels tend to be normal in patients with chronic
pancreatitis.
The gold standard for diagnosis is tissue diagnosis, but
this is invasive and rarely performed. Therefore, the
diagnosis is based on a combination of clinical, radiological and functional findings.
The hallmark of this disease is abdominal pain and exocrine dysfunction.
The most common cause is chronic alcohol ingestion, with

a typical history of heavy alcohol (150 g) or more daily for
6or more years. Other causes include:
idiopathic
hereditary pancreatitisgenetic mutations have been
identified in subgroups of patients; the mutations occur
in the cationic trypsinogen gene (R122H, N29, R117H)
or the pancreatic secretory trypsin inhibitor gene (PSTI/
SPINKI [serine protease inhibitor Kazal-type 1]);
cystic fibrosis
pancreas divisum
tumor
hyperparathyroidism
autoimmune pancreatitisrare (<1 %), but important
to recognize.
The clinical presentation involves an initial asymptomatic
phase followed by recurrent abdominal pain.
Abdominal pain can be referred to either the left or the
right, or radiates to the back. If diaphragmatic involvement is present, pain may be pleuritic in nature and felt
in the shoulder.
The natural history of the disease results from progressive exocrine dysfunction leading to steatorrhea and
diarrhea, and endocrine dysfunction leading to diabetes.
The classic triad of recurrent abdominal pain with pancreatic calcification, diabetes and steatorrhea (fecal fat
>20 g/day) increases the likelihood of the diagnosis of
chronic pancreatitis.
Investigations
Blood tests are neither sensitive nor specific for the diagnosis of chronic pancreatitis. Fecal elastase is a useful screening test for moderate to severe disease. Secretin stimulation
testing using a nasoduodenal tube for duodenal sampling for
bicarbonate is both sensitive and specific, but not well tolerated or readily available.
Imaging modalities that help confirm the diagnosis
include:
CT abdomen to confirm the presence of calcified pancreas (Figure 12-14, overleaf). The differential diagnosis of calcified pancreas includes alcoholic pancreatitis,
hyperparathyroidism and hereditary pancreatitis.
Endoscopic ultrasonography (EUS) is both sensitive and
specific, and may confirm the diagnosis when the CT
scan is normal. However, differentiating chronic pancreatitis and pancreatic cancer is not always accurate because
the echoendoscopic features of lobular architecture and
hypoechoic changes in pancreatic parenchyma are similar. EUS with FNA is needed to confirm the diagnosis.
Magnetic resonance cholangiopancreatography (MRCP)
can aid in the diagnosis of chronic pancreatitis and help
detect stones in the common bile duct (CBD) and other
biliary disease.
ERCP is invasive and can precipitate pancreatitis. This
approach is beneficial if CBD or pancreatic duct stones
are present.
361
Figure 12-14 Calcied pancreas shown on computed tomography scan

From: Herring W. Learning radiology: recognizing the basics, 2nd ed. Philadelphia: Elsevier, 2012.
Complications
The main complications of chronic pancreatitis are related
to exocrine dysfunction leading to steatorrhea and fat malabsorption, with associated fat-soluble vitamin deficiency
(A, D, E or K) and low vitamin B12. Endocrine dysfunction occurs when >80% of the pancreas is destroyed (late
onset). Diabetes is more likely to occur with a family history
of type1 or type 2 diabetes.
Other complications include:
pseudocyst (10%), secondary to ductal disruptions
rather than from peripancreatic fluid accumulation as in
acute pancreatitis
duodenal and bile duct obstruction (510%)
pancreatic ascites and pleural effusion, secondary to
disruption of the pancreatic duct and fistula formation between the abdomen and the chest, or rupture
of pseudocyst with tracking of pancreatic fluid into the
peritoneal cavity
splenic vein thrombosis secondary to inflammation of
the splenic vein
pseudoaneurysm of vessels close to the pancreas (rare).
Treatment
The treatment is directed at managing pancreatic exocrine
and endocrine dysfunction, with a multidisciplinary team.
Pancreatic enzymes are replaced by oral pancreatic
enzymes (20,00030,000 units of lipase per meals).
A PPI is added to prevent gastric acid breaking down the
enzymes.
At present, managing the chronic pain is difficult and
the potential for narcotic addition is high. Modalities
such as pancreatic enzyme supplementation, endoscopic
therapy and nerve block, as well as surgery for relief of
refractory pain, may be tried.

Autoimmune pancreatitis is a rare cause of pancreatitis
(<1%). It is an important diagnosis to make, and its treatment often results in a good prognosis for the patient.
362
CLINICAL PEARL
Autoimmune pancreatitis type 1 is associated with elevated immunoglobulin G4 levels, while type 2 is associated with inammatory bowel disease. Most patients
respond to corticosteroids, but 3040% will relapse.
The usual clinical picture is obstructive jaundice (70%),

with dramatic clinical and histopathological response to
corticosteroids.
The picture may be confused clinically with pancreatic
cancer. Pancreatic cancer is much more common than
autoimmune pancreatitis.
Autoimmune pancreatitis is classified into types 1 and 2
(Box 12-12).
Pancreatic histology is essential to make the definitive diagnosis of autoimmune pancreatitis. An
important clinical clue to making the diagnosis is
the involvement of other organs in autoimmune
pancreatitis type 1.
AIP is occasionally associated with other autoimmune
diseases (most commonly Sjgrens syndrome, primary
sclerosing cholangitis, systemic lupus erythematosus and
ulcerative colitis).
The underlying pathogenesis is unknown.
The key imaging modalities to aid in the diagnosis
include:
CT abdomen shows a diffusely swollen, sausage-shaped
pancreas with a narrowed pancreatic duct.
EUS shows a diffusely hypoechoic gland.
EUS is also used as a guide to obtain a core biopsy. This
is important, as the pancreatitis is not uniformly involved
in the disease process. Biopsy from the major duodenal
papilla has a high specificity but low sensitivity.
ERCP findings include a long, narrow stricture (more
than one-third of the main pancreatic duct) with lack of
upstream dilatation, multiple non-contiguous strictures,
and stricture arising from the narrowed portion of the
main pancreatic duct.
Box 12-12
Classication of autoimmune pancreatitis (AIP)

Type 1
More commonly found in Japan and Korea
Peak incidence in the 6th or 7th decade
Men are affected twice as often as women
Associated with elevated serum immunoglobulin G4
(IgG4) levels (usually twice the upper limit of normal)
Elevated ANA (antinuclear antibodies) may be present
IgG4 levels have sensitivity of 95% and specicity of 97%
for AIP type 1
It characteristically involves other organs, in particular
bile ducts, salivary glands, lymph nodes, kidneys and
retroperitoneum synchronously or metachronously
(see Chapter 16)
Treatment
The mainstay of treatment is corticosteroids, with improvement in morphology, biochemical and exocrine function.
IgG4 levels can help in monitoring the response to
treatment, as well as cross-sectional imaging.
If a stent has been placed, this is usually removed at
68weeks after initiation of treatment.
3040% of cases have clinical, radiological, serological or histological relapse following treatment. These
patients will need a prolonged course of corticosteroids.
Use of azathioprine/6-mercaptopurine long-term has
been only in case reports.
All patients should be monitored for residual pancreatic
exocrine and endocrine insufficiency.
Pancreatic cysts
Type 2
More commonly found in Europe
It affects younger patients; usually 10 years earlier than
AIP type 1
There is no gender predilection
Not associated with elevated IgG4 levels
No systemic organ involvement
Inammatory bowel disease in 30%
Many different types of lesion exist.

No malignant potential:
pseudocysts (result of inflammation, most often
pancreatitis)
benign (serous cystadenomas)
Potentially malignant:
mucinous cysts, intraductal papillary mucinous
neoplasms (IPMNs)
serous cystic tumors
mucinous cystic neoplasms (MCNs)
solid pseudopapillary neoplasms
CLINICAL PEARL
The larger the size of the cystic lesion, the higher the
chance of malignancy. Generally, cystic lesions of
>3 cm can be observed with serial imaging.
Pancreatic cystic lesions are increasingly diagnosed with

the growing use of cross-sectional imaging. Most are found
incidentally in asymptomatic patients.
363
1 A 74-year-old man with dyspepsia and chronic obstructive pulmonary disease (FEV1 66% of predicted), type 2 diabetes
mellitus and a body mass index of 36 kg/m2 undergoes esophagogastroduodenoscopy for an upper gastrointestinal
hemorrhage. A duodenal ulcer is found and treated. At the time of endoscopy, Barretts esophagus is suspected in a
4 cm tongue of abnormal mucosa. There are no raised lesions or nodules. Biopsies and repeat biopsies after 1 month
conrm high-grade dysplasia. In this patient, the most appropriate next step is:
A High-dose proton-pump inhibitors and repeat biopsies in 3 months
B Referral for esophagectomy
C Liquid nitrogen ablation
D Endoscopic mucosal resection
E Radiofrequency ablation
2 A 34-year-old asthmatic male presents with food bolus obstruction for the third time in 6 years. He suffers mild
dysphagia to solids at times, but at other times is fairly asymptomatic. He uses ibuprofen once per fortnight for muscle
ache associated with exercise. He admits to smoking 5 cigarettes daily. There has been no weight loss. The most likely
diagnosis is:
A Esophageal adenocarcinoma
B Achalasia
C Esophageal stricture
D Eosinophilic esophagitis
E Zenkers diverticulum
3 A 54-year-old man is hospitalized with an upper gastrointestinal hemorrhage. He takes aspirin due to a family history of
heart disease. Endoscopy identied a 2cm gastric ulcer with an overlying clot. This was treated and no further bleeding
occurred. The duodenum was normal. The rapid urease test was positive, indicating likely infection with Helicobacter
pylori. The most appropriate discharge plan is:
A Treat for H. pylori and schedule repeat endoscopy.
B Treat for H. pylori and only perform repeat endoscopy if eradication fails.
C Check fecal antigen status as an outpatient and only treat H. pylori if positive. Repeat endoscopy not required.
D Stop aspirin and ignore H. pylori positivity, as the aspirin was the likely culprit.
E Treat for H. pylori if urease test on repeat endoscopy remains positive.
4 A 23-year-old woman is referred to the gastroenterology outpatient clinic with bloating and alternating diarrhea and
constipation. Symptoms have been present for 5 years. There is no weight loss. Stress makes her symptoms worse. She
is concerned about celiac disease, and has adhered to a strict gluten-free diet for 12 months. This has improved her
symptoms somewhat. Which of the following tests has the highest negative predictive value for celiac disease in this
setting:
A Anti-tissue transglutaminase antibodies
B Total immunoglobulin A (IgA)
C HLA DQ2 DQ8 analysis
D Biopsies of the second part of the duodenum
E Video-capsule endoscopy
5 A 37-year-old man falls ill during a Mediterranean cruise. His symptoms are diarrhea, vomiting and crampy abdominal
pain. He is febrile. He consumed shellsh the day before becoming unwell, and several other travel companions who
ingested the shellsh are also sick. There is no blood or mucus in his stool. What is the most likely cause for his acute
diarrheal illness?
A Staphylococcus aureus infection
B Bacillus cereus infection
C Norovirus outbreak
D Clostridium perfringens infection
E Enterohemorrhagic Escherichia coli infection
6 A 50-year-old man is hospitalized for recurrent epigastric pain, anorexia and diarrhea. He was diagnosed with diabetes
mellitus 4 months ago. He describes his stools as loose, greasy and foul-smelling and difficult to ush. He has had four
previous admissions with acute pancreatitis. He currently drinks 15 standard drinks of alcohol per day and has done so
for a number of years. Serum amylase and lipase levels are normal. He has also noticed poor night vision lately. What is
the most likely diagnosis for his recurrent abdominal pain?
A Acute pancreatitis
B Chronic pancreatitis
C Peptic ulceration
D Protein-losing enteropathy
E Gastritis
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7 A 65-year-old woman with a background history of gastroesophageal reux disease and hypertension was dehydrated
with acute renal impairment due to severe diarrhea. She was recently treated with ciprooxacin by her local physician
for a urinary tract infection. She describes no recent travel or exposure to ill persons. Stool analysis conrmed the
presence of Clostridium difficile toxin A. She was treated with IV uids and oral metronidazole as an inpatient for
2days. Following the resolution of her renal impairment and improvement in diarrhea, she was discharged home on
oral metronidazole for 14 days in total. However, she re-presents to the hospital emergency room 2 weeks later with
ongoing diarrhea and severe dehydration. What is the most appropriate next step in managing this patient?
A Retreatment with oral metronidazole for 14 days
B Oral vancomycin and intravenous metronidazole for 14 days
C Intravenous vancomycin for 10 days
D Fecal bacteriotherapy
E Oral rifaximin for 14 days
8 A 70-year-old asymptomatic man underwent initial screening colonoscopy 3 weeks previously for positive fecal
occult blood testing and a positive family history of colorectal cancer (one rst-degree relative affected at age 59). His
routine blood results, including iron studies, were normal. The bowel preparation was adequate and the instrument
was inserted to the cecum. No polyps were found. Which of the following is the most appropriate recommendation for
colorectal cancer surveillance for this patient?
A Repeat colonoscopy within 6 months
B Repeat colonoscopy in 3 years
C Repeat colonoscopy in 5 years
D Repeat colonoscopy in 10 years
E No further colonoscopy required
9 A 39-year-old woman with a background of Crohns disease presents with increased ileostomy output and upper
abdominal pain. The pain is cramping and worse after meals. On clinical examination there is mild abdominal
distension, but no guarding or rigidity. She is currently on methotrexate weekly. Her stool cultures are negative for
Clostridium difficile, Giardia and Cryptosporidium. Her inammatory markers are slightly raised. Recent gastroscopy
was normal, with normal duodenal biopsies. You suspect recurrent Crohns disease. Which of the following
investigations is contraindicated in this patient?
A Computed tomography of the abdomen with contrast
B Small-bowel series with follow-through
C Colonoscopy
D Video-capsule endoscopy
E Magnetic resonance imaging enteroclysis
10 A 26-year-old woman has a 15-year history of ulcerative colitis. At present she is well, with only occasional diarrhea
and bleeding while on mesalamine (mesalazine). She has not required corticosteroids for the past few years. Her last
colonoscopy, about 12 months ago, showed mild chronic colitis in the rectum. Her liver function tests are elevated
and a magnetic resonance imaging cholangiogram is highly suggestive of primary sclerosing cholangitis. Which of the
following options is most appropriate for this patient to prevent colon cancer?
A Colonoscopy with biopsies at age 50 years and repeat at 5-yearly intervals
B Colonoscopy now and repeat every 12 months with biopsies
C Computed tomography colonography second-yearly
D Colonoscopy with biopsies only when patient is symptomatic or refractory to medical treatment
E Proceed to total colectomy
11 A 43-year-old man presents to hospital with a body mass index of 15 kg/m2. Eight months ago he had vomiting
secondary to severe NSAID-induced peptic ulcer disease leading to gastric-outlet obstruction. He subsequently
underwent a Bilroth II subtotal gastroenterostomy procedure. Since his hospital discharge he has been losing weight
and has developed chronic diarrhea. His fat-soluble vitamin levels are normal. Fecal elastase is normal, but his fecal
alpha-1 antitrypsin is elevated. Urine analysis is normal. Gastroscopy shows post-surgical changes, and colonoscopy is
normal. A small-bowel series with follow-through revealed a blind loop with slow transit of contrast. What is the most
likely cause of this clinical presentation?
A Dumping syndrome
B Crohns disease
C Small-bowel bacterial overgrowth
D Short bowel syndrome
E Pancreatic insufficiency
12 An 18-year-old rst-year university student presents with non-bloody diarrhea for the past 8 months. She describes
510 bowel motions per day, which are watery. She has not been able to concentrate on her studies lately. Stool
cultures were negative. Celiac serology and thyroid function tests were normal. No recent travel was noted.
Gastroscopy and colonoscopy with biopsies were normal. Despite the above attempts to determine the cause, no
cause was found. An inpatient work-up to quantify her diarrhea was undertaken. Stool osmolality was 13 mOsm/kg and
serum osmolality was 285 mOsm/kg. Stool sodium, potassium and magnesium were within normal ranges. What is the
most likely diagnosis?
365
A
B
C
D
E
Laxative abuse
Tropical sprue
Whipples disease
Irritable bowel syndrome, diarrhea-predominant
Factitious diarrhea
13 Which of the following vaccinations is not contraindicated while on induction therapy with anti-TNF-alpha therapy for
Crohns disease?
A Hepatitis B
B Varicella
C Polio
D Typhoid
E MMR (measles-mumps-rubella)
14 A 60-year-old man presents with a history of rectal bleeding and iron-deciency anemia. He has a positive family
history of colon cancer (adenocarcinoma). At colonoscopy there were at least 30 colonic polyps throughout his bowel,
averaging 1mm in size. Several of these polyps were excised (polypectomy). Histology showed hyperplastic polyps.
Which of the following surveillance options is most appropriate for this patient?
A Colonoscopy at 5-yearly intervals
B Colonoscopy at 15-year intervals
C Colonoscopy at 10-yearly intervals
D Colonoscopy at 3-yearly intervals
15 A postmenopausal 52-year-old woman presents with vague abdominal discomfort, bloating and diarrhea. Her
symptoms have been present for the past 6 months. Stress seems to worsen her symptoms, and she feels better
after each evacuation. She has lost 5 kg and her family physician has mentioned that she was low in iron. Her family
history is negative for gastrointestinal disease. Abdominal and rectal examination is unremarkable. What is the most
appropriate next step in her evaluation?
A Reassure her that her symptoms t the criteria for irritable bowel syndrome (IBS). Ask her to try increasing her
consumption of ber and review her in 1 month.
B Proceed to endoscopic evaluation after explaining the risks and benets to her.
C Commence iron replacement and review symptoms in 3 months.
D Perform the fecal occult blood test and only investigate further if this is positive.
E Proceed to abdomino-pelvic computed tomography studies as the rst step.
16 A 39-year-old man who was admitted 5 days previously with acute alcohol-related pancreatitis is complaining of
ongoing severe epigastric pain that radiates to the back, plus nausea and vomiting. He has not been able to eat or
drink and has not had a bowel movement since being admitted. On physical examination he is febrile at 38.5C,
but normotensive. His heart rate is 101 beats/min. There is no scleral icterus or jaundice. The abdomen is distended
and diffusely tender with hypoactive bowel sounds. His blood count reveals a leukocytosis of 12,000/mm3. His liver
function tests are deranged, and lipase remains elevated at 855 U/L. A progress computed tomography scan of the
abdomen shows a diffusely edematous pancreas with a few peripancreatic uid collections. There is no evidence of
pancreatic necrosis or free gas within the abdomen. Which of the following is the most appropriate next step in the
management of this patient?
A Insert a naso-jejunal feeding tube and start enteral nutrition.
B Refer to surgical opinion for consideration of necrosectomy.
C Commence broad-spectrum intravenous antibiotics.
D Oral feeding facilitated by antiemetics.
E Commence parenteral nutrition via a central venous line.
17 A 43-year-old woman has presented to hospital for the fth time in 3 months with nausea, vomiting and dehydration.
She has longstanding type 1 diabetes mellitus with suboptimal glycemic control. A gastric emptying study performed
2 years previously was consistent with gastroparesis. This has been managed with metoclopramide, but recently she
developed intolerable extra-pyramidal side-effects and this medication was ceased. A trial of oral erythromycin has
failed to improve her ability to tolerate even a liquid diet per mouth. She has lost 8 kg in the past 3 months. A recent
blood test shows that she is not hypothyroid and identies no other abnormality to explain her symptoms. Which of
the following is the most appropriate next step in her management?
A Commence total parenteral nutrition.
B Insert a gastrostomy (PEG) tube.
C Re-commence metoclopramide.
D Commence naso-jejunal feeding.
E Repeat the gastric emptying study.
18 A 50-year-old man undergoes colonscopy due to a positive fecal occult blood test. He has no personal or family
history of colonic polyps, cancer or inammatory bowel disease. The colonoscopy reveals large internal hemorrhoids,
but no polyps or cancers. Which of the following is the most appropriate screening schedule for this patient?
366
A
B
C
D
E
Repeat colonoscopy in 1 year

Repeat colonoscopy in 3 years
Repeat fecal occult blood test in 5 years and proceed to colonoscopy if positive
19 A 48-year-old man suffers from longstanding ulcerative colitis. Since his diagnosis 15 years ago he has had several
ares, but is currently reasonably well-controlled on 6-mercaptopurine (6-MP) and oral mesalazine. He has not
required corticosteroids in the past few years. He attends for a colonoscopy, which shows active proctitis but very little
colonic disease activity. Random biopsies are taken and yield high-grade dysplasia in the ascending colon as well as
low-grade dysplasia in the sigmoid colon. Which of the following treatment options is most appropriate?
A Total colectomy
B Right-sided colectomy with annual surveillance of the remaining colon
C Annual surveillance colonoscopy with random colonic biopsies
D Add a biological agent (TNF-alpha blocker)
E Perform a carcinoembryonic antigen (CEA) level and proceed to colectomy if this is elevated
20 A 68-year-old man presents with an upper gastrointestinal hemorrhage. He has a 2-year background of heartburn and
dyspepsia. His bowel motions have also been looser than normal over this time. He takes no regular medicationsand
denies the use of over-the-counter analgesics. Physical examination is unremarkable, but blood testing shows
iron deciency. Helicobacter pylori serology is negative. Endoscopy shows multiple ulcers in the stomach and the
duodenum and some prominent gastric folds. One of the ulcers has a visible vessel, which is treated endoscopically.
Which is the next most appropriate step?
A Somatostatin receptor scintigraphy
B Measurement of urinary 5-HIAA (5-hydroxyindoleacetic acid) levels
C Measurement of a serum gastrin level
D Computed tomography (CT) scan of the abdomen
E Urinary NSAID (non-steroidal anti-inammatory drug) assay
21 A 70-year-old Japanese man is hospitalized because of a 2-week history of progressive jaundice, mild epigastric
discomfort and anorexia. Physical examination reveals tenderness in the epigastric area and overt jaundice.
Liver function tests reveal elevated bilirubin, alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase
(GGT). Abdominal ultrasonography reveals an intrahepatic duct and common duct dilatation without evidence of
choledocholithiasis. Subsequent abdominal computed tomography (CT) shows a 5 cm pancreatic mass within the main
pancreatic duct in addition to a diffusely swollen sausage-shaped pancreas with a narrowed pancreatic duct. Serum
immunoglobulin G4 (IgG4) was elevated. What will be your next step in conrming the diagnosis of this patient?
A Cholecystectomy
B ERCP (endoscopic retrograde cholangiopancreatography)
C Endoscopic ultrasonography with biopsy of the pancreas and immunohistochemical staining for IgG4
D Tumor markers
E MRCP (magnetic resonance cholangiopancreatography)
ANSWERS
1 E.
For this man with many comorbidities, esophagectomy is undesirable. Repeating biopsies is unnecessary when the
diagnosis is already conrmed by two biopsies. Endoscopic mucosal resection is appropriate when raised lesions are
present, and liquid nitrogen ablation is currently an experimental therapy. Radiofrequency ablation has a good chance of
eradicating his high-grade dysplasia and preventing progression to esophageal adenocarcinoma.
2 D.
With a history of intermittent food bolus obstruction and asthma, eosinophilic esophagitis is the most likely scenario. The
lack of progressive symptoms makes a malignancy or motor disorder such as achalasia less likely. Zenkers diverticulum is
an unlikely cause of food bolus obstruction.
3 A.
All gastric ulcers require repeat endoscopy to assess healing. The rapid urease test is reliable when positive, and
Helicobacter eradication should be undertaken. There is no need to perform other tests to conrm H. pylori status, but
such tests may be appropriate when the rapid urease test is negative, which it often is despite infection with H. pylori when
blood is present.
4 C.
It is difficult to make a diagnosis of celiac disease when gluten has already been eliminated from the diet. Elimination of
gluten makes histology and antibody testing unreliable. The total IgA is useful only for making sure that IgA deciency is not
367
causing a falsely negative anti-tissue transglutaminase antibody test. Video-capsule endoscopy has no role in this setting.
The HLA test is useful if negative, as the likelihood of having celiac disease with negative DQ2 and DQ8 is less than 1%.
5 C.
The travel history and duration of onset of illness are helpful in determining the likely pathogen causing acute diarrhea and/
or vomiting. The man was on a cruise ship which served shellsh for dinner. The most likely cause of his acute diarrhea and
vomiting is related to undercooked seafood. Norovirus is the most likely pathogen. Staphylococcus aureus infection usually
presents within 6 hours of exposure and is often due to contaminated salad, dairy or meats. Bacillus cereus infection presents
within 6 hours of exposure and is due usually to contaminated rice and meats. Clostridium perfringens presents within
816 hours after exposure to contaminated meat and poultry.
6 B.
The symptom complex of recurrent epigastric pain, anorexia and diarrhea with loose stool that is foul-smelling is in
keeping with steatorrhea and fat malabsorption secondary to pancreatic insufficiency related to chronic pancreatitis. The
heavy alcohol use is likely to cause chronic pancreatitis in those predisposed. Serum amylase and lipase can be normal in
chronic pancreatitis and rule out acute pancreatitis. The poor night vision is indicative of vitamin A deciency. Fat-soluble
vitamins (A, D, E and K) may be low in pancreatic insufficiency. Acute pancreatitis leads to an elevated amylase and lipase
level. Peptic ulcer disease does not induce diarrhea or steatorrhea (unless due to the rare ZollingerEllison syndrome).
Gastritis does not cause this symptom complex and is usually asymptomatic. Patients with protein-losing enteropathy
often have diarrhea, but usually not steatorrhea.
7 A.
The most likely cause of her ongoing symptoms is recurrent Clostridium difficile infection. She needs retreatment with oral
metronidazole for 14 days. If this does not cure her diarrhea, then oral vancomycin 125mg four times a day for 14 days
followed by a tapering dose to ensure complete eradication of infection is appropriate. Oral vancomycin and intravenous
metronidazole are often used in fulminant disease. Third-line treatments such as rifaximin should be considered when
vancomycin has failed. Fecal bacteriotherapy is utilized as salvage therapy in selected patients who have failed usual
management. Intravenous vancomycin does not lead to sufficient drug levels within the colon, and therefore has no role
in the treatment of C. difficile infection.
8 C.
After a negative colonoscopy with no polyps, a patient with a family history of colorectal cancer should have a repeat
procedure in 5 years (low risk). If there was no family history, 10 years would be reasonable. If a polyp was detected, then
after a complete clearing colonoscopy had been accomplished after initial polypectomy, repeat colonoscopy to check for
metachronous adenomas should be performed in 3 years for a patient at high risk of developing metachronous advanced
adenomas. This includes those who at baseline examination have multiple (>2) adenomas, a large (>1cm) adenoma, an
adenoma with villous histology or high-grade dysplasia, or a family history of colorectal cancer. After one negative followup surveillance colonoscopy, subsequent surveillance may be increased to 5-yearly.
9 D.
Capsule endoscopy is contraindicated as there is likely to be subacute bowel obstruction from stricturing Crohns disease.
The small-bowel series could be helpful in determining the presence of active Crohns disease. Colonoscopy in this patient
is an invasive procedure. It can be reserved for second-line investigation if the small-bowel series is inconclusive and the
pre-test probability of active Crohns disease is high. An MRI enteroclysis provides excellent images of the small bowel but
is expensive and labor-intensive.
10 B.
The cumulative incidence of colorectal cancer is 818% after 2030 years of ulcerative colitis. The cumulative incidence
of colorectal cancer among patients with extensive disease (pancolitis) ranges from 650% after 30 years of the disease.
The cumulative risk of colorectal cancer does not seem to be higher than that of the general population until 810years
after the diagnosis, and thereafter the increase in risk is 0.51% each year. This patient with a history of ulcerative colitis of
more than 7 years, pancolitis and primary sclerosing cholangitis is at high risk for developing colorectal cancer. Current
guidelines recommend regular colonoscopy surveillance with biopsy after 7 years of left-sided colitis or pancolitis in
both ulcerative colitis and Crohns disease. This should be done at least on a yearly basis. Patients with primary sclerosing
cholangitis should begin colonoscopy surveillance immediately.
11 C.
The elevated fecal alpha-1 antitrypsin suggests protein-losing enteropathy. The small-bowel series indicates the presence
of a blind loop with slow transit. The likely cause of the presentation is thus small-bowel overgrowth. Fecal elastase is low
in pancreatic insufficiency. Dumping syndrome leads to characteristic symptoms of sweating and tachycardia after meals.
Short bowel syndrome occurs when less than 200 cm of small bowel remains, which is not the case after a Bilroth II
procedure. If his symptoms were due to Crohns disease, the small-bowel series is likely to have been abnormal.
12 E.
The increase in the fecal osmolal gap indicates the presence of unmeasured solute, which can be due to laxatives
containing magnesium, sorbitol, lactose, lactulose or polyethylene glycol as active ingredients (>50 mOsm/kg). The fecal
368
osmolal gap is helpful in factitious diarrhea resulting from the addition of water to the stool; this diagnosis is suspected if
the measured stool osmolality is lower than that of plasma, since the colon cannot dilute stool to an osmolality less than
that of plasma. In irritable bowel syndrome the fecal osmolar gap is normal. Whipples disease often results in abnormal
duodenal biopsies, where PAS-positive macrophages are identied. Tropical sprue affects residents and travelers in the
tropics, and usually a 4- to 6-week stay in a high-risk area is required to acquire the disease.
13 A.
All live vaccinations are contraindicated while on anti-TNF-alpha therapy. Hepatitis B vaccination does not involve a live
vaccine.
14 D.
This patient has the hyperplastic polyposis syndrome, which is phenotypically dened by at least 5 histologically diagnosed
hyperplastic polyps proximal to the sigmoid colon, two of which are larger than 1cm, or any number of hyperplastic
polyps occurring proximal to the sigmoid colon in an individual who has a rst-degree relative with hyperplastic polyposis
syndrome, or 20 hyperplastic polyps of any size but distributed throughout the colon. This condition is usually diagnosed
between the ages of 40 and 60 years. The genetic basis has not yet been identied. This condition is inheritable in 5% of
cases. Colorectal cancer is found synchronously in at least 50% of cases. Current guidelines recommend 1- to 3-yearly
colonoscopy surveillance, and rst-degree relatives over the age 40 (or 10 years earlier than the age of the index case)
should be offered screening.
15 B.
Although her symptoms t the Rome II criteria for IBS, there are red ags present. New-onset symptoms after the age of
50, weight loss and iron deciency are worrisome and may indicate malignancy. A diagnosis of IBS should not be made,
and endoscopic evaluation is currently the gold standard for ruling out bowel cancer.
16 A.
Nutrition is required for recovery, and in this clinical scenario oral nutrition is not likely to be established for some time due
to pain and vomiting. Enteral feeding via the mouth will also stimulate the pancreas, which can be avoided by
naso-jejunal feeding if the tip of the feeding tube is passed distally to the ligament of Treitz. Enteral feeding is preferable
due to a lower risk of complications. Parenteral nutrition can lead to sepsis and is more expensive. Pancreatic debridement
and intravenous antibiotics are appropriate if pancreatic necrosis is present.
17 D.
In the setting of severe gastroparesis impairing a persons nutrition, prompt action is needed. If a trial of naso-jejunal
feeding is successful, a jejunostomy may allow long-term enteral feeding. A PEG tube does not bypass the stomach and is
unlikely to help her symptoms. Repeating the gastric emptying study is unlikely to change management. Total parenteral
nutrition is a last resort when enteral feeding is contraindicated or unsuccessful. Recommencing metoclopramide is
contraindicated if extra-pyramidal (tardive) symptoms have already occurred.
18 D.
The most appropriate interval for screening is 10 years. In some countries, second-yearly fecal occult blood tests are also
considered adequate. Repeated colonoscopy in 1 year is recommended if a bowel cancer was identied and resected.
Patients with large adenomas (>1 cm) or more than 3 adenomas should have a colonoscopy repeated in 3 years. Patients
with small (<1 cm) or 2 or fewer adenomas can be next screened at a 5-year interval.
19 A.
This patient requires total colectomy. High-grade dysplasia in patients with ulcerative colitis has a high chance of
synchronous carcinoma in situ or rapid progression to cancer. Adding further therapy or partially resecting the colon
is therefore inappropriate. A CEA level can be useful for monitoring disease progression in a patient with conrmed
colorectal cancer, but plays no role in decision-making for this patient.
20 C.
This patient probably has a gastrinoma. The diagnosis should be suspected in patients with multiple ulcers without NSAID
exposure or H. pylori infection. An elevated gastrin level in the absence of regular proton-pump inhibitor therapy is highly
suggestive. Somatostatin receptor scintigraphy is a highly sensitive test for diagnosis, but a CT is usually performed rst.
If gastrinoma is suspected based on the serum gastrin, a urinary NSAID assay can be ordered if occult NSAID use is
suspected. Measurement of urinary 5-HIAA is a screening test for carcinoid tumor.
21 A.
The two important differential diagnoses in this case are pancreatic cancer or uncommonly autoimmune pancreatitis.
CT abdomen demonstrates a diffusely swollen sausage-shaped pancreas with a narrowed pancreatic duct. This nding
is more in keeping with autoimmune pancreatitis. IgG4 levels further support the diagnosis of autoimmune pancreatitis
type 1. To conrm the diagnosis, EUS with core biopsy of the pancreatic mass is required with IgG4 staining.
369
CHAPTER 13
HEPATOLOGY
Robert Gibson, Magnus Halland and Nicholas J Talley
CHAPTER OUTLINE
PORTAL HYPERTENSIVE BLEEDING
LIVER FUNCTION TESTS AND THEIR

ABNORMALITIES
PORTOSYSTEMIC ENCEPHALOPATHY (PSE)
Serum enzymes
APPROACH TO THE PATIENT WITH LIVER

DISEASE
BILIRUBIN METABOLISM AND JAUNDICE
VIRAL HEPATITIS
Hepatitis A
Hepatitis B
Hepatitis C
CIRRHOSIS
Prognosis
Management
ASCITES
Management
HEPATORENAL SYNDROME (HRS)

Management
HYPONATREMIA
SPONTANEOUS BACTERIAL PERITONITIS
(SBP)
Treatment
Management
Persistent PSE
PORTOPULMONARY HYPERTENSION (POPH)

HEPATOPULMONARY SYNDROME (HPS)
CIRRHOTIC CARDIOMYOPATHY
ACUTE LIVER FAILURE (ALF)
LIVER TRANSPLANTATION
DRUGS AND THE LIVER
Acetaminophen (paracetamol) and acute liver
disease
ALCOHOL AND THE LIVER

SPECIFIC LIVER DISEASES
Non-alcoholic fatty liver disease (NAFLD) and
non-alcoholic steatohepatitis (NASH)
Wilsons disease (hepatolenticular degeneration)
Alpha-1 anti-trypsin (A1AT) deciency
Hemochromatosis
AUTOIMMUNE LIVER DISEASES

Primary biliary cirrhosis (PBC) and primary
sclerosing cholangitis (PSC)
371
SYSTEMIC DISEASE AND THE LIVER
PORPHYRIAS
PREGNANCY AND LIVER DISEASE

GALLBLADDER AND BILIARY TREE
Gallstones
with certain medications. One important use is supporting the likelihood that an elevated ALP is from
theliver.
LIVER FUNCTION TESTS AND

THEIR ABNORMALITIES
Liver function tests are simply serum enzyme levels:
alanine aminotransferase (ALT), also called serum
glutamic pyruvic transaminase (SGPT)
aspartate aminotransferase (AST), also called serum
glutamic oxaloacetic transaminase (SGOT)
gamma-glutamyl transpeptidase (GGT), and
alkaline phosphatase (ALP)
as well as tests of synthetic function:
prothrombin time (PT)
albumin, and
bilirubin.
The pattern of abnormality is helpful in assessing the cause
and severity of liver disease, but no pattern is specific to any
given diagnosis. The serum enzymes are best thought of as
either hepatocellular (raised transaminases) or cholestatic (raised
GGT and ALP).
Serum enzymes

Prothrombin time (PT)/international normalized ratio
(INR)coagulation studies are useful for assessing liver
synthesis. Vitamin K deficiency due to poor nutrition
should be considered as a cause of an elevated PT, as should
malabsorption due to pancreatic or biliary disease. Reversal
of coagulopathy with 10 mg of parenteral vitamin K supports the PT elongation being unrelated to synthesis.
Hypoglycemia occurs in severe liver dysfunction.
APPROACH TO THE PATIENT

WITH LIVER DISEASE
The presence of liver disease may sometimes be suggested
by symptoms. These can include right upper abdominal discomfort and cholestatic symptoms (jaundice, itch,
dark urine). More commonly, symptoms are nonspecific
such as nausea or fatigue. Most commonly, liver disease
Hepatocellular enzymes
The measurement of these liver enzymes is essentially a
measure of liver damage as opposed to liver function.
ALT is a cytosolic enzyme that is more hepatospecific
than AST. It is pyridoxine-dependent, which explains its
relative deficiency compared with AST in alcoholic liver
disease, as alcoholic patients are depleted of pyridoxine.
AST is a mitochondrial enzyme that is not specific to
hepatocellular damage. It is found, in decreasing order
of concentration, in liver, myocardium, skeletal muscle,
kidneys, brain, pancreas and erythrocytes.
CLINICAL PEARL
Serum transaminases (ALT, AST) dont predict
dysfunctionprothrombin time, albumin, bilirubin,
ascites and encephalopathy are true indicators of liver
dysfunction.
Cholestatic enzymes
ALP is not specific to the liver, being commonly found
in bone and the placenta. It may be high in the rapid
growth phase of adolescence and in pregnancy.
GGT is a very sensitive marker of biliary disease,
although it may also be elevated in alcohol abuse and
372
Box 13-1
Clinical clues suggesting chronic

liver disease
Symptoms
Fatigue, pruritus, bleeding, abdominal pain, nausea,
anorexia, myalgia, jaundice, dark urine, pale stools,
fever, weight loss; may be no symptoms
Signs
Peripheral signs of chronic liver disease with
hepatocellular dysfunction:
Spider naevi, palmar erythema, white nails,

gynecomastia, body hair loss, testicular atrophy,
hepatomegaly
Signs of portal hypertension:
Splenomegaly, ascites, peripheral edema
Signs of poor hepatocellular synthetic function:
Bruising, peripheral edema (reecting depleted

coagulation factors and albumin levels)
Signs of end-stage liver disease:
Wasting, progressive severe fatigue, encephalopathy

(asterixis, fetor, coma)
Chapter 13 Hepatology
is detected in the asymptomatic person on routine biochemical testing.

It is important to distinguish acute from chronic liver disease. Clues to the cause of liver disease (Box 13-1) are provided by a careful history and examination.
Obesity, diabetes and dyslipidemia may suggest fatty
liver. A careful alcohol history is mandatory. A commonly overlooked area is medication, including herbal
and nutritional supplements, especially high-protein
supplements. The history here must be meticulous and
include commencement times.
Risk factors for viral hepatitis must be sought; these
include intravenous drug use, sexual behavior, especially
men who have sex with men, migration from a highprevalence area, and blood transfusion prior to routine
screening.
Occasionally the physical examination may provide
diagnostic clues.
Parotidomegaly and Dupuytrens contractures (Figure 13-1) occur in alcoholism.
Acanthosis nigricans (see Figure 23-8) and skin tags
occur in the metabolic syndrome and fatty liver
disease.
Other signs of more advanced liver diseases are palmar erythema (Figure 13-2), gynecomastia, spider
nevi (Figure 13-3), splenomegaly, jaundice, ascites
and encephalopathy.
An enlarged liver can be due to many causes (Box 13-2,
overleaf).
Laboratory tests may guide you toward a hepatocellular or
a cholestatic etiology. Alcohol as a cause should be increasingly suspected as the AST/ALT ratio rises above 2, at
which point around 90% of patients will have alcoholic liver

disease.
The magnitude of transaminase rise may also guide
etiology:
An ALT of >500 U/L is almost never due to alcohol
alone and should prompt a search for an alternative
explanation.
Transaminases of >1000 U/L are usually due to ischemic hepatopathy, acute viral hepatitis, acetaminophen
(paracetamol) toxicity, or acute biliary obstruction.
Rarely, other medication reactions can cause such a
picture.
If the transaminases are normal or near-normal but both
the ALP and GGT are elevated, this suggests liver disease (cholestasis).
Figure 13-2 Palmar erythema

From Kluger N and Guillot B. Erythema palmare hereditarium
(Lanes red palms): a forgotten entity? J Am Acad Dermatol
2010;63(2):e46.
Figure 13-1 Dupuytrens contracture in the hands
Figure 13-3 Spider nevi
From Gudmundsson KG. Jnsson T and Arngrmsson R. Guillaume

Dupuytren and nger contractures. Lancet 2003;363(9378):1658.
From Gruber G and Hansch A. Kompaktatlas Blickdiagnosen in der

Inneren Medizin, 2nd ed. Munich: Urban & Fischer/Elsevier, 2009.
373
Box 13-2
Causes of hepatomegaly
1. Diffusely enlarged and smooth
Massive
Metastatic disease
Alcoholic liver disease with fatty inltration
Myeloproliferative diseases (e.g. polycythemia rubra
vera, myelobrosis)
Moderate
The above causes
Hemochromatosis
Hematological disease (e.g. chronic myeloid leukemia,
lymphoma)
Fatty liver (e.g. diabetes mellitus)
Mild
The above causes
Hepatitis (viral, drugs)
Cirrhosis
Biliary obstruction
Granulomatous disorders (e.g. sarcoidosis)
Inltrative disorders (e.g. amyloidosis)
Human immunodeciency virus infection
2. Diffusely enlarged and irregular
Metastatic disease
A history of right upper quadrant pain points toward a biliary cause.

If the pain is persistent, the liver should be considered as
the cause.
If severe and episodic, then biliary pain is suggested.
If the patient is a middle-aged woman, primary biliary
cirrhosis is an important consideration, and a liver ultrasound and anti-mitochondrial antibody (AMA) should be
performed.
Common causes of hepatitis and cholestasis, and the specific diagnostic tests, are listed in Table 13-1.
CLINICAL PEARL
If the liver function tests suggest cholestasis (elevation
of ALP and GGT), image the biliary tree but also think
about drugs, and autoimmune and inltrative disease.
An abdominal ultrasound is recommended not only to

exclude extrahepatic biliary disease, but also to detect the
presence of steatosis, possible cirrhosis, portal hypertension
or tumors. Assessment of the splenic size as well as portal vein patency and flow adds valuable information to the
assessment.
Once the above strategy has been used to define the etiology of abnormal liver function tests without a diagnosis
being forthcoming, it is most probable that the diagnosis is
non-alcoholic fatty liver disease.
374
Cirrhosis
Hydatid disease
Polycystic liver disease
3. Localized swelling
Riedels lobe (a normal variantthe lobe may even be
palpable in the right lumbar region)
Metastasis
Large simple hepatic cyst
Hydatid cyst
Hepatoma
Liver abscess (e.g. amebic abscess)
4. Hepatosplenomegaly
Chronic liver disease with portal hypertension
Hematological disease (e.g. myeloproliferative disease,
lymphoma)
Infection (e.g. acute viral hepatitis, infectious
mononucleosis)
Inltration (e.g. amyloidosis, sarcoidosis)
Connective tissue disease (e.g. systemic lupus
erythematosus)
CLINICAL PEARL
Celiac disease can cause a moderate elevation of alanine aminotransferase and aspartate aminotransferase,
but bilirubin is usually normal.
BILIRUBIN METABOLISM AND

JAUNDICE
Bilirubin is formed from the metabolism of heme, with a
much lesser contribution from myoglobin and cytochromes.
Its metabolism begins in the reticuloendothelial system,
especially the spleen, where it is fat-soluble and is therefore
bound to albumin for transport to the liver. There are three
hepatic phases: uptake, conjugation and excretion (Figure 13-4,
overleaf).
Uptake is via a large-capacity facilitated transport system.
Once in the hepatocyte, bilirubin is solubilized by conjugation with glucuronide for biliary excretion. This
reaction is dependent on the enzyme glucuronosyltransferase.
The final phase of excretion into the biliary system is via
multidrug-resistance-like protein 2 (MRP2).
The terms direct and indirect bilirubin correspond to conjugated and unconjugated bilirubin (Box 13-3).
Table 13-1 Common causes of hepatitis and cholestasis, and diagnostic tests
CAUSE
DIAGNOSTIC TESTS
Hepatitis
Hepatitis A virus (HAV)
Anti-HAV immunoglobulin M (IgM)
Hepatitis B virus (HBV)
Surface antigen or hepatitis B IgM if acute
Hepatitis C virus (HCV)
Anti-HCV antibodies
Alcoholic liver disease
AST/ALT >2; ALT <500 U/L
NAFLD
Imaging, clinical assessment
ALT 2002000 U/L

ANA, ASMA, ALKMA
Raised globulins
Liver biopsy
Ischemic hepatopathy
ALT in the 1000s U/L with rapid resolution
Hemochromatosis
Serum iron studies

HFE gene mutation
Wilsons disease
Serum copper and ceruloplasmin; urinary and liver copper levels

Slit-lamp examination
Drug-induced hepatitis
Improvement off suspect culprit drug
Cholestasis
Primary biliary cirrhosis
Anti-mitochondrial antibody
Liver biopsy
Primary sclerosing cholangitis
Ulcerative colitis
Cholangiography
Common duct obstruction (tumor, stone,

stricture)
Ultrasound
Cholangiography
Inltration (malignancy, sarcoid, amyloid)
Ultrasound, CT, liver biopsy
Drug-induced cholestasis
Resolution off suspected culprit drug
ALKMA, anti-liver-kidney microsomal antibodies; ALT, alanine aminotransferase; ANA, anti-nuclear antibodies; ASMA, anti-smooth-muscle
antibodies; AST, aspartate aminotransferase; CT, computed tomography; NFALD, non-alcoholic fatty liver disease.
Box 13-3
Classication of jaundice
Unconjugated
1 Hemolysis
2 Impaired conjugation (decreased activity of glucuronyl
transferase)
a Gilberts syndrome (diagnosed by exclusion of
hemolysis, the presence of normal liver function,
and a rise in the bilirubin level after fasting)
b CriglerNajjar syndrome (types I and II)
Conjugated
1 Hepatocellular disease
a Hepatitisviral, autoimmune, alcoholic
b Cirrhosis
c Drugs and toxins
d Venous obstruction
2 Cholestatic disease
a Intrahepatic cholestasisdrugs, recurrent jaundice
of pregnancy, primary biliary cirrhosis, benign
recurrent intrahepatic cholestasis (BRIC)
b Extrahepatic biliary obstructionstones, carcinoma
of the pancreas or bile duct, strictures of the bile
duct
3 Familial, e.g. DubinJohnson syndrome
375
Figure 13-4 Bilirubin metabolism and jaundice. Biliary excretion of conjugated bilirubin by way of MRP2
(multidrug-resistance-like protein 2) into the bile canaliculus is an energy-dependent active transport system
and is the rate-limiting step in hepatic bilirubin processing. This explains why in liver failure most excess bilirubin
remains conjugated
From Gilmore I and Garvey CJ. Jaundice. Medicine 2009;37(1);426.
376
The normal levels of bilirubin are up to 1.5 mg/dL

(25 micromol/L), with the conjugated portion up to
0.3mg/dL (5 micromol/L).
Clinical jaundice (icterus) occurs at about 2.5 mg/dL
(42micromol/L).
The first step in solving the cause of hyperbilirubinemia is
reviewing the serum liver enzymes and looking for clinical
and ultrasound evidence of chronic liver disease.
If abnormal, then a search should be undertaken for a
specific diagnosis. An abnormal blood film can indicate
a hematological cause for the hyperbilirubinemia.
If the serum enzymes are normal, fractionation should
be done to determine the proportion of direct and indirect bilirubin. This will allow distinction between overproduction from hemolysis, and a conjugation defect or
secretion problem from medication or Dubin-Johnson
syndrome.
ETIOLOGY
EXAMPLES
Hepatitisinfectious
Mycobacterium avium
intracellulare, tuberculosis,
cytomegalovirus
Hepatitisdrugs
Isoniazid, AZT,
sulfonamides
AIDS cholangiopathy
Cytomegalovirus,
Cryptosporidium
Veno-occlusive disease
Antineoplastic drugs
(e.g. busulfan)
Neoplasm
Lymphoma, Kaposis
sarcoma
AIDS, acquired immunodeciency syndrome; AZT,

azidothymidine or zidovudine.
CLINICAL PEARL
Pruritis and jaundice suggest intrahepatic or posthepatic cholestasis.
In the postoperative patient who becomes jaundiced, the

differential diagnosis includes intra-operative exposures (e.g.
hypotension, drugs), infection, and less common causes
(Table 13-2).
Table 13-2 Distinguishing features that help to
determine the cause of postoperative jaundice
ETIOLOGY
Table 13-3 Common causes of jaundice in

immunosuppressed patients
FEATURE
Hypotension
ALT >1000U/L, LDH elevation
Drugs, e.g. halothane
No specic features
Infection
Increased white cell count,

fever
Total parenteral
nutrition (TPN)
Liver function test proles

rise 14 weeks after TPN is
commenced
Hematoma resorption
Unconjugated bilirubin increase
Cardiac failure
Elevated jugular venous

pressure, enlarged pulsatile
liver
Hemolysis
Unconjugated bilirubin and

LDH increase; haptoglobin
decrease if intravascular
hemolysis
Abnormal blood smear
Renal failure
Creatinine rise
Bile duct injury,

retained gallstone
SAP elevation
ALT, alanine aminotransferase; LDH, lactate dehydrogenase; SAP,

serum alkaline phosphatase.
A different differential diagnosis list must be considered

in immunosuppressed patients (Table 13-3).
VIRAL HEPATITIS
Hepatitis A (RNA virus)
Hepatitis A virus (HAV) is transmitted by the fecaloral
route. Immunization has decreased its incidence.
HAV is diagnosed by anti-HAV immunoglobulin M
(IgM) in serum. Patients with chronic liver disease or hepatitis
C should all be immunized against hepatitis A (to prevent fulminant hepatitis). The aged are also at risk of severe disease.
CLINICAL PEARL
Hepatitis A can uncommonly cause prolonged cholestasis in an adult for months (and this may lead to diagnostic confusion).
Hepatitis B (DNA virus)

Hepatitis B virus (HBV) is one of the main causes of endstage liver disease and hepatocellular carcinoma (HCC). It
chronically infects 400 million people worldwide, and kills
more than 1 million people a year from end-stage liver cirrhosis and HCC. Transmission is percutaneous, sexual and
perinatal.
In active hepatitis B infection there is a lifetime risk of
liver-related death of 40%. Risk factors are multiple sexual
partners, men who have sex with men, injecting drug use,
tattoos obtained in non-sterile environments, unscreened
blood transfusions, and being born in a high-prevalence
region. There has been an 80% decline in incidence in
countries with vaccination programs. As there are highly
effective treatments for hepatitis B infection, those at high
risk should be screened.
377
Prevention of hepatitis B is possible through vaccination,

and ensuring that exchange of body fluids does not occur.
The transmission rate from an e-antigen-positive
mother to her child at parturition is 85%. Vaccination
and administration of hepatitis B immune globulin
(HBIG) reduces this by 95%, although in extremely
high viral loads (>108 copies/mL) this may be attenuated.
In addition, vaccination of high-risk groups is important. Among adults, hepatitis B vaccine should be
offered to men having sex with men, adults with multiple sexual partners, injectiing drug users, hemodialysis
patients, healthcare workers, and household members
of carriers.
Diagnosis
Viral serology (Figure 13-5) is the mainstay for diagnosis
of HBV. It includes HBsAg, HBsAb, HBeAg, HBeAb and
HBcAb and involves both antigen and antibody testing.
HBV DNA has become an important predictor of disease
progression and HCC.
Antigen testing
Surface antigen (sAg) is a marker of viral replication and
therefore infection. It is a soluble HBV-shell protein.
e-antigen (eAg) is a marker of high-level infection and
replication with high HBV DNA levels and infectivity.
It is a soluble core antigen.
Core antigen (cAg) is an insoluble core antigen. AntiHBcAg reflects its presence. Its main use is to confirm that there has been viral exposure rather than
vaccination.
Antibody testing
IgM anti-HBcAb is a marker of acute HBV infection.
IgG anti-HBcAb reflects past infection.
Anti-HBsAg reflects exposure to the virus, immunity
or vaccination.
Natural history
The natural history of HBV infection (Figure 13-6) depends
on the age of the person at infection. In endemic areas characterized by vertical transmission, more than 90% of those
infected progress to chronic infection (Table 13-4). In lowprevalence areas, most transmission is via high-risk sexual
and injecting drug practice in adults, and only 5% progress
to chronic hepatitis B infection, although they are at risk of
severe acute hepatitis.
There are four phases of chronic hepatitis B infection:
1. immunotolerant
2. eAg-positive chronic hepatitis
3. eAg-negative chronic hepatitis
4. inactive carrier state.
Hepatic injury occurs during the active hepatitis phases. It is
those phases that require treatment.
Figure 13-5 Serology of hepatitis B virus (HBV). Shaded bars indicate the duration of seropositivity in selflimited acute hepatitis B infection. Pointed bars indicate that HBV-DNA and HBeAg can become seronegative
during chronic infection. Only IgG anti-HBcAg is detectable after resolution of acute hepatitis or during
chronic infection. The y-axis is schematic concentration of serum ALT and anti-HBV antigens. ALT, alanine
aminotransferase; DNA, deoxyribonucleic acid; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e-antigen;
IgG, immunoglobulin G
From Liaw YF and Chu C-M. Hepatitis B virus infection. Lancet 2009;373:58292.
378
Figure 13-6 Natural history of chronic hepatitis B virus (HBV) infection acquired perinatally and during infancy.
The reactivation phase is similar in every aspect to the immune-clearance phase, except for HBeAg status.
Adult-acquired infection usually presents in the immune-clearance or reactivation phases (inset). The events
during the immune-clearance and reactivation phases could lead to cirrhosis and hepatocellular carcinoma
(HCC). ALT, serum alanine aminotransferase; anti-HBe, hepatitis B e-antigen antibody; BCP, basal core
promoter; HBeAg, hepatitis B e-antigen; pre C, pre-core
From Liaw YF and Chu C-M. Hepatitis B virus infection. Lancet 2009;373:58292.
Table 13-4 Viral and clinical features of chronic hepatitis infection
IMMUNOTOLERENT
eAgPOSITIVE
CHB
eAgNEGATIVE
CHB
INACTIVE
CARRIER
RESOLVED
INFECTION
VACCINATION
s-antigen
Positive
Positive
Positive
Positive
Negative
Negative
e-antigen
Positive
Positive
Negative
Negative
Negative
Negative
Anti-HBe
Negative
Negative
Positive
Positive
Positive
Negative
Anti-HBs
Negative
Negative
Negative
Negative
Positive
Positive
Anti-HBc
Negative
Negative
Negative
Pos/Neg
Positive
Negative
HBV-DNA
>20,000 IU/mL
(>105 copies/mL)
>20,000 IU/mL
(>105 copies/
mL)
>2000 IU/mL
(>104 copies/
mL)
<200 IU/mL
(<103 copies/
mL)
ALT
Normal
High
High
Normal
Normal
Normal
Histology
Normal
Hepatitis
Hepatitis
Normal
Normal
Normal
ALT, alanine aminotransferase; eAG, e-antigen; s-antigen, surface antigen; anti-HBe, antibody to hepatitis B e-antigen;
anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; CHB, chronic hepatitis B;
HBV-DNA, hepatitis B virus deoxyribonucleic acid.
379
CLINICAL PEARL
Determine the phase of hepatitis B based on the history, e.g.:
A 23-year-old Vietnamese woman is found to have
the following test results: ALT 12, HBVsAg +, HBVeAg
+, HBVeAb , and HBV-DNA 1010 IU/mL. There is no
risk-taking behavior. Her mother had been diagnosed
with hepatocellular carcinoma.
See Figure 13-6. This is the immunotolerant phase. This
phase causes no active hepatitis and lasts for between
10 and 30 years. This patient should be observed for
onset of the immune clearance phase, characterized
by active hepatitis (eAg-positive hepatitis B).
There is a loss of e-antigen and e-antigen seroconversion

at a rate of 10% per year. This can mean that one of two
events has occurred:
either the active phase has resolved into a silent carrier
state (75%)
or there has been the emergence of core promotor or
pre-core mutants, i.e. eAg-negative chronic hepatitis
B (25%).
eAg-negative chronic hepatitis B is due to the emergence of
viral strains with mutations in the pre-core and core regions
of the genome responsible for the soluble e-antigen and
nucleocapsid core antigens. Such mutants are responsible for
severe and progressive hepatitis.
Importantly, about 20% of those with eAg loss and normal ALT may reactivate, i.e. redevelop eAg positivity
and a raised ALT. This mandates lifelong monitoring
even in the silent carrier state.
Entry into the eAg-negative chronic hepatitis B phase
leads to either persistent or fluctuating necroinflammation and a high risk of progression to advanced liver
disease. This must be distinguished from the inactive
carrier state. This will require monitoring of the HBVDNA, the ALT and, at times, liver biopsy.
Chronic hepatitis can lead to cirrhosis, hepatic decompensation, HCC and death.
Hepatitis B has eight genotypes. The most significant
is genotype B, having a relative early eAg seroconversion
and slower progression to cirrhosis and hepatocellular carcinoma. Genotypes A and B have the highest rate of response
to pegylated interferon.
CLINICAL PEARL
Patients with chronic hepatitis B require hepatocellular carcinoma (HCC) surveillance even in the absence
of cirrhosis due to the ability of the virus to suppress
tumor suppressor genes and prime tumor oncogenes.
HBeAg-positive:
Decompensated cirrhosis
Cirrhosis with HBV-DNA >2000 IU/mL or raised
ALT
HBV-DNA >20,000 IU/mL and hepatitis reflected
by a raised ALT or on liver biopsy
HBeAg-negative:
HBV-DNA >2000 IU/mL and hepatitis (raised
ALT or inflammatory histology)
Before starting immunosuppression or chemotherapy
Cirrhosis and detectable HBV-DNA
In young patients (and women wishing to become pregnant), pegylated interferon is primary therapy but only twothirds at best obtain a complete remission at 1 year (higher in
HBeAg-negative cases).
Any patient with decompensated cirrhosis should be
treated with entecavir or tenofovir, rather than interferon.
Referral to a transplant center should occur if the patient is
transplant-eligible.
Otherwise, entecavir or tenofovir is preferred primary
therapy because of high potency and low resistance, but
therapy is required long-term.
Vaccination
If vaccinated, HBsAb will be positive (and HBcAb negative). Vaccination is safe in pregnancy.
CLINICAL PEARL
If the HBsAg is positive in someone who otherwise
appears well and has a normal ALT, consider whether
the patient is a hepatitis B carrier (so neither vaccination nor hepatitis B immune globulin helps) or has early
hepatitis B. The carrier state requires demonstration of
very low HBV-DNA levels. It is important to note that
the term carrier should be avoided; it should now
be termed the low replicative state, which while sustained is low-risk.
Close contacts of an acute hepatitis B case should be

administered HBIG, then vaccinated. This includes pregnant women.
Hepatitis B mutations
There are two main clinically relevant types:
1 Mutations of the structural proteins: the core promoter
and pre-core mutations result in loss of soluble core
antigen (eAg). This is the cause of e-antigen chronic
hepatitis. The pre-S and S mutations are responsible for
vaccine escape (ineffectiveness). Other forms result in
failure of HBIG immunoprophylaxis in the post-liver
transplant setting.
2 Polymerase gene mutations. These relate to nucleoside resistance. The best known is the tyrosine
methionineaspartateaspartate (YMDD) locus.
Treatment
Drug resistance
Indicators for commencement of treatment of chronic hepatitis B infection are as follows.
This is diagnosed in the adherent patient with rising HBVDNA levels. Phenotypic resistance is defined as an increase
380
HBV DNA (Log10 IU/mL)
Virologic rebound
ALT (U/L)
Virologic breakthrough
Hepatitis flare
4
Biochemical
breakthrough
Genotypic resistance
2
ULN
0
1
Years
Figure 13-7 Serial changes in serum HBV-DNA. ALT, alanine aminotransferase; ULN, upper limit of normal ALT
levels
From Keefe EB et al. Chronic hepatitis B: preventin, detecting and managing viral resistance. Clin Gastroenterol Hepatol 2008;6(3):26874.
in HBV-DNA by >1log unit from the nadir on treatment

or a rebound to pre-treatment levels (Figure 13-7). The
hepatitis flare is the last event to occur, underpinning the
requirement to monitor HBV-DNA.
CLINICAL PEARL
Resistance may be minimized by ensuring adherence
and using the more potent nucleoside analogues such
as entacavir and tenofovir.
Hepatitis C (RNA virus)

Hepatitis C virus (HCV) is a common cause of chronic liver
disease. It is parenterally transmitted (injecting drug users,
blood transfusions [prior to screening], needlestick injuries,
unsafe tattooing). The disease is endemic in some parts of
the world, e.g. Asia and the Middle East (Egypt has a 9%
prevalence).
HIV is often found as a co-infection with hepatitis C
(1:3), so should always be screened for.
CLINICAL PEARL
Remember the rough rule of 2s:
2% acquire hepatitis C from a needlestick injury
2% of infected cirrhotic patients develop hepatocellular carcinoma every year
2% of the population is infected (based on US
gures).
Diagnosis
Diagnosis is established by HCV antibody screening. Positive results must then be confirmed with HCV-RNA (for
viremia).
Acute hepatitis C
This is rarely diagnosed.
If acute hepatits C is suspected, both HCV antibodies

and HCV-RNA should be measured, and HCV-RNA
then rechecked 24 months later to determine whether
the disease is chronic (if untreated, 80% of cases become
chronic).
Once confirmed with a positive PCR (polymerase chain
reaction), pegylated interferon provides viral eradication
in about 90% of cases.
Chronic hepatitis C
Most chronic infection is initially asymptomatic (75%),
but there is chronic hepatitis and this progresses to cirrhosis after 20 years in 25% of cases. Patients may have
insidious fatigue and raised transaminases; this is variable,
depending on which other risk factors for chronic liver
disease are present.
Extrahepatic manifestations of hepatitis C
These are important to remember:
Mixed cryoglobulinemiathis has a very strong association with hepatitis C and presents with palpable purpura (Figure 13-8, overleaf); this can also occur in other
chronic liver diseases
Porphyria cutanea tarda (see Figure 23-12)
Polyarthralgias and polyarthritis
Glomerulonephritis (membranoproliferative)
Lichen planus
B-cell lymphoma
Treatment
Successful treatment of hepatitis C (sustained virological
response) reduces hepatic decompensation, liver-related
death, liver transplantation and HCC, particularly in those
with more advanced fibrosis (bridging fibrosis or cirrhosis).
381
In the US, sofosbuvir and simeprevir have been approved

for the treatment of chronic hepatitis C. When combined
with pegylated interferon and ribavirin, sustained viral
response (SVR) rates of almost 90% are achieved in genotype 1. Highly efficacious interferon-free regimens are now
undergoing testing, with minimal side-effects for genotype
1 the SVR is above 90% even for patients with early-stage
cirrhosis or those who failed previous therapy at 12 weeks.
Figure 13-8 Palpable purpura

From Kitchens CS, Konkle BA and Kessler MD. Consultative
hemostasis and thrombosis, 2nd ed. Philadelphia: Elsevier, 2007.
General management
General management includes:
vaccinating against hepatitis A and B, if not immune
managing chronic liver disease, if present
advising against dangerous alcohol consumption
aiming at a healthy bodyweight
regular surveillance for HCC in those with cirrhosis (by
ultrasound every 6 months; alpha-fetoprotein testing
may add little extra value, but some recommend it).
Specic antiviral therapy
This is not indicated in end-stage liver disease. Otherwise,
unless contraindicated (Box 13-4), therapy is offered for
chronic infection with elevated transaminases.
Duration of treatment is driven by viral genotype:
genotype 11 year of therapy
genotype 2 or 36 months of therapy.
An early response to therapy can also alter the treatment
duration.
Genotype 1
The therapy comprises a three-drug cocktail (triple therapy)
and achieves up to a 75% response in treatment-nave cases:
Pegylated interferon (injected weekly); this is relatively
contraindicated in depression.
Ribavirin (oral)this can cause hemolysis (which can
be managed, if mild, with erythropoietin).
Protease inhibitor (e.g. boceprevir or telaprevir). Boceprevir is given after 4 weeks of the above dual therapy.
It should be noted that drug interactions (via CYP3A4
or CYP3A5) with anticonvulsants (e.g. phenytoin)
and rifampin may lead to loss of efficacy. Adherence
is mandatory to minimize drug-resistant viral strains
emerging.
Response to genotype 1 therapy is measured by HCVRNA at 8 and 24 weeks.
382
Other genotypes
For other genotypes, dual therapy (interferon and ribavirin) for 6 months is standard, but should be ceased if HCVRNA has not decreased by 2 log units at 12 weeks.
For genotype 2 disease, 12 weeks of sofosbuvir and ribavirin is highly effective, providing an SVR of over 80%.
This should be considered as an interferon-free regimen
in countries where sofosbuvir is available.
In genotype 3 hepatitis C, sofosbuvir is less effective,
and should be reserved for those intolerant of interferon
and for people who have previously failed therapy.
Factors predictive of poor treatment response
Genotype 1
Advanced fibrosis (bridging fibrosis or cirrhosis)
High viral load (>6 log units)
Obesity
Non-compliance
Prior non-response
Hepatitis D (RNA virus)infection only occurs
with hepatitis B virus surface-antigen positivity, and
the risk factors are similar. Superinfection in a hepatitis
Box 13-4
Absolute contraindications to
anti-HCV treatment
Major uncontrolled depressive illness if using interferon

Solid-organ transplant (renal, heart or lung)
Autoimmune hepatitis or other autoimmune condition
known to be exacerbated by pegylated interferon and
ribavirin
Untreated thyroid disease
Patient pregnant or unwilling to comply with adequate
contraception
Severe concurrent medical disease such as severe
hypertension, heart failure, signicant coronary
heart disease, poorly controlled diabetes, chronic
obstructive pulmonary disease
Known hypersensitivity to drugs used to treat HCV
HCV, hepatitis C virus.

Adapted with permission from John Wiley and Sons. Marc G,
Ghany D and Strader D. Diagnosis, management, and treatment
of hepatitis C: an update. Hepatology 2009;49(4):133574.
B carrier can lead to severe disease and death. Successful

hepatitis B vaccination or immunity is protective.
Hepatitis E (RNA virus)this should be considered
in a traveler from the developing world with acute hepatitis and negative serology for hepatitis A and B. In the
3rd trimester of pregnancy, this is particularly dangerous with a high risk of fatal fulminant hepatitis.
Hepatitis Gthis is a rare cause of hepatitis, and not
a cause of chronic liver disease. There are two types:
hepatitis G and GB virus type C. GBV-C may protect
against HIV replication in co-infected patients.

Tests for other viruses causing acute hepatitis are listed in
Table 13-5.
CIRRHOSIS
Cirrhosis is a histological diagnosis characterized by
advanced (bridging) fibrosis, and architectural (nodule formation) and microvascular distortion. Its clinical features
relate to loss of synthetic function, portal hypertension and
HCC.
Cirrhosis represents a disease generally associated with a
reduced life expectancy, particularly if there are features of synthetic dysfunction or portal hypertension (decompensation).
The dominant causes in the Western world are non-alcoholic
fatty liver disease, alcohol and viral hepatitis, although in developing nations hepatitis B is the major etiology.
Clinical features are:
Leukonychia, palmar erythema, spider angiomata, loss of
male-pattern body-hair distribution, and gynecomastia.
Signs of decompensation are jaundice, asterixis (together
with impaired mentation) and hepatic fetor.
Examination of the abdomen may reveal a firm irregular liver, splenomegaly, caput medusa and ascites. In
advanced disease, muscle wasting is usually present.
Signs that may direct to a diagnosis are parotidomegaly in alcoholic cirrhosis, hypogonadism in alcohol- and
hemochromatosis-related cirrhosis, and xanthelasma in
primary biliary cirrhosis (PBC).
Abdominal ultrasound may show a small, irregular liver
or splenomegaly. Ultrasound may identify complications such as ascites, portal vein thrombosis or HCC.
Computed tomography (CT) and magnetic resonance
imaging (MRI) are reserved for diagnosis of HCC and
confirming suspected portal vein thrombosis.
Most imaging modalities are insensitive for advanced
fibrosis. Fibroscan (elastography) in a cirrhotic patient
is useful, as a liver stiffness of less than 21 kPa has a high
negative predictive value for complications of portal
hypertension over the following 2 years.
Blood tests are not diagnostic but are supportive of cirrhosis;
in particular, thrombocytopenia has been validated as a reasonable serum marker of advanced fibrosis. In the presence
of clinical suspicion, normal serum enzymes are not reassuring, as up to 15% of biopsy-proven cirrhosis is accompanied
by normal transaminases.
Once a diagnosis of cirrhosis is established, it is inevitable
that decompensation will occur. This involves development
of any of the following: ascites, hepatic encephalopathy (portosystemic encephalopathy, PSE), jaundice or coagulopathy.
A search for a precipitant must be made (Box 13-5).
CLINICAL PEARL
Suspect cirrhosis based on the history and physical
examination ndings. Look for thrombocytopenia. The
transaminases can sometimes be normal in cirrhosis.
Prognosis
Prognosis is dependent on the presence or absence of
decompensation as well as the presence of an ongoing insult
such as alcohol or untreated viral hepatitis. The frequency
of decompensation is about 4% per year in hepatitis C and
10% per year in hepatitis B infection. It is higher with severe
alcohol excess. Once decompensation has occurred, mortality is as high as 85% over 5 years.
The ChildsPughTurcotte score is predictive of survival
(Table 13-6, overleaf). The Model for End-Stage Liver Disease (MELD) score was established initially as a predictive
Table 13-5 Tests for other viruses causing acute hepatitis
TEST
MEANING OF A
POSITIVE RESULT
COMMENT
Cytomegalovirus (CMV) lgM
Recent acquisition of CMV
Acute hepatitis illness is likely to be due to CMV
EpsteinBarr virus (EBV) lgM
Recent acquisition of EBV
Acute hepatitis illness is likely to be due to EBV
Anti-HIV
HIV-AIDS
Opportunistic hepatobiliary infections
Toxoplasmosis serology
Consider toxoplasmosis
Adenopathy with hepatosplenomegaly characteristic
Q fever serology
Consider Q fever
Think of this in pneumonia with hepatitis
AIDS, acquired immunodeciency syndrome; HIV, human immunodeciency virus; IgM, immunoglobulin M.
383
tool of survival post transjugular intrahepatic portosystemic

shunting (TIPS). This was adapted to predict survival on
transplant waiting lists. It utilizes the predictive variables of
INR, bilirubin and, importantly, creatinine. This is the best
predictor of survival as well as selection of patients for liver
transplant.
MELD = [0.957loge(creatinine, micromol/L)
+ 0.378loge(bilirubin, micromol/L)
+ 1.12loge(INR) + 0.643] w 10
Management
Management should be directed at the underlying cause,
and in particular alcohol cessation is mandatory.
Treatment of viral hepatitis needs consideration. In
the compensated state, hepatitis C infection should be
treated if present. A nucleoside analog should be used if
active hepatitis B is present.
Any possible offending medication should be ceased.
Specific management of autoimmune liver disease,
Wilsons disease and hemochromatosis should be
commenced.
General factors such as a high-energy and high-protein
diet as well as moderate exercise should also be encouraged. A high-energy meal prior to bedtime helps prevent catabolism leading to muscle loss.
Nutritional deficiencies if suspected should be corrected, particularly vitamin D and thiamine.
The complications of cirrhosis are ascites, hepatorenal
syndrome, PSE, portal hypertensive bleeding, portopulmonary hypertension, hepatopulmonary syndrome and cirrhotic cardiomyopathy. Hepatocellular carcinoma is covered
Box 13-5
Causes of hepatic decompensation

in cirrhosis
Infection
UTI, SBP, pneumonia, primary bacteremia, cellulitis
Metabolic
Renal failure, hyponatremia, uremia, volume depletion
(variceal bleed)
Drugs
Alcohol, acetaminophen (paracetamol) especially
Also NSAIDs, diuretics, benzodiazepines, opiates,
phenothiazines, anticonvulsants
Viral infection
Hepatitis A, B, C, D; cytomegalovirus, EpsteinBarr virus
Malignancy
HCC, cholangiocarcinoma, metastasis
Vascular
Portal vein thrombosis, BuddChiari syndrome
HCC, hepatocellular carcinoma; NSAIDs, non-steroidal antiinammatory drugs; SBP, spontaneous bacterial peritonitis; UTI,
urinary tract infection.
Table 13-6 ChildsPughTurcotte (CPT) score for survival in cirrhosis
1 POINT
2 POINTS
3 POINTS
Encephalopathy
Absent
Medically controlled
Poorly controlled
Ascites
Absent
Controlled medically
Poorly controlled
Bilirubin (mg/L)
<20
2030
>30
Albumin (g/L)
<35
2835
<28
INR
<1.7
1.72.2
>2.2
Classication:
CPT CLASS
LIFE EXPECTANCY (YEARS)
PERIOPERATIVE MORTALITY
(ABDOMINAL SURGERY)
A (56 points)
1520
10%
B (79 points)
414
30%
C (1015 points)
13
80%
INR, international normalized ratio.

Adapted from Schuppan D and Afdhal NH. Liver cirrhosis. Lancet 2008;371(9615):83851.
384
elsewhere. Table 13-7 summarises the specific management

of the most common complications.
CLINICAL PEARL
Always tap new-onset ascites to exclude spontaneous
bacterial peritonitis.
ASCITES
Ascites and hepatorenal syndrome are a part of the same
pathophysiological spectrum. They are a manifestation of
hepatic resistance to blood flow, splanchnic vasodilatation
and portosystemic shunt formation, with release of systemic
vasodilators leading to activation of the reninangiotensin

aldosterone axis and the sympathetic nervous system. This
leads to compensatory sodium and therefore water retention. As refractory ascites (and type 2 hepatorenal syndrome)
occurs, progressive renal vasoconstriction results. There is
marked impairment of excretion of sodium and often free
water, the latter being largely responsible for hyponatremia
in end-stage cirrhosis.
Once ascites is diagnosed, a cause must be found (Table
13-8, overleaf). A diagnostic paracentesis should always be
performed when new-onset ascites is detected.
The most useful measure for ascites is the serum ascites
to albumin gradient (SAAG; a difference, not a ratio).
If the SAAG is over 11 g/L, then the ascites is almost
always due to portal hypertension.
Table 13-7 Prevention and treatment of complications of cirrhosis
PREVENTION
TREATMENT
Variceal bleeding
Non-selective beta-blockers*
Variceal band ligation
Acute:
resuscitation
vasocontrictors
sclerotherapy
band ligation
TIPS
surgical shunts
Chronic:
variceal obliteration
TIPS
surgical shunts
Ascites
Low-sodium diet
Low-sodium diet
Diuretics
Large-volume paracentesis
Peritoneovenous shunt
Renal failure
Avoid hypovolemia
Discontinue diuretics
Rehydration
Albumin infusion
Hepatorenal syndrome: add terlipressin or midodrine
(noradrenaline) and somatostatin (octreotide)
Encephalopathy
Avoid precipitants
Treat precipitating factors

Infection
Bleeding
Electrolyte imbalance
Sedatives
High protein intake
Lactulose
Neomycin, metronidazole, rifaximin
Spontaneous bacterial
peritonitis
Treat ascites
Early diagnosic paracentesis, >250 neutrophils/mL:

intravenous antibiotics (plus albumin)
Secondary prophlaxis with oral antibiotics such as
levooxacin
* Nadolol, propranolol.
Vasopressin, octeotride (somatostatin), terlipressin.

TIPS, transjugular intrahepatic portosystemic shunt.
Reprinted from Schuppan D and Afdhal NH. Liver cirrhosis. Lancet 2008;371(9615):83851.
385
Table 13-8 Diagnosis of ascites
CLASSIFICATION OF ASCITES BY SERUM ASCITESALBUMIN GRADIENT (SAAG)

SAAG HIGH (11g/L)
SAAG LOW (<11g/L)
Cirrhosis
Alcoholic hepatitis
Cardiac ascites
Massive liver metastases
Fulminant hepatic failure
Cirrhosis plus another cause
Peritoneal carcinomatosis
Tuberculous peritonitis
Pancreatic ascites
Bile leak
CHARACTERISTICS OF PARACENTESIS FLUID
ETIOLOGY
SAAG
(g/L)
COLOR
WBCs
(CELLS/
MICROL)
RBCs
CYTOLOGY
OTHER
Cirrhosis
Straw
11
Few
<250
Protein <25g/L
Infected ascites
Straw
11
Few
250 polymorphs or
>500 cells
Positive
culture
Neoplastic
Straw/
hemorrhagic/
mucinous
<11
Variable
Variable
Tuberculosis
Clear/turbid/
hemorrhagic
<11, 70%
lymphocytes
High
>1000
Acid-fast
bacilli +
culture
Protein >25g/L
Cardiac
failure
Straw
11
<250
Protein >25g/L
Pancreatic
Turbid/
hemorrhagic
<11
Variable
Variable
Amylase
increased
Lymphatic
obstruction or
disruption
White
<11
Fat globules on
staining
Malignant cells
Protein >25g/L
RBC, red blood cell; WBC = white blood cell.
On initial fluid analysis, fluid should be tested for infection and cytology. Fluid protein, lactate dehydrogenase
(LDH), microscopy, and culture and cytology should be
performed.
Management
Initially, management of ascites due to cirrhosis is
simple: either a no-added-sodium diet or initiation
of diuretics. The aim is to achieve a negative sodium
balance.
Inevitably a diuretic becomes necessary. Spironolactone 100mg, often combined with furosemide 40mg,
is a common regimen. Serum biochemistry must be
monitored.
A response is noted by a fall in extravascular fluid,
best measured by weight, and an increase in urinary
sodium excretion (well over 20mmol/L).
386
In those with edema, weight loss may be 1 kg/day;

if no edema, 0.5kg/day.
As liver disease progresses, sodium and therefore water
excretion diminishes, leading to refractory ascites.
Initially, increased diuretics are required until either
maximal doses are reached or more commonly complications of these drugs occur. These are renal impairment, hypotension, electrolyte imbalance and often
hepatic encephalopathy.
The presence of dietary sodium excess must be sought.
If the patient is excreting more than 78 mmol/day
or the spot urine Na/K is >1, it is likely that dietary
sodium excess is present. The use of non-steroidal antiinflammatory agents must be excluded.
The options are then large-volume paracentesis, transjugular intrahepatic portosystemic shunt (TIPS) or liver
transplant.
Large-volume paracentesis in the outpatient setting is safe and widely accepted. IV albumin should
be given at a dose of 8 g for every litre of ascites
removed. This helps prevent orthostatic hypotension and renal failure resulting from fluid shifts.
TIPS is an option. Ascites improves at a cost of
increased hepatic encephalopathy. It is essential that
patients have an echocardiogram to ensure that the
left ventricular ejection fraction is greater than 60%,
to minimize the risk of shunt-induced congestive
cardiac failure.
As 6-month mortality in those with refractory ascites is 20%, consideration should be given to liver
transplantation if the patient is otherwise eligible.
HEPATORENAL SYNDROME
(HRS)
There are two clinical types of hepatorenal syndrome:
Type 1 hepatorenal syndromerapidly progressive
reduction of renal function as defined by doubling of
the initial serum creatinine to a level of >2.5 mg/dL
(226micromol/L) in less than 2 weeks.
Clinical pattern: acute renal failure.
Type 2 hepatorenal syndromemoderate renal failure (serum creatinine ranging from 1.25 to 2.5mg/dL
or 113226 micromol/L) with a steady or slowly progressive course.
Clinical pattern: refractory ascites.
HRS is a marker of decompensated cirrhosis, requiring the
presence of ascites. It is characterized by a rising creatinine
level in the absence of other causes of renal failure.
Pre-renal failure, obstructive renal failure and renal
parenchymal disorders must be excluded.
It is common to find a precipitant, most commonly
bacterial infection and in particular spontaneous bacterial peritonitis (SBP), GI hemorrhage and occasionally
large-volume paracentesis.
HRS types 1 and 2 are separated mainly by prognosis
and rate of deterioration of renal function. Type 1 HRS
has a median survival of 2 weeks, while type 2 HRS has
a median survival of 46 months.
Diagnosis requires diuretic cessation, volume expansion and
adequate treatment of infection, as well as exclusion of renal
parenchymal disease and renal tract obstruction. All patients
require full septic screen including diagnostic paracentesis.
Management
Management of type 2 HRS is avoidance of nephrotoxins, cessation of diuretics, and a low-sodium diet. Terlipressin will often reverse this, although it has no survival
benefit. Liver transplantation is the only treatment that
can lead to long-term survival in those eligible.
Type 1 HRS is rapidly lethal. If survival is the aim, then
liver transplant is usually required.
The management is the same as for type 2 HRS,

although liver transplantion must be strongly considered and discussion with a liver transplant center
must take place immediately.
The use of vasoconstrictors is also indicated. Providing splanchnic and systemic vasoconstriction
allows for improved renal perfusion and correction
of HRS in 50% of patients. Terlipressin, a vasopressin analogue, should be administered if available. Midodrine with octreotide is a reasonable
alternative. Albumin infusion given with terlipressin improves efficacy. There is a short-term survival benefit with vasoconstrictor therapy; however,
it must be emphasized that liver transplant must be
strongly considered.
TIPS may be considered if vasoconstrictor therapy fails and there are no contraindications. TIPS
has been shown to improve renal function in HRS
type1.
CLINICAL PEARL
The most common cause for acute renal failure in
end-stage liver disease with ascites is not hepatorenal
syndrome but pre-renal failure (40%) and acute tubular
necrosis (40%).
HYPONATREMIA
Hyponatremia is a common problem in end-stage cirrhosis. It is due to impaired free-water excretion from increased
antidiuretic hormone secretion. Hyponatremia is a marker
of poor prognosis both before and after liver transplant.
Treatment should be considered once the sodium is
below 130 mmol/L. The patient must be assessed as hypovolemic or hypervolemic.
If the patient is hypovolemic, then correction of the
cause and volume replacement is the treatment. Most
commonly this will involve diuretic cessation.
If hypervolemic with ascites and edema, fluid restriction
is the initial management. This becomes difficult once
fluids are below 1200ml/day.
Vaptans (e.g. tolvaptan) block V2 vasopressin (ADH) receptors, increasing free water excretion. These agents improve
serum sodium, urine volume and free water clearance.
Great care must be taken not to reverse hyponatremia
too quickly because of the risk of osmotic demyelination syndrome. The rate of correction must be no more
than 35 mmol/day.
Because of the risk of rapid osmotic reversal, these
agents need to be commenced only on inpatients with
a normal mentation and who can access water. Sideeffects include thirst, hypernatremia, renal impairment
and dehydration.
Vaptans where available should be considered in patients
with a sodium level of 125mmol/L or less, particularly if
liver transplantation is an option.
387
CLINICAL PEARL
Do not correct hypronatremia too quickly or you will
risk osmotic demyelination syndrome (central pontine
myelinolysis).
SPONTANEOUS BACTERIAL
PERITONITIS (SBP)
Spontaneous bacterial peritonitis is common and is a highrisk problem in cirrhotic patients with ascites. Presentation may be with abdominal pain and signs of peritonitis,
although more commonly patients present with deteriorating liver function, encephalopathy, renal failure or shock.
Up to 30% develop HRS (see above).
SBP may be asymptomatic. A diagnosis is made only by
ascitic fluid analysis. A positive diagnosis is made by any one
of the following:
neutrophil (PMN) count >250 cells/microL
white cell count >500 cells/microL
positive ascitic fluid culture.
Culture alone has a sensitivity of only 40%, so the neutrophil count is the most important indicator. Bacterial yield
is increased by sending a sample in blood culture bottles.
The most common organisms are Gram-negative rods,
particularly Escherichia coli, and streptococci, particularly
Enterococcus.
A secondary cause for peritonitis (e.g. bowel perforation)
is more likely with localizing peritoneal signs or a polymicrobial ascitic fluid culture.
Treatment
Empirical treatment with cefotaxime or ceftriaxone should
be commenced and adjusted according to sensitivities once
available.
Treatment should be culture- and sensitivity-based, as
30% of Gram-negative rods are quinolone-resistant.
Nephrotoxic agents such as aminoglycosides must be
avoided.
Antibiotics must continue for 7 days, although if there is
rapid patient improvement, IV antibiotics may be ceased
and an oral preparation such as ciprofloxacin or amoxicillin/clavulanic acid commenced.
If there are concerns about patient improvement, a
repeat paracentesis after 2 days should take place. If the
ascitic fluid neutrophil count has not dropped to 25% of
the original count, a resistant organism should be suspected and antibiotics changed.
To reduce the risk of hepatorenal syndrome, IV albumin infusion should be given for at least 3 days.
General management of shock, portal hypertensive
bleeding, encephalopathy and renal dysfunction must
continue.
388
Antibiotic prophylaxis should be given to all patients with

ascites who have a high risk of SBP, including:
those with past SBP, and
those with active variceal bleeding (see section below).
Those with a past episode of SBP have a 70% chance of recurrence within 12 months and a poor prognosis. Secondary
prophylaxis with norfloxacin should be considered, although
ciprofloxacin or co-trimoxazole are reasonable alternatives.
This strategy is effective in infection prevention, although a
survival benefit has not been demonstrated.
Those with no prior episodes of SBP should receive primary prophylaxis with norfloxacin 400mg daily if they have
a fluid protein content of under 10g/L or have a bilirubin
>2.5mg/dL. This improves short-term survival and reduces
the risk of HRS.
PORTAL HYPERTENSIVE
BLEEDING
This may occur from esophageal, gastric or rarely duodenal and small-intestinal varices. Another common finding
is portal hypertensive gastropathy; this tends to present with
anemia rather than obvious GI hemorrhage.
The risk of bleeding relates to a portal pressure of
12 mmHg or above. The measurement of portal pressure
is not routine, so clinical features are the mainstay of risk
assessment. This relates to stage of liver disease and endoscopic features.
The higher the ChildPughTurcotte score (Table
13-6), the more likely the patient is to have varices.
The endoscopic features indicating higher risk are the
size and presence of red wale signs (a red streak overlying a varix that suggests recent bleeding).
Large varices have a risk of bleeding of 30% over 2 years,
and must therefore be considered for primary prophylaxis
(Figure 13-9).
The best-proven medical treatment for this is a betablocker such as propanolol. An alternative is carvedilol.
There is much debate over the use of endoscopic band
ligation as a primary preventative measure.
In high-risk varices, both medical and endoscopic prophylaxis should be attempted. The development of
high-risk esophageal varices is about 9% over 3 years.
All patients with definite or suspected cirrhosis should
have upper endoscopy performed to look for esophageal varices. If normal, this should be repeated every
2years.
Management
Management of acute variceal bleeding has two components: the acute phase and the secondary prophylaxis phase.
The acute phase involves:
General measures, including volume resuscitation and
blood transfusion.
Screening endoscopy (EGD)
None
Follow-up endoscopy
in 2 years or at time
of decompensation
High risk
Low risk
MAP >85 mmHg

No contraindication
to beta-blockers
MAP <85 mmHg

CHF, COPD
Beta-blockers
EVL is alternative
EVL
Follow-up endoscopy
in 1 year
Figure 13-9 An algorithm for the primary prophylaxis of variceal hemorrhage. CHF, congestive heart failure;
COPD, chronic obstructive pulmonary disease; EGD, esophagogastroduodenoscopy; EVL, endoscopic variceal
ligation; MAP, mean arterial pressure
Redrawn from Sanyal AJ et al. Portal hypertension and its complications. Gastroenterology 2008;134(6):171528.
Correction of coagulopathy and thrombocytopenia if

severe.
Management of alcohol withdrawal.
Management of comorbid conditions such as chronic
obstructive pulmonary disease.
If there is a large GI bleed, activation of a massive transfusion protocol and intensive care admission should
occur. The most likely problems to arise will be sepsis,
hepatic encephalopathy and renal failure.
Empirical antibiotics such as ceftriaxone or norfloxacin
are given as prophylaxis. This improves outcomes.
Some centers advocate endotracheal intubation to prevent aspiration.
Careful volume management, resolving active bleeding, and prevention and early aggressive management of
infection are the keys to the renal management.
The bleeding requires specific management with a
somatostatin analogue such as octreotide, or a vasopressin analogue such as terlipressin.
However, upper endoscopy is indicated urgently to
provide endoscopic band ligation of high-risk varices (those bleeding or with fibrin clot or red wale
signs).
If the above measures fail to control bleeding,
endoscopy should be reattempted, reserving balloon tamponade or TIPS for endoscopic failure. It
is becoming apparent that in a center that has TIPS
available, control of bleeding is more reliable and
complications are fewer if TIPS is used. It should be
considered for first-line management.
Secondary prophylaxis includes an aggressive variceal
banding regimen to obliteration, and propanolol.
Gastric varices tend to bleed less often but more dramatically. They are more likely to be associated with noncirrhotic portal hypertension.
Portal hypertensive gastropathy (PHG) most often
presents with anemia or low-grade bleeding. If there is evidence of bleeding, the patient requires propanolol. If ineffective, then TIPS should be considered.
PORTOSYSTEMIC
ENCEPHALOPATHY (PSE)
Portosystemic encephalopathy refers to the neurological and
psychiatric dysfunction that occurs in individuals with significant hepatic dysfunction and with portosystemic shunts.
It presents as a spectrum varying from subtle neuropsychiatric symptoms to deep coma.
It is usual to find a reversible precipitant in overt encephalopathy. There are three forms of PSE in portal hypertension: precipitant-induced PSE, persistent PSE and minimal PSE.
Diagnosis relies on objective clinical findings in the context of cirrhosis. They are confusion and drowsiness and,
in extreme cases, coma. Asterixis and hepatic fetor are supportive signs, although their absence does not exclude PSE.
An approach is outlined in Figure 13-10 (overleaf). Grading
of encephalophathy (Box 13-6) does not include minimal
hepatic encephalopathy.
Box 13-6
Encephalopathy grading
Grade 1Minor lack of awareness, euphoria, shortened

attention span, impaired performance of addition or
subtraction
Grade 2Lethargy or apathy, minor disorientation to
time or place, personality changes and inappropriate
behavior
Grade 3Drowsiness, remaining responsive to verbal
stimuli; gross confusion and disorientation
Grade 4Coma (unresponsive to all stimuli)
Removal of precipitating factors will often resolve the
episode (Table 13-9, overleaf).
Once PSE has occurred, lactulose should be given as
secondary prophylaxis. The dose should be titrated to
cause 23 semi-formed stools per day. An alternative is
rifaximin (a non-absorbable antibiotic).
389
Cirrhosis + acute change in mental state
Exclusion of alternative
neurological disorders
1.
2.
3.
4.
5.
6.
Medical history + physical exam:

presence of headache, focal
neurological signs, meningeal signs
Basic analysis: glycemia, PCO2
Toxins in blood or urine:
benzodiazepines (consider fumazenil if
suspicous), alcohol...
Assess B1 deficit in blood (or give
thiamine if suspicion)
Neuroimaging (CT, MRI) if any
abnormality in 1 or coma (unless rapid
improvement)
EEG if suspicion of seizures or
non-convulsive status
Search for precipitating factors

1.
2.
3.
4.
5.
Medical history + physical exam: explore signs of gastrointestinal

bleeding, constipation, dehydration, infection (fever, localized
signs)
Basic analysis: hemoglobin, leukocytes, creatinine, Na, K, pH
Leukocytes in urine and ascites (if present)
X-rays (thorax and abdomen)
Cultures of blood, urine, ascites or other body fluids (if abnormal)
Liver function and porto-systemic circulation

1.
2.
3.
Acute-on-chronic liver failure
Factor that induces injury (alcohol, infection...), usually

ìnflammatory-mediated
Recent decompensation (24 weeks)
Jaundice (bilirubin > 5 mg/dL)
Circulatory dysfunction (hypotension, renal failure...)
Medical history + physical exam: signs of complications of

cirrhosis
Blood test: bilirubin, albumin, prothrombin, AST, ALT
Imaging of liver and porto-systemic circulation: CT, MRI...
Episodic HE
Prior to HE: good performance

status
Underlying:
precipitating factor or large
porto-systemic shunts
Terminal
Prior to HE: low performance

status
Underlying:
advanced hepatocarcinoma or
severe cirrhosis
Figure 13-10 Evaluation of a patient with cirrhosis and an acute change in mental status should be initiated
by excluding toxic, metabolic and structural encephalopathies. In parallel, the patient should be assessed
following a protocol to investigate precipitating factors and should undergo blood tests and imaging studies
to evaluate liver function and portalsystemic circulation. According to the results, patients are classied as
episodic HE (hepatic encephalopathy), acute-on-chronic liver failure, or terminal liver disease, and are managed
accordingly. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomography; EEG,
electroencephalograpy; MRI, magnetic resonance imaging; PCO2, partial pressure of carbon dioxide
From Crdoba J. New assessment of hepatic encephalopathy. J Hepatol 2011;54:103040.
Dietary protein avoidance is not recommended, as it

makes no difference to outcome and will jeopardise the
already tenuous nutrition in those with decompensated
cirrhosis.
Supplementation with branched-chain amino acids
should be considered, although robust evidence for its
benefits is lacking.
Persistent PSE
This may be due to the presence of a large dominant
portosystemic shunt, which can be closed radiologically
if liver function is well preserved (normal bilirubin) and
more conservative measures fail.
More commonly, a dominant shunt is not present
and medical treatment is indicated. This addresses the
known mechanisms of PSE.
Ammonia is one of the leading candidates as the
culprit substance in the blood leading to PSE.
Non-absorbable disaccharides (lactulose) are firstline treatment in persistent PSE. They work by acidifying the colon, reducing the absorbable ammonia
load and reducing cerebral water content.
390
Antibiotics have a role as second-line agents.

Neomycin or rifaximin are the best choices.
Gamma-aminobutyric acid (GABA)-receptor
blockade with flumazenil may help reverse deep
encephalopathy, although it is not available for
chronic use.
This consists of subtle cognitive dysfunction without the
features of overt PSE. It is not noted by the physician, usually being detected by close family members and work colleagues. Its prevalence is 15% in Childs A cirrhosis and 50%
in Childs C cirrhosis.
Investigation requires psychometric testing, and should
not be routinely sought as there is little benefit to be gained
from treatment.
Investigation is indicated if a patient or family member
wishes this to be done on the basis of declining work
performance or for symptoms such as forgetfulness or a
perception of confusion.
Those at risk of accidents, such as active drivers or those
responsible for dangerous machinery, should also be
screened.
There is no consensus on the best diagnostic tests.
Table 13-9 Managing precipitants of portosystemic encephalopathy
PRECIPITANT
MANAGEMENT
Volume depletion
Commonly from diuretics. Correct with IV albumin and stop diuretics
Infection
Treat specic infection. If SBP, give antibiotics and IV albumin
Renal failure and electrolyte

imbalance
Identify cause and correct
Alcohol
Cease and manage withdrawal
Sedatives
Cease
Portosystemic shunt (TIPS)
Lactulose or rifaximin
Hepatocellular carcinoma
Specic management; see section on liver tumors
Protein load, including GI bleed
Endoscopy and management of portal hypertensive bleed. Dietary protein restriction is

rarely required and should not be chronically commenced to avoid malnutrition
Constipation
Lactulose
GI, gastrointestinal. IV, intravenous; SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portosystemic shunt.
While this may be treated with lactulose or rifaximin,

the evidence for a benefit remains unclear, although these
medications can improve driving performance in a driving
simulator.
PORTOPULMONARY
HYPERTENSION (POPH)
This condition is defined as the presence of pulmonary arterial hypertension (PAH) in the presence of portal hypertension once other secondary causes have been excluded. It
is present in 6% of people with cirrhosis; those at highest
risk are females and those with autoimmune hepatitis. The
condition is associated with high perioperative mortality,
including liver transplantation.
Presenting symptoms are breathlessness on exertion,
fatigue, and occasionally chest pain and palpitations.
Clinical features are of right heart strain and failure.
Other causes of pulmonary hypertension need to be
excluded. They are left heart disease, chronic obstructive pulmonary disease, sleep apnea, pulmonary thromboembolism and connective tissue disease such as
scleroderma.
The initial investigation is echocardiography, and confirmation is by right heart catheterization.
The success of liver transplantation is dependent on response
to medical pulmonary vasodilator therapy, and should be
reserved for responders only. Treatment attempts with vasodilators such as prostaglandins and phosphodiesterase-5
inhibitors are indicated. Other agents to be considered are
bosentan or sildenafil.
HEPATOPULMONARY
SYNDROME (HPS)
This is a syndrome of increased pulmonary perfusion without an increase in ventilation, leading to hypoxemia. Pulmonary vascular dilatation and the opening of vascular channels
between pulmonary arteriole and vein lead to increases in
blood flow (lower transit time) beyond the capacity of the
alveoli to oxygenate.
HPS is a risk factor for death after adjustments for severity of liver disease. Prevalence is around 5% in those
with cirrhosis.
HPS should be suspected if there is severe hypoxemia
(pO2<60mmHg) in the presence of chronic liver disease. Dyspnea on exertion and at rest is the most common symptom. Due to increasing ventilationperfusion
mismatch, dyspnea may deteriorate in the upright position (platypnea). This phenomenon should be accompanied by a fall in partial arterial oxygen pressure (PAO2)
of at least 4mmHg (orthodeoxia).
There are no specific findings, although clubbing, cyanosis and the stigmata of chronic liver disease, particularly spider nevi, are usually present.
Diagnosis is made by demonstrating intrapulmonary vascular shunts. Qualitative echocardiography is the least invasive and most sensitive test. The echo is performed while
microbubbles are injected in a peripheral vein. These are
detected in the left atrium 36 cardiac cycles after the right
atrium, thus detecting a shunt as these bubbles would not
flow through normal pulmonary vasculature.
There is no proven treatment other than liver transplantation. This should be considered in those with proven
HPS and an arterial pO2 below 60mmHg.
391
CLINICAL PEARLS
Suspect HPS in a patient who has cirrhosis and
becomes hypoxemic. Ask if dyspnea deteriorates in
the upright position (platypnea), and look for a fall
inpartial arterial oxygen pressure of at least 4mmHg
(orthodeoxia). Look for a shunt on echo.
Consider POPH in cirrhosis and progressive dyspnoea on exertion. Conrm with right heart catheterization.
A meticulous medication review is required (Box 13-7).

About 15% of cases do not receive a causal diagnosis.
Box 13-7
Initial laboratory testing for acute

liver failure (ALF)
CIRRHOTIC CARDIOMYOPATHY
In cirrhotic cardiomyopathy there is evidence of systolic
dysfunction, diastolic dysfunction and QT prolongation in
cirrhotic patients.
The systolic function is usually normal at rest, with dysfunction becoming apparent with stress. There is a link
between systolic dysfunction and the development of
hepatorenal syndrome.
As cirrhosis becomes more advanced, diastolic dysfunction becomes more prominent. The clinical relevance of
this is particularly related to increases in preload occurring
after TIPS, with the cirrhotic heart unable to accommodate increases in flow. The presence of measurable diastolic dysfunction is predictive of death after TIPS.
QT prolongation is present in 50% of cirrhotic patients
and is unrelated to etiology. In alcohol-related cirrhosis
this is related to sudden cardiac death, although probably not in cirrhosis with other etiologies. In those cirrhotic patients with a prolonged QT interval there is a
prolonged mechanical systole, i.e. an altered excitation
contraction association that contributes to systolic
dysfunction.
The main clinical relevance is the contribution to HRS,
post-TIPS cardiac failure and death, and perioperative
performance in liver transplantation. The cardiac changes
largely resolve post liver transplant.
Treatment is relatively undefined, although it should
include diuretics, particularly spironolactone, and nonselective beta-blockers such as carvedilol and propranolol.
Angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin-receptor blockers should be avoided because of
the risk of HRS.
Prothrombin time/international normalized ratio

Chemistries:
sodium, potassium, chloride, bicarbonate, calcium,
magnesium, phosphate, glucose
AST, ALT, ALP, GGT, total bilirubin, albumin
creatinine, blood urea nitrogen
Arterial blood gases
Arterial lactate
Complete blood count
Blood type and screen
Acetaminophen (paracetamol) level
Toxicology screen
Viral hepatitis serologies:
anti-HAV lgM, HBsAg, anti-HBc lgM, anti-HEV*,
anti-HCV, HCV-RNA#, HSV1 lgM, VZV
Ceruloplasmin level
Pregnancy test (females)
Ammonia (arterial if possible)
Autoimmune markers:
ANA, ASMA, immunoglobulin levels
HIV-1, HIV-2
Amylase and lipase
* If clinically indicated.
#
Done to recognize potential underlying infection.
Done only if Wilsons disease is a consideration (e.g. in patients

younger than 40 years without another obvious explanation
for ALF); in this case uric acid level and bilirubin to alkaline
phosphatase ratio may be helpful as well.
Has implications for potential liver transplantation.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; ASMA, anti-smooth-muscle antibodies; AST,
aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase;
HAV, hepatitis A virus; HCV, hepatitis C virus; HEV, hepatitis E virus;
HIV, human immunodeciency virus; IgM, immunoglobulin M;
RNA, ribonucleic acid; VZV, varicella zoster virus.
From Lee WM, Larson AM and Stravitz RT. AASLD Position Paper.
The management of acute liver failure: update 2011. Baltimore,
MD: American Association for the Study of Liver Diseases; 2011
Sep 26.
ACUTE LIVER FAILURE (ALF)

ALF is a frightening and often rapidly lethal disease caused
by loss of hepatocellular function. It is characterized by the
development of coagulopathy and altered mentation in a
patient with no known chronic liver disease.
The usual causes are drug-induced liver injury (DILI),
acetaminophen (paracetamol) overdose, mushroom
poisoning (Amanita phalloides) and viral hepatitis.
Rarer causes such as Wilsons disease, BuddChiari
syndrome, autoimmune hepatitis and ischemic hepatopathy may require consideration.
392
CLINICAL PEARL
Acute liver failure is a clinical syndrome dened by
altered mentation due to cerebral edema and/or
encephalopathy in the setting of jaundice and coagulopathy. The serum enzymes are not part of this diagnosis, although are usually abnormal. Management
should be carried out in a liver transplant unit.
Management is supportive, with aggressive diagnosis

and treatment of infection. Death is commonly due to raised
intracerebral pressure, which may require hyperventilation

or mannitol. Liver transplantation is often required. It is
important to treat specific etiologies if detected. They are:
acetaminophen (paracetamol) overdoseN-acetylcysteine
mushroom poisoningN-acetylcysteine and penicillin G
acute hepatitis Bnucleoside analogue
autoimmune hepatitisprednisolone or other corticosteroid.
However, delaying transplantation while waiting for specific
treatment to occur is unwise in the deteriorating patient.
CLINICAL PEARLS
If acetaminophen (paracetamol) toxicity is suspected, give N-acetylcysteine immediately.
If the arterial pH is <7.3 in acetaminophen-induced
acute liver failure (ALF) or the international normalized ratio (INR) is >6.5 in ALF of another cause,
the patient needs an urgent liver transplant (Kings
College criteria).
LIVER TRANSPLANTATION
Disease-specific indications for transplantation
include: end-stage cirrhosis (any cause), primary sclerosing cholangitis, Carolis disease (intrahepatic biliary
tree; multiple cystic dilatations), BuddChiari syndrome, and fulminant hepatic failure.
Hepatitis C patients do as well as others despite
recurrent infection in the graft usually occurring.
In active hepatitis B, graft survival is reduced by up
to 20% but prophylactic HBIG increases the success rate, as does pre-treatment with a nucleoside
analogue such as lamivudine.
Absolute contradictions include: active sepsis outside
the biliary tract, metastatic hepatobiliary malignancy,
HIV infection and advanced cardiopulmonary disease.
Relative contradictions include: older age (>60 years),
biliary infection, unreformed alcoholism, a blocked portal vein, previous major upper abdominal surgery, major
renal impairment, and other medical disease (e.g. poorly
controlled diabetes).
Figure 13-11 provides an algorithm for treatment decisions,
and post-transplant complications are outlined in Figure
13-12 (overleaf).
Variceal hemorrhage
Is disease severe
enough?
Decompensation
Resistant ascites
Nutrition and
hepatopulmonary
syndrome
MELD ~ <15
Resistant encephalopathy
Symptoms ++
e.g. intractable itch
HCC
Milan criteria
Nutrition
Lung
TTE/LV function
EKG
CT chest/brain
HCC staging
EtOH
Compliance
CXR/Spine/Hip
Bone scan
Viral serology
Psychosocial
evaluation
Coping skills
Shunt study
Previous malignancy
(>5 yrs prob safe)
Risk of infection
or cancer
Supports
Lung function
Heart
Vascular anatomy
Fitness for posttransplant care
ABG
Stress echo
Cardiopulmonary
evaluation
Fitness for
surgery
Treat
reversible
factors
Insight and motivation
LIVER TRANSPLANT WORK-UP

Figure 13-11 Work-up for liver ABG, arterial blood gases; CT, computed tomography; CXR, chest X-ray;
EKG, electrocardiography; EtOH, alcohol; HCC, hepatocellular carcinoma; LV, left ventricular; MELD, model for
end-stage liver disease; TTE, trans-thoracic echocardiogram
Redrawn from an original gure created by Dr Gokulan Pavendranathan, Central Clinical School, AW Morrow Gastroenterology and Liver
Centre, NSW, Australia.
393
Liver transplant complications

Immediate (post-op)
surgical complications
primary non-function
sepsis
rejection
vascular and biliary breakdown or occlusion

infections/collections
anastamotic
biliary strictures
ischemic
Medium term
biliary strictures
rejection
infection (viral, e.g. CMV)
recurrence of underlying disease
(e.g. HCV)
Long term
metabolic
cancer
bone
infections
chronic rejection/non-compliance
recurrence
hepatic artery
stenosis/thrombosis
weight gain
cholesterol (CSA > Tac)
diabetes mellitus (Tac > CSA)
hypertension
renal impairment
hepatitis C or B
PSC/PBC/AIH
alcohol
skin
PTLD
solid organ
VASCULAR
RISK
SMOKING
Figure 13-12 Complications post-liver transplant . AIH, autoimmune hepatitis; CSA, cyclosporine A (ciclosporin
A); PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PTLD, post-transplant lymphoproliferative
disorder; Tac, tacrolimus
Redrawn from an original gure created by Dr Gokulan Pavendranathan, Central Clinical School, AW Morrow Gastroenterology and Liver
Centre, NSW, Australia.
DRUGS AND THE LIVER

Drugs are an important cause of liver disease (Table 13-10).
CLINICAL PEARLS
Very few diagnoses cause transaminase levels
above 1000 U/Lthink about drug/toxin reactions
(not alcohol), acute biliary obstruction, acute viral
hepatitis and ischemic hepatopathy.
In a patient with arrhythmias on therapy and liver
test abnormalities, consider amiodarone toxicity.
The contraceptive pill can cause or stimulate the growth

of hepatic adenoma (and very rarely hepatocellular carcinoma); it can also cause focal nodular hyperplasia (FNH)
and peliosis hepatitis, although the association with FNH
is very vague. Other associations include BuddChiari syndrome, cholestasis, cholesterol gallstones, and unmasking
DubinJohnson syndrome.
Acetaminophen (paracetamol) and

acute liver disease
The livers cytochrome P450 system oxidizes 5% of acetaminophen, producing the potent hepatotoxin N-acetylp-benzoquinoneimine (NAPQI). Glutathione protects
the liver from this toxin. In its absence, the result is severe
hepatic necrosis, liver failure (fulminant hepatitis) and death
unless transplantation is performed.
Acetaminophen is dangerous in the following settings:
Overdose, where glutathione is overwhelmed.
394
Chronic moderate alcohol use or a binge, a risk factor

for acetaminophen-induced liver failure at therapeutic
dosages. Alcohol reduces the amount of liver glutathione, plus it turns on the cytochrome P450 system
leading to more NAPQIdouble jeopardy!
Little or no eating (malnutrition, dieting) leads to glutathione deficiency.
ALCOHOL AND THE LIVER

CLINICAL PEARL
A high AST/ALT ratio suggests alcoholic liver disease in
the absence of cirrhosis.
The key facts to remember are:

Distinguishing alcoholic liver disease from nonalcoholic fatty liver disease can be challenging. An AST/
ALT ratio over 2 and a disproportionally raised GGT
can occur in both, but is much more typical of alcohol.
Acute alcoholic hepatitis is treated by alcohol withdrawal, supportive care and nutritional supplementation; if severe (based on the prothrombin time and
bilirubinMaddrey score), corticosteroids are indicated (prednisolone for 4 weeks, then taper off).
Acetaminophen (paracetamol) is dangerous even in
therapeutic doses in alcoholics, who not only may be
drinking heavily but also may be malnourished.
Complications of alcoholism are given in Box 13-8.
Table 13-10 Drugs and the liver
LIVER DISEASE
DRUG EXAMPLES
Acute hepatitis
Halothane, phenytoin, chlorothiazide
Cholestasis
Hypersensitivity reaction:* chlorpromazine, other phenothiazines,

sulfonamides, sulfonylureas, rifampicin, nitrofurantoin, erythromycin
Dose-related: anabolic steroids, contraceptive pill
Mixed cholestasis/hepatitis
Amoxicillin/clavulanic acid
Fatty liver
Tetracycline, valproic acid, salicylate, amiodarone, vitamin A, zidovudine

(microvesicular); methotrexate, alcohol, corticosteroids, cisplatin
(macrovesicular)
Peliosis hepatitis (large blood-lled cavities)
Anabolic steroids, contraceptive pill, tamoxifen
Cytotoxic (liver cell necrosis)
Acetaminophen (paracetamol), carbon tetrachloride (zone 3)
Angiosarcoma
Vinyl chloride, thorotrast, arsenic
* Canalicular bile plugs portal tract inammatory inltrate with eosinophils.
No inammatory inltrate or necrosis.
Amoxicillin/clavulanic acid can cause acute cholestatic hepatitis.
Box 13-8
Complications of alcoholism
Gastrointestinal tract
1 Chronic liver disease (alcoholic hepatitis, cirrhosis)
2 Hepatomegaly (fatty liver, chronic liver disease)
3 Diarrhea (watery due to alcohol), or steatorrhea due to
chronic alcoholic pancreatitis or rarely liver disease
4 Pancreatitis (although acute attacks occur, usually there
is underlying chronic disease)
5 Acute gastritis (erosions)
6 Parotitis/parotidomegaly
Cardiovascular system
1 Hypertension
2 Cardiomyopathy
3 Arrhythmias
Nervous system
1 Nutrition-related problems: Wernicke encephalopathy,
Korsakoff syndrome (thiamine deciency), pellagra
(dermatitis, diarrhoea, dementia due to niacin
deciency)
2 Withdrawal syndromes: tremor, hallucinations, rum
ts, delirium tremens
3 Dementia (cerebral atrophy, MarchiafavaBignami
disease, nutritional deciency)
4 Cerebellar degeneration
5 Central pontine myelinosis (causing pseudobulbar
palsies, spastic quadriparesis)
6 Autonomic neuropathy
7 Proximal myopathy
8 Acute intoxication
Hematological system
1 Megaloblastic anemia (dietary folate deciency, rarely
B12 deciency due to chronic pancreatitis with failure to
cleave B12R-protein complex)
2 Iron-deciency anemia due to bleeding erosions or
portal hypertension
3 Aplastic anemia (direct toxic effect on the bone
marrow)
4 Thrombocytopenia (bone marrow suppression,
hypersplenism)
Metabolic abnormalities
1 Acidosis (lactic, ketoacidosis)
2 Hypoglycemia
3 Hypocalcemia, hypomagnesemia
4 Hypertriglyceridemia, hyperuricemia
395
SPECIFIC LIVER DISEASES

This is a varied group of disorders with the common link
of hepatic outflow obstruction. This may occur at varying
levels, including hepatic sinusoids, venules, veins, vena cava
and right atrium.
The clinical presentation depends on the rate of thrombus formation. It may be classified as fulminant, acute, subacute
and chronic.
Fulminant BCS presents with severe necrosis and jaundice, with hepatic encephalopathy developing within
8weeks.
In acute BCS the development of collaterals has not
occurred, so pain, hepatic necrosis and ascites dominate
the clinical picture.
With a subacute (most common) and chronic BCS, collaterals have developed so hepatic necrosis is minimal.
Presentation of subacute BSC is with unexplained splenomegaly or varices.
Chronic BCS presents as decompensated cirrhosis.
CLINICAL PEARL
Suspect BuddChiari syndrome in a younger patient
(more often female) presenting with acute-onset
abdominal pain, hepatomegaly and ascites.
Causes
The cause is usually a hypercoagulable state (Box 13-9),
although rarely an inferior vena caval web is responsible.
Box 13-9
Causes of BuddChiari syndrome

Think: hypercoagulable states
Inherited
Factor V Leiden mutation
Antithrombin III deciency
Protein C deciency
Protein S deciency
Prothrombin mutation
Acquired hypercoagulable state
Pregnancy
Oral contraceptives
Paroxysmal nocturnal hemoglobinuria (PNH)
Other
Antiphospholipid syndrome
Cancer
396
Diagnosis
Diagnosis depends on demonstration of impaired hepatic
outflow.
The best test is Doppler ultrasonography, although
CT and MRI are of value and may also find associated
malignancy.
If the suspicion is high and tests remain negative, then
hepatic venography should be performed; this may also
find a caval web.
The ALT is elevated in fulminant and acute BCS, but may
be near normal or normal in the chronic form.
Treatment
This includes management of ascites with diuretics, sodium
restriction and, if required, large-volume paracentesis.
Management of complications of cirrhosis (encephalopathy,
HRS) should occur as previously outlined. Anticoagulation
lifelong is generally accepted as necessary.
Treatment of acute forms of BuddChiari syndrome
should be directed at reperfusion treatment or liver
transplantation.
Non-alcoholic fatty liver disease

(NAFLD) and non-alcoholic
steatohepatitis (NASH)
These are the most common causes of chronic liver disease
in the developed world. Fatty liver disease represents a spectrum from excess fat to inflammation. A subset of 520% of
patients progress to cirrhosis. These tend to have inflammatory histology (NASH) rather than bland steatosis.
Clinical features are those of the metabolic syndrome.
Patients are usually asymptomatic, although dull right
upper quadrant discomfort may be present. Hepatomegaly is common. Signs of cirrhosis and portal hypertension may be present.
The diagnosis is usually clinically based, with abnormal
transaminases in the right clinical setting (e.g. obesity,
diabetes mellitus or hyperlipidemia); other causes for
liver disease are excluded, especially alcohol, but also
viral hepatitis, medication and iron overload.
The abdominal ultrasound is usually consistent,
although may be normal in 10% of cases.
Other causes of hepatic steatosis are given in Box 13-10.
CLINICAL PEARL
Cardiovascular disease and malignancy remain the
most common cause of morbidity and mortality in
non-alcoholic fatty liver disease. Management must
include preventative measures for these diseases.
The treatment should address insulin resistance. This

includes the following:
Diet and weight lossa low-glycemic-index and lowfat diet should be adopted, and a goal of 10% total bodyweight loss over 6 months should be achieved. This has
been shown to improve liver function and histology.
Box 13-10
Other causes of hepatic steatosis

1 Protein-calorie malnutrition or starvation*
2 Total parenteral nutrition*
3 Drugs, e.g. glucocorticoids*, estrogens*, aspirin,
calcium-channel blockers*, amiodarone, tamoxifen*,
tetracycline, methotrexate*, valproic acid, cocaine,
antivirals (e.g. zidovudine*)
4 Lipodystrophy*
5 Acute fatty liver of pregnancy
Figure 13-13 KayserFleischer (KF) ring
6 Inammatory bowel disease*

* Causes macrovesicular steatosis.
Causes microvesicular steatosis.
Exerciseexercise alone has been shown to improve

liver function.
The use of insulin-sensitizing drugs in selected patients.
However, the insulin-sensitizing drug therapy evidence
is very borderline. Metformin is the only drug that
is used at this stage. The role of thiazolidinediones is
controversial.
Alcohol must be stopped.

degeneration)
This is a rare but important autosomal recessive disease of
copper excess secondary to mutation in the ATP7B copper
transport gene.
The disease presents in young adult life (usually up to
age 35; it is extremely rare over 40, so those above this
age with unexplained liver disease would not normally
be screened for Wilsons disease).
Wilsons disease may present with liver disease, neurological disease (e.g. parkinsonian features, psychiatric
disease), or both. Those with neurological disease usually have detectable liver disease if it is sought.
CLINICAL PEARL
A young patient with neurological symptoms and liver
diseaseexclude Wilsons disease!
Liver disease from Wilsons disease is highly variable. It may be that of an uncomplicated chronic
hepatitis, decompensated cirrhosis, or acute liver
failure. It should be suspected in a young patient
with hemolysis and acute liver failure.
Neurological signs (e.g. tremor, rigidity) are present
in one-third of cases.
KayserFleisher (K-F) rings are present in almost
all Wilsons patients with neurological disease, and
about half with hepatic disease (Figure 13-13).
Diagnosis depends on combination testing: slit-lamp exam
(for K-F rings), serum ceruloplasmin (reduced) and 24-hour
urine copper (excess). It is unusual for all screening tests to

be positive. Liver biopsy is required for definitive diagnosis.
CLINICAL PEARL
Ceruloplasmin is an acute-phase reactant, and may be
elevated falsely in hepatitis and depressed in cirrhosis
with impaired synthetic function. Diagnosis of Wilsons
disease relies on combination testing.
Treatment is with penicillamine (plus pyridoxine),

which promotes urinary copper excretion and inhibits GI
copper absorption, or with trientine and/or oral zinc, which
are chelators. There is growing evidence that trientine is as
effective and better tolerated than penicillamine and may be
considered as first-line therapy.
Liver transplant is indicated in fulminant disease and is
curative.
Alpha-1 anti-trypsin deciency

This is an autosomal recessive disease and can present in
adults. Diagnosis is with serum electrophoresis (A1AT phenotype). Transplantation in end-stage liver disease is curative (of liver disease).
Hemochromatosis
This is an important and relatively common disease of iron
overload. There are two types:
1 Hereditary (autosomal recessive)affecting 1 in 250
Caucasians. The genetic defect leads to abnormal iron
absorption. The gene is HFE and there are two wellknown mutationsC282Y and H63D. Most patients
with this disease are homozygous for C282Y. Only a
few cases are compound heterozygotes (C282Y and
H63D). Homozygotes for H63D probably have no
risk of hemachromatosis. There are rare cases with no
known mutations.
2 Acquiredsecondary to multiple blood transfusions,
or secondary erythropoiesis (e.g. thalassemia or sideroblastic anemia).
Most patients with hereditary hemochromatosis present in
the asymptomatic phase, as a result of iron studies being
found to be abnormal for other reasons.
397
Men are much more likely to present with clinical features, as women are protected by menses until the
menopause. Classical clinical features in advanced disease
(Figure13-14) include:
hepatomegaly (from iron deposition; most cases)
diabetes mellitus (in two-thirds)
pigmentation (bronzed diabetes is a classic but rare
finding in a subgroup of patients)
arthropathy (big knuckles; 2nd and 3rd metacarpophalangeal (MCP) joints) (in two-fifths)
cardiomyopathy (dilated) (in one-sixth)
erectile dysfunction (secondary to pituitary iron overload).
CLINICAL PEARL
In a patient with diabetes mellitus and evidence of liver
disease, screen for hemochromatosis with iron studies.
Screening is by looking for an increased fasting transferrin saturation of >62% in men and >50% in women, and
a raised ferritin level of which >300 microg/mL in men
and >200 microg/mL in women is suggestive, and >1000
microg/mL very suggestive.
It should be noted that the ferritin can be raised as an
acute-phase reactant in any inflammatory process,
including NASH, alcoholic liver disease and chronic
viral hepatitis. An important feature that helps distinguish between reactive causes and true iron overload is
the progression of the ferritin, with fluctuation in reactive cases and a progressive rise in hemochromatosis.
Hemochromatosis often remains undiagnosed in
women until after the menopause.
If the diagnosis is suspected on iron studies, genetic testing is helpful to confirm the disease in most cases. If nondiagnostic or uncertain, liver biopsy and chemical iron
staining should be performed to determine the hepatic iron
Figure 13-14 Hemochromatosis: this liver biopsy

reveals increased iron stores (blue-green staining)
398
index (usually >1.9). Liver biopsy is indicated if the ferritin is above 1000 microg/mL, as 40% of patients will have
cirrhosis (unless cirrhosis is clinically obvious).
CLINICAL PEARL
Beware of the hemochomatosis patient who stops
requiring venesectionthey may need investigation for
gastrointestinal blood loss.
Treatment includes the following:

Avoidance of excess alcohol.
Regular venesection (weekly initially and with monitoring of iron studies until iron is depleted to a normal
ferritin level, then third-monthly). This should be modified according to response. Arthropathy and endocrine
changes do not respond to venesection, as the organs are
irreparably destroyed.
Screening for HCC should occur 6-monthly if there is
underlying cirrhosis. If there is no cirrhosis, the HCC
risk is not increased once the patient is venesected and
iron-depleted.
AUTOIMMUNE LIVER DISEASES

These include autoimmune hepatitis (AIH), primary biliary
cirrhosis (PBC) and primary sclerosing cholangitis (PSC).
Overlap syndromes may also occur. Diagnosis relies on a
combination of clinical assessment, liver enzyme pattern and
autoantibodies. Histology and cholangiography are required
in most patients.

Autoimmune hepatitis is an idiopathic necroinflammatory
liver disease that is characterized by the presence of autoantibodies, elevated globulins and interface hepatitis on liver
biopsy. Presentation is varied.
It can be diagnosed in the investigation of the well
patient with abnormal liver enzymes, or present as either
decompensated cirrhosis or acute liver failure.
Fatigue and arthralgia are common complaints. If
advanced, jaundice, splenomegaly and ascites may be
present.
The globulins are typically elevated and autoantibodies are present. These include anti-nuclear antibodies
(ANA), anti-smooth muscle antibodies (ASMA) (type
1 AIH) and anti-liver-kidney microsomal antibodies
(ALKMA) (type 2 AIH).
Diagnosis is made based on the presence of these features
and the exclusion of other causes of liver disease. Liver
biopsy is recommended in suspected cases. The histological
hallmark is interface hepatitis with a prominent plasma cell
infiltrate.
Treatment of AIH is based on immune suppression,
initially with prednisone and often with the addition of an
immunosuppressant such as azathioprine. Management of
decompensated liver disease is the same as for any other etiology and may include liver transplantation.
Primary biliary cirrhosis (PBC) and

primary sclerosing cholangitis (PSC)
It is important to distinguish between PSC and PBC
(Table13-11).
Both are cholestatic liver diseases and can cause jaundice
and pruritis, and the alkaline phosphatase (ALP) will be
elevated.
PBC affects middle-aged women, causing fatigue and
pruritus.
PSC typically affects men who have ulcerative colitis.
Diagnosis is based on serum liver enzymes and autoantibodies.
Cholangiography is required in the case of PSC. MRCP
is the modality of choice, with endoscopic retrograde
cholangiopancreatography (ERCP) reserved for cases
with non-diagnostic MR cholangiography where the
index of suspicion remains high. ERCP can also treat
dominant strictures, and allows for biliary brushing and
biopsy for suspected cholangiocarcinoma or a dominant
stricture. Liver biopsy has a role in the setting of diagnostic uncertainty.
Antimicrobial antibody (AMA) is positive in 95% of

cases of PBC. Liver biopsy is required to diagnose and
stage PBC.
Treatment:
There is no proven treatment for PSC, although ERCP
with biliary stenting may be required to relieve cholestatic symptoms if there is a dominant stricture.
Ursodeoxycholic acid at 15 mg/kg/day is the recommended treatment for PBC.
Both PSC and PBC may progress to cirrhosis, which
when complicated requires specific therapy. Surveillance for esophageal varices and hepatocellular carcinoma should occur once cirrhosis is diagnosed.
Management of osteopenia and osteoporosis is important in both diseases.
Measurement and replacement of vitamin D should be
undertaken.
PSC may be complicated by cholangiocarcinoma and intermittent cholangitits. These must be sought if there is a rapid
change in the liver function tests.
Table 13-11 Primary sclerosing cholangitis (PSC) vs primary biliary cirrhosis (PBC)
FEATURE
PSC
PBC
Age
Young
Middle-aged and elderly
Sex
Typically men (70%)
Typically women (90%)
Clinical
Pain
Cholangitis
Hepatosplenomegaly
ALP elevated
Pruritus
Xanthomas, xanthelasma
Hyperpigmentation
Hepatosplenomegaly
ALP elevated
Liver function tests
Bilirubin uctuates
Antimitochondrial antibody
Negative
Positive in 90% (also elevated in chronic

hepatitis, connective tissue disease)
pANCA
Positive (up to 90%)
Negative
MRCP
Irregular and beaded ducts
Pruned ducts
Associated diseases
Ulcerative colitis (70%)

Crohns disease (rare)
Sjgrens syndrome (rare)
Thyroiditis (rare)
Hypothyroidism (rare)
Pancreatitis (rare)
Retro-orbital and retroperitoneal brosis (rare)
CREST syndrome
Sjgrens syndrome
Thyroiditis
Complications
Portal hypertension
Liver failure
Bile duct carcinoma
Osteomalacia
Steatorrhea (due to bile acid deciency,
associated pancreatic insufficiency or
coexisting celiac disease)
Portal hypertension, liver failure (late)
Treatment
Ursodeoxycholic acid
Liver transplant
Liver transplant
ALP, serum alkaline phosphatase; CREST, calcinosis, Raynauds syndrome, esophageal dysmotility, sclerodactyly and telangiectasia; MRCP,
magnetic resonance cholangiopancreatography; pANCA, peri-nuclear anti-neutrophil cytoplasmic antibody.
399
SYSTEMIC DISEASE AND THE

LIVER
GALLBLADDER AND BILIARY

TREE
Remember that a number of diseases may affect not just

the liver, but also other organs. Some diagnostic hints to
remember are presented in Box 13-11.
The major diseases to consider are gallstones, cholangitis

(infection of the bile secondary to obstruction, usually from
a stone or tumor) and cholestasis (obstructive, e.g. stone or
tumor; or hepatocellular, see above).
Box 13-11
Gallstones
Diagnostic hints: liver and other

systemic disease
1 Liver and cardiac diseaseconsider underlying cardiac
failure, constrictive pericarditis, hemochromatosis,
alcoholism, amyloidosis, amiodarone
2 Liver and lung diseaseconsider underlying alpha-1
antitrypsin deciency
3 Liver and neurological diseaseconsider underlying
Wilsons disease, hepatic encephalopathy or alcohol
4 Liver disease and photosensitivityconsider
underlying porphyria cutanea tarda and hepatitis C
5 Liver and renal diseaseconsider hepatorenal
syndrome, but carefully consider acute tubular
necrosis or pre-renal failure
PREGNANCY AND LIVER

DISEASE
It is important to recognize both the specific liver diseases
that occur in pregnancy and the effects in pregnancy of other
liver diseases (Table 13-12).
Most gallstones are asymptomatic. Gallstones can cause biliary pain (severe, constant pain in the epigastrium or right
upper quadrant lasting at least 30 minutes that occurs in
discreet episodes and is unpredictable).
Natural history of asymptomatic gallstones:
80% remain asymptomatic, and cholecystectomy is not
recommended unless symptoms occur.
Fewer than 20% who experience symptoms will develop
complications, but cholecystectomy is indicated.
Associated with an increased incidence of cholesterol gallstones are:
increasing age
female gender, estrogen therapy, the contraceptive pill
(more lithogenic bile)
race, e.g. Native Americans
obesity (lithogenic bile)
intrahepatic cholestasis of pregnancy
pancreatitis
drugs, e.g. clofibrate (lithogenic bile), ceftriaxone (biliary sludge).
Associated with an increased incidence of calcium bilirubinate (pigment) stones are:
Table 13-12 Liver disease in pregnancy
DISEASE
Incidental to
pregnancy
Related to
pregnancy (possibly
inuenced by
hormones present
in pregnancy)
Specic to
pregnancy
400
CAUSE
Viral hepatitis
COMMENT
Most common cause of liver disease in pregnancy
Alcohol-related
Autoimmune chronic hepatitis
Most prevalent in females of reproductive age
Complicated gallstone disease
Bile ducts enlarge in pregnancy, tend to regress after

delivery
Hepatic adenoma
May enlarge and bleed, rare
Focal nodular hyperplasia
Unclear whether enlargement of nodules is

promoted in pregnancy
BuddChiari syndrome
Hepatic venous outow obstruction
Intrahepatic cholestasis
Pruritus, jaundice in 3rd trimester
Vomiting, pain, jaundice, liver failuredeliver

immediately
HELLP (hemolysis, elevated liver enzymes,

low platelets)
In preeclampsia
Can be confused with AFLP
Deliver immediately
chronic hemolysis
ileal disease, e.g. Crohns disease
cirrhosis
biliary infection.
At increased risk of complications are the elderly, diabetics,
those with large stones, and those with a non-functioning or
calcified gallbladder.
Diagnosis of gallstones
An ultrasound, rather than a CT scan, is the first-line
test.
If the liver function tests and ultrasound are normal, a
common duct stone is unlikely.
If a common duct stone is a consideration (e.g. persistent
pain and abnormal liver function tests), an MRCP should
be performed. ERCP is used to remove the stone.
Hepatobiliary iminodiacetic acid (HIDA) scanning is
useful to diagnose acute cholecystitis (acute cystic duct
obstruction).
CLINICAL PEARL
Charcots triadright upper quadrant pain, fever and jaundicesuggests cholangitis, but patients may just present
initially with mental status change or hypotension.
This should be considered in a very ill patient where the
gallbladder is enlarged on imaging. If the patient is too ill for
a cholecytectomy, cholecystostomy is lifesaving.
A palpable gallbladder (Box 13-12) usually indicates
longstanding biliary obstruction or gallbladder cancer rather
than gallstones.
CLINICAL PEARL
If an X-ray shows a calcied gallbladder outline (porcelain gallbladder), operateas this is likely to be cancer.
Box 13-12
Causes of a palpable gallbladder

With jaundice
1 Carcinoma of the head of the pancreas
2 Carcinoma of the ampulla of Vater
3 Mucocele of the gallbladder due to a stone in
Hartmanns pouch and a stone in the common bile
duct (rare)
Without jaundice
1 Mucocele of the gallbladder
2 Carcinoma of the gallbladder
Investigation
Acute attacksincreased urinary porphobilinogen
(PBG) and delta-aminolevulinic acid (ALA), thus the
urine is dark; fecal porphyrins are normal.
Between acute attacks, the findings are the same.
DNA testing confirms the diagnosis (mutation in porphobilinogen deaminase gene).
Treatment
Stop alcohol and medications that are known to be
unsafe, e.g. estrogens, carbemazepine, non-steroidal
anti-inflammatory drugs (NSAIDs).
Treat any intercurrent infection.
Manage SIADH (syndrome of inappropriate secretion
of antidiuretic hormone) if present.
Monitor vital capacity (bulbar paralysis).
Intravenous hemin (intravenous glucose only if mild).

In PCT, the defect is uroporphyrinogen decarboxylase
deficiency. Iron overload is a determinant of the clinical
expression.
Clinical features
PORPHYRIAS
There are no acute attacks in PCT and they are not usually drug-related.
The skin shows bullae and hyperpigmentation on
exposed areas (similar to VP).
Underlying hepatitis C is common; alcoholic liver disease may be present.
In AIP the defect is a partial deficiency of porphobilinogen

deaminase.
Investigations
There are several major porphyria syndromes in adults

(which are all autosomal dominant).
Clinical features (similar to lead poisoning)

Abdominal pain, vomiting, constipation
Peripheral neuropathy (motor)
The skin is never affected
Attacks may be precipitated by drugs (alcohol, barbiturates,
sulfonamides, and the contraceptive pill).
Normal PBG and ALA in urine, and normal porphyrins

in stools.
Greatly increased uroporphyrin in urine, causing red
urine.
Treatment
Phlebotomies are performed to reduce serum ferritin.
401
1
A 35-year-old man presents with a 4-day history of jaundice, dark urine and upper abdominal pain. Over the past
3months he has noted a 6 kg weight loss and his appetite has also decreased. He has been on mesalamine for 8 years for
the treatment of ulcerative colitis. He has not had any recent are. He drinks about 60 g/day of alcohol and he is a type 2
diabetic on metformin and insulin. On clinical examination he is obese and jaundiced. Abdominal examination shows only
a previous laparoscopic cholecystectomy scar. His family physician had noted slightly deranged liver function tests over
the past few years, and it was thought to be related to fatty liver disease. During his present inpatient stay, an abdominal
ultrasound showed dilated intrahepatic ducts and common hepatic duct, and no features of fatty liver were noted.
The common bile duct was not dilated. The following are his liver function tests: bilirubin 100micromol/L (reference
range [RR] 315), alkaline phosphatase 820 U/L (RR 30115), alanine aminotransferase 2800 U/L (RR 140), aspartate
aminotransferase 240 U/L (RR 130). Which of the following is the most appropriate next step?
A Endoscopic retrograde cholangiopancreatography (ERCP)
B Magnetic resonance cholangiopancreatography (MRCP)
C Tumor markers:Ca19.9, CEA and AFP
D Endoscopic ultrasonography with ne-needle aspiration biopsy
E Start ursodeoxycholic acid
A 29-year-old man presents with hematemesis after ingesting 150 g of alcohol the previous night. He denies retching
prior to the episode of hematemesis. Despite his young age, stigmata of chronic liver disease are present. His blood
pressure is 70/40 mmHg and his heart rate is 128 beats/min. He appears pale. Rectal examination is normal. He
continues to vomit blood in the emergency room. An articial airway is placed and uid resuscitation commenced.
Emergency endoscopy is likely to show:
A Gastric ulcer
B Duodenal ulcer
C MalloryWeiss tear
D Gastric antral vascular lesion
E Esophageal varices
A 54-year-old man is noted to be anemic (hemoglobin 74g/L). He has no clinical signs of end-organ dysfunction, but
feels fatigued after exercise. His iron studies show:
Ferritin
3.5 ng/mL (normal range 40200)
Transferrin saturation
5% (normal range (2050)
Serum iron
4 mmol/L (normal range 1027)
Total iron binding capacity (TIBC)
78 micromol/L (normal range 4880)
Vitamin B12 and folate studies are normal. His red cells are hypochromic and microcytic. In addition to undertaking
investigations for his iron deciency, the most appropriate initial action in terms of managing his iron deciency is:
A Await investigations prior to commencing iron replacement.
B Infuse 1g iron sucrose intravenously.
C Infuse 1 g iron polymaltose intravenously.
D Commence oral iron replacement.
4 A 32-year-old woman is referred by her family physician with joint aches, jaundice and fatigue. Her liver function
tests are abnormal, showing an elevated bilirubin and transaminases three times the upper limit of normal. Alkaline
phosphatase and gamma-GT are just above normal. She has no signicant medical background and has not recently
travelled overseas. She takes no regular medications, but occasionally takes sh oil and a multivitamin. She drinks
2030 g of alcohol every 2nd weekend. Her family history is positive for maternal hypothyroidism. On examination, her
observations are within normal limits. Scleral icterus and jaundice are present. No signs of chronic liver disease can be
found. Further blood tests show:
Antinuclear antibody (ANA)
1:40
Anti-smooth-muscle antibody (ASMA)
1:640
Anti-mitochondrial antibody (AMA)
Not detected
Hepatitis B and C serology
Negative
Which of the following is the most likely diagnosis?

A Hepatitis associated with lupus
B Autoimmune hepatitis
C Primary biliary cirrhosis
D Primary sclerosing cholangitis
E Drug-induced liver injury
402
A 60-year-old businessman is referred with abnormal liver function tests for investigation. His past medical history is
positive for diabetes, hypercholesterolemia and osteoarthritis. His current medications include long-acting insulin,
rosuvastatin, acetaminophen (paracetamol) and occasional use of non-steroidal anti-inammatory drugs (NSAIDs).
He denies illicit drug use, and states that he drinks 1020 g of alcohol less than once a month. He was adopted and
has no knowledge of any family history. He has three adult sons. He has no tattoos and has not travelled overseas
recently. Physical examination shows a normotensive but slightly overweight man. His cardiorespiratory examination
is unremarkable. He has palmar erythema, but no spider nevi or hepatosplenomegaly. There are no signs of hepatic
encephalopathy. His blood tests reveal:
Hemoglobin
144 g/L (reference range [RR] 138172)
Glucose (fasting)
8.0 mmol/L (RR 3.66.0)
Bilirubin (total)
18 micromol/L (RR 315)
Aspartate aminotransferase (AST)
68 U/L (RR 130)
Alanine aminotransferase (ALT)
82 U/L (RR 140)
Alkaline phosphatase (ALP)
134 U/L (RR 30115)
Albumin
42 g/L (RR 3647)
Ferritin
1267 ng/mL (RR 40200)
85% (RR 2050)
Which of the following is the next most appropriate step?

A Commence immediate venesection.
B Start oral deferoxamine therapy.
C Cease all alcohol intake and repeat iron studies in 3 months.
D Perform genetic testing mutations in the HFE gene.
E Perform a liver biopsy with separate core for iron staining.
6 A 23-year-old woman is referred by her family physician with a 3-week history of jaundice, fatigue and anorexia. She
is an injecting drug user who also consumes 60100 g of alcohol on weekends. There is no personal or family history
of liver disease. On examination she has scleral icterus and jaundice. Her cardiorespiratory examination is normal.
Abdominal examination reveals tender hepatomegaly, but no splenomegaly. There are no signs of chronic liver disease.
Her blood tests reveal:
Bilirubin
68 micromol/L (reference range [RR] 315)
420 U/L (RR 130)
680 U/L (RR 140)
134 U/L (RR 30115)
Gamma-glutamyl transpeptidase (GGT)
222 U/L (RR 030)
Albumin
36 g/L (RR 3647)
Coagulation prole
Normal
Hepatitis B surface antigen
Negative
Hepatitis C antibody
Negative
Hepatitis A IgG and IgM
Negative
An ultrasound conrms hepatomegaly, but shows no masses or intra- or extrahepatic duct dilatation. Which of the
following is the most appropriate next diagnostic test?
A Liver biopsy
B Hepatitis C RNA
C Hepatitis B DNA
D Hepatitis delta serology
E Observe and repeat hepatitis serology in 6 weeks
403
A 42-year-old woman is referred with uncomfortable abdominal fullness which has been present for 6 weeks. She is
alcohol-dependent, drinking 100 g of alcohol on a daily basis for the past 12 years. Her background medical history is
positive for diabetes mellitus and thyroid disease, and she takes metformin as well as thyroxine. She has no signicant
family history and denies intravenous drug use. On examination her blood pressure is 110/80 mmHg with a pulse rate
of 80 beats/min. She has scleral icterus and spider nevi across the precordium. The abdomen is distended, with 8 cm
shifting dullness. There is no palpable hepatomegaly or splenomegaly. Blood tests reveal thrombocytopenia and an
elevated bilirubin level of 76 micromol/L (reference range [RR] 315). Her coagulation prole is abnormal with an INR
(international normalized ratio) of 2.0. There is mild transaminitis. The creatinine is 280 micromol/L (RR 4585). An
abdominal ultrasound conrms the presence of ascites. The liver has increased echotexture and is small. No portal or
hepatic vein obstruction is seen. What is the next most appropriate step in management?
A Perform a diagnostic paracentesis.
B Commence ceftriaxone intravenously and give intravenous albumin.
C Commence uid restriction along with frusemide and spironolactone.
D Perform urinary electrolyte analysis.
E Arrange transjugular intrahepatic shunting (TIPS).
8 A 64-year-old man is referred with abnormal iron studies. He has no diagnosed medical conditions, but appears mildly
obese. He works as a truck driver, and was adopted as a child and hence is unaware of any family history of illnesses.
He has drunk 6080 g of alcohol on a daily basis since his teenage years. He smokes 40 cigarettes daily. He takes no
regular medications nor any over-the-counter or herbal preparations. Examination shows a ruddy complexion of the
face, along with central adiposity without palpable organomegaly. Spider nevi and palmar erythema are present. His
iron studies show:
Ferritin
678 ng/mL (normal range 40200)
Iron
25 mmol/L (normal range 1027)
Total iron binding capacity (TIBC)
54 micromol/L (normal range 4880)
34% (normal range 2050)
His hemoglobin is 165 g/L and both mean cell volume (MCV) and mean cell hemoglobin (MCH) are elevated. Which of
the following is the most likely cause for his elevated ferritin?
A C282Y homozygote
B C282Y heterozygote
C Alcohol
D H63D homozygote
E H63D heterozygote
9 A 54-year-old diabetic man is referred with abnormal liver function tests. He has previously suffered a myocardial
infarction, and commenced statin therapy for hypercholesterolemia 6 months ago. He also receives insulin therapy
along with baby-dose aspirin. He drinks 12 standard drinks most days of the week. He denies overseas travel, has
no tattoos and has never used intravenous drugs. He did receive a blood transfusion in 2003 after a motor vehicle
accident. Physical examination is unremarkable apart from a body mass index of 34 kg/m2. His liver function tests are
as follows:
125 U/L (normal range 30115)
Gamma-glutamyl transpeptidase (GGT)
160 U/L (normal range (030)
His albumin and coagulation prole are normal. His platelet count is normal. You proceed to liver biopsy. Which of the
following is the most likely abnormality on the liver biopsy?
A Hepatic steatosis
B Normal liver histology
C Chronic inammation consistent with viral hepatitis
D Advanced brosis
E Drug induced liver injury from statin therapy
404
ANSWERS
1
A.
This patient most likely has primary sclerosing cholangitis on a background of ulcerative colitis. ERCP is most helpful as a
diagnostic and therapeutic tool, allowing stent placement to help with drainage of bile. MRCP would also probably provide
the diagnosis, but this patient needs biliary drainage. Tumor markers are often elevated in the setting of biliary obstruction
and would not help guide management in this scenario. An endoscopic ultrasound would give excellent images of the
pancreatic and biliary ducts, but a biliary stent needs to be placed in this patient. Ursodeoxycholic acid is useful in many
cholestatic liver diseases, but should not be commenced in the setting of obstructive jaundice.
E.
The most likely cause of this signicant upper gastrointestinal hemorrhage is esophageal varices due to portal
hypertension. Young patients often suffer MalloryWeiss tears associated with retching and vomiting, but the history and
severity of bleeding makes this less likely here. Although bleeding gastric or duodenal ulcers could present like this, they
are uncommon in the young without comorbidities.
D.
Commence oral iron replacement. There is no reason to delay replacement, although clearly further investigations are
needed. Intravenous iron does lead to a more rapid hemoglobin response as iron stores take longer to restore with oral
therapy, but in this case there is no urgency as the patient is not compromised, and oral replacement is less hazardous.
Intramuscular injections should be avoided and only used if other treatment methods are not available.
4 B.
The most likely scenario here is autoimmune liver disease. Young females are often affected. A personal or family history
of autoimmune disease is often present. Lupus can cause liver function test abnormalities, but the ANA is strongly positive
in the majority of cases. Primary biliary cirrhosis usually presents later in life (age 4060 years), and typically the AMA is
positive. Primary sclerosing cholangitis leads to a markedly elevated alkaline phosphatase and is often associated with
ulcerative colitis. Drug-induced liver injury could present in this manner, but multivitamins and sh oil are not usual causes.
5
D.
Although the rst-line treatment of genetic hemochromatosis is venesection, the diagnosis needs to be conrmed rst.
This will also facilitate genetic counseling and potential testing of offspring. Iron-chelation therapy is reserved for patients
who are anemic and cannot tolerate regular venesection. His alcohol consumption is a very unlikely explanation for the
abnormalities observed. A liver biopy is likely to conrm iron deposition, but is not the next appropriate step.
6 B.
The most appropriate step is to determine whether this is acute hepatitis C, as seroconversion can take 2 months. In the
setting of abnormal liver function tests and negative hepatitis B antibodies, the presence of hepatitis B is very unlikely
(seroconversion occurs prior to clinical disease in most patients). A liver biopsy could be considered if the noninvasive liver
screens were negative. The hepatitis delta virus is a defective virus which requires the presence of hepatitis B infection to
survive.
7
A.
This patient requires a diagnostic paracentesis. With new-onset ascites it is important to exclude spontaneous bacterial
peritonitis (SBP). This also gives an opportunity to measure the serum ascitesalbumin gradient (SAAG), which if above
11 g/L usually indicates ascites from portal hypertension. Intravenous ceftriaxone is appropriate treatment for SBP, but a
diagnostic paracentesis is the rst step. Fluid restriction along with diurectics is inappropriate in the setting of an elevated
creatinine level. It may precipitate or worsen hepatorenal syndrome. TIPS is not rst-line therapy for new-onset ascites.
Urinary electrolytes are helpful in identifying sodium retention due to reninangiotensin system activation, and to guide
diuretic therapy.
8 C.
This mans abnormal liver function tests and iron studies are likely to be due to alcohol. His ferritin is elevated, which
does occur in hemochromatosis as well. However, the most sensitive marker in iron studies for hemochromatosis is the
iron saturation, which almost universally is elevated. C282 homozygosity certainly confers risk for iron overload, while
heterozygotes are generally unaffected carriers. Compound heterozygotes (C282Y and H63D) are also at risk. H63D
homozygotes can rarely develop iron overload.
9 A.
The most likely scenario here is fatty liver disease. He has no risk factors for viral hepatitis, and transmission via blood
transfusion is extremely unlikely after 1992. Advanced brosis and cirrhosis is unlikely, given that there are no signs of
chronic liver disease on physical examination and the platelet count is normal. Drug-induced liver injury from statin therapy
is possible, but this usually presents with an acute hepatocellular picture (high AST and ALT). Completely normal liver
histology is unlikely in an obese diabetic with abnormal liver function tests.
405
CHAPTER 14
HEMATOLOGY
Harshal Nandurkar
CHAPTER OUTLINE
HEMOSTASIS
Essential concepts
DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
Diagnosis
Treatment
COAGULOPATHY IN INTENSIVE CARE

PATIENTS
VENOUS THROMBOSIS

Treatment of venous thromboembolism (VTE)
ANTIPHOSPHOLIPID SYNDROME (APS)

Treatment
THROMBOSIS AT UNUSUAL SITES

MYELOPROLIFERATIVE DISORDERS
LEUKEMIA
CANCER AND THROMBOSIS

BLEEDING DISORDERS

Hemophilia A
Hemophilia B
Bleeding disorders due to deciencies of other
coagulation factors
PLATELET DISORDERS
Thrombotic thrombocytopenic purpura (TTP)
and hemolytic uremic syndrome (HUS)

Chronic lymphocytic leukemia and other B-cell
disorders
NON-HODGKIN LYMPHOMAS
Diagnosis
Staging
Burkitts lymphoma (BL)
Cutaneous lymphomas
HODGKIN LYMPHOMA (HL)

407
Staging
Risk stratication
Treatment
PLASMA CELL DISORDERS

signicance (MGUS)
Symptomatic myeloma
HEMOSTASIS
Essential concepts
Interaction between coagulation,
inammation and immunity
Coagulation and innate immunity have co-evolved to provide a multifaceted attack to repel infections.
Neutrophils and platelets form extracellular traps that
kill bacteria.
There are close interactions between the cellular and
soluble components of the hemostatic and immune systems. For example, thrombinthe key enzyme that
generates fibrinalso activates platelets and complement proteins C3 and C5. Activated C5a can in turn
stimulate neutrophils and endothelial cells.
Endothelial cells and platelets must be sufficiently activated past a threshold for a clot to form.
While the hemostatic processes are primarily designed to be
protective, their unrestricted activity can also be detrimental, e.g. thrombotic thrombocytopenic purpura (TTP) and
disseminated intravascular coagulation (DIC). Hence, there
is a very efficient and prompt counterbalance provided by
coagulation-inhibitory systems.

Platelets
Steps in platelet activation and aggregation
In undisturbed vasculature, platelets may roll along endothelial surfaces without any significant interaction, and platelets
circulate in close proximity to fibrinogen and von Willebrand factor (vWF) without demonstrating spontaneous
activation and aggregation. A sufficient threshold of stimulation has to be crossed before platelets proceed through the
sequential steps of:
1 adhesion
2 activation
3 aggregation.
408
ANEMIA
Common laboratory tests used for diagnostic
work-up
Thalassemias
Macrocytic anemias
Hemolytic anemias
Non-immune acquired hemolytic anemias
Platelet adhesion
Injury to the protective endothelial surface exposes major
matrix proteins such as collagen, vWF and other proteins
including thrombospondin, laminin and fibronectin, all of
which can interact with platelet integrin receptors.
Interaction of platelets with damaged endothelium proceeds through the steps of:
1 tethering
2 rolling
3 activation
4 firm adhesion.
In veins and large arteries, collagen is the principal plateletadhesive macromolecule. Platelet receptors glycoprotein VI
and F2G1 are the principal contacts with collagen. In small
arteries and areas of atherosclerosis and stenosis, the interaction of vWF with the platelet receptor glycoprotein IbF
(GPIbF) is critical for platelet recruitment. GPIbF is a part
of a large receptor complex that includes integrins GPIG,
GPIX and GPV.
Interaction between the coagulation pathways and primary hemostasis is exemplified by the role of thrombin as
an important platelet activator. Inactive precursor zymogen
prothrombin is converted to its active form thrombin by
both intrinsic and tissue factor (TF)-initiated clotting pathways (see below). In addition to its role in generating fibrin
from fibrinogen, thrombin is a potent activator of platelets
by signaling via the protease-activated receptors 2 and 4
(PAR2 and PAR4).
Platelet activation
Interaction of platelet integrin receptors GPVI (ligand
collagen) and GPIbF (ligand vWF) initiates intracellular signaling cascades that involve activation of:
Src kinases (Fyn, Lyn and Syk)
phospholipase CL2 (PLCL2), which leads to an increase
in cytosolic Ca2+ and generation of diacylglycerol
(DAG).
The final step in platelet activation is the inside-out activation of the fibrinogen receptor.
Platelet integrin FIIbG3 is the most abundant integrin
on the platelet surface (up to 80,000 copies per cell) and,
Chapter 14 Hematology
in resting platelets, exhibits an inactive conformation that

does not recognize fibrinogen. Following platelet activation,
raised cytosolic Ca2+ and DAG lead to a sequence of events
that result in a transformation of FIIbG3 from a bent inactive form to an extended active form that permits interaction
with fibrinogen.
Amplication of platelet activation
Platelets contain three types of granules:
1 alpha granules (contain vWF, fibrinogen and
chemokines)
2 dense granules (contain Ca2+ ions, nucleotides such
as adenosine diphosphate [ADP], histamine and
serotonin)
3 lysosomes (containing a variety of enzymes).
Platelet activation leads to a release of the granular content in
the proximity of the endothelialplatelet milieu.
The release of granules initiates signaling via several pathways that serve to amplify platelet activation. ADP released
from activated platelets in turn interacts with its receptors
P2Y1 and P2Y12 to initiate G-protein-coupled receptor
signaling. The importance of the contribution of ADP is
confirmed by the efficacy of the thienopyridine class of antiplatelet agents such as ticlopidine, clopidogrel and prasugrel.
Increased Ca2+ leads to activation of phospholipase
A2, followed by the release of arachidonic acid from fatty
acids. Arachidonic acid in turn forms a substrate for cyclooxygenase and is converted to cyclic endoperoxides; which,
in turn, are converted to thromboxane A2 (TA2) by the
action of thromboxane synthase. TA2 provides a positive
feedback loop; TA2 interacts with thromboxane receptor
(TP) to initiate signaling that further consolidates platelet
activation.
Platelet aggregation
Platelet activation culminates in the unfolding of the FIIbG3
receptor, which then interacts with fibrinogen.
Fibrinogen has multiple platelet interaction sites, resulting in a stable aggregate mesh of platelets and fibrinogen
on injured endothelium.
Raised cytosolic Ca2+ generated in the process of platelet

activation triggers platelet membrane reorganization, with
exposure of negatively charged phosphatidylserine (PS)
on the surface. PS together with Ca2+ ions forms a procoagulant surface for the binding and activation of clotting
factors, leading to thrombin and fibrin generation.
Thrombin amplifies platelet activation via the PAR2
and PAR4 receptors.
Coagulation
The depiction of coagulation as part of an intrinsic or an
extrinsic pathway, and the series of activation events as a
cascade, has been replaced by a model that explains the
cell-surface-dependency of the clotting process.
The new model takes into account the concentration of
coagulation factors at the site of a developing thrombus, and
explains the place of the hemophilia proteins fVIII and fIX.
It also lends itself to the understanding of the processes that
restrict clotting to the physiological need.
The new cell-based model describes four overlapping
phases (Figure 14-1):
1 Initiation. This occurs on the surface of a TF-bearing
cell. A break in the vessel wall permits subendothelial
TF to come into contact with fVII in the plasma. The
TF/fVIIa complex can then activate both fX and fIX;
the fXa (activated factor X) thus produced cooperates
with fVa to generate a small amount of thrombin.
2 Amplification. Amplification of coagulation is stimulated by the small amount of thrombin generated in
the first step. Thrombin activates platelets, fVIII and
fXI, each of which plays an important role in the maintenance of the coagulation process. Activated platelets
release fV and expose a negatively charged phosphatidylserine (PS)-containing surface. The platelets integrin receptor binds vWF and makes it accessible for
activation by thrombin. Activated platelets also display
high-affinity binding sites for fIXa, fXa and fXI. Thus,
a perfect clot-promoting surface is created with the
presence of fVIIIa, fVa and assembly of the coagulation
proteases.
FIX
TF
FVII
FXIa
FXI
FVIIa
Initiation phase
TF
FIXa
FX
FVIIIa
FXa FXa
FX
Fva
Prothrombin
Plasminogen
Fibrinolytic phase
tPA
Cross-linked
fibrin
FVIII
Amplification and propagation

phases
FV
Thrombin
Fibrin
FXIIIa
Fibrinogen
FXIII
Stabilization phase
Plasmin
Fibrin degradation products
Figure 14-1 Coagulation and brinolysis. TF, tissue factor; tPA, tissue plasminogen activator
409
3 Propagation. In this phase, efficient assembly of the

tenase (fVIIa/fIXa), leading to the generation of fXa
and subsequent prothrombinase (fXa/fVa), results in
significant generation of thrombin (fIIa), more than can
be achieved in the initiation phase. Thrombin converts
fibrinogen to fibrin monomers.
4 Stabilization. Thrombin activates the generation of
fXIIa, which cross-links fibrin monomers to form a
stable hemostatic plug.
The brinolytic system
The fibrinolytic system is designed to restrict the fibrin clot
to the area of injury. Key components of this pathway are:
plasminogen (PLG)
tissue plasminogen activator (tPA).
Both are associated with the developing fibrin clot, and thus
clot dissolution is finely tuned to clot formation.
PLG binds to the lysine (Lys) residues on cross-linked
fibrin, and this creates an optimal environment for PLG to
be activated by tPA, which is also fibrin-bound.
PLG and tPA form a self-activation loop, wherein PLG
cleaves tPA and enables it to bind fibrin with higher affinity,
and this increases the ability of tPA to cleave PLG to form
active plasmin.
CLINICAL PEARL
Fibrin is proteolyzed by plasmin to form a number
of brin degradation products (FDPs), of which the
disulde-linked fragment D (D-dimer) is detected in a
commonly used laboratory assay and incorporated in
a clinical algorithm to predict venous thrombosis.
Inhibitory control of coagulation

The coagulation pathway activated by injury must be
restricted to hemostatic need. There are two groups of
inhibitors operational in the coagulation pathways:
1 serine protease inhibitors
2 inhibitors of coagulation cofactors fVa and fVIIIa.
The critical role of these inhibitors is underscored by the
observation that haplo-insufficiency with activity between
50% and 70% of normal levels is associated with an increased
risk of thrombosis. Homozygous deficiencies either cause
embryonic mortality, or cause devastating thrombosis in
early life.
Tissue factor pathway inhibitor (TFPI)
This is a Kunitz-type protease inhibitor that inactivates fXa
and fVIIa. Almost 85% of TFPI is associated with endothelial cells, in part by binding to glycosoaminoglycans.
TFPI in the circulation is bound to lipoproteins and has
greatly reduced activity. Hence, quantification of TFPI in
plasma is of doubtful value.
Serine protease inhibitors (serpins)
Antithrombin and heparin cofactor II (HCII) are two serpins
active in clotting. Antithrombin forms a 1:1 complex with
thrombin and fXa, and to a lesser extent with fIXa and fXIa.
410
Unfractionated heparin interacts with antithrombin as

well as thrombin, and improves the capacity to inhibit
thrombin and fXa 2000-fold.
Inactivation of thrombin requires the heparin molecule
to bind antithrombin as well as thrombin, while fXa
inhibition is achieved by the association of heparin with
just antithrombin.
Low-molecular-weight heparins can only potentiate the
inhibition of fXa, as they are not of adequate length to
interact with both antithrombin and thrombin.
Homozygous antithrombin deficiency in mice causes
embryonic death from thrombosis, and antithrombin
deficiency in humans is an important risk factor for
familial thrombophilia.
HCII inhibits only thrombin and has no effect on fXa. Heparin also increases the ability of HCII to inhibit thrombin;
however, this effect is less prominent when compared with
the activity of antithrombin in the presence of heparin.
Protein C pathway and inhibition of fVa and fVIIIa
Protein C (PC) is converted to activated protein C (APC)
by thrombin-mediated proteolysis. This process is considerably facilitated when thrombin is in complex with thrombomodulin, an endothelial protein.
APC inhibits fVa and fVIIIa bound to the procoagulant
phospholipid surface of platelets, and this inhibition
is facilitated by the interaction of APC with cofactor
protein S (PS).
As fVa and fVIIIa are essential cofactors for the procoagulant thrombinase and tenase complexes,
respectively, their inactivation is a potent inhibitor of
the coagulation pathway. The important role played
by this pathway is demonstrated by the factor V Leiden
mutation (Arg506Gln). This mutation alters the protease cleavage site of fVa, rendering it less susceptible to
inactivation by APC. Thus in the presence of factor V
Leiden, there is reduced inhibition of the thrombinase
complex and this is associated with a threefold increased
risk of venous thrombosis for the heterozygous state.
Reduced levels of protein C (and to a lesser extent of
protein S) are an important etiology of familial thrombophilia. PC is produced in the liver and is subject to
the effect of warfarin more rapidly than factors II, VII,
IX and X are. Hence, patients commencing warfarin are
simultaneously treated with heparin to prevent a relative
prothrombotic state.
VENOUS THROMBOSIS
Thrombosis follows the perturbation of one or more arms
of Virchows triad:
1 stasis
2 hypercoagulable state
3 vascular wall injury.
Up to 50% of all episodes of venous thromboembolism
(VTE) may be provoked (hospitalization, trauma, surgery),
while the remaining are spontaneous, possibly in part due

to thrombophilia. The current panel of thrombophilia tests
fails to identify the underlying predisposition to venous
thrombosis in almost 25% of cases.
Prothombotic risk factors are listed in Box 14-1.
Two or more thrombophilic factors may synergize to
increase the risks of thrombosis; for example the oral contraceptive pill in the presence of factor V Leiden is associated
with increased risk of venous thrombosis compared with
that contributed by the individual risk factors (Table 14-1).

Clinical suspicion
Lower limb deep vein thrombosis (DVT) typically presents
with calf swelling and pain, with worsening of symptoms
when the ankle is abruptly dorsiflexed while the knee is kept

flexed at 90 (Homans sign). Homans sign has poor positive and negative predictive value.
Laboratory diagnosis
Fibrinolysis of the venous thrombus releases D-dimers.
However, elevated D-dimers are not specific for VTE as
they can occur with recent surgery, pregnancy, infection,
trauma and with increasing age. The best use for a D-dimer
assay is in the algorithm to exclude VTE. A negative D-dimer assay has a >90% negative predictive value in patients
with a low clinical pre-test probability. There are considerable differences in the sensitivities and specificities of the
various D-dimer assays which, in turn, can affect the diagnostic algorithm.
Diagnostic imaging of DVT

Box 14-1
Prothrombotic risk factors

Hematological conditions and genetic factors
Factor V Leiden mutation
Prothrombin gene mutation
Deciencies of endogenous anticoagulants
antithrombin, protein C and protein S
Dysbrinogenemia
Increased levels of coagulation factors VIII, IX, XI
Hyperhomocysteinemia
Paroxysmal nocturnal hemoglobinuria
Patient factors
Increasing age
Obesity
Smoking
Hormonal supplementation (oral contraceptive pills,
hormone replacement therapy)
Varicose veins
Pregnancy/puerperium
Long-distance air travel (>45 hours)
Medical factors
Myocardial infarction
Stroke
Active cancer
Acute respiratory disease
Vasculitis, e.g. granulomatosis with polyangiitis
Surgical factors
Major lower limb surgery, including joint replacement
Abdominal or pelvic surgery, particularly for cancer
Trauma and immobilization
Lower limb casts/splints after surgery or injury
Adapted from Colledge NR, Walker BR and Ralston SH (eds).
Davidsons Principles and practice of medicine, 21st ed. Churchill
Livingstone, 2010.
Contrast venography is considered to be the gold standard test, but it is rarely performed.
Compression ultrasound is the most commonly used
modality to diagnose DVT, with a sensitivity and specificity of over 95% for the diagnosis of symptomatic
proximal DVT.
Compression ultrasound has 70% sensitivity in the
diagnosis of calf vein DVT with a positive predictive
value of 80%.
Table 14-1 Increased predisposition to venous

thrombosis with coexisting risk factors
THROMBOTIC FACTOR
RELATIVE
RISK (%)
OCP use
24
Hyperhomocysteinemia
2.5
FVL heterozygous
FVL heterozygous + HRT
FVL heterozygous + OCP use
310
15
3040
FVL heterozygous + pregnancy
35
FVL homozygous
79
FVL homozygous + OCP use
100
Prothrombin gene mutation
15
Prothrombin gene mutation + FVL
610
Prothrombin gene mutation + OCP use
16
Protein, C, S, ATIII deciencies + OCP

use
10
ATIII, antithrombin III; FVL, factor V Leiden; HRT, hormone

replacement therapy; OCP, oral contraceptive pill.
411
Treatment of venous
thromboembolism (VTE)
Persistent thrombosis after 6 months of therapeutic anticoagulation may confer an increased risk of recurrence.
Anticoagulation is initiated with low-molecular-weight

heparin (LMWH), usually as a daily dose (e.g. enoxaparin 1.5mg/kg daily or 1mg/kg twice a day subcutaneously). LMWH dosing should be reduced in patients
with severe renal impairment.
Warfarin is the mainstay of long-term anticoagulation,
and is commenced concomitantly with LMWH.
At least 5 days of initial heparin therapy is recommended,
and heparin should be continued until the international
normalized ratio (INR) has been in the target range for
2 days.
New oral anticoagulants that target thrombin (dabigatran)
or factor Xa (rivaroxaban, apixaban, and others) have
shown promising results in the management of VTE, and
are in various stages of the regulatory approval process
prior to general availability. In particular, oral rivaroxaban
and apixaban can be used as sole agents without the need
for initial heparin therapy. These new anticoagulants do
not need regular monitoring with INR testing.
Generally, 6 months of anticoagulation with warfarin
(target INR 2.03.0) is recommended for proximal
DVT.
Longer-term anticoagulation is reserved for patients
presenting with multiple spontaneous thrombotic
events, the presence of strong thrombophilia, thrombosis at unusual sites (see below) or when thrombosis has
occurred in the presence of ongoing cancer.
Thrombolytic therapy is reserved for the very rare presentations with impending venous gangrene.
CLINICAL PEARL
LMWH dosing should be reduced in patients with
severe renal impairment.
Inferior vena cava lters

Inferior vena cava filters will reduce the incidence of pulmonary embolism in the first 2 weeks of DVT. Their use is
reserved for clinical situations where anticoagulant therapy
is contraindicated due to bleeding risk or the need for frequent surgery (e.g. multi-trauma).
Most of the filters in use now can be successfully
removed, usually within 23 weeks of placement, when
the contraindication to anticoagulation is resolved.
The purpose of the filter is to make suspension of anticoagulation safer.
Anticoagulation is commenced as soon as it is safe to do
so, especially if filters are to remain in situ for the longer
term.
Recurrence of DVT after the rst episode

The overall risk of recurrence of DVT after a spontaneous episode is 510% per year, with a lifetime risk of
up to 30%.
412
Thrombus that is not promptly resolved by the action

of the fibrinolytic system and scavenger cells adheres to
the vessel wall, and will eventually destroy venous valves
during the repair process.
This can lead to gravity-assisted stasis in the lower
limbs, extravasation of tissue fluid, chronic edema, skin
discoloration, atrophy and venous ulceration.
Symptoms of PTS may occur in up to 30% of patients
with proximal DVT. The best prevention is by:
strictly maintaining the INR in the therapeutic range
prolonged use of well-fitting, graduated compression stockings.
ANTIPHOSPHOLIPID
SYNDROME (APS)
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antibodies that react
with proteins that bind negatively charged phospholipids,
and are collectively called antiphospholipid antibodies.
A large number of protein and phospholipid targets have
been identified in vitro and some of them have been demonstrated to be relevant in vivo in mouse models.
Currently the most accepted explanation is that pathogenic antiphospholipid antibodies:
recognize beta2-glycoprotein-1 (beta2-GPI), a naturally
occurring five-domain protein with weak anticoagulant
function that exists in a circular conformation
bind to phospholipids on the cell surface, changing the
conformation of B2-GPI to an open structure that
exposes new epitopes that react with antiphospholipid
antibodies.
Antibody-stabilized B2-GPI subsequently interacts with
a number of cell-surface proteins, and triggers signaling
pathways on placental trophoblasts, endothelial cells and
monocytes to cause generation of a pro-coagulant and proinflammatory environment.
Second messenger systems altered by the B2-GPIantibody complexes include:
activation of the complement cascade
inhibition of the normal protective function of annexin5
activation of the Toll-like receptors
inhibition of the protein C pathway and fibrinolytic
pathways.
Antiphospholipid antibodies are conventionally detected
either in:
a clotting assay containing phospholipid (lupus anticoagulant, LA)
or solid-phase enzyme-linked immunosorbent assay
(ELISA) of immobilized anti-cardiolipin and B2-GPI.
LA is an in vitro phenomenon, as it competes with coagulation factors for binding to the phospholipid reagent and
thereby prolongs the clotting time.
Correlation of clinical disease with antibody subtypes
suggests that decreasing rates of pathogenicity are seen with:
antiphospholipid antibodies with LA activity
anti-B2-GPI antibodies of immunoglobulin G (IgG)
isotype
low-titer anti-cardiolipin antibodies without LA activity and without B2-GPI positivity.
Coagulation tests with limited availability of phospholipid
increase the sensitivity of LA detection. LA is confirmed by
the demonstration of phospholipid-dependent shortening of
the clotting time with addition of excess phospholipid.
Clinically, APS is associated with venous and/or arterial
thrombosis and the occurrence of miscarriages and pregnancy complications. Thrombotic events are characteristically recurrent in the same vascular bed.
Treatment
Anticoagulation with warfarin (INR target 2.03.0)
is standard therapy. The duration of therapy is usually
indefinite, or at least until antiphospholipid antibodies
are undetectable.
A higher target INR (2.53.5) may be necessary for
recurrent events.
Arterial thromboses are treated with warfarin and
aspirin or clopidogrel.
Pregnancy morbidity can be managed with a combination of heparin or LMWH plus aspirin.
Catastrophic APS, a more intense disease with multiorgan involvement and small vessel thrombosis, requires
intensive anticoagulation together with plasmapharesis and
immunosuppression.
Despite the high incidence (approximately 30%) of cerebral hemorrhage that follows venous infarcts, heparin therapy was formerly considered to be dangerous. The current
consensus, based on prospective cohort studies and small
randomized trials, is that heparin therapy (unfractionated
or LMWH) significantly reduces mortality and the benefits
outweigh the risks.

Portal vein thrombosis results from a combination of local
and systemic prothrombotic factors.
The most common local precipitant is hepatic cirrhosis.
Other risk factors are hepatic cancer, abdominal inflammatory conditions (diverticulitis, appendicitis, pancreatitis), and injury to the abdominal veins (splenectomy,
cholecystectomy).
Myeloproliferative disorders are now considered to be
the major etiology for idiopathic PVT, manifestations
of which can pre-date clinical hematological disease.
Mutations in the Janus kinase 2 (JAK2) gene are the
hallmark of almost all patients with polycythemia rubra
vera and in approximately 50% of patients with essential
thrombocytosis and myelofibrosis. The JAK2 mutation
may be seen in ~30% of patients with PVT without
overt evidence of myeloproliferative disease.
Patients with acute PVT present with abdominal pain, while
chronic disease may be accompanied by signs and symptoms
of portal hypertension. Diagnosis is generally made with
Doppler ultrasonography.
Anticoagulation is most effective in acute PVT without
concomitant cirrhosis, and long-term anticoagulation
should be considered in patients with a hypercoagulable
state including myeloproliferative disease.
CLINICAL PEARL
THROMBOSIS AT UNUSUAL
SITES
When portal vein thrombosis (PVT) is identied in cirrhosis, treat the underlying liver disease as indicated
without anticoagulation for the PVT.

Cerebral vein thrombosis is a rare condition that affects large
central venous sinuses and may extend into the cortical veins.
Symptoms and signs may range from those attributable
to intracranial hypertension (headache, photophobia) to
those due to cortical infarction (hemiparesis, aphasia).
Magnetic resonance imaging (MRI) and computed
tomography (CT) venography have replaced cerebral angiography as the diagnostic tests of choice, with
MRI documented to have a sensitivity and specificity
between 75% and 100%.
CVT is more frequently seen in young women, due to
the prothrombotic association of the oral contraceptive
pill and pregnancy.
Genetic or acquired thrombophilia, head trauma, and
infections of surrounding sites (e.g. ear infections, meningitis) play a contributory role.
CANCER AND THROMBOSIS

Patients with active cancers are predisposed to venous
thrombosis as a consequence of:
the procoagulant milieu generated by cancer cells
(examples are the expression of TF and the liberation of
mucins that activate leukocytes and platelets)
the effects of chemotherapy (examples include thalidomide, lenalidomide and bevacizumab)
stasis created by bed rest and surgery
endothelial irritation by the placement of central lines.
Primary thromboprophylaxis in ambulatory patients is generally not recommended; exceptions include selected malignancies such as pancreatic adenocarcinoma.
Patients with myeloma will benefit from aspirin when
treated with thalidomide or lenalidomide alone, and heparin
413
is recommended in combination with high-dose steroids or

chemotherapy.
Primary thromboprophylaxis for central lines is not routinely recommended.
CLINICAL PEARL
Low-molecular-weight heparins have higher efficacy
than warfarin in the treatment of patients with venous
thromboembolism in the context of cancer.
BLEEDING DISORDERS
Suspicion of the presence of a bleeding disorder is raised
by a clinical presentation with unusual bruising or bleeding, either spontaneously or after minimal trauma or postoperatively. Prolongation of prothrombin time (PT) and
activated partial thromboplastin time (APTT) on routine
coagulation screen tests also prompts investigation.
The history and clinical presentation (Table 14-2)
can easily separate bleeding disorders from a failure in
hemostasis:
primary (platelet function defect)
secondary (coagulation defect).
While von Willebrand disease and hemophilia A or B
(Figure 14-2) are the most common congenital bleeding
disorders, acquired etiologies are common causes of excessive bleeding in hospitalized patients (Box 14-2) and need to
be considered while planning diagnostic tests.

Von Willebrand factor is:
encoded by a gene on chromosome 12
produced as a single-chain pro-vWF monomer; two
monomers dimerize via the C-terminal domain in the
endoplasmic reticulum and the dimer is exported to
theGolgi apparatus. Dimers undergo N-terminal association via formation of disulfide bonds to form multimers ranging from 1000 to 20,000 kDa. vWF is also
Figure 14-2 Ecchymoses and hemarthrosis in a male

with hemophilia
From Little JW et al. Dental management of the medically
compromised patient, 7th ed. St Louis: Mosby Elsevier, 2008.
Box 14-2
Causes of excessive bleeding

Congenital
Hemophilia A and B (X-linked)
Von Willebrand disease (autosomal)
Individual or combined deciencies of clotting factors
(other than fVIII and fIX) (autosomal) and of brinogen
(autosomal)
Acquired
Liver disease (impaired synthesis, platelet sequestration
in hypersplenism)
Disseminated intravascular coagulation
Acquired hemophilia and coagulation factor inhibitors
Drug-induced
Antiplatelet therapy (e.g. aspirin, dipyridamole,
clopidogrel, etc.)
Warfarin, heparins, rivaroxaban, dabigatran, apixaban
Table 14-2 Primary and secondary bleeding disorders
PLATELET DISORDERS
PRIMARY
COAGULATION DISORDERS
SECONDARY
Petechiae
Characteristic
Rare
Supercial ecchymoses
Small, multiple
Large, solitary
Hematoma
Rare
Characteristic
Hemarthrosis
Rare
Characteristic
Late bleed
Rare
Common
Gender
More prevalent in females
Mainly in males
Family history
Variable
Common
414
heavily glycosylated, and a significant amount of glycosylation is as an ABO blood group antigen
primarily formed in endothelial cells
also synthesized to a much smaller extent in
megakaryocytes
released constitutively as a steady state concentration, or
rapidly released after stimulation by a number of agonists including thrombin, epinephrine (adrenaline) and
vasopressin.
vWF serves two principal functions:
Primary hemostasis: vWF binds to collagen at the
site of vascular injury and to the platelet integrin receptors GPIb and FIIbG3, which also function as the fibrinogen receptor. vWF therefore recruits platelets to the
sites of vascular injury; this function is maximal with
high-molecular-weight multimers. The role of vWF is
most prominent in small arterioles and in areas of vascular plaque, leading to the formation of a shearstress
gradient across flowing blood.
Secondary hemostasis: vWF interacts with fVIII in
the circulation and protects fVIII from proteolysis. This
interaction also serves to enrich fVIII at the site of a
developing thrombus.
Classication
Von Willebrand disease is described in terms of a quantitative deficiency or qualitative defects, with either reduction
in high-molecular-weight multimers or abnormalities in the
capacity of vWF to interact with platelets or to bind fVIII
(Table 14-3).
Clinical features
Clinical presentation is typically with easy bruising, epistaxis, menorrhagia, or excessive bleeding after trauma, dental extraction or surgery. The severity of symptoms depends
on the extent of vWF deficiency. Type 3 vWD, with complete absence of vWF and fVIII activity of 12%, may present with clinical features resembling hemophilia.
Diagnosis
Common investigations are full blood examination (FBE)
(for thrombocytopenia), vWF quantification (either as an
antigen or by ristocetin cofactor activity) and fVIII activity. Sub-classification of type 2 VWD requires an estimation of multimers (either by gel analysis or by the ability to
bind collagen) and demonstration of an increased capacity
to bind platelets (type 2B) by ristocetin-induced platelet
agglutination.
Treatment
Tranexamic acid is useful for mucosal bleeding and
menorrhagia.
Desmopressin (1-desamino-8-D-arginine vasopressin,
DDAVP) is useful in type 1 disease through stimulating release of vWF from the endothelial stores. Frequent administration can be less effective until vWF is
re-synthesized.
DDAVP is ineffective in other varieties of type 2 and in
type 3 vWD.
Coagulation factor concentrates containing vWF and
fVIII are necessary to treat type 3 vWD.
CLINICAL PEARL
DDAVP (1-desamino-8-D-arginine vasopressin) is contraindicated in type 2B von Willebrand disease, as
enhanced release of abnormal vWF with increased
platelet binding will cause thrombocytopenia.
Table 14-3 Classication of von Willebrand disease
CLASSIFICATION
vWF
DEFICIENCY
vWF
FUNCTION
vWF
MULTIMERS
vWF
ASSOCIATION
WITH
PLATELETS
fVIII-BINDING
CAPACITY
Type 1
Quantitative
Normal
Normal
Normal
Normal*
Type 2A
Qualitative
Abnormal
Reduced
Reduced
Normal*
Type 2B
Qualitative
Abnormal
Reduced
Increased
Normal*
Type 2M
Qualitative
Abnormal
Normal
Decreased
Normal*
Type 2N
Qualitative
Abnormal
Normal
Normal
Markedly reduced
Type 3
Quantitative
vWF undetectable
vWF undetectable
vWF undetectable
vWF undetectable
* Common nding.
vWF, von Willebrand factor.
Adapted from: Sadler JE, Budde U, Eikenboom CJ et al. The Working Party on von Willebrand Disease Classication. Update on the
pathophysiology and classication of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost
2006;4:210314; and Federici AB. Diagnosis and classication of von Willebrand disease. Hematol Meeting Rep 2007;1:619.
415
Hemophilia A
In the propagation phase of the clotting cascade, fVIII and
fIX are essential for forming the tenase leading to the generation of fXa, and consequently the amplification of the
clotting cascade.
Genes for both fVIII and fIX are located on the long
arm of the X chromosome.
Deficiencies in fVIII and fIX cause hemophilia A and
hemophilia B, respectively.
fVIII is synthesized primarily in the liver, and to a minor
extent in endothelial cells. After release from the liver, most
of the fVIII circulates bound to vWF. fVIII is activated by
thrombin-mediated cleavage, and fVIIIa is released from
vWF. The procoagulant actions of fVIIIa are controlled
by activated protein C (APC), which inactivates fVIII by
proteolysis.
Hemophilia-causing alterations of the fVIII gene comprise mutations (missense, nonsense, frame-shift, splicing)
in approximately 50% of cases. One-third of cases are due
to inversion through intron 22, which results in the disruption of the mRNA and severe deficiency in the production
of functional fVIII. Inversion of intron 22 contributes to
almost 50% of the cases of severe hemophilia.
The consequences of recurrent hemarthrosis and muscle bleeds are joint ankylosis, muscle contractures and
wasting.
There is no family history in almost one-third of cases
because of occurrence of new mutations. The disease may
manifest after interventions such as circumcision or when an
infant starts to walk and is prone to minor injuries.
Investigation
Mild hemophilia manifesting as a bleeding disorder in later
life or acquired hemophilia (see below) may be suspected
during a work-up of prolonged APTT.
Diagnosis in all cases is confirmed by a quantitative
assessment of fVIII activity.
In a woman known to be at risk of being a carrier, chorionic venous sampling or cord blood sampling will help
to verify fetal genotype and fVIII level with a view to
genetic counseling.
During the course of treatment with fVIII, many
patients develop inhibitors necessitating quantification
of inhibitor activity, as this reduces the efficacy of supplemental fVIII.
Treatment
Clinical features
Almost all patients are male, with the disease rarely
occurring in females (see below).
The severity of symptoms depends on the level of
residual fVIII (Table 14-4), with spontaneous bleeding
predominantly occurring only when fVIII activity is
<1U/dL.
Spontaneous mucosal bleeding is rare in this disease.
Spontaneous central nervous system (CNS) bleeding
is uncommon. However, minor head trauma can have
devastating consequences.
Bleeding is common in load-bearing joints and in
load-bearing muscle groups (in the thigh, calf, iliopsoas
and posterior abdominal wall). Hemarthrosis causes
an inflammatory response to the synovium, leading to
synovial proliferation, friability and further cycles of
bleeding and proliferation. Blood components are also
toxic to the joint cartilage and chondrocytes, leading to
degenerative arthropathy.
Replacement with fVIII concentrates prepared from donor

plasma or recombinant fVIII protein is the cornerstone of
therapy.
Donor-derived fVIII is screened for hepatitis B, hepatitis C and HIV and undergoes viral elimination
processing.
Recombinant fVIII was made possible by cloning of
the fVIII gene, and recombinant proteins are produced
either as full-length molecules or with domain deletions. Recombinant fVIII is now produced to reduce
inhibitor development and to prolong in vivo half-life of
fVIII.
Factor VIII replacement can be either on-demand, in the
situation of bleeding, or as prophylaxis in young boys to
reduce the incidence of hemarthrosis and muscle bleeds.
Therapeutic fVIII in response to a bleed is administered 23
times daily to maintain fVIII levels at 30100%, dependent
on the severity and site of bleeding (hemarthrosis 3050%;
surgery and CNS bleed 50100%).
Table 14-4 Severity of hemophilia symptoms
fVIII OR fIX LEVEL

(U/dL)
INCIDENCE IN
HEMOPHILIA A
CLINICAL PICTURE
INCIDENCE IN
HEMOPHILIA B
<1
Severe spontaneous bleeding
70%
50%
15
Moderate bleeding with minimal

trauma or surgery
15%
30%
530
Mild bleeding with trauma or

surgery
15%
20%
416
Development of inhibitors and management

Some 2530% of patients with severe hemophilia will
develop inhibitors to fVIII due to an immune response to
donor fVIII.
Inhibitors may be transient and with low-level inhibitory activity; however, high-activity inhibitors occur in
1015% of cases.
Most inhibitors develop during childhood with initial
exposure to fVIII.
CLINICAL PEARL
The propensity for inhibitor development correlates
with the type of mutation in the fVIII gene. Large deletions are particularly susceptible to inhibitor development, and approximately 25% of patients with intron 22
inversion develop inhibitors.
Porcine fVIII is biologically functional in humans, and

its activity is neutralized to a lesser extent by inhibitors.
Recombinant porcine fVIII is currently undergoing
clinical development.
The most effective therapy to combat bleeding in patients
with inhibitors is to administer coagulation activity that will
bypass the inhibitor effect.
The most common method is administration of recombinant activated fVII (fVIIa).
An alternative is the plasma-derived prothrombin
complex concentrate containing activated coagulation
factors.
Immune-tolerance induction regimens are in use and
are most useful in younger patients.
Management of high-activity inhibitors may also require
immunosuppressive therapy and plasmapharesis.
Hemophilia in females
As females possess two X chromosomes which undergo
random inactivation, carriers of hemophilia display
approximately 50% activity.
Skewed inactivation preferentially of the normal X chromosome can produce a mild hemophilia phenotype.
A new mutation in the sperm of the father will generate
a female carrier without prior family history.
or recombinant fIX. As fIX has a longer half-life, oncedaily administration will generally suffice during episodes of
bleeding, and twice-weekly prophylaxis is adequate.
Development of inhibitors occurs uncommonly (~3%)
in patients with severe hemophilia B, and situations of
bleeding are managed similarly to hemophilia A.
Bleeding disorders due to deciencies

of other coagulation factors
Inherited deficiencies of the coagulation factors II, V, VII,
X, XI and XIII are uncommon and are grouped as rare
bleeding disorders (RBDs). Studies in mice have confirmed
the pivotal role played by these proteins in the maintenance
of normal hemostasis.
Homozygous deficiency of fII, fV, fVII and fX is incompatible with life. Similarly, complete deficiency of
enzymes participating in the vitamin K pathway (GGCX
and VKORC1) leads to life-threatening bleeding. Diagnosis of individual deficiencies relies on quantification of
coagulation factor activities and family studies.
Combined deficiencies of fV and fVIII occur at an incidence of 1 in 1 million and are due to abnormalities in
the genes for LMAN1 and MCFD2, which encode proteins that regulate the folding and intracellular transport
of fV and fVIII.
fXI deficiency differs from hemophilia A and B, as
bleeding frequency does not correlate with factor levels.
Both mild and severe deficiencies exhibit similar incidences of bleeding. Spontaneous bleeding is rare; bleeding occurs preferentially in sites with high fibrinolytic
activity such as the oral cavity and urogenital tract.
Deficiency of fXII is commonly detected during a
work-up for prolongation of APTT, and does not lead
to a bleeding phenotype.
fXIII is critical for cross-linking of fibrin monomers
to form a stable clot; the enzyme activity is delivered
by a complex of two catalytic and two carrier subunits.
Patients with fXIII deficiency have a severe bleeding
tendency and also demonstrate slow healing. fXIII has
a very long in vivo half-life (1114 days) and management is by administration of fXIII (cryoprecipitates,
concentrates or recombinant protein) at 3- to 4-weekly
intervals.
CLINICAL PEARL
PLATELET DISORDERS
Von Willebrand disease is the most common differential diagnosis in females with low fVIII activity.
Idiopathic thrombocytopenic purpura

(ITP)
Hemophilia B
Pathophysiology
Mutations in the fIX gene are also located on the long arm
of the X chromosome, and cause hemophilia B. The clinical
features correlate with residual fIX activity.
Management of hemophilia B is based on replacement of
fIX using donor-plasma-derived high-purity concentrates
An autoimmune disorder with platelet destruction

mediated by autoantibodies and also cell-mediated
immunity.
Enhanced clearance of antibody-bound platelets is commonly recognized as the basis of the disease.
417
There is also evidence of suppression of thrombopoiesis,

leading to the use of thrombopoiesis-stimulating drugs
as an adjunct to immunosuppressive therapies.
May be a truly idiopathic primary disorder, a feature
of other autoimmune diseases (e.g. SLE), or related to
chronic infections such as HIV, hepatitis C, and Helicobacter pylori.
Adult ITP is more frequent in young females, with no
gender preponderance in older adults.
Diagnosis
Diagnosis requires exclusion of recognizable causes such as:
medication effects
infections
autoimmune diseases
disseminated coagulopathy
portal hypertension.
Other blood parameters, including hemoglobin, white cell
count and blood film, should remain normal. Characterization of anti-platelet antibodies is not essential. Bone marrow
biopsies are usually restricted to patients over 60 years, or if
there is suspicion of myelodysplasia or bone-marrow-infiltrative disorders, and prior to splenectomy.
Treatment
The need for treatment is dictated by platelet count and
comorbidities.
Generally, no intervention is necessary for a platelet
count >30 w 109/L. Coexisting conditions that may
need higher platelet counts to ensure hemostasis, such as
menorrhagia, concomitant anti-platelet therapy, history
of peptic ulcer, or impending major surgery, may trigger
intervention at a higher count.
First-line therapy is usually with corticosteroid regimens such as prednisolone 1mg/kg/day for 24 weeks
followed by tapering, or dexamethasone 40mg/day for
4 days repeated 2- to 4-weekly for 24 cycles.
Emergency therapy for very severe thrombocytopenia
with evidence of bleeding is intravenous immunoglobulin (IVIG) 1g/kg/day for 12 days.
Platelet transfusions are ineffective and are not used
unless there are extenuating circumstances.
Second-line therapies are indicated to minimize corticosteroid exposure and to improve response. These
include immunosuppressive drugs such as azathioprine,
cyclosporine (ciclosporin) and rituximab, and danazol.
Splenectomy is considered to be the standard of care for
patients not responding to prednisolone or other immunosuppressive therapies or in the presence of unacceptable side-effects. Almost two-thirds of patients achieve
and maintain durable responses.
Two thrombopoietin receptor agonists (TRAs), romiplostin and eltrombopag, are now available for patients
not responding to corticosteroids and are generally
reserved for use after splenectomy, unless surgery is contraindicated. TRAs bind the thrombopoietin receptor
418
and initiate signaling in hemopoietic stem cells and progenitors, stimulating platelet production.
Thrombotic thrombocytopenic
purpura and hemolytic uremic
syndrome
Thrombotic thrombocytopenic purpura (TTP) and
hemolytic uremic syndrome (HUS) share the common
pathophysiological features of:
consumption thrombocytopenia
microvascular thrombosis
microangiopathic hemolytic anemia.
Clear separation between the two diagnoses can sometimes
be difficult.
Identification of the presence of ultra-large vWF multimers with an enhanced ability to bind with platelet
integrin GPIb and initiate aggregation and consequent
thrombosis in the microcirculation provides an explanation for the findings of multi-organ ischemia and
thrombocytopenia in the absence of overt coagulopathy.
An explanation for the persistence of the highmolecular-weight multimers in TTP is provided by the
identification of a deficiency of ADAMTS-13, a vWFcleaving protease that normally functions to regulate the
abundance of vWF multimers to physiological need.
While TTP is characterized by an inherited or acquired
deficiency of ADAMTS-13, the enzyme levels are
mostly normal in HUS; hence, while the spectrum of
pathological alterations shows significant overlap, differences remain between the two diseases.
Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic occurs as an inherited form
due to mutations in the ADAMTS-13 gene (autosomal recessive), or as an acquired form with deficiency of ADAMTS-13
due to autoantibodies or to release of large quantities of ultralarge vWF multimers due to endothelial activation.
Congenital TTP is a rare disease due to homozygous
or double heterozygous mutations of the ADAMTS-13
gene located on chromosome 9. Most mutations are
missense and lead to decreased production or reduced
function of the protease.
There is considerable heterogeneity in the presentation, varying from occasional episodes to frequent manifestations. Also, the same genetic defect
can lead to a very different spectrum of the disease
within families.
Autoimmune TTP is more common, and is due to
the presence of antibodies that either impair activity of
the ADAMTS-13 protease or enhance its clearance.
The antibodies are directed to epitopes that are important for enzyme activity as well as binding to vWF.
TTP is a clinical diagnosis. Patients may be febrile and
demonstrate the presence of severe thrombocytopenia, red
cell fragmentation (schistocytes), high lactate dehydrogenase
(LDH) levels and end-organ ischemia typically associated
with renal impairment and a myriad of neurological symptoms (stroke, seizures, other focal deficits and fluctuating
consciousness).
CLINICAL PEARLS
Thrombotic thrombocytopenic purpura classically
presents with a pentad of signs: remember with FAT
RNfever, anemia, thrombocytopenia, renal failure
and neurological signs.
Hemolytic uremic syndrome is clinically similar, but
renal rather than neurological features predominate.
therapies found to be useful include corticosteroids and

immunoglobulin. Resistant disease may benefit from chemotherapy (cyclophosphamide, vincristine) and rituximab
(anti-CD20).
CLINICAL PEARL
Treatment of thrombotic thrombocytopenic purpura should not be delayed until the availability of
ADAMTS-13 assays.
Hemolytic uremic syndrome (HUS)

Laboratory diagnosis
The diagnosis of TTP is strongly suggested with
schistocytes and
thrombocytopenia
in the absence of coagulopathy.
Confirmation of the diagnosis is dependent on the
demonstration of:
reduction in ADAMTS-13 protease activity in the
plasma, by impaired ability of the patients plasma to
either proteolyze exogenously added vWF multimers or
cleave specific short vWF peptides
the presence of autoantibodies to ADAMTS-13, either
by ELISA or immunoblotting.
The clinical utility of ADAMTS-13 assays is still debated;
while very low protease activity in the presence of other laboratory features confirms the diagnosis of TTP, a considerable
variation exists within the spectrum of disease. It is unclear
whether the presence of reduced protease activity or autoantibodies predict the prognosis or likelihood of recurrence.
Box 14-3 gives the differential diagnosis of TTP.
Box 14-3
Differential diagnosis of thrombotic

thrombocytopenic purpura and
thrombotic microangiopathies

Catastrophic antiphospholipid syndrome
Heparin-induced thrombocytopenia
Disseminated malignancy
HELLP syndrome (Hemolysis, Elevated Liver enzymes
and Low Platelets) and preeclampsia
Management
The cornerstone of treatment is plasma exchange, with
replacement (preferably) with cryoprecipitate-depleted
plasma (although the advantage of cryoprecipitate-depleted
plasma over fresh frozen plasma [FFP] is debatable). Daily
exchanges should continue until there is improvement in
thrombocytopenia and clinical resolution.
In the absence of facilities to deliver plasma exchange,
prompt infusion of FFP is recommended. Additional
The most common form of HUS is associated with gastrointestinal (GI) infection with toxin-producing bacteria
(Escherichia coli 0157:H7 and Shigella dysenteriae).
Toxin produced by the bacteria is absorbed into the
circulation and causes activation and desquamation of
glomerular capillary endothelial cells, with consequent
renal impairment.
There is systemic endothelial activation, with fibrin
deposition and evidence of compensated coagulopathy.
The presence of ultra-large vWF multimers is less common as compared to TTP, and ADAMTS-13 levels
may be normal or only mildly reduced.
Most cases of diarrhea-associated HUS remit without
recurrence. Temporary renal support with dialysis is often
necessary, although permanent renal failure can occur in up
to one-third of cases.
CLINICAL PEARL
In the setting of Escherichia coli O157:H7, do not prescribe antibiotics as this may precipitate HUS.
Atypical HUS occurs as a familial form with mutations

of complement regulatory proteins (factor H, factorI, MCP
[membrane cofactor protein] and factor B), with consequent unrestricted complement activation and endothelial
toxicity. Mutations in thrombomodulin, an endothelial cell
surface glycoprotein, have been recently identified and also
result in the failure of complement regulation. Treatment of
atypical familial HUS is by either replacement of the missing
factor or renal transplantation.
DISSEMINATED
INTRAVASCULAR
COAGULATION (DIC)
Coagulation is a tightly regulated homeostatic system which
limits physiological clotting to the site of need and for the
duration of injury; any failure of the regulatory process
will result in clot formation that is in vast excess of need
(disseminated) and causes consumption of platelets and
coagulation proteins.
The main driver of clotting is the generation of
thrombin, most commonly by the TF-mediated extrinsic
419
pathway. Thrombin activates platelets and the intrinsic

pathway to amplify clotting, and simultaneously initiates
fibrinolysis by plasminogen conversion to plasmin and
generates activated protein C that functions to inactivate
fV and fVIII.
Various disease processes that are associated with DIC
(Box 14-4) share the common feature of excessive TF exposure, leading to deregulation of thrombin activity. Other
pathological processes that commonly contribute to DIC are
endothelial activation (platelet aggregation, TF expression)
and inflammation (cytokines and interleukins lead to accumulation of neutrophils, activation of complement cascade
and coagulation).
Diagnosis
Establishing the diagnosis of DIC requires clinical suspicion
and:
PT (prolonged)
APTT (prolonged)
thrombin time (prolonged)
D-dimers (raised due to formation and breakdown of
disseminated clotting)
fibrinogen quantification (reduced due to consumption)
FBE (thrombocytopenia due to consumption, and leukocytosis secondary to sepsis or inflammation).
The International Society on Thrombosis and Haemostasis
has proposed a scoring system for the diagnosis of DIC, to
be used in patients with an underlying disorder known to be
associated with DIC (Table 14-5).
Treatment
Treatment of DIC is complicated by the dual risks of bleeding from platelet and clotting factor deficiency, and the risk
of thrombosis.
Platelet transfusion should be reserved for patients who
are actively bleeding or at high risk of bleeding and are
thrombocytopenic with a platelet count <50 w 109/L.
Box 14-4
Diseases associated with

disseminated intravascular
coagulation
Sepsis
Typically Gram-negative releasing lipopolysaccharide,
but can be seen with any micro-organism
Pregnancy and obstetric complications
Preeclampsia
Placental abruption
Amniotic uid embolism
Malignancy
Acute promyelocytic leukemia (characteristic feature)
Solid tumors
Trauma
Burns
Fat embolism
Severe trauma
Envenomation and immunological reactions
ABO-incompatible red cell transfusion
Snake bite
Miscellaneous
Severe pancreatitis
Giant hemangiomas
FFP can be used for patients who are bleeding or at high

risk of bleeding and have prolonged coagulation times.
Evidence of thrombosis should be treated with therapeutic doses of intravenous unfractionated heparin.
Treatment of the underlying cause of the DIC (e.g.
sepsis, pregnancy complications) is essential.
Table 14-5 Scoring system for diagnosis of disseminated intravascular coagulation (DIC)
PLATELET
COUNT
( 109/L)
SCORE
FDPs OR
D-DIMERS
PROLONGATION
OF PT (s)
FIBRINOGEN
(g/L)
>100
No increase
<3
>1
<100
>3 and <6
<1
<50
Moderate increase
>6
Strong increase
A score 5 is compatible with DIC

FDPs, brin degradation products; PT, prothrombin time.
Proposed by the International Society on Thrombosis and Haemostasis (www.isth.org).
420
COAGULOPATHY IN INTENSIVE
CARE PATIENTS
Abnormalities in coagulation tests are commonly observed
in patients in intensive care. The etiology is multifactorial,
and a thorough history of anticoagulant or antiplatelet therapy is essential in the interpretation of tests. Abnormalities
in the commonly used coagulation tests are described in
Table 14-6.
Binding of erythropoietin (Epo) to its receptor initiates

a signaling cascade involving the recruitment of JAK2
to the EpoR and subsequent phosphorylation of downstream targets, including the transcription factor STAT3.
The Val617Phe mutation renders JAK2 constitutionally
active, leading to erythroid hyperplasia in the absence of
erythropoietin.
Erythropoietin levels are suppressed in PV by a negative
feedback mechanism. Patients with PV and an absence of
the Val617Phe mutation display mutations in other regions
of JAK2 serving the same proliferative effect.
MYELOPROLIFERATIVE
DISORDERS
These are clonal disorders of myelopoiesis and include:
polycythemia rubra vera
essential thrombocytosis
primary myelofibrosis.
Chronic myeloid leukemia shares morphological features of
myeloproliferation, but it is an independent disease as the
genetic abnormality, prognosis and treatment options are
markedly different from the myeloproliferative disorders.

The pathogenetic hallmark of PV is the demonstration of the
proliferative autonomy of erythroid precursors in agar cultures
without the need for exogenous erythropoietin stimulation.
In most cases (>98%), Val617Phe mutation of the JAK2
gene can be identified on molecular testing. JAK2 is a
cytoplasmic tyrosine kinase that mediates signal transduction downstream of the erythropoietin receptor (EpoR).
Figure 14-3 Bone marrow trephine showing increase

in erythroid precursors in polycythemia rubra vera
From Aster JC, Podznyakova O and Kutok JL (eds).
Hematopathology: a volume in the High Yield Pathology Series.
Table 14-6 Typical laboratory ndings for coagulation disorders in intensive care patients
PLATELET
COUNT
CONDITION
APTT
PT
FIBRINOGEN
THROMBIN
TIME
D-DIMER
DICa
rb
Liver failure
r/N
r/N
Vitamin K deciency
p/Nc
Acquired
hemophilia
Heparin effect
p/N
Abnormal platelet
function
a Differential diagnosis is TTP (usually normal coagulation and high levels of schistocytes.
b Fibrinogen level may be normal in compensated DIC.
c In early or mild vitamin K deciency, only PT is prolonged. In more severe deciency, APTT is also prolonged.
APTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulopathy; N, normal; PT, prothrombin time; TTP,
thrombotic thrombocytopenic purpura.
Table modied from: Shander A, Walsh CE and Cromwell C. Acquired hemophilia: a rare but life-threatening potential cause of bleeding in
the intensive care unit. Intensive Care Med 2011;37:12409.
421
Clinical features
Patients may appear plethoric, with symptoms of erythromelalgia (derived from three Greek words: erythros
red, melos extremities, and algos pain).
Pruritus, particularly after a warm shower, is also a common feature.
Palpable splenomegaly may be identified in approximately 30% of patients, although splenomegaly by
radiological criteria is more frequent.
Some patients may present with thrombosis as the
disease-identifying illness.
Arterial occlusive diseases (ischemic heart disease and
stroke) can occur with uncontrolled hematocrit.
Increasingly, myeloproliferative disorders are suspected
on the basis of abnormalities on incidental blood tests
and patients may be asymptomatic.
CLINICAL PEARLS
Patients with polycythemia rubra vera (PV) may present with microcytosis and low ferritin, and inadvertent iron supplementation leads to a rapid increase
in hemoglobin with increased risk of thrombotic
events.
A high proportion of patients with splanchnic vein
thrombosis display the JAK2 mutation without evidence of overt PV.
It is essential that patients are commenced on aspirin

as antiplatelet therapy. PV also predisposes to venous
thrombosis at uncommon sites.
Diagnosis
Figure 14-4 outlines criteria for diagnosis of PV.
Treatment
Venesection is the treatment modality in the absence of
thrombocytosis, where the intention is to deplete iron
stores so that the hematocrit is maintained at <0.45.
The presence of thrombocytosis and constitutional
symptoms will need cytoreductive therapy.
The most common drug is hydroxyurea at the dose
of 0.52.0 g daily. Careful monitoring is required
to prevent leukopenia and, rarely, thrombocytopenia. Hydroxyurea is generally well tolerated. A rare
but significant complication is leg ulcers, which is
a contraindication for ongoing use. While there is
concern that hydroxyurea is potentially leukemogenic, the probability is very low when it is used as
a single agent.
The leukemogenic effects are higher for busulfan,
which is often used in older patients. The advantage of busulfan is that, unlike hydroxyurea, it can
be given intermittently and doses can be several
months apart.
Elevated hemoglobin or hematocrit

Red cell mass and
plasma volume
measurements
Elevated red cell mass
O2 saturation
>93%
<93%
JAK2 V617F
Hypoxic
erythrocytosis
+
Polycythemia vera
Both normal
Normal red cell mass

Decreased plasma volume
Tobacco use
Androgens
Diuretics
Hypertension
Pheochromocytoma
Serum erythropoietin level
Normal or low
Polycythemia vera
JAK2 exon12 mutation
Sleep apnea
EPO-receptor mutation
Renal disease (cysts, tumors,
renal artery stenosis)
Tumors
High-affinity hemoglobin
Elevated
Renal disease (cysts, tumors, renal artery stenosis)
Tumors
VHL mutation
High-affinity hemoglobin
Figure 14-4 World Health Organization criteria for the diagnosis of polycythemia rubra vera
From Spivak JL and Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and
primary myelobrosis. Blood 2008;112:2319.
422
An alternative to hydroxyurea in younger patients is

interferon-alpha, usually at the dose of 3 million units
three times a week. Interferon is effective in controlling the hematocrit as well as thrombocytosis. Its
use is restricted by cost and the side-effects of fatigue,
myalgia (resembling influenza) and depression.
Anagrelide is an effective therapy for patients with
PV who have thrombocytosis that works by inhibiting megakaryocytic differentiation. It is, however,
expensive and the common side-effects are headache, fluid retention and palpitations.
Recommendations for the management of PV are given in
Box 14-5.
Box 14-5
BCSH recommendations for

management of polycythemia
rubra vera
Long-term complications
Increased reticulin in the bone marrow may be identified in
about 15% of patients at the time of diagnosis; overt myelofibrosis occurs in 1015% after a period of observation of
15 years.
The probability of leukemic transformation is determined by therapy; the risk is very small (13%) in patients
treated only with hydroxyurea, and rises significantly if
radioactive phosphorus, irradiation and other chemotherapeutic agents are used in the treatment.
Differential diagnosis of erythrocytosis
Polycythemia rubra vera causes primary erythrocytosis, but
secondary causes are more common and need to be considered (Box 14-6).
Venesection to maintain the hematocrit to <0.45

Aspirin 75 mg/day unless contraindicated
Cytoreduction should be considered if there is:
poor tolerance of venesection
symptomatic or progressive splenomegaly
other evidence of disease progression, e.g. weight
loss, night sweats
thrombocytosis
BCSH, British Committee for Standards in Haematology.

From McMullin MF et al. and the General Haematology Task
Force of the British Committee for Standards in Haematology.
Guidelines for the diagnosis, investigation and management of
polycythaemia/erythrocytosis. Br J Haematol 2005;130:17495.
Blackwell Publishing Ltd.

Essential thrombocytosis should be diagnosed only after
elimination of secondary (reactive) etiology (Box 14-7,
overleaf).
ET is a clonal disorder, with up to 55% of patients
demonstrating the presence of the Val617Phe mutation
in the JAK2 gene.
Box 14-6
Classication of erythrocytosis
Primary erythrocytosis
Polycythemia rubra vera
Secondary erythrocytosis
Congenital
High-oxygen-affinity hemoglobin
2,3-Biphosphoglycerate mutase deciency
Erythropoeitin receptor-mediated
Chuvash erythrocytosis (VHL mutation)
Acquired
EPO-mediated
Hypoxia-driven
Central hypoxic process
chronic lung disease
right-to-left cardiopulmonary vascular shunts
carbon monoxide poisoning
smokers erythrocytosis
hypoventilation syndromes including sleep apnea
(high-altitude habitat)
Hypoxia-driven (continued)
Local renal hypoxia
renal artery stenosis
end-stage renal disease
hydronephrosis
renal cysts (polycystic kidney disease)
Pathological EPO production
Tumors
hepatocellular carcinoma
renal cell cancer
cerebellar hemangioblastoma
parathyroid carcinoma/adenomas
uterine leiomyomas
pheochromocytoma
meningioma
Exogenous EPO
Drug-associated
treatment with androgen preparations
postrenal transplant erythrocytosis
idiopathic erythrocytosis
EPO, erythropoietin.
From McMullin MF et al. and the General Haematology Task Force of the British Committee for Standards in Haematology. Guidelines for
the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005;130:17495. Blackwell Publishing Ltd.
423
Box 14-7
Causes of thrombocytosis
Primary
Essential thrombocythemia
Primary myelobrosis
Myelodysplasia with dcl(5q)
Refractory anemia with ring
sideroblasts associated with marked
thrombocytosis
Chronic myeloid leukemia
Chronic myelomonocytic leukemia
Atypical chronic myeloid leukemia
MDS/MPN-U
Secondary
Infection
Inammation
Tissue damage
Hyposplenism
Postoperative
Hemorrhage
Iron deciency
Malignancy
Hemolysis
Drug therapy (e.g. corticosteroids, epinephrine)
Cytokine administration (e.g. thrombopoietin)
Rebound following myelosuppressive
chemotherapy
Spurious
Microspherocytes (e.g. severe
burns)
Cryoglobulinemia
Neoplastic cell cytoplasmic
fragments
Schistocytes
Bacteria
Pappenheimer bodies
MDS/MPN-U, myelodysplastic/myeloproliferative neoplasms, unclassiable.

From Harrison CN et al. and the British Committee for Standards in Haematology. Guideline for investigation and management of adults
and children presenting with a thrombocytosis. Br J Haematol 2010;149:35275. Blackwell Publishing Ltd.
CLINICAL PEARL
The combination of high Hb and thrombocytosis in the
presence of JAK2 mutation is more likely to be polycythemia rubra vera than essential thrombocytosis.
Homozygous mutations of the JAK2 gene are uncommon in ET, in contrast to PV.
Leukocytosis may occur in ET, and it has clinical implications (see below).
Mutations in the thrombopoietin receptor gene MPL

are noted in 5% of patients with ET.
Clinical features
Patients with JAK2 mutations and ET demonstrate:
more bone marrow hypercellularity
a higher likelihood of leukocytosis
a higher risk of thrombotic events
more likelihood of progressive myelofibrosis
a greater possibility of transformation to leukemia.
Table 14-7 Proposed diagnostic criteria for essential thrombocythemia

Diagnosis requires A1A3 or A1 + A3A5
A1
Sustained platelet count >450 109/L
A2
Presence of an acquired pathogenetic mutation (e.g. in the JAK2 or MLP genes)
A3
No other myeloid malignancy, especially PV,* PMF, CML or MDS
A4
No reactive cause for thrombocytosis and normal iron stores
A5
Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of
morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin
is generally not increased (grades 02/4 or grade 0/3)
* Excluded by a normal hematocrit in an iron-replete patient; PV, polycythemia rubra vera.
Indicated by presence of signicant marrow bone marrow brosis (greater than or equal to 2/3 or 3/4 reticulin) AND palpable
splenomegaly, blood lm abnormalities (circulating progenitors and tear-drop cells) or unexplained anemia PMF, primary myelobrosis.
Excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood; CML, chronic myeloid leukemia.
Excluded by absence of dysplasia on examination of blood lm and bone marrow aspirate; MDS, myelodysplastic syndrome.
These criteria are modied from WHO diagnostic criteria.
From Harrison CN et al. and the British Committee for Standards in Haematology. Guideline for investigation and management of adults
and children presenting with a thrombocytosis. Br J Haematol 2010;149:35275. Blackwell Publishing Ltd.
424
Platelet count
>450x109/L
Review blood film

Acute phase
reactants (e.g. CRP;
ESR)
Iron status
Iron deficiency
Acute phase response

Normal
Treat
Repeat blood
count
Reactive thrombocytosis
Repeat blood count
Persistent unexplained
thrombocytosis
Further investigation
Molecular genetics
(JAK2 V617F; MPL)
Bone marrow examination
(aspirate and trephine biopsy)
Cytogenetics
Diagnosis
(see text for diagnostic features)
Figure 14-5 Diagnostic pathway for the investigation

of thrombocytosis. CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate
From Harrison CN et al. and the British Committee for Standards
in Haematology. Guideline for investigation and management of
adults and children presenting with a thrombocytosis. Br J Haematol
2010;149: 35275. Blackwell Publishing Ltd.
Proposed diagnostic criteria are given in Table 14-7 and a

diagnostic pathway in Figure 14-5.
CLINICAL PEARL
The presence of JAK2 mutation in essential thrombocytosis suggests a higher risk of thrombotic events,
progression to myelobrosis, and transformation to
leukemia, although the risk is lower than in patients
with polycythemia rubra vera.
and should be treated with a combination of hydroxyurea

and aspirin.
Interferon-alpha should be considered for younger
patients, and is the preferred treatment in pregnancy, as
hydroxyurea and anagrelide are associated with teratogenic potential.
Anagrelide is not usually first-line therapy, and the
combination of anagrelide and aspirin is associated
with more thrombotic and myelofibrotic events than
hydroxyurea and aspirin.
Low-risk patients (<40 years, without any high-risk features) should probably be given only aspirin without cytoreductive therapy.
Intermediate-risk patients (age 4060 years, without
high-risk features) should receive aspirin. In this group the
decision for cytoreduction is individualized.

This is a clonal hemopoietic stem cell disorder characterized by the proliferation of hemopoietic lineages
accompanied by bone marrow fibrosis.
Approximately 50% of patients exhibit the JAK2
Val617Phe mutation, indicating an overlap with PV and
ET.
While myelofibrotic transformation is a longer-term
consequence for a limited number of patients with ET
and PV, primary myelofibrosis occurs without overt
preceding myeloproliferative disorder and is associated
with a worse prognosis.
Clinical features
Splenomegaly is characteristic of the disease, and PMF
should be considered as a differential diagnosis in the evaluation of massive splenomegaly. Splenic infarcts are common
sequelae of splenomegaly. Splenomegaly is a consequence of
extramedullary hemopoiesis and blood pooling.
Systemic symptoms of:
fever
weight loss, and
night sweats
are a consequence of a hypercatabolic state and imply worse
prognosis.
Leukemic transformation occurs in up to one-third of
cases and has a poor prognosis.
Diagnosis
Management
Elevated platelet count on its own is not an indication for
intervention. Management is based on the level of risk.
High-risk patients:
are >60 years of age
and have one or more of:
a platelet count >1500 w 109/L and prior history of
thrombotic events
the presence of thrombotic risk factors such as diabetes and hypertension
Box 14-8 (overleaf) lists diagnostic criteria.

Characteristic blood film findings are of a leukoerythroblastic picture (the presence of immature myeloid cells
including occasional blasts, nucleated red cells and tear-drop
red cells). Pancytopenia is common in later stages of the
disease.
Treatment
Supportive therapy is the only option in older patients.
Anemia may respond to androgens such as danazol or
oxymetholone.
425
Box 14-8
Diagnostic criteria for primary

myelobrosis
Leukoerythroblastic blood picture

Increased marrow reticulin in the absence of an
inltrative or granulomatous process
Splenomegaly
JAK2 V617F assay (peripheral blood; expression
establishes the presence of an MPD but not its type;
PV is always a consideration; absence does not
exclude an MPD)
Increased circulating CD34+ cells (>15 106/L)
and no increase in marrow CD34+ cells by in situ
immunohistochemistry
Characteristic cytogenetic abnormalities (peripheral
blood: del(13q), 9p, del(20q), del(12p), partial
trisomy1q, trisomy 8, and trisomy 9)
Absence of Bcr-Abl, AML, or MDS cytogenetic
abnormalities by FISH (peripheral blood)
AML acute myeloid leukemia; FISH, uorescence in situ

hybridization; MDS, myelodysplastic syndrome; MPD,
myeloproliferative disorder; PV, polycythemia rubra vera.
From Spivak JL and Silver RT. The revised World Health
Organization diagnostic criteria for polycythemia vera, essential
thrombocytosis, and primary myelobrosis: an alternative
proposal. Blood 2008;112:23139.
Cytoreductive therapy, most commonly hydroxyurea,

will assist in the control of systemic symptoms.
Splenectomy or splenic irradiation may be considered.
Splenomegaly is associated with painful infarcts and
constitutional symptoms. However, splenectomy is
often complicated with postoperative bleeding and an
increased risk of thrombosis.
There is considerable hope placed in the development of
tyrosine kinase inhibitors targeting JAK2. Current trials
reveal that the available drugs are also active in patients without JAK2 mutations.
Most of the benefit is in improvement of constitutional
symptoms and reduction of spleen size.
Reversal of bone marrow fibrosis has not yet been
documented.
Allogeneic bone marrow transplantation should be considered for patients up to 55 years with features of rapid
progression. Conventional myeloablative transplantation is
associated with significant transplantation-related mortality and morbidity. Reduced-intensity conditioning may
expand the availability of allogeneic transplantation to older
patients, although it remains to be established for this disease.
LEUKEMIA
Acute myeloid leukemia is one of the most common
hematological malignancies and is increasing in frequency
426
due to an aging population. The peak incidence is in the

7th decade, but it occurs in all age groups.
AML is a clonal disorder with the leukemic transforming
event having occurred in the hemopoietic stem cells.
The transformed cells retain a proliferative advantage
and demonstrate an associated failure of differentiation
into mature cells, thus leading to an accumulation of the
leukemic blast cells.
This replaces bone marrow with blasts, and pancytopenia ensues with the clinical presentation being fatigue,
bruising or infection.
Lymphadenopathy is uncommon, and tissue infiltration
with blasts is noted in certain subtypes (e.g. gum hypertrophy in acute monocytic and acute myelomonocytic
leukemias).
Acute promyelocytic leukemia uniquely presents with
disseminated intravascular coagulation (DIC).
While radiation and chemical exposure may play a role, the
causative agent is not identified in the vast majority of cases.
Classication of subtypes
In the World Health Organization (WHO) classification,
the presence of 20% or more blasts in the peripheral blood
or bone marrow is considered to be:
AML when it occurs de novo
evolution to AML when it occurs in the setting of
a previously diagnosed myelodysplastic syndrome
(MDS) or myelodysplastic/myeloproliferative neoplasm
(MDS/MPN)
blast transformation in a previously diagnosed myeloproliferative neoplasm (MPN).
Prognostic variables determining

outcome in AML
Age
Increasing age and poor performance status at diagnosis
adversely affect prognosis. Older patients tolerate the complications of chemotherapy poorly, with a significant risk of
death during induction chemotherapy.
The impact of age on the overall survival of children
and adults treated in successive AML trials is shown in
Figure14-6.
Tumor burden
Poor prognosis is associated with:
high blast count
organomegaly
raised LDH.
Cytogenetic abnormalities
Genetic events identified at diagnosis are one of the most
important predictors of outcome, and are incorporated in
the WHO classification of AML (Table 14-8).
Molecular mutations and overexpression
These are point mutationssmall genetic modifications or
overexpression of genes that are not identifiable by conventional
Overall survival
100
Age
Age
Age
Age
Age
% still alive
75
014
1534
3544
4559
60+
63%
55%
50
46%
35%
25
14%
Years from entry
Figure 14-6 Impact of age on overall survival of

children and adults (n = 11,421) treated in successive
Medical Research Council (MRC-UK) AML trials
Adapted from Smith ML, Hills RK and Grimwade D. Independent
prognostic variables in acute myeloid leukaemia. Blood Rev
2011;25:3951.
cytogenetics but have an impact on the outcomes, particularly

in cytogenetically defined intermediate-risk patients.
1 FLT3 mutation: FLT3 is a member of the class III
receptor tyrosine kinase (RTK) family and is expressed
on hematopoietic progenitors. Mutations are seen in
approximately one-third of patients, resulting in constitutive activation of the receptor and adverse prognosis.
2 KIT: KIT (CD117) is the receptor for stem cell factor (SCF) (KIT ligand), and is expressed on stem cells.
KIT mutations have an adverse impact on prognosis.
3 Molecular markers of overexpression of genes: overexpression of the Brain and Acute Leukemia, Cytoplasmic (BAALC) gene and the ETS-related gene
(ERG1) are further independent adverse factors in
normal-karyotype AML. The mechanisms underlying
the overexpression remain to be understood.
4 NPM1: a variety of mutations have been identified
within the NPM1 gene and predict improved CR and
reduced risk of relapse.
Table 14-8 Acute myeloid leukemia risk stratication by cytogenetic abnormalities found at diagnosis
ADULT
CYTOGENETIC ABNORMALITY
PEDIATRIC
INCIDENCE
CYTOGENETIC ABNORMALITY
INCIDENCE
Favorable risk
t(15;17)(q24;q21)
513%
t(15;17)(q24;q21)
811%
t(8;21)(q22;q22)
57%
t(8;21)(q22;q22)
1113%
inv(16)(p13.1q22)/t(16;16)(p13.1;q22)
58%
inv(16)(p13.1q22)/t(16;16)(p13.1;q22)
36%
t(1;11)(q21;q23)
3%
Intermediate risk
t(9;11)(p21;q23)
2%
t(9;11)(p21;q23)
10%
Normal karyotype
4045%
t(1;22)(p13;q13)
23%
3%
Normal karyotype
2025%
10%
<3 abnormalities
67%
inv(3)(q21q26)/t(3;3)(q21;q26)
12%
inv(3)(q21q26)/t(3;3)(q21;q26)
12%
5/del(5q)/ add(5q)
412%
5/del(5q)/ add(5q)
56%
7/del(7q)/ add(7q)
8%
7/del(7q)/ add(7q)
12%
t(8;16)(p11;p13)
<1%
t(11q23) [excluding t(9;11)]
1822%
t(11q23) [excluding t(9;11)]
34%
t(6;9)(p23;q34)
1%
t(6;9)(p23;q34)
12%
t(9;22)(q34;q11.2)
1%
t(9;22)(q34;q11.2)
1%
17/abn(17p)
2%
17/abn(17p)
5%
Complex (3 unrelated abnormalities)
10%
Complex (3 unrelated abnormalities)
6%14%
+8
b
Adverse risk
a Irrespective of additional cytogenetic abnormalities.

b Excluding favorable cytogenetic abnormalities.
Adapted from Morrissette J and Bagg A. Acute myeloid leukemia: conventional cytogenetics, FISH, and moleculocentric methodologies.
Clin Lab Med 2011;31:65986.
427
5 CEPBA: CEBPA encodes the transcription factor

CCAAT enhancer binding protein alpha (C/EBPF),
which is important in the regulation of myeloid differentiation. CEBPA mutations are now recognized as a
good prognosis factor.
Treatment
The goals of treatment need to be individualized to patients,
particularly with reference to age and performance status.
In younger, fit patients the goal is to induce complete
remission and consolidate gain.
Further options such as allogeneic stem cell transplantation depend on stratification to intermediate and poor risk
categories. Young patients with a high risk of relapse
will benefit from allogeneic bone marrow or stem cell
transplantation from a matched sibling or unrelated
donor. The advantage in improvement in disease-free
survival must be balanced against transplant-related
mortality and morbidity from infections and acute and
chronic graft-versus-host disease.
Induction treatment consists of 12 cycles of an anthracycline (daunorubicin, doxorubicin), cytosine arabinoside (intermediate or high doses) and occasionally a
third drug. Achievement of response is confirmed by
bone marrow morphology, immunophenotyping, and
cytogenetic studies to confirm the resolution of any
genetic abnormality detected at diagnosis.
Consolidation therapy consists of 23 courses of
combination chemotherapy using cytosine arabinoside,
anthracyclines, etoposide or m-amsacrine.
With advancing age and frailty, the plan should be toward
supportive care and maintenance of the quality of life.
Therapy-related AML (t-AML)

Therapy-related acute myeloid leukemia is a complication
of the cytotoxic therapy used for primary cancer treatment
and accounts for 1020% of myeloid neoplasms.
t-AML is observed after ionizing radiation as well as
conventional chemotherapy including alkylating agents,
topoisomerase-II inhibitors and antimetabolites.
t-AML may appear de novo or progress through an intermediate stage of myelodysplastic syndrome.
Some differences between t-AML arising after alkylating agents and after topoisomerase inhibitors are shown
in Table 14-9.
Achievement of complete response is low in t-AML,
and patients should be recommended for stem cell
transplantation or experimental therapies.

Acute promyelocytic leukemia is characterized by specific
chromosomal translocations that always involve the retinoic
acid receptor alpha (RARA) gene on chromosome 17 to
create a variety of XRARA fusions. The most common
is the t(15;17) translocation encoding PMLRARA fusion,
which is associated with >98% of cases. The PML-RARA
fusion protein exhibits a dominant negative activity, disrupting the role of retinoic acid (RA) in the differentiation
of multiple progenitors as well as myeloid cells; it also disrupts PML nuclear bodies.
Patients often present with overt DIC or display laboratory abnormalities consistent with subclinical DIC.
Morphological features are typical, with abundance of
abnormal promyelocytes with increased granulation and
clusters of Auer rods. Microgranular variants are less
common.
Table 14-9 Therapy-related acute myeloid leukemia: associations with different therapeutic agents
THERAPY
ABNORMALITY
FREQUENCY
MDS PHASE
APPROXIMATE
TIME FROM
EXPOSURE
70%b
Common
Long latency
(510 years)
MLL rearrangements
332%
Rare
RUNX1 rearrangements
2.54.5%
Short latency
(15 years)
t(15;17)
2%
inv(16)/t(16;16)
2%
Others
1520%
Alkylating agents70% (e.g.

melphalan, cyclophosphamide,
chlorambucil)
Ionizing radiation therapy
5q deletion/
monosomy 5a
Topoisomerase inhibitors30%
(e.g. etoposide, daunorubicin,
mitoxantrone)
7q deletion/
monosomy 7a
a Often associated with additional cytogenetic abnormalities [del(13q), del(20q), del(11q), del(3p), 17, 18, 21, +8].
b Of abnormalities of chromosome 5, 7, or both.
MDS, myelodysplastic syndrome.
Adapted from Morrissette J and Bagg A. Acute myeloid leukemia: conventional cytogenetics, FISH, and moleculocentric methodologies.
Clin Lab Med 2011;31:65986.
428
Complete remission can be induced in over 90% of

cases and cure in >80%, using all-trans retinoic acid and
anthracyclines. The addition of arsenic trioxide enables
the therapeutic approach of rationally targeted frontline protocols with minimal or no traditional cytotoxic
chemotherapy.
Patients are at a significant risk of DIC during the induction phase and require significant blood product support.
A unique complication of treatment in APML is the
differentiation syndrome, characterized by pulmonary
infiltration by differentiating APML blasts. It requires
treatment with steroids at the earliest symptom or sign.
Quantitative PCR for the fusion PML-RARA
transcript is useful in monitoring for minimal residual
disease and relapse.

Acute lymphoblastic leukemia is characterized by the
accumulation of malignant immature lymphoid cells in the
bone marrow.
It is the most common malignancy in children, representing one-third of pediatric cancers.
It has an age-adjusted incidence rate of 1.6 per 100,000
per year, and follows a bimodal distribution with a peak
between the ages of 4 and 10 years and a second peak
after the age of 50 years.
Clinical presentation in adults is generally with:
nonspecific constitutional symptoms
features of pancytopenia.
Bone pain, splenomegaly and lymphadenopathy are common.
Diagnosis is established on the basis of morphology and
immunophenotype. Cytogenetic analysis and molecular
studies are essential at diagnosis, especially the detection of
t(9;22) translocation (Philadelphia chromosome) by fluorescence in situ hybridization (FISH) and PCR so that tyrosine kinase therapy (imatinib, nilotinib and dasatinib) can be
incorporated into the treatment.
Poor prognosis on clinical grounds correlates with:
age (>35 years)
elevated white blood cell count at the time of diagnosis (v100 w 109/L for T lineage and v30 w 109/L for
B lineage)
CNS involvement at presentation
achievement of complete remission >28 days after the
initiation of induction therapy.
Cytogenetic abnormalities are independent determinants of
prognosis.
Treatment of adult ALL

The aim of therapy is to obtain complete remission. Effective chemotherapy drugs include:
L-asparaginase anthracyclines (especially in young
people)
corticosteroids
vincristine
cytosine arabinoside
cyclophosphamide.
Achievement of complete remission is followed by consolidation and maintenance therapy.
CNS prophylaxis is important to prevent relapse, and
consists of cytosine arabinoside and methotrexate given
intrathecally and systemically.
CLINICAL PEARL
Because of the high incidence of relapse, adult patients
in rst remission of acute lymphoblastic leukemia
should be considered for allogeneic transplantation.
Philadelphia-positive ALL constitutes a poor prognostic

group. However, the recent incorporation of tyrosine
kinase inhibitors has considerably improved prognosis.
Detection of minimal residual disease by sensitive techniques (PCR, FISH, immunophenotype) is associated
with poorer outcomes in adults and children, and serves
to identify patients who need further treatment intensification, allogeneic transplantation or use of novel
agents.

Myelodysplastic syndromes are clonal stem cell disorders
characterized by the presence of peripheral blood cytopenias due to impaired production from a dysplastic bone
marrow.
The most common peripheral blood abnormalities are:
macrocytic anemia, occurring in more than 80% of
patients
thrombocytopenia, noted in 3045% of MDS cases
neutropenia, a feature in approximately 40% of patients.
MDS is a disease of the elderly, with more than 60% of
patients over the age of 70 years at the time of diagnosis.
There is an increased risk of leukemic transformation.
Etiology
MDS may appear de novo or following exposure to chemotherapy (alkylating agents, topoisomerase inhibitors,
nucleoside analogs).
Aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) show an increased risk of progression to
MDS.
Constitutional genetic disorders (trisomy 21, trisomy 8
mosaicism, familial monosomy 7) and DNA repair deficiencies (e.g. Fanconi anemia) also increase the risk of
developing MDS.
Classication
The original FAB classification relied solely on morphology and blast count. The newer WHO system incorporates
cytogenetics and recognizes the importance of mono- and
bi-cytopenias.
429
There is emerging evidence for iron chelation, particularly for patients in low-risk IPSS category.
Prognosis stratication
The International Prognostic Scoring System (IPSS; Table
14-10) separates patients into discrete survival subgroups
(related to the risk of progression to AML) using:
the percentage of bone marrow blasts
cytogenetic abnormalities
the number of cytopenias.
Median survival varies from 0.4 years in patients with IPSSdefined high-risk disease, to 5.7 years in patients with lowrisk disease.
Management
The principal point of stratification is to determine suitability for allogeneic stem cell transplantation.
Younger patients with an intermediate-2 or high-risk
IPSS score should be considered for transplantation.
Low-risk subtypes may be managed conservatively.
Patients with del5q and symptomatic anemia respond to
thalidomide and lenalidomide.
Intermediate-2 or high-risk MDS patients not suitable
for allogeneic transplantation should be considered for
the use of hypomethylating agents.
Azacitidine and decitabine are cytosine nucleoside analogs that inhibit methyltransferase activity,
leading to hypomethylation of DNA. This results
in restoration of normal growth control and differentiation to mature hematopoietic cells. The
response to hypomethylating agents is slow, and
first response may be delayed until the 6th cycle.
Hypoplastic MDS, especially with the presence of PNH
clones, responds to immunosuppressive therapy.
Supportive care with blood and platelet transfusions and
management of infections is central to the management
of MDS.

Chronic myeloid leukemia results from a specific genetic
event: the Philadelphia (Ph) chromosome, a reciprocal
translocation of long-arm segments between chromosomes
9 and 22, t(9;22)(q34;q11).
The long arm of chromosome 9 contains ABL1, a nonreceptor tyrosine kinase, and the breakpoint cluster
region (BCR) is on 22q, the function of which is less
clear.
The translocation generates the Ph chromosome
(BCR-ABL1) and the derivative 9q+ (ABL1-BCR).
BCR-ABL1 is functionally a tyrosine kinase with
deregulation of its activity which initiates a number of
signaling events that are responsible for the malignant
phenotype (see below).
An important corollary is that selective inhibition of
BCR-ABL1 tyrosine kinase activity by targeted drugs
such as imatinib have the capacity to induce remission.
CLINICAL PEARL
BCR-ABL1 is also present in almost 30% cases of adult
acute lymphoblastic leukemia (Ph+ ALL).
Cell biology
The pivotal oncogenic role of the deregulated tyrosine
kinase activity of BCR-ABL1 is confirmed by the observation that tyrosine kinase inhibitors as single agents are able
to induce morphological and molecular remission. BCRABL1 phosphorylates a number of proteins that participate
in downstream oncogenic events such as cell proliferation,
survival and escape from apoptosis.
Table 14-10 International Prognostic Scoring System (IPSS) for myelodysplastic syndromes
IPSS
PROGNOSTIC
VARIABLE
SCORE VALUE
0
0.5
1.0
1.5
2.0
Bone marrow blast (%)
<5
510
1120
2130
Karyotype
Good
(normal, Y, del5q,
del20q)
Intermediate
(other abnormalities)
Poor
(complex (3
abnormalities) or
chromosome 7
abnormalities)
Cytopenias
0/1
2/3
IPSS risk score groups

Low = 0
Intermediate-1 = 0.51.0
Intermediate-2 = 1.52.0
High = 2.5
Data from Greenberg P et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:207988.
430
Clinical features
Untreated CML progresses through the following phases:
Chronic phaseperipheral blood blasts fewer than 10%
in the blood and bone marrow.
Accelerated phase
myeloblasts are 1019% in the blood or bone
marrow
>20% basophils in the blood or bone marrow
persistent thrombocytopenia (<100 w 109/L) unrelated to therapy, or persistent thrombocytosis
(>1000 w 109/L) unresponsive to therapy
increasing white blood cells and spleen size unresponsive to therapy
cytogenetic evidence of clonal evolution with
new abnormalities in addition to the Philadelphia
chromosome.
Blast crisis
myeloblasts or lymphoblasts v20% in the blood or
bone marrow
extramedullary blast proliferation (chloroma)
large foci or clusters of blasts on bone marrow
biopsy.
Symptoms and signs correlate with the stage of disease at
presentation.
Fatigue, increased sweating, easy bruising and presence
of splenomegaly are features of advanced disease.
Lymphadenopathy is rare, and helps to clinically separate lymphoma from CML.
Testicular swelling, headaches and meningeal irritation
should alert clinicians to the development of a leukemic
phase, particularly ALL.
Most patients are now identified on the basis of abnormalities on incidental full blood count tests.
CLINICAL PEARL
Lymphadenopathy is rare in chronic myeloid leukemia,
and helps to distinguish it clinically from lymphoma.
Diagnosis
Typically, FBE identifies leukocytosis with left shift and the
presence of basophilia. While myelocytes are commonly
present, blasts are rare in the chronic phase of CML.
Diagnosis is confirmed by the typical morphological features of increased cellularity and myeloid proliferation with
a left shift and eosinophilia and basophilia; megakaryocytes
are commonly small in size and monolobular. Increase in
blast presence in the peripheral blood or bone marrow is
indicative of accelerated and blastic transformation.
Staging and prognosis

Several prognostic algorithms (Sokol and Hasford indices)
have been developed to predict prognosis and response to
therapy. These take into account:
age
leukocytosis
platelet, eosinophil, basophil and blast counts

spleen size.
Treatment
Neither hydroxyurea nor busulfan decrease the cells expressing Ph+ chromosome. Hydroxyurea is only used now to
decrease the count while awaiting commencement of specific therapy. Occasionally, leukapharesis may be necessary
for patients presenting with very high white cell counts.
Tyrosine kinase inhibitors (TKIs)
Development of specific tyrosine kinase inhibitors has dramatically changed the treatment algorithm and prognosis.
Imatinib used as initial therapy (400mg daily) for chronicphase CML generates a complete cytogenetic response in
83% of patients, with an overall survival rate at 96 months
of 85% and an event-free survival rate of 81%.
Recent studies have confirmed that initial treatment with higher doses (600mg or 800mg daily)
translate to improved molecular response; however,
the higher doses are not well tolerated.
Side-effects include fatigue, skin rash and fluid
retention, which are treated symptomatically.
Myelotoxicity is a feature more commonly noted
in the first 23 months of therapy. Dose reduction should be avoided, and temporary support with
granulocyte colony-stimulating factors (G-CSFs)
may be used.
Therapy is continued indefinitely. Recent evidence suggests that it may be possible to cease therapy after 2 years
of complete molecular response with the benefit preserved
in approximately 50% of patients. Vigilance by quantitative
polymerase chain reaction (Q-PCR) monitoring is essential, and re-institution of imatinib on the basis of increasing
Q-PCR will re-establish response.
Role of interferon-alpha and chemotherapy
Interferon-alpha can induce a complete hematological
response in 7080% of patients with CML, and there is
some degree of cytogenetic response in approximately 50%
of patients, which is complete in up to 2025%.
Achievement of complete response translates to an
improved survival (10-year survival rate of 75% or more for
complete response, compared with <40% for those having a
partial response and <30% for individuals having a smaller
or no response).
Combination of interferon-alpha with cytarabine
improves the response rate.
Monitoring
Monitoring the response to CML therapy begins at diagnosis and carries on serially throughout the entire course of
the disease.
Complete morphological remission is an easily achievable goal with tyrosine kinase inhibitor therapy and significant advances in technologies to detect BCRABL
positive cells have now refocused therapeutic goals on
cytogenetic and molecular endpoints.
431
Cytogenetic and molecular responses provide a measure

of minimal residual disease, guide treatment choices and
predict long-term outcome.
Complete cytogenetic response (CCyR) is achieved
when no Ph+ metaphases are detectable in the bone
marrow.
Karyotyping or FISH studies are not routinely indicated for disease monitoring, but have a place to monitor development of additional genetic changes that may
herald poor prognosis.
Response to therapy is now monitored by quantification of peripheral blood BCR-ABL1 transcript by
quantitative reverse transcriptase PCR (RT-PCR).
Major molecular response (MMR) occurs when there is
v3-log reduction of BCR-ABL mRNA, and complete
molecular response (CMR) is defined as BCR-ABL
mRNA undetectable by RT-PCR
Treatment failure on imatinib
The most frequently identified mechanism of resistance to
imatinib is the development of mutations at the ABL kinase
domain.
Rising BCR-ABL1 levels in patients compliant with
imatinib therapy is an indication to sequence for BCRABL1 mutations.
Mutations are identified in 4060% of patients with
imatinib resistance, with the most frequent occurring in
the P-loop that prevents access of the drug to the catalytic site.
Not all mutations confer the same level of resistance to
imatinib, and some may be overcome by increased concentrations of imatinib. The decision to change therapy
and the choice of 2nd-generation inhibitors are guided
by the specific mutations.
2nd-generation inhibitors
Dasatinib and nilotinib are two of the most widely available
2nd-generation TKIs. Their use is recommended for patients
who demonstrate failure of imatinib therapy and for severe
intolerance to imatinib. However, recent trials have provided
evidence that use of these drugs as first-line therapy is more
efficacious than imatinib in achieving molecular response,
with lower rates of progression to accelerated and blast phases.
Dasatinib has a different structure to imatinib; it can
inhibit the Src family of kinases in addition to BCRABL1. This extended repertoire of enzyme activity may
contribute to its improved effectiveness, but also to the
side-effect profile which may include pleural effusions
and myelosuppression.
Nilotinib is based on the structure of imatinib with
modifications to improve potency, generating an
improved cytogenetic response. Common side-effects
include myelosuppression and elevation of hepatic and
pancreatic enzymes.
CML with T315I mutation
1st- and 2nd-generation TKIs are not effective against
this mutation. A 3rd-generation inhibitor, ponatinib, and
432
a protein translation inhibitor, omacetaxine (homoharringtonine), have been shown to be useful in early studies.
However, these drugs are not yet readily available.
Younger patients with T315I mutation should be considered for allogeneic bone marrow transplantation.
Role of allogeneic transplantation in CML
Allogeneic bone marrow transplantation (BMT) was the
cornerstone of therapy in young patients with CML who
had compatible donors. This modality of treatment is potentially curative, although transplant-related mortality and
morbidity from graft-versus-host disease have to be considered. With the availability of TKI therapy, allogeneic BMT
is now restricted to patients with disease failure to 2nd- or
3rd-generation TKIs.
Chronic lymphocytic leukemia and

other B-cell disorders
Chronic lymphocytic leukemia (CLL)
This is increasingly diagnosed early in asymptomatic patients
with a mild lymphocytosis found incidentally when a full
blood examination is done for another reason.
CLL is the most common of all leukemias in adults over
the age of 50 years, with a male:female ratio of 2:1.The
median age of presentation is 6570 years.
810% of patients have a family history, although no
single causative gene has been found. Some association has been seen with interferon regulatory factor 4
(IRF4), a key regulator of lymphocyte maturation and
proliferation.
Approximately 50% of CLL cases retain an unmutated
immunoglobulin heavy chain. There is also preferential
use of a restricted set of B-cell receptors and variable
heavy-chain genes. It is hypothesized that CLL proliferates due to stimulation by yet unknown antigens. There
is emerging evidence that chemokines secreted by bonemarrow stromal cells can activate signaling pathways in
CLL cells, leading to survival signals.
Diagnosis
The diagnosis of CLL requires the presence of v5 w 109/L
B-lymphocytes in the peripheral blood for at least 3 months,
with monoclonality confirmed by flow cytometry.
CLL cells typically co-express the T-cell antigen CD5
and the B-cell surface antigens CD19, CD20 and
CD23.
Peripheral blood film reveals characteristic smear cells.
Bone marrow examination is generally not required for
the diagnosis of CLL.
Coexisting cytopenias directly related to leukemia-cell
infiltration of the marrow may be present.
Serum LDH and beta-2 microglobulin are important
measures for prognostication.
Other tests performed at the time of diagnosis should include
assessment of the mutational status of the immunoglobulin heavy chain, phosphorylation of the B-cell signaling
messenger Zap70, and cell-surface expression of CD38.

Karyotype abnormalities common in CLL include deletions
of 17p (loss of the tumor suppressor p53), 11q and 13q.
Prognostic factors
Poor outcomes correlate with:
unmutated immunoglobulin heavy chain
the presence of CD38 on the CLL cell surface
high beta-2 microglobulin levels
non-responsiveness to fludarabine
11q and 17p deletions
p53 mutations.
Clinical staging
The Rai and Binet scores are the two most widely accepted
staging systems, of which the Rai score is described here. It
has three prognostic categories:
1 Low-risk disease is defined by the presence of lymphocytosis only.
2 Intermediate-stage disease includes lymphocytosis,
lymphadenopathy at any site, and splenomegaly and/or
hepatomegaly.
3 High-risk disease includes patients with disease-related
anemia (Hb<110g/L) or thrombocytopenia (platelet
count <100w109/L.
Treatment
1 Early-stage patients without symptoms do not need
treatment, as there is no survival benefit.
2 Patients with intermediate-stage and high-risk disease
will benefit from treatment. Treatment options include:
a Alkylating drugs such as chlorambucil, cyclophosphamide and bendamustine. Chlorambucil is
very well tolerated and is preferred in the elderly;
the complete remission rate is very low when
chlorambucil is used as the sole agent. Bendamustine is a nitrogen-mustard derivative; its efficacy
in CLL has been proved recently and is superior
to chlorambucil as a sole therapy.
b Purine analogs are increasingly used, particularly in younger patients. Fludarabine is the most
commonly used drug from this class and is frequently combined with cyclophosphamide and
the anti-CD20 antibody rituximab as the FCR
regimen. This combination should be considered
as a first-line option in physically fit patients, as it
delivers overall response rates in excess of 90%,
complete remission in approximately 50% of
patients and 3-year survival in more than 80%.
3 Patients with del17p (lacking the tumor suppressor protein p53) are considered as high-risk and do
not respond satisfactorily to FCR. In this cohort, a
promising strategy is the use of alemtuzumab, a fully
humanized IgG1 antibody, which targets the CD52
cell-surface antigen expressed on most B- and T-cell
lymphomas, either on its own or in combination with
other drugs.
Other newer therapies include:

lenalidomide, an immunomodulatory drug more
commonly used in myeloma
flavopiridol, a synthetic flavon that targets cyclindependent kinases
consideration of allogeneic transplantation.
Richter transformation in CLL
Large-cell transformation (the Richter syndrome) may
occur in one or several lymph nodes. This is accompanied
by systemic symptoms of weight loss and night sweats, and
laboratory tests demonstrate raised LDH levels. The histology resembles diffuse, large B-cell lymphoma and intensive
treatment is necessary in common with large cell lymphoma.
Monoclonal B-cell lymphocytosis (MBL)

This condition is defined as <5 w 109/L monoclonal
B-lymphocytes in the peripheral blood with an immunophenotype identical with CLL. There is absence of lymphadenopathy, splenomegaly, cytopenias or symptoms related
to the disease. MBL may progress to CLL at a rate of 12%
per year. No specific intervention is necessary.
Prolymphocytic leukemia
Patients present with high peripheral blood lymphocyte
counts and splenomegaly. Anemia and thrombocytopenia
are also common. The typical appearance on a film is of
large cells with abundant cytoplasm and a prominent nucleolus. Treatment includes intensive chemotherapy, radiotherapy and sometimes splenectomy.
Hairy cell leukemia

Hairy cell leukemia (HCL) is more prevalent in males
(male:female ratio is 4:1).
Patients present with splenomegaly, neutropenia and
monocytopenia. Anemia and thrombocytopenia may
occur due to bone marrow infiltration and splenic
sequestration.
Diagnosis is established by the presence of large lymphocytes with abundant cytoplasm and hairy villous
projections (Figure 14-7, overleaf).
Bone marrow biopsy reveals diffuse infiltration with a
clear zone around each cell. The immunophenotype is
typically CD5, FMC7+, CD25+ and CD123+.
Differential diagnosis includes HCL variant, characterized by a high lymphocyte count and splenomegaly, and
splenic lymphoma with villous lymphocytes (SLVL).
Neither HCL variant nor SLVL express CD25 and
CD123.
Splenectomy and interferon-alpha are well-established
treatments but have been replaced by the use of the purine
nucleoside analogs cladribine and pentostatin.
These drugs achieve an overall complete remission rate
of over 80% and median relapse-free survival in excess
of 15 years.
Relapsing patients respond to retreatment and addition
of rituximab (monoclonal antibody against CD20).
433
In situ hybridization is also performed, as required,

to detect viral integration (e.g. EpsteinBarr virus in
aggressive diffuse large B-cell and Burkitts lymphoma)
and gene alterations (e.g. cyclin D1 in mantle-cell
lymphoma).
Tissue samples should be collected in the absence of
fixative, and immunophenotyped by flow cytometry.
Staging
Full blood count, electrolytes, creatinine, liver function tests,
LDH and bone marrow biopsy are commonly performed.
Anatomical staging is conventionally done with CT
tomography and described using the Ann Arbor system
(Table 14-11). Increasingly, positron emission tomography
(PET) imaging is also incorporated in the staging algorithm.

Figure 14-7 Blood lm of hairy cell leukemia; note
the large lymphocytes with abundant cytoplasm
Management of DLBCL is individualized based on performance status, age, stage and the International Prognostic
Index risk group (Box 14-9).
From Hoffbrand AV, Pettit JE and Vyas P. Color atlas of clinical

hematology, 4th edn. Philadelphia: Elsevier, 2010.
Patients commonly experience fever and neutropenia in the

immediate period following nucleoside analogs, and need
supportive care. Prophylaxis with co-trimoxazole and acyclovir (aciclovir) is also suggested.
NON-HODGKIN LYMPHOMAS
These comprise a diverse group encompassing malignancies arising from clonal B cells or T cells and with a clinical
spectrum extending from indolent low-grade disease to an
aggressive phenotype.
Certain viruses are implicated in the pathogenesis of
some of the lymphomas:
human herpesvirus 8 in lymphoma, Kaposis sarcoma
and multicentric Castleman disease
hepatitis C virus in splenic marginal zone lymphoma
and essential mixed cryoglobulinemia
human T-cell lymphotropic virus type I (HTLV-I) in
adult T-cell leukemia/lymphoma (ATLL)
EpsteinBarr virus in endemic Burkitts lymphoma and
post-transplant lymphoproliferative disease.
Localized chronic antigenic stimulation by Helicobacter pylori
is implicated in the development of mucosa-associated lymphoid tissue (MALT) lymphoma.
A number of recurrent genetic alterations have implicated oncogenes in the pathogenesis of non-Hodgkin
lymphomas.
Table 14-11 Ann Arbor staging system (with

Cotswold modications A, B, E and X)
Stage I
Involvement of a single lymph-node region or

extralymphatic site
Stage II
Involvement of two or more lymph-node

regions on the same side of the diaphragm;
localized contiguous involvement of only one
extralymphatic site and lymph-node region
(IIE)
Stage III
Involvement of lymph-node regions or

lymphoid structures on both sides of the
diaphragm
Stage IV
Disseminated involvement of one or more

extralymphatic organs with or without lymphnode involvement
Any involvement of liver or bone marrow
No symptoms
Unexplained weight loss of >10% of

bodyweight during the 6 months before
staging investigation
Unexplained, persistent, or recurrent fever
with temperatures >38C during the previous
month
Recurrent drenching night sweats during the
previous month
Localized, solitary involvement of

extralymphatic tissue, excluding liver and
bone marrow
Largest deposit is >10cm (bulky disease),

orthe mediastinum is wider than one-third
ofthe chest on a chest X-ray
Diagnosis
Adequate tissue sample from a core biopsy or an excision biopsy is required. The tissue sample is processed
for histology, including immunochemistry for proteins
specific to each disease.
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Box 14-9
International Prognostic Index for

aggressive lymphoma
Prognostic factors: one point awarded to each if
present
Age >60 years
Ann Arbor stage III or IV
Raised serum lactase dehydrogenase
ECOG* performance score >2
Involvement of more than one extranodal site
Scoring
Very good risk (0 prognostic factors): 4-year survival
of 94%
Good risk (12 prognostic factors): 4-year survival of 80%
Poor risk (3 or more prognostic factors): 5-year survival
of 55%
* ECOG, Eastern Cooperative Oncology Group scale (now the
World Health Organization Performance Scale), in which 0
indicates that the patient has no symptoms; 1 indicates that
the patient has symptoms but is ambulatory; 2 indicates that the
patient is bedridden less than half the day; 3 indicates that the
patient is bedridden half the day or longer; and 4 indicates that
the patient is chronically bedridden and requires assistance with
the activities of daily living.
Data from The International Non-Hodgkins Lymphoma
Prognostic Factors Project. A predictive model for aggressive
non-Hodgkins lymphoma. N Engl J Med 1993;329:98794.
Treatment
Non-bulky localized disease (stage I): dual modality
therapy comprising 4 cycles of R-CHOP (rituximab,
cyclophosphamide, adriamycin, vincristine and prednisolone) and involved-field radiotherapy are generally adequate and confer a 5-year overall survival of above 90%.
Stages IIIV are best managed with 68 courses of
R-CHOP with additional radiotherapy to any site
of bulky disease (>10 cm). Relapse requires intensive
salvage therapy followed by stem-cell collection and
transplantation.

Double hit lymphomas are defined by a chromosomal
breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a
t(14;18)(q32;q21) involving BCL2.
DH lymphomas often have a complex karyotype with
many additional genetic alterations.
The prognosis is generally poor, with a median overall
survival of only 0.21.5 years.
Burkitts lymphoma
Burkitts lymphoma is aggressive. There are three subtypes:
1 The endemic variant is associated with malaria endemicity and EpsteinBarr virus (EBV) is found in almost
all cases; the variant comprises about half of all cancers

diagnosed in childhood.
2 The sporadic type occurs in the rest of the world, being
mainly predominant in North America and Europe.
The median age at diagnosis is 68 years; it is rarely
associated with EBV infection.
3 The immunodeficiency-related type is seen most often
in patients with HIV infection. Less than 40% of US
and European cases are associated with EBV.
Patients with endemic Burkitts lymphoma most frequently
present with jaw or periorbital swellings, or abdominal
involvement. The most common presentation of sporadic
BL is as an abdominal mass followed by lymphadenopathy
in the neck, and involvement of tonsils and sinuses.
Diagnosis
Diagnosis is made by the observation of intermediate-size
cells containing coarse chromatin and prominent basophilic
nucleoli. Macrophages ingesting apoptotic cells against a
deep basophilic cellular background give the appearance of
a starry sky.
Diagnosis is confirmed by immunophenotype and
demonstration of translocations involving the MYC gene
and heavy [t(8;14)] or light [t(2;8) or t(8;22)] chains of
immunoglobulin.
Treatment
BL has an excellent cure rate and survival in children, with
the use of intensive multi-agent chemotherapy. Combinations such as such as CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin and methotrexate, alternating
with ifosfamide, mesna, etoposide and cytarabine) are frequently used in adults.
Resection plays an important role in children with limited stage I disease.

Follicular lymphoma is generally an indolent B-cell lymphoproliferative disorder of transformed follicular-center Bcells.
The median age of presentation is 5560 years.
FL is characterized by diffuse lymphadenopathy and
bone marrow involvement is common.
In general, cytopenias can occur but constitutional
symptoms of fever, night sweats and weight loss are
uncommon.
Diagnosis is based on histology of, preferably, biopsy of a
lymph node.
Immunohistochemical staining is positive in virtually allcases for cell-surface CD19, CD20, CD10 and
monoclonal immunoglobulin, as well as cytoplasmic
expression of bcl-2 protein.
The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 gene.
The Follicular Lymphoma International Prognostic Index
(FLIPI) prognostic model uses five independent predictors
of inferior survival:
435
1 age >60 years

2 hemoglobin <12 g/dL
3 serum LDH > normal
4 Ann Arbor stage III/IV
5 number of involved nodal areas >4.
The presence of 01, 2 and 3 adverse factors defines low,
intermediate and high-risk disease respectively.
The median 10-year survival rates in the pre-rituximab
era approximately was 71, 51 and 36 months, respectively.
Addition of rituximab has considerably improved outcomes.
Treatment
Low-volume asymptomatic disease requires monitoring
only.
Localized stage I disease responds well to involved-field
radiotherapy.
Advanced-stage lymphoma is now treated with rituximab plus chemotherapy combinations such as CVP
(cyclophosphamide, vincristine and prednisolone).
The use of fludarabine together with rituximab and
alkylating agents is increasing. Addition of maintenance
rituximab has demonstrated improved survival.
Autologous stem cell transplant and allogeneic stem cell
transplant should be considered in suitable patients.

Patients with MCL have a median age in their 60s and male
predominance (2:1). Patients generally have stage III/IV
disease and present with:
extensive lymphadenopathy
blood and bone marrow involvement
splenomegaly.
Approximately 50% have gastrointestinal involvement.
Morphological appearance is typically of monomorphic
small to medium-sized lymphoid cells with irregular nuclear
contours.
The hallmark chromosomal translocation t(11;14) identifies MCL. The oncogene on chromosome 11 is CCND1
and encodes a D-cyclin involved in cell-cycle control.
As standard therapy does not cure patients with MCL,

a watch and wait strategy is appropriate for elderly
patients with asymptomatic disease.
Cutaneous lymphomas
Primary cutaneous lymphomas are a heterogeneous group
of extranodal non-Hodgkin lymphomas.
In contrast to nodal non-Hodgkin lymphoma, most of
which are B-cell-derived, approximately 75% of primary
cutaneous lymphomas are T-cell-derived (cutaneous
T-cell lymphoma, CTCL), two-thirds of which may be
classified as mycosis fungoides (MF) or Szary syndrome (SS).
The incidence of CTCL increases significantly with
age, with a median age at diagnosis in the mid-50s and a
four fold increase in incidence in patients over 70 years.
The cell of origin:
in SS is the central memory T cell
in MF is the effector memory T cell.
MF is frequently characterized by clinical stages of cutaneous disease comprising patch/plaques, tumors and
erythroderma with extensive skin involvement.
Patch/plaque lesions develop in a bathing suit distribution and vary in size, shape and color. These
lesions are frequently large (>5 cm), pruritic and
multifocal.
SS is defined as a leukemic form of CTCL associated
with erythroderma.
Staging
Staging by TNMB (tumor, node, metastasis and blood)
remains an important prognostic factor in MF and SS.
Patients with only patches and plaques have:
stage IA (<10% body surface area involved, or T1)
stage IB (>10% body surface area involved, or T2).
For practical purposes, the area of one hand (including both palm and digits) represents approximately
1% of body surface area.
Further stages depend on:
lymph node involvement
erythroderma
leukemic involvement.
Treatment
Combination of rituximab with the CHOP regimen
(cyclophosphamide, doxorubicin, vincristine and prednisolone) or bendamustine may be given for symptomatic
patients in this age group.
Younger patients need aggressive treatment.
The most widely used regimens include R-HyperCVAD (rituximbab, cyclophosphamide, vincristine,
doxorubicin and dexamethasone) with high-dose
cytarabine ( methotrexate) or R-CHOP (rituximab
CHOP) followed by autologous stem cell transplant.
Mantle cell lymphoma may respond to initial treatments but
relapses are frequent.
The median duration of remission is 1.53 years and
the median overall survival is 36 years with standard
chemotherapy.
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Treatment
Early-stage disease is managed with topical therapy (steroids, nitrogen-mustard, carmustine) and with PUVA
(psoralen with ultraviolet radiation) and narrow-band
ultraviolet A (NB-UVA).
Systemic chemotherapy is reserved for advanced-stage
disease, using methotrexate, doxorubicin, retinoids,
and bexarotene combined with denileukin diftitox
(immunotoxin).
HODGKIN LYMPHOMA (HL)

Hodgkin lymphoma most frequently affects young adults
in the age group 1529 years. The incidence is about 3 per
100,000 in resource-rich countries. A previously reported
second peak of incidence in older adults is probably due to

misclassification of non-Hodgkin lymphomas.
Familial HL represents 4.5% of all newly diagnosed
cases. HLA associations have been described in familial HL,
including HLA A1, B5, B18, DPB1, DRB1, DQA1 and
DQB1.

Based on cellular composition, HL can be divided into classic HL, which is the most common (95%), and nodular
lymphocyte-predominant HL (NLPHL). It is important to
distinguish between the two categories, since they differ in
prognosis and treatment options.
Sub-classification of classic HL is described in Box
14-10.
In classic HL, the tumor cells are designated Hodgkin
and ReedSternberg (HRS) cells, while in NLPHL they are
now called LP (lymphocyte-predominant) cells.
Detection of clonally rearranged immunoglobulin V
(IgV) heavy chain and light chain genes confirm the origin of HRS cells from mature B cells at a germinal center
(GC) or post-GC stage of differentiation. However, several of the classic cell-surface markers and transcription
factors that are present in B cells are not detectable in
HRS cells, and the molecular basis for re-programming
of B cells to the HRS phenotype remains unclear.
Molecular profiling of LP cells suggests that they resemble GC B cells but have already acquired features of
memory B cells, indicating that these cells may derive
from late-GC B cells at the transition to memory
B cells.
HRS cells thrive in a microenvironment that is enriched
for B and T cells, plasma cells, eosinophils and plasma
cells. HL is unique among all cancers because malignant
cells are greatly outnumbered by reactive cells in the
tumor microenvironment and make up only approximately 1% of the tumor.
Expression of a variety of cytokines and chemokines
by the HRS and LP cells is believed to be the driving
force for an abnormal immune response, inflammatory environment, and the maintenance of a malignant
phenotype.
EpsteinBarr virus DNA and peptides can be identified
in 20100% of HRS cells, and EBV is probably implicated in the disease process.
Box 14-10
World Health Organization

classication of Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma

(NLPHL) (5%)
Classic Hodgkin lymphoma (95%)
Nodular sclerosing
Mixed cellularity
Lymphocyte-rich
Lymphocyte-depleted
Immunosuppressive states such as HIV increase the risk

of developing HL; however, the risk surprisingly does
not correlate with low CD4 count, and the incidence
of HL has actually increased with the introduction of
highly active antiretroviral therapy and improvement in
CD4 cell counts. HIV-associated HL is usually mixed
cellularity or lymphocyte-depleted, is of advanced stage
at diagnosis, and has a near-universal association with
EBV infection.
Immunophenotype
The presence of CD30 and CD15 identify HRS from
LP cells (where these markers are usually absent).
In classic HL, a minority of HRS cells express CD20 to
a variable intensity. EBV antigens (EBNA, LMP1) can
be detected in HRS cells.
In contrast, LP cells exhibit their B-cell origin more
prominently than HRS by the expression of several
B-cell markers, including CD20 and Ig.
Staging
The Cotswold modification maintains the original fourstage clinical and pathological staging framework of the Ann
Arbor staging system, but also adds information regarding
the prognostic significance of bulky disease (denoted by an
X) and regions of lymph-node involvement (denoted by
an E) see Table 14-11. The A and B designations denote
the absence or presence of symptoms, respectively; the
presence of symptoms correlates with treatment response.
The importance of imaging modalities, such as computed
tomography (CT) scanning, is also underscored.
Risk stratication
Based on the clinical scenario, staging and degree of endorgan damage, patients with HL can be categorized into the
following three groups:
1 early-stage favorable
2 early-stage unfavorable (bulky and non-bulky)
3 advanced stage.
This classification affects treatment selection and so must be
performed carefully in every patient with HL.
Patients with advanced disease are further risk-stratified
using the International Prognostic Score (IPS), which
includes the following risk factors. For each factor present,
the patient receives 1 point.
Albumin <4 g/dL (<40 g/L)
Hemoglobin <10.5 g/dL (105 g/L)
Male
Age 45 years
Stage IV disease
Leukocytosis: white blood cell (WBC) count > 15,000/
microL
Lymphopenia: lymphocyte count <8% of WBC count
and/or absolute lymphocyte count <600 cells/microL
437
Based on the IPS score, patients with advanced disease can

be categorized as follows:
good riskIPS 01
fair riskIPS 23
poor riskIPS 47.
Treatment
Treatment options for classic HL
Good-risk classic HL is now a curable disease in most
patients. Treatment options are determined by stage (early/
advanced) and risk factors.
Early-stage disease with favorable risk factors is managed with 23 cycles of chemotherapy (most commonly
the combination of doxorubicin, bleomycin, vinblastine
and dacarbazine, ABVD) with involved-field radiotherapy (up to 30 Gy).
Advanced-stage disease with a poor risk score needs
intensive chemotherapy. Common regimens include
68 courses of ABVD and BEACOPP (bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine and prednisolone given as standard dose
or with dose escalation). Bulky sites (>10cm in diameter) need supplementation with radiotherapy.
Relapsed disease needs intensive salvage chemotherapy,
mobilization of peripheral blood stem cells, followed by
autologous stem cell transplantation.
Treatment options for nodular lymphocytepredominant HL
This entity is different from classic HL in terms of its biology and prognosis, and has a better prognosis than classic
HL. Patients commonly present early with limited-stage
disease and the natural history is that of an indolent, relapsing nature. Less aggressive approaches are preferred.
Localized disease may need radiotherapy to the involved
region.
Advanced disease requires combination chemotherapy
with the inclusion of rituximab (anti-CD20 antibody).
PLASMA CELL DISORDERS

The characteristic feature is the proliferation of a single
clone of plasma cell that produces a monoclonal protein
(M-protein). The disease spectrum extends between monoclonal gammopathy of uncertain significance, asymptomatic
myeloma, symptomatic multiple myeloma, and plasma cell
leukemia. Prognosis and initiation of therapy depend on the
disease category.

signicance (MGUS)
Also known as benign monoclonal gammopathy, MGUS
increases in frequency with advancing age and has a prevalence of approximately 5% at the age of 70 years. It is
defined by the presence of:
serum M-protein of <30g/L
438
<10% plasma cells in the bone marrow

absence of organ damage caused either by proliferation
of plasma cells or by toxicity of M-protein (relatedorgan tissue injury, ROTI)
no evidence of any other B-lymphoproliferative
disorder.
MGUS is a benign disease with an annual rate of progression
to myeloma of approximately 1%. There is no need to treat,
and management is usually 6- to 12-monthly review with
quantification of M-protein, renal function and other tests
for organ damage.
Also known as smoldering myeloma, this is an intermediate
stage defined by:
M-protein >30g/L, and/or
10% or more plasma cell infiltration in the bone marrow
without evidence of ROTI.
Treatment decisions need to be individualized; close monitoring alone is acceptable based on the level of M-protein and
the degree of plasma cell infiltration in the bone marrow.
Symptomatic myeloma
This stage is defined by the presence of ROTI (Table 14-12),
including:
Pancytopenia due to extensive plasma-cell proliferation
Nephrotoxicity
cast nephropathy due to accumulation of excreted
light chains in the renal tubules
glomerular deposition of immunoglobulin (light
and/or heavy chains)
osteolysis causing hypercalcemia
Hyperviscosity (secondary to M-protein)
Immune-deficiency states due to the suppression of
normal immunoglobulin production
Table 14-12 Related-organ tissue injury (ROTI) in
myeloma
Increased calcium
level
Corrected serum calcium

>0.25mmol/L above the upper limit
of normal, or >2.75mmol/L
Renal
insufficiency
Creatinine >173mmol/L
Anemia
Hemoglobin <100g/L, or 20g/L

below the lower limit of normal
Bone lesions
Lytic lesions, or osteoporosis with

compression fractures on magnetic
resonance imaging or computed
tomography
Other
Symptomatic hyperviscosity,
amyloidosis, recurrent bacterial
infections (>2 episodes in 12
months)
Skeletal involvement is a particularly common feature,

including:
osteoporosis
discrete osteolytic lesions.
An important pathogenetic mechanism for osteolysis is the
secretion of RANK-L (receptor activator of NF-kappaB
ligand), a potent activator of osteoclast activity.
Almost one-third of patients with myeloma are anemic
at presentation; neutropenia and thrombocytopenia are less
frequent. The etiology of anemia includes
extensive bone-marrow infiltration with plasma cells
renal impairment.
Box 14-11 outlines the initial diagnostic work-up.

Prognostic markers at diagnosis identify high-risk patients
for stratification to more intensive therapy, while sparing
those who may do well without intensification.
The International Prognostic Index model utilizes serum
beta2 microglobulin (B2M) and albumin. This can create
three prognostic groups:
Stage I includes those with serum B2M <3.5mg/L and
serum albumin >35g/L. Median survival is 62 months.
Stage II is the intermediate category when criteria for stages I and III are not met. Median survival is
45months.
Stage III contains patients with serum B2M >5.5mg/L.
Median survival is 29 months.
Box 14-11
Initial diagnostic work-up in

myeloma
Full blood count and blood lm examination

Biochemistry including electrolytes, renal function,
calcium, phosphate, lactate dehydrogenase, liver
function tests
Beta2 microglobulin
Serum protein electrophoresis (SPEP) and
immunoxation electrophoresis (IFE)
24-hour urine collectionprotein excretion, creatinine
clearance, BenceJones protein
Serum free light chain (SFLC)
Bone marrow aspirate and trephine
Cytogenetics (if percentage of plasma cells in the
aspirate is >15%)
FISH for: t(4;14), t(14;16), 17p del, 1q21 amplication
Skeletal imaging by X-ray, MIBI scan or MRI (in selected
cases with back pain, suspected vertebral fractures or
solitary plasmacytoma)
Bone densitometry (in selected cases with suspicion of
osteoporosis)
FISH, uorescence in situ hybridization; MIBI,

methoxyisobutylisonitrile; MRI, magnetic resonance imaging.
Chromosomal abnormalities, including deletion (del) 17p

and t(4;14) and t(14;16), also carry poor prognosis.
Myeloma is incurable. The therapeutic aim is to maintain response and avoid complications of the disease and
treatment.
Treatment is indicated only for symptomatic myeloma
with evidence of ROTI. Patients needing treatment are
stratified based on the feasibility of autologous stem-cell
transplantation.
The best outcome in patients eligible for autologous
transplant is with induction therapy to achieve as deep
a remission as possible, followed by high-dose therapy
and autologous stem-cell transplant. This approach
maximizes the progression-free survival and overall
survival.
Induction therapy includes steroids, cyclophosphamide, thalidomide and newer drugs such as
revlimid and bortezomib (a proteasome inhibitor).
Peripheral blood stem cells are collected after mobilization with granulocyte-colony stimulating factor, followed by high-dose melphalan and stem-cell
re-infusion.
Evlimid, thalidomide and corticosteroids are also
used as maintenance therapy after transplantation to
improve the event free and overall survival.
A combination of corticosteroids, melphalan and thalidomide is effective as initial therapy in patients who
are not fit for autologous transplantation. Relapsed
myeloma can be treated with drugs such as revlimid
and bortezomib, especially if they have not been used
in prior cycles of chemotherapy. Treatment with anthracyclines and vincristine is now less commonly used as
initial therapy.
Other modalities of treatment include radiotherapy for
osteolytic areas and spinal cord compression, and surgical fixation of pathological fractures.
Allogeneic stem cell transplantation is an option for a very
select group of relapsed patients.
Supportive therapy
Erythropoietin may improve the anemia in myeloma.
Bisphosphonates have demonstrated benefit in:
reducing bone pain
reducing the number and delaying the onset of
fractures
reducing hypercalcemia.
1 Benign monoclonal gammopathy.
2 Waldenstroms macroglobulinemia, a lymphoplasmacytic lymphoma resulting in overproduction of IgM,
characterized by:
a monoclonal IgM peak on the electrophoretogram
b splenomegaly and anemia
c frequently, hyperviscosity.
439
ANEMIA
Anemia is defined as reduction in hemoglobin levels below
the normal range appropriate for age and gender. While the
diagnosis of anemia is made on laboratory criteria, the
impact of the condition is modified by clinical parameters:
for example mild anemia may cause more symptoms when
coexistent with coronary artery disease or lung disease. Most
anemias can be diagnosed by a combination of history, physical examination and the common laboratory parameters of:
mean red cell volume
red cell morphology (Figure 14-8)
reticulocyte count.
Etiological descriptors of anemias comprise the following.
1 Disorder of production:
a Bone-marrow failure, e.g. aplastic anemia, red
cell aplasia
b Decreased erythropoietin, e.g. chronic renal
impairment
2 Disorder of maturation:
a Nuclear maturation defects: B12 or folate
deficiency, myelodysplasias
b Cytoplasmic maturation defects, e.g. iron deficiency, thalassemias
3 Decreased survival:
a Inherited defects, e.g. spherocytosis, G6PD
deficiency, sickle-cell anemia
b Acquired defects, e.g. autoimmune hemolysis,
malaria, DIC, TTP
4 Sequestration in spleen: e.g. hypersplenism
5 Blood loss: e.g. gastrointestinal hemorrhage, perioperative bleeding
Figure 14-8 Blood lm of iron-deciency anemia;

note the pale, small cells and variability in cell size
(anisocytosis) and shape (poikilocytosis)
From Bain BJ et al. Dacie and Lewis Practical Haematology, 11th ed.
Elsevier, 2012.
The full work-up for anemia diagnosis is given in Table

14-13, and differential diagnosis is outlined in Table 14-14.

The etiology of iron-deficiency anemia in a female of
childbearing age is usually a combination of diet, multiparity in quick succession, and menstrual blood loss.
Occasionally, malabsorption syndromes may be present.
Management usually requires just the replenishment of
iron stores.
Iron deficiency in an older person should be regarded
as a sign of another underlying disease; in resourcerich countries, particular attention should be made to
exclude a source of gastrointestinal bleeding.
Causes of iron deficiency are listed in Box 14-12 (overleaf).
Stages of iron deciency
Common laboratory tests used for

diagnostic work-up
Full blood examination (FBE) is used to ascertain the
following:
Hb: indicates the severity of the anemia
mean cell volume (MCV): demonstrates microcytosis,
macrocytosis or normocytosis
WBC count and platelets: indicate whether anemia is
a part of pancytopenia or other primary bone-marrow
conditions including leukemia, or an infiltrative
disorder
blood film: typical appearances of red cells give clues to
the diagnosis, e.g. sickle cells
reticulocyte count: indicates the presence of compensatory erythropoiesis
hemolytic parametersserum LDH, haptoglobin,
bilirubin
direct Coombs test: to detect autoimmune hemolysis
Hb electrophoresis: for diagnosis of thalassemia.
440
Anemia occurs only after persistent depletion of iron stores.

The preceding events sequentially progress through:
biochemical depletion of iron stores (normal Hb and
MCV, reduced ferritin)
iron-deficient erythropoiesis (normal Hb, with fall in
transferrin saturation, MCV reduced or normal, and
low ferritin)
iron-deficiency anemia (microcytic and hypochromic
red cells with falling Hb, increased transferrin, decreased
transferrin saturation and low ferritin).
Systemic effects of iron deciency

Persistent and severe iron deficiency may result in extrahemopoietic manifestations, which include:
brittle and ridged nails (koilonychia)
angular stomatitis
thinning hair
glossitis
pharyngeal webs with dysphagia (PatersonKelly
syndrome).
Table 14-13 Anemia work-up
PARAMETERS
History
Examination
Red cell size and

hemoglobinization
INTERPRETATION
Diet (meat and green vegetables)
Risk of malnutrition if lacking: suggests susceptibility to iron

and folic acid deciency
Blood loss
Obvious gastrointestinal bleeding

Chronic subclinical blood loss, e.g. NSAIDs, colon polyps,
hereditary telangiectasias, menorrhagia
Gastrointestinal surgery
Gastrectomy or ileal resection: vitamin B12 deciency

Small-bowel resections: iron, folate deciency
Comorbidity
Chronic infections and inammatory disorders suggest risk of

anemia of chronic disease
Pallor
Severity of anemia
Icterus
May suggest hemolysis
Lymphadenopathy, hepatomegaly,
splenomegaly, bone tenderness
Coexistence of another primary hematological disorder
Evidence of portal hypertension
Hypersplenism and potential for variceal bleed
Microcytic hypochromic
Iron deciency
Thalassemia
Sideroblastic anemia
Normocytic
Acute bleeding
Bone-marrow inltration
Aplastic anemia
Renal failure
Macrocytic
Vitamin B12/folate deciencies

Myelodysplasia
Medication effects
Other medical conditions: hypothyroidism, liver impairment
NSAIDs, non-steroidal anti-inammatory drugs.
Table 14-14 Differential diagnosis of microcytic hypochromic anemia
IRONDEFICIENCY
ANEMIA
PARAMETER
ANEMIA OF
CHRONIC
DISEASE
THALASSEMIAS
SIDEROBLASTIC
ANEMIA
MCV
r/N
r/N
Serum iron
r /N
TIBC
r/N
Serum transferrin
receptor
N/p
Serum ferritin
p/ N
Serum hepcidin
N/r
Bone-marrow iron
stores
p/ N
p/ N
p/ N
Ring sideroblasts
MCV, mean cell volume; N, normal; TIBC, total iron-binding capacity
441
Box 14-12
Causes of iron deciency

Inadequate intake
Veganism, dietary choices
Inadequate absorption
High gastric pH or antacid therapy
Excess tannins and phytates in diet
Bowel resection
Celiac disease
Increased physiological requirement
Pregnancy and breastfeeding
Infancy, puberty
Increased loss
Gastrointestinal blood loss
Genitourinary blood loss
Menorrhagia
Operative blood loss
Parasitosis
Trauma
Excessive phlebotomy
Impairment of bacterial killing by neutrophils and impaired

cell-mediated immunity can also occur.

Oral iron supplementation is the most convenient treatment if the patient is adherent and there are no ongoing
losses. All iron preparations are similarly absorbed, and
the usual dose is 105mg/day elemental iron or 325mg/
day ferrous sulfate. Higher doses often cause gastrointestinal intolerance, which may limit adherence.
Parenteral iron preparations should be reserved for
patients who are intolerant of oral supplements, those
with malabsorption syndromes, and for patients with
ongoing losses and large store deficits. Iron polymaltose
is available as a deep intramuscular injection. Particular
attention to the injection technique is essential, as leakage under the skin leads to prolonged discoloration.
Iron dextran and iron sucrose preparations are available
for intravenous infusions. Potential side-effects of intravenous preparations include allergic reactions that may
extend to anaphylaxis, so should only be administered
under close medical supervision.

The underlying pathogenesis of the anemia of chronic
disease is the suppression of erythropoiesis by a variety of
mechanisms in the context of prolonged systemic illness or
inflammation. Commonly associated conditions are:
infections
cancers
442
autoimmune disease
the chronic inflammatory state that contributes to the
anemia of aging.
The main pathogenetic mechanisms include the suppression
of erythropoiesis by:
inflammatory cytokines (tumor necrosis factor alpha,
interleukin-1)
reduced erythropoietin production as a response to
anemia
a relative inhibition of the proliferative capacity of the
erythron in response to the available erythropoietin.
Hepcidin is now considered to be the key mediator of this
condition. Hepcidin levels are increased as a consequence of
inflammatory signaling, and hepcidin leads to inhibition
of iron absorption by the enterocytes and sequestration of
iron within the hepatocytes and macrophages.
Diagnosis is suggested by the presence of:
microcytic hypochromic indices
elevation of inflammatory markers (e.g. C-reactive
protein)
raised ferritin levels.
Two advances to improve diagnostic specificity include:
the measurement of soluble transferrin receptor (sTFR).
An sTFR/ferritin ratio of <1 makes anemia of chronic
disease likely
quantification of hepcidin levels, which are elevated in
this condition and reduced in iron-deficiency anemia.
Treatment should be directed toward correction of the
underlying condition. Iron supplementation is generally
without effect. Erythropoiesis-stimulating agents should be
used with caution, as increased cardiovascular events and
thrombotic episodes have been observed. There is also concern about tumor progression when used in patients with
active malignancy.
Thalassemias
The thalassemias are a group of hereditary anemias due to
impairment in the synthesis of one of the polypeptide globin
chains, alpha and beta, resulting in alpha-thalassemia and
beta-thalassemia.
Each Hb molecule in adults (HbA) contains two alpha
and two beta chains, denoted F2G2. Stable HbA requires the
presence of F- and G-globin dimers which combine to form
a tetramer. Imbalances in the proportion of F- or G-globins
results in unstable HbA.
There are two genes for F-globin on each chromosome
16, giving four genes in total as autosomes exist as pairs.
The globin product from each gene is identical, and thus
each gene contributes to one-quarter of the product.
The G-globin locus on chromosome 11 contains several
genes that are sequentially arranged and synthesize globin chains during specific stages of development.
The J gene is expressed in early embryogenesis, followed by
the L gene during fetal development. Thus fetal Hb (HbF)
is F2L2. Just prior to birth there is a progressive switch to
synthesis of G-globins, and L-globin synthesis reciprocally
diminishes. However, L-globin synthesis is not completely

lost and most adults contain traces (<2.0%) of HbF. Persistence of HbF in some patients with beta-thalassemia has
the capacity to ameliorate the severity of the phenotype.
Alpha-thalassemias
Deletion of one out of the four F-globin genes does not
lead to a hematological abnormality; this is a silent carrier state.
Deletion of two genes causes mild microcytic anemia.
Southeast Asian populations with two-gene deletion
often carry both deleted genes on the same chromosome. There is increased risk of the occurrence of
severe alpha-thalassemia syndrome (HbH disease) with
coinheritance from the other parent of a single gene
deletion, and of hydrops fetalis with coinheritance of a
two-gene deletion.
HbH disease (three-gene deletion) is manifested as
moderately severe microcytic anemia. Excess G-globins
cause Hb instability and precipitate, leading to removal
by the spleen and hemolysis.
Deletion of four genes causes hydrops fetalis, with stillbirth or death in the early postnatal period.
Beta-thalassemias
Mutations may either completely block G-globin production
or may dampen it.
Loss of one G-globin gene leads to thalassemia trait, presenting as mild microcytic hypochromic anemia.
Thalassemia major results from the deletion of both
G-globin genes. The fetus and newborn infant are normal, as L-globin synthesis is unaffected and HbF contains F2L2. As the postnatal switch from L-chains to
G-chains occurs, there is development of severe anemia
with symptoms of pallor, growth retardation and hepatosplenomegaly due to extramedullary hematopoiesis.
Typical morphology includes:
microcytosis
target cells
poikilocytosis
precipitation of excess F-globin aggregates visible
on supravital stain
the presence of nucleated red cells.
Diagnosis and treatment

Additional laboratory tests for the work-up of thalassemia
include the quantification of HbF, HbA2 (F2I2), Barts Hb
(L4) and HbH (G4) on Hb electrophoresis. Supravital stain
demonstrates precipitated excess G-globin in HbH disease
and hydrops fetalis, and excess F-globin in beta-thalassemia
major.
Treatment of the thalassemias involves a red cell transfusion program and iron chelation.
This group of disorders is characterized by the presence of
at least 15% ring sideroblasts, which are erythroblasts that
contain more than four perinuclear iron granules covering

one-third or more of the nuclear circumference.
These anemias occur as inherited or acquired forms.
Inherited sideroblastic anemias are either X-linked due to
mutations in the delta-aminolevulinate synthase 2(deltaALAS2) locus or to mutation in the ATP-binding
cassette transporter gene (ABCB7), or autosomal.
CLINICAL PEARL
Delta-aminolevulinate synthase 2 (delta-ALAS2) catalyzes heme biosynthesis and utilizes pyridoxal phosphate as a cofactor; hence anemia due to mutations in
delta-ALAS2 is responsive to dietary supplementation
with pyridoxine (vitamin B6).
ABCB7 mutations cause anemia and nonprogressive cerebellar ataxia due to iron toxicity to
neuronal mitochondria.
Autosomal sideroblastic anemias result from mutations of several genes important in mitochondrial
heme synthesis. One of the mutations is in the gene
SLC192A that encodes a thiamine transporter, and
the anemia can respond to supplementation with
excess thiamine.
Refractory anemia with ring sideroblasts is an acquired
sideroblastic anemia and a form of myelodysplasia.
Causes of secondary sideroblastic anemias include:
drugs (isoniazid, chloramphenicol)
lead poisoning
alcoholism with malnutrition.
Macrocytic anemias
Macrocytic anemias occur with or without features of
abnormal megaloblastic maturation. The diagnosis of megaloblastic differentiation can only be made after visualization of erythroid precursors on a bone marrow biopsy, or
in peripheral blood in the case of a leukoerythroblastic phenotype. Megaloblastic anemias are often due to cobalamin
(vitamin B12) and folate deficiencies; other causes of macrocytic anemia without megaloblastosis are hypothyroidism,
liver disease, alcoholism, and myelodysplasia.
Peripheral blood findings in megaloblastic anemias
(Figure 14-9, overleaf) are:
ovalomacrocytes with MCV >100fL
considerable anisocytosis
characteristic hypersegmentation of neutrophils (more
than 5 lobes).
Leukopenia, thrombocytopenia and leukoerythroblastic
appearance (Figure 14-10, overleaf) may also be noted.
Cobalamin (vitamin B12) deciency

Cobalamin deficiency results in neurological disturbances
as well as hematological abnormalities, which distinguishes
it from folate deficiency which has no neurological deficits.
Neurological and hematological disturbances do not necessarily occur together, and patients may display neurological
443
Figure 14-9 Blood lm of megaloblastic anemia. The

red arrows identify macrocytes and the blue arrow
indicates hypersegmentation of neutrophil
Teaching collection of Vicky Smith, ASH Image Bank 2014; 201416885. 2014 American Society of Hematology
Figure 14-10 Blood lm showing leukoerythroblastic

features. The red arrow identies a myelocyte and the
blue arrow a nucleated red cell
and the only available source is from food of animal origin.

The highest concentration of cobalamin is in liver and kidney,
and to a lesser extent in muscle meats and shellfish.
Cobalamin absorption proceeds through a number of
discrete steps involving the requirement of cofactors and a
functioning stomach and terminal ileum.
Almost all cobalamin is actively absorbed via the
terminal ileum in conjugation with intrinsic factor (IF).
Passive absorption of oral cobalamin through the gastrointestinal tract is less than 1%.
The stomach is vital to cobalamin absorption through
the secretion of free acid, pepsin and IF. Gastric acidity
facilitates the release of cobalamin from food complexes,
and free cobalamin binds with the R binder secreted in
the saliva. Pepsin produced in the stomach and duodenum releases cobalamin for the R-binder, and this conjugates with IF that is released by the parietal cells of the
stomach.
IF-bound cobalamin transits through the intestine.
Epithelial cells in the terminal ileum contain receptors
for IFcobalamin complex that mediate transfer to the
plasma, where it binds to the transport protein transcobalamin II (TCII). The TCcobalamin complex binds
to specific receptors present on the surface of target cells
and is taken up into the lysosome; cobalamin is then
released from TCII and transferred into the cytoplasm.
Cobalamin participates in two distinct cellular pathways, in
the mitochondria and in the cytoplasm proper.
1 Within the mitochondria, cobalamin catalyzes the
conversion of methylmalonyl-coenzyme A (CoA) to
succinyl-CoA, which is an important intermediate in
the Krebs cycle for energy production.
2 In the cytoplasm, cobalamin is essential for the synthesis
of homocysteine to methionine and the conversion of
5-methyl-tetrahydrofolate to tetrahydrofolate (THF).
THF is then converted to 5,10-methylene-THF, which
is important in DNA synthesis.
manifestations in the absence of anemia. The pathogenesis

includes:
peripheral neuropathy
demyelination of the posterior columns and pyramidal
tracts
optic atrophy
impaired cognition.
Typical symptoms include paresthesiae, weakness and gait
disturbance.
Bone marrow morphology in cobalamin deciency

During normal erythroid development, nuclear maturation
is seen as progressive condensation of the nucleus and then
loss of the nucleus as the cytoplasm of the erythroid progenitors acquire Hb and differentiate to ultimately form reticulocytes that exit the bone marrow. The characteristic finding
in cobalamin deficiency is dissociation between nuclear
and cytoplasmic maturation in the erythroid progenitors.
Nuclear maturation is delayed and the nucleus displays fine,
dispersed chromatin (open chromatin), while cytoplasmic
maturation and hemoglobinization proceed normally.
Other lineages are also affected, explaining the occurrence of pancytopenia. Metamyelocytes are typically large
and abnormal, and megakaryocytes are also large and hyperpolyploid. Severe megaloblastic changes may be confused
with acute erythroleukemia.
Cobalamin metabolism
The obligatory requirement of cobalamin is 2.4 microg/day.
The body stores 23mg which is adequate for 34 years even if
intake ceases. Vegetables and fruits do not contain cobalamin
Etiology of cobalamin deciency

Dietary cobalamin deficiency only occurs in strict vegans.
Cobalamin deficiency in a non-vegetarian diet is almost
always due to perturbations in the absorption process.
Hussain Said Baden, ASH Image Bank 2011; 2011-3926. 2011

American Society of Hematology.
444
Pernicious anemia
This is an autoimmune disease in which autoantibodies
directed against gastric parietal cell and IF cause chronic
atrophic gastritis. A familial predisposition exists for this
condition.
Pernicious anemia may occur in association with other
endocrine diseases such as Hashimotos thyroiditis, vitiligo
and Addisons disease. Pernicious anemia results in cobalamin deficiency by the process of neutralization of IF by
autoantibodies, and atrophic gastritis produces gastric achlorhydria which impairs the release of dietary cobalamin from
food complexes.
Chronic atrophic gastritis
This condition causes patchy gastritis extending from the
antrum. The main consequence is decreased acid and pepsin production, which impairs the release of cobalamin from
food complexes and also R-binder. There is no impairment
of IF production.
Structural defects in the gastrointestinal tract
Partial or total gastrectomy, or resection of the terminal
ileum, interrupts the cobalamin absorption pathway. Blind
loops of bowel result in bacterial overgrowth and high cobalamin demand. Crohns disease affecting the terminal ileum
impairs IFcobalamin absorption.
Tests for cobalamin deciency
Once reduced levels of vitamin B12 are detected, quantification in the serum of autoantibodies toward parietal cells (present in almost 90% patients, but less specific for pernicious
anemia) and IF (noted in approximately 55% cases, but more
specific for pernicious anemia) should be performed. This
will detect the vast majority of autoimmune cases of cobalamin deficiency. In rare cases, the Schilling test using radioactive cobalamin can be used to detect absorption defects.
Treatment of cobalamin deciency
Parenteral (intramuscular) replacement is effective. Tissue
stores are replenished with the administration of 2501000
microg of cobalamin on alternate days for 12 weeks and
then 250 microg weekly until blood counts are normal.
Maintenance may require lifelong supplementation of 1000
microg every 23 months.
Folate deciency
Folate deficiency results in megaloblastic anemia but
without the neurological complications seen with cobalamin deficiency. Treatment of cobalamin deficiency with
folate supplementation only may transiently improve the
blood parameters but neurological deficits will continue to
worsen.
The daily folate requirement is about 100 microg, with
total body stores being 10 mg. Hence, malnutrition that
causes folate deficiency occurs far earlier than cobalamin
deficiency.
Fresh fruit and vegetables are a good source of folate, but
cooking can destroy biologically active folate.
Folates are absorbed through the small bowel, with the

upper jejunum demonstrating the most capacity.
Folate is needed for synthesis of thymidylate (a DNA
nucleotide). Drugs such as methotrexate inhibit dihydrofolate reductase and disrupt the role of folate in thymidylate
synthesis.
Etiology of folate deciency
Common causes include:
Nutritionaltotal cessation of folate intake will deplete
stores within 36 months, and poor diet is a common
precipitant of folate deficiency. Fresh food is relatively
expensive, and the poor and aged are particularly susceptible. Other at-risk groups are those with poor dentition and alcoholics.
Malabsorptionceliac disease, tropical sprue, Crohns
disease, extensive jejunal resection.
Increased demandpregnancy, prematurity, chronic
hemolysis (folate is not completely re-utilized and is lost
in excretion).
Anti-folate drugsmethotrexate, trimethoprim, phenytoin, barbiturates.
Investigation of folate deciency
This requires measurement of serum and red cell folate.
Serum folate levels are altered by recent diet and blood
should be drawn for testing before nutritional correction.
CLINICAL PEARL
Red cell folate reects tissue stores better than serum
folate and is not altered by recent diet.
Treatment of folate deciency

Oral supplementation with 5 mg folic acid daily for 4 months
is effective.
Hemolytic anemias
Hemolytic anemias are classifiable as hereditary or acquired,
and also as extracorpuscular or intracorpuscular, based on the site
of the lesion (Table 14-15, overleaf).
Features of hemolysis
In hemolytic anemias due to membrane defects, hemolysis is extravascular and takes place in the liver and
spleen, mediated by the reticuloendothelial tissues.
During intravascular hemolysis, free Hb is released into
the plasma that is filtered by the urine as hemoglobinuria and hemosiderinuria. A portion is bound to plasma
albumin as methemalbuminemia.
Anemias due to enzyme defects
Red cells need to generate energy to maintain the integrity of the cell membrane and for the proper functioning
445
Table 14-15 Classication of hemolytic anemias

Intracorpuscular
1. Abnormalities within cytoplasm
Hereditary
Enzyme defects
Hemoglobinopathies
2. Cell membrane abnormalities (extravascular)
Hereditary spherocytosis
Paroxysmal nocturnal hemoglobinuria
Extracorpuscular
Acquired
Spur cell anemia

3. Extrinsic causes
Immune hemolysis
Microangiopathic hemolysis
Hypersplenism
of the ion channels. Red cells can only produce ATP by

anaerobic glycolysis, as they lack mitochondria.
A reducing capacity is also necessary to counteract
oxidative stress and to reduce methemoglobin to deoxyhemoglobin with the capacity to bind oxygen.
Reduced nicotinamide adenine dinucleotide (NADH) produced from NAD as a part of the glycolytic pathway reduces
methemoglobin. The pentose phosphate pathway and the
glutathione cycle linked with the glycolytic pathway generates reduced nicotinamide adenine dinucleotide phosphate
(NADPH) and glutathione (GSH) to provide the reducing capacity to detoxify free oxygen radicals and hydrogen
peroxide.
Pyruvate kinase deciency
Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate, associated with the generation of
ATP. There are two genes which produce four types of PK
in different tissues (e.g. PKR in red cells).
PK deficiency presents as an autosomal recessive disorder with a prevalence of 50 per million.
It leads to impairment of ATP production and
accumulation of upstream intermediates such as
2,3-diphosphoglycerate (2,3-DPG). The increased
concentration of 2,3-DPG reduces the oxygen affinity
of Hb, thereby permitting greater delivery of oxygen to
the metabolizing tissues even in the presence of anemia.
The severity of the phenotype and the age of onset of
manifestation varies.
The common phenotype is chronic non-spherocytic
hemolysis.
Jaundice may be noted, gallstones are frequent, and
spleen size correlates with severity of hemolysis.
Laboratory features are anemia in the absence of spherocytes, reticulocytosis and crenated cells. Typical features of spur cells and acanthocytes become prominent
post splenectomy. Demonstration of low red cell PK
446
establishes the diagnosis. Elevated levels of 2,3-DPG

can be indicative.
Anemia can be well tolerated due to the shift in oxygen
affinity of Hb. Chronic and symptomatic hemolysis may be
managed with splenectomy. Folic acid supplementation is
recommended to compensate for the increased requirement.
Glucose-6-phosphate dehydrogenase deciency
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the
conversion of glucose-6-phosphate to 6-phosphogluconate
with the generation of NADPH and, subsequently, glutathione (GSH).
G6PD is an essential component of all cells, although
deficiency causes only a red-cell phenotype with a rare
abnormality of leukocyte function.
There are more than 100 mutants known, and the most
common consequence is an alteration in RNA stability.
As a result, reticulocytes have high amounts of G6PD,
which decrease with red-cell aging.
G6PD deficiency is prevalent in the Mediterranean
areas, Africa, the Middle East, Southeast Asia and the
Indian subcontinent. The high prevalence of mutations
correlates with regions where Plasmodium falciparum is
endemic, as G6PD deficiency offers protection from
lethal malaria.
Glucose-6-phosphate dehydrogenase deficiency is an
X-linked disease with manifestation in males. Heterozygous
females remain susceptible to oxidative stress. Patients with
G6PD may present with four syndromes:
1 neonatal jaundice
2 favismhemolysis is precipitated by exposure to fava
(broad) beans
3 chronic non-spherocytic hemolytic anemia
4 drug-induced hemolysis.
Table 14-16 World Health Organization classication of G6PD deciency
CLASS
ENZYME ACTIVITY
(% OF NORMAL)
CLINICAL CHARACTERISTICS
<2
Chronic non-spherocytic hemolytic anemia
II
<10
Favism
Severe episodic drug-induced hemolysis
Neonatal jaundice
III
1060
Episodic drug-induced hemolysis

Neonatal jaundice
IV
100
None
G6PD, glucose-6-phosphate dehydrogenase.
Table 14-17 Agents that precipitate hemolysis in

G6PD deciency*
CLASS
AGENTS
Antimalarials
Primaquine, chloroquine, mepacrine
Antibiotics
Sulfonamides, co-trimoxazole, dapsone,

chloramphenicol, nitrofurantoin,
naladixic acid
Antihelminths
B-naphtol, stibophan, niridazole
Analgesics
Aspirin, phenacetin
Other drugs
Sulfasalazine, phenothiazines, vitamin

K, vitamin C (high doses), hydralazine,
procainamide
Chemicals
Naphthalene (mothballs), methylene

blue
Foods
Raw fava beans (broad beans)
*The drugs listed are representative examples and not a

complete list. Many other drugs produce hemolysis in
particular individuals.
G6PD, glucose-6-phosphate dehydrogenase.
G6PD deficiency is classified as shown in Table 14-16, and

agents that precipitate hemolysis are described in Table
14-17.
Diagnosis
Blood films reveal ghost, blister or bite cells, with evidence of biochemical parameters of hemolysis. Quantification of G6PD enzyme activity establishes the diagnosis.
Older red cells are more susceptible to oxidative stress.
CLINICAL PEARL
Reticulocytes contain higher levels of glucose-6phosphate dehydrogenase, and testing for this enzyme
may yield false-normal results if the test is done during
the early period of recovery when reticulocyte counts
are high.
Structural hemoglobin variants causing

hemolysis
Unstable hemoglobins
These are a result of mutations that cause structural
changes in the hemoglobin molecule that lead to intracellular precipitation and spleen-mediated removal of affected
red cells.
The clinical presentation is that of chronic hemolytic
anemia with splenomegaly.
Heinz bodies are present.
Testing for instability at high temperatures confirms
diagnosis.
Splenectomy and blood transfusions may be needed in
severe cases.
Sickle cell disease
This is the first disorder to be characterized at the molecular
level.
It results from a single substitution of valine for glutamic
acid in the 6th amino acid position of the G-globin
hemoglobin chain; the resultant hemoglobin is denoted
by HbS.
Deoxygenated HbS leads to exposure of a hydrophobic
area on the G-globin surface that binds to hydrophobic
patches on other G-globin molecules, ultimately causing
polymerization.
Acidosis and elevated 2,3-DPG levels promote polymerization by reducing the affinity for oxygen binding.
The presence of HbA and HbF inhibits polymerization
by diluting the HbS, and also because of amino acid differences between HbS and HbF.
Sickle cell disease has a high prevalence in regions endemic
for Plasmodium faliciparum, including Africa, Mediterranean
countries, Saudi Arabia and India.
Clinical manifestations
Clinical syndromes associated with HbS are:
anemia
vaso-occlusive crisis
447
impaired growth and development

infections (pneumococcal, Haemophilus, Salmonella)
neurological events (cerebral infarction and hemorrhage)
acute chest syndrome (due to vaso-occlusion, infection
and fat embolization)
renal complications (papillary necrosis, loss of concentration capacity)
priapism (vaso-occlusion of the corpora cavernosa)
bone complications (bone infarction, avascular necrosis)
leg ulcers
ocular complications (vaso-occlusion is typical in the
variant HbSC disease).
Diagnosis
Peripheral blood reveals:
polychromasia
nucleated red cells
HowellJolly bodies
sickled red cells.
Diagnosis is established by hemoglobin electrophoresis.
Prenatal diagnosis is available by direct detection of the
mutation in fetal cells.
Management
Good care involves a multidisciplinary approach in a
specialized center. The cornerstones of care include:
blood transfusion
rapid treatment of infections
pain relief.
CLINICAL PEARLS
4 Sickle cell hereditary persistence of HbF

elevated HbF levels inhibit HbS polymerization and
the clinical course is benign.
Anemias with hereditary red-cell membrane

abnormalities
The red-cell membrane is a lipid bilayer in close association
with cellular proteins. There are two types of membrane
protein interactions:
1 membrane-integral proteins such as ion channels
(band3), which interact with each other and also with
the second group of proteins
2 proteins that form the cytoskeleton (F- and G-spectrin).
Ankyrin is a protein that bridges G-spectrin to band 3.
Mutations of the integral proteins usually result in spherocytosis, while abnormalities of the cytoskeletal proteins cause
elliptocytosis and other abnormalities. Gallstones (pigment
stones) are also frequent and cause episodes of cholecystitis
and biliary colic.
Hereditary spherocytosis
This is a chronic hemolytic anemia with an autosomal dominant inheritance.
It is characterized by the presence of spherocytes on
peripheral blood examination and evidence of jaundice.
The clinical phenotype may vary, and anemia is exacerbated by coincident viral or bacterial infections. Parvovirus infections can precipitate severe anemia due to
marked inhibition of erythropoiesis.
Splenomegaly is common, since the spleen is the site for
the removal of spherocytes.
Diagnosis is made by family history, blood film examination
(Figure 14-11) and tests for red cell fragility. The osmotic
fragility test measures the capacity to withstand cell swelling
In sickle cell disease, hydroxyurea therapy increases

HbF levels and leads to a signicant reduction in
acute chest syndrome, vaso-occlusive crises, and
transfusion requirements.
Hemopoietic stem-cell transplantation using a
matched sibling donor is used for subgroups with
high risk of severe disease.
Variants of sickle cell syndromes

1 Sickle cell traitgenerally there is no hematological manifestation; impairment of urine-concentrating
function and splenic infarction (at high altitudes) can
occur. Sickling and vaso-occlusive crisis can be precipitated in young athletes.
2 HbSC diseasea compound heterozygous state in
African patients due to high prevalence of HbC.
Proliferative retinopathy is present at very high incidences. Vaso-occlusive crises and splenic infarctions
also occur.
3 Sickle cell beta-thalassemiaa compound heterozygote state with a mild phenotype that correlates with
the relative amounts of HbA and HbS.
448
Figure 14-11 Peripheral blood lm showing marked

spherocytosis, including microspherocytic cells
From Hoffbrand AV, Pettit JE and Vyas P. Color atlas of clinical
hematology, 4th edn. Philadelphia: Elsevier, 2010.
in the presence of a hypotonic environment. Normal biconcave red cells are able to change shape and tolerate hypotonic
cell swelling better than spherocytes that hemolyze at higher
solute concentrations.
Splenectomy is indicated for chronic symptomatic hemolysis but carries an early risk of precipitating thrombosis and
a long-term risk of sepsis with encapsulated microorganisms. Folate supplementation is also recommended to keep
up with the increased requirements in chronic hemolysis.
Table 14-18 Etiology of autoimmune hemolytic

anemia
ETIOLOGY
DISEASES
Idiopathic
None
Autoimmune

(SLE), rheumatoid arthritis,
ulcerative colitis
Hereditary elliptocytosis and

pyropoikilocytosis
Lymphoproliferative
disorders
Lymphoma, chronic lymphocytic

leukemia (CLL)
These are less common than hereditary spherocytosis. Diagnosis is suspected on the basis of distinct red cell morphology. Folate supplementation and splenectomy are useful in
severe cases.
Infections
Hepatitis C, human
immunodeciency virus
Drugs
Cephalosporins, methyldopa
Immune hemolytic anemias

In this group of disorders, antibodies recognize and bind to
antigens on the surface of red cells.
The site of hemolysis is mainly extravascular:
splenic macrophages bear receptors for the Fc portion of
the IgG and bind and opsonize IgG-coated red cells
complement-coated red cells are mainly destroyed in
the liver, as liver macrophages recognize the complement component C3b.
Hemolysis can be intravascular if the antibodies fix complement avidly and generate the membrane attack complex.
Antibodies are defined as autoantibodies when formed by the
patient and directed against self-antigens, or alloantibodies
when produced by the patient to recognize antigens on foreign cells. Hemolysis after incompatible blood transfusion is
an example of an alloantibody destroying transfused donor
red cells.
Autoimmune hemolytic anemia (AIHA)
Autoimmune hemolytic anemia may be:
idiopathic or
secondary to:
another immune disease (e.g. SLE)
hematological malignancies (e.g. CLL)
drug exposure.
Antibodies are classified based on the optimal temperature at
which they recognize the antigen (37C, warm; 4C, cold),
and on whether IgG or IgM is involved.
Diagnosis of AIHA
Biochemical evidence of hemolysis
Peripheral blood film reveals spherocytes and polychromasia (reticulocytosis)
Nucleated red cells may be noted if the hemolysis is particularly brisk
Additional disease-specific features may be present (e.g. lymphocytosis in CLL, or lymphoma cells in circulation; Table
14-18). A key diagnostic aid is the direct antiglobulin test
(DAT, also called the Coombs test). This test detects antibody
and/or complement components that are already present on
red cell surfaces. The indirect Coombs test is used in blood

cross-matching, as it detects antibodies in recipient serum
that have the capacity to recognize donor red cells.
Warm-type AIHA
Antibodies are usually polyclonal, of the IgG subtype,
and react at 37C. Antibodies are pan-reactive, i.e. react
with nonspecific antigen specificity. Rhesus antigenspecific antibodies are noted in 1015% of cases.
Approximately 30% cases of warm AIHA are idiopathic.
The highest frequency is in early childhood, with a second peak in the 3rd decade.
The tempo of presentation may vary, but it is often
insidious.
Tiredness and dark urine may be the only symptoms. Pallor, jaundice and mild splenomegaly are
often the only signs in idiopathic AIHA.
Hemolysis secondary to other diseases may be
accompanied by signs specific to that condition
(e.g. lymphadenopathy in CLL, or arthritis and rash
with SLE).
Corticoteroids are first-line treatment in warm AIHA.
Most patients respond initially, but only 1520% may
remain in long-term remission. Steroids should be
tapered off slowly to prevent relapse.
Azathioprine and cyclophosphamide are added as
steroid-sparing drugs. Other immunomodulators
include cyclosporin (ciclosporin) and mycophenolate mofetil.
Splenectomy is an option for resistant cases and those
dependent on high-dose steroids. One-third of patients
remain in remission; in another third the dose of steroids can be significantly reduced, with the remaining
third showing transient or no response.
Other emerging treatments now include rituximab.
Cold-type AIHA
These disorders are etiologically grouped as:
1 Cold hemagglutinin disease (CHAD). Idiopathic
CHAD comprises 15% of cases and is due to a IgM
449
antibody directed against I antigen. Hemolysis worsens at cold temperatures. Typically, there is acrocyanosis due to sluggish circulation in the extremities,
caused by red-cell agglutination. Blood films reveal
gross hemagglutination. DAT is positive only for complement, as IgM elutes from the cell surface leaving
C3d behind.
2 Secondary cold agglutinin syndromes. May be
associated with lymphoproliferative disorders (monoclonal IgM or IgG against antigen I or i), or with
infections such as Mycoplasma pneumoniae and infectious
mononucleosis (polyclonal against I). Antibodies are
produced as a consequence of the infection and crossreact against red cells.
3 Paroxysmal cold hemoglobinuria. This is a disease
of children following viral infections. The presentation
is acute with abdominal pain, pallor and dark urine.
The disease occurs when a polyclonal antibody reacts
against P antigen. The antibody is biphasic, binding
red cells at 20C, and fixing complement and causing
complement-mediated hemolysis at 37C. The disease is usually self-limiting; it is important to maintain
warmth.
Treatment of idiopathic and secondary cold agglutinin
disease is difficult; remaining in a warm environment is
important.
Corticosteroids are generally ineffective.
Chlorambucil may be useful in the setting of lymphoproliferative disorder. Idiopathic CHAD is particularly
resistant to treatment and chlorambucil is commonly
ineffective.
Blood transfusions should only be given using an in-line
blood warmer.
Rituximab therapy has shown promise in early studies.
CLINICAL PEARL
Splenectomy in secondary cold agglutinin syndromes
is ineffective, as hemolysis takes place in the liver via
recognition of C3d on red cells.
There are four pathogenetic mechanisms underlying druginduced hemolysis.
450
1 Drug adsorption. The typical drug implicated is penicillin; in high doses, penicillin adsorbs on the surface
of red cells by nonspecific interaction with membrane
proteins. Patients may develop high-titer anti-penicillin
IgG antibodies that bind to red-cell surfaces and cause
extravascular hemolysis.
2 Immune-complex mechanism. This is seen with
3rd-generation cephalosporins and rifampicin. The
drugs interact with plasma proteins, and antibodies are formed against the haptencarrier complex.
Hemolysis typically occurs after the second or third
drug exposure.
3 Membrane-modification mechanism. Cephalosporins and carboplatin are examples of drugs that bind
to red-cell membranes and modify them so that immunoglobulins, complement components and plasma proteins bind nonspecifically. Hemolysis is uncommon.
4 Autoimmune mechanism. This is typically seen
with methyldopa after 6 weeks. IgG antibodies are
raised, causing extravascular hemolysis.
Non-immune acquired hemolytic

anemias
These occur secondary to diverse conditions that include:
1 Infections: malaria (intracellular organism causing
hemolysis), meningococcal sepsis (toxin-mediated
DIC), mycobacteria (activation of hemophagocytosis).
2 Mechanical fragmentation: thrombotic thrombocytopenic purpura (shear in fibrin-occluded microcirculation), perivalvular leak (due to shear), march
hemoglobinuria (mechanical shearing).
3 Acquired membrane modifications: paroxysmal
nocturnal hemoglobinuria (somatic mutation causing
failure of complement-regulatory mechanisms, leading
to sensitivity to complement-mediated lysis by formation of a membrane attack complex), liver disease
(acanthocytes due to modification of red-cell membrane by lipids and cholesterol changes).
4 Chemicals and physical agents: drugs (oxidative damage), drowning (osmotic stress), burns (heat
trauma).
1
A 70-year-old woman presents to her family physician for an annual health check. Routine full blood count reveals
hemoglobin 125 g/L (reference range [RR] 115165), white cell count 23.5 w 109/L (RR 4.011.0) with differential of
neutrophils 7.0 w 109/L (RR 2.07.5), lymphocytes 15.0 w 109/L (RR 1.54.0), normal numbers of monocytes, eosinophils
and basophils, and platelets 395 w 109/L (RR 150400). Blood lm ndings report the presence of smear cells. She has
no particular symptoms. Clinical examination does not identify any lymphadenopathy or hepatosplenomegaly. Routine
biochemical tests, including lactate dehydrogenase, are within normal limits. Which of the following is the best next
step in her management?
A Request serological evidence for infectious mononucleosis.
B Arrange for bone marrow biopsy to conrm lymphoma/leukemia.
C Verify the presence of abdominal lymphadenopathy by computed tomography (CT).
D Request peripheral blood ow cytometry.
E Arrange a time to discuss chemotherapy options.
A 78-year-old male of Italian descent complains of fatigue that has developed over the past few months. On inquiry,
he admits to some weight loss but his diet has not been optimal in the past 34 months. He takes low-dose aspirin
for previous ischemic heart disease and occasional naproxen 500mg tablets for arthralgia. He has no complaints
of dyspepsia. The patient has commenced taking laxatives to maintain bowel regularity. Preliminary tests by his
family physician reveal hemoglobin (Hb) 70 g/L (reference range [RR] 130180), mean cell volume 68 fL (RR 8098),
with normal white cell count and platelet numbers. Blood lm comments are of hypochromia, microcytosis and
pencil cells. Urea and electrolytes are not perturbed but liver function tests reveal elevation in gamma-glutamyl
transpeptidase (GGT) and alkaline phosphatase (ALP) to three times the upper limit of the normal range. The full blood
examination and biochemical parameters were normal when last tested 4 years previously as a part of a general checkup. Which of the following is the best next step?
A Correct anemia with oral iron supplementation or intravenous iron infusion, followed by regular follow-up to
conrm improvement.
B Anemia is due to aspirin and naproxen use and these should be discontinued and proton-pump inhibitors
commenced.
C Refer him for gastroscopy and colonoscopy.
D His Mediterranean heritage and hypochromic microcytic anemia are suggestive of thalassemia and should be
conrmed with Hb electrophoresis.
E Anemia is due to liver abnormalities, so patient should be advised to cease alcohol intake.
A 24-year-old woman is experiencing heavy menstrual bleeding and easy bruising. Her younger sister and mother also
give similar histories. She is constantly tired and this is interfering with her training for a triathlon. Her medications
include the oral contraceptive pill, an iron supplement, non-steroidal anti-inammatory drugs (NSAIDs) 23 times
per week for musculoskeletal pain from endurance training, and over-the-counter multivitamin preparations. She has
developed a ligament tear after a fall from her bike and knee arthroscopy needs to be performed. A coagulation screen
prior to arthroscopy reveals activated partial thromboplastin time (APTT) 50 seconds (reference range [RR] 2738),
international normalized ratio (INR) 1.2 (RR 0.81.2), and normal thrombin time and plasma brinogen levels. Further
preoperative coagulation tests are performed. Mixing with normal plasma corrects APTT and the factor VIII level is 35%
(RR 50150). Factors IX, XI and XII are normal. The patient wishes to proceed with the arthroscopy and ligament repair
as soon as possible. Which of the following is the most correct statement?
A Menorrhagia and prolonged APTT are because of the anti-platelet effects of NSAIDs. Arthroscopy should proceed
after suspension of NSAIDs for 1 week.
B The most likely interpretation is the presence of lupus anticoagulant causing coagulopathy leading to menorrhagia
and prolongation of APTT.
C She should be investigated for von Willebrands disease.
D Low factor VIII levels make mild hemophilia A the likely diagnosis, and arthroscopy can proceed with factor VIII
supplementation.
E Coagulopathy will always remain a contraindication to arthroscopy.
4 A 70-year-old man is on warfarin for non-valvular atrial brillation as his CHADS2 score is 4. He is brought to the
emergency department with bruising over his right hip after a fall from a three-step ladder. There is some suspicion
of head trauma from the fall, although there is no obvious scalp discoloration or tenderness and no symptoms of any
change in consciousness. There is no clinical suspicion of deep-tissue hematoma or anatomical derangement of the
affected hip. He is otherwise well and has no other complaints. He adheres to his warfarin intake, and frequency of
international normalized ratio (INR) monitoring is once every 4 weeks. Tests in the emergency department reveal INR
5.0 (reference range 0.81.2), consistent with warfarin effect. The best approach to correct the coagulopathy will be:
A Withhold next dose of warfarin and recommence at a lower dose.
B Warfarin continuation will be contraindicated in the future due to this fall.
C Aspirin is the preferred drug to prevent stroke in his case, as he is at high risk of warfarin-associated bleeding.
D Warfarin effect should be reversed with vitamin K.
E Warfarin effect should be reversed with prothrombin complex concentrates.
451
A 68-year-old man presents with pleuritic chest pain and shortness of breath developing after a 90-minute ight. He
has symptoms of dry cough and runny nose without fevers in the preceding 3 days. He had partial colectomy for cancer
2 years ago and is currently on chemotherapy for new hepatic metastasis. He has complained of a sore right calf for
the past week but attributed it to his cycling sessions on a stationary bike at home which he has commenced to remain
t while on chemotherapy. He is known to have prior smoking-related chronic obstructive pulmonary disease (COPD)
requiring bronchodilator therapy. Clinical examination reveals a swollen right calf with mild pedal edema, mild wheeze, a
pulse rate of 100/min (regular) and normal blood pressure. Which of the following is the most correct statement?
A Pulmonary embolism is likely, caused by his plane ight.
B Pulmonary embolism is likely, provoked by his malignancy.
C Pneumothorax is likely, due to the COPD and the plane ight.
D Respiratory tract infection is the most likely explanation for his pleuritic pain and preceding cough.
E Pre-test probability for venous thromboembolism is low, and another diagnosis such as lung metastasis should be
considered.
6 A 30-year-old male presents with fatigue and unexplained weight loss of 23kg over 4 months. Full blood examination
reveals white cell count 68 w 109/L (reference range [RR] 4.011.0), hemoglobin 160 g/L (RR 130180) and platelets
600 w 109/L (RR 150400). Blood lm reveals a left shift with the presence of numerous myelocytes, metamyelocytes
and basophils. Blasts were not present. Clinical examination reveals palpable splenomegaly, 1cm below the costal
margin. Subsequent cytogenetic studies reveal the presence of the Philadelphia chromosome. Which of the following
is the most correct statement?
A The most likely diagnosis is essential thrombocytosis as evidenced by the high platelet count.
B Philadelphia chromosome is detected on karyotypic analysis as the t(15;17) translocation.
C Philadelphia chromosome leads to the generation of an aberrant BCR-ABL fusion protein.
D Philadelphia chromosome leads to over-expression of the ABL tyrosine kinase by the promoter effects of the BCR
gene.
E The patient will require regular bone marrow biopsies for the karyotype assessment of the Philadelphia
chromosome to monitor response to therapy.
7
A 72-year-old woman is noted to have comments of rouleaux on a blood lm performed as part of a routine
check-up. Further investigations reveal normal full blood examination, electrolytes, renal function and calcium levels.
A monoclonal IgG (kappa) paraprotein of 5.5 g/L is noted on serum electrophoresis. There is no immune paresis, and
serum free light chains were absent. She is asymptomatic. Which of the following is the most correct statement?
A Bone marrow biopsy should be organized to consider a diagnosis of myeloma.
B Magnetic resonance imaging of the spine is indicated to look for bone lesions.
C Bisphosphonate therapy should be commenced for protection from bone fractures.
D She is at an increased risk of recurrent infections.
E The risk of progression is low, approximately 1% annually.
8 A 28-year-old female presents with symptoms of hallucinations, fever and rash developing over 5 days. Examination
reveals bruises at multiple sites. There is no arthritis. Tests reveal hemoglobin 99 g/L (reference range [RR]
115165), normal mean cell volume, normal white cell count and platelets 80 w 109/L (RR 150400). A blood lm
reveals schistocytes. Biochemical tests indicate acute renal failure. International normalized ratio, activated partial
prothrombin time, brinogen and liver function tests are normal. The most likely diagnosis is:
A Thrombotic thrombocytopenic purpura
B Idiopathic thrombocytopenic purpura
C Disseminated intravascular coagulation
D HELLP syndrome
E IgA vasculitis (Henoch-Schnlein purpura)
9 A 55-year-old woman presents with tiredness. She is jaundiced on examination and there is no lymphadenopathy
or hepatosplenomegaly. Full blood examination (FBE) reveals hemoglobin 80 g/L (reference range [RR] 115165),
mean cell volume 101 fL (RR 8098), and normal white cell count and platelets. A blood lm reveals the presence
of spherocytes and polychromasia. Coagulation tests are normal. She has recently returned from a trip to India and
took malarial prophylaxis. An incidental FBE 5 years ago was completely normal. The most correct of the following
statements is:
A A direct antiglobulin test (DAT, also known as a direct Coombs test) should be performed.
B The presence of anemia and the history of a trip to India makes malaria very likely despite prophylaxis.
C The most likely diagnosis is hereditary spherocytosis.
D Drug-induced oxidative hemolysis secondary to malaria prophylaxis is most likely.
E Reticulocytopenia is an expected nding.
10 A 60-year-old male is admitted with pneumonia and sepsis requiring intravenous antibiotics. During admission he
develops an acute coronary syndrome and is commenced on an unfractionated heparin infusion. Development of
thrombocytopenia is noted 2 days after the commencement of heparin. Platelet nadir is 80 w 109/L, from a previously
normal platelet count of 280 w 109/L (reference range 150400). The patient develops deep vein thrombosis (DVT)
despite the heparin infusion. He discloses a history of unfractionated heparin given for thromboprophylaxis three
weeks ago for an elective arthroscopy. Which of the following statements is the most correct?
452
A
B
C
D
E
Thrombocytopenia is due to idiopathic thrombocytopenic purpura (ITP).

Unfractionated heparin should be immediately replaced by low-molecular-weight heparin (LMWH).
Drug-induced thrombocytopenia secondary to antibiotics is the most likely explanation.
The presence of DVT requires commencement of warfarin anticoagulation as soon as possible.
Heparin-induced thrombocytopenia (HIT) is likely despite the thrombocytopenia developing only 2 days after
heparin therapy.
ANSWERS
1
D.
The most likely diagnosis is chronic lymphocytic leukemia (CLL). This is commonly identied by mild lymphocytosis
in routine blood lms. The presence of smear cells is a typical nding. Flow cytometry will conrm the diagnosis
and exclude the possibility of other lymphoproliferative disorders. Routine CT scans or bone-marrow biopsies are not
necessary. Early introduction of therapy is not indicated, as there is no improvement in survival. Routine full blood
examination and clinical examination is adequate for early-stage CLL.
C.
Although this patient is of Italian ethnicity, a previously normal full blood examination will exclude thalassemia trait
signicant enough to cause anemia. Anemia is most likely due to iron deciency and should be conrmed by assessment
of iron stores. While iron supplementation will be necessary, it is vital to exclude gastrointestinal blood loss in a person of
his age. Non-steroidal anti-inammatory drug (NSAID)-induced chronic low-volume blood loss can be the cause, but it will
be incorrect to assume this and not investigate further. Gastroscopy and colonoscopy should be arranged. The description
of weight loss and constipation raises signicant concerns of colon cancer. Abnormalities in GGT and ALP suggest the
possibility of liver metastasis, but this is not the typical appearance of anemia associated with liver disease.
C.
The close family history of menorrhagia and bruising make von Willebrands disease (vWD) the most likely differential
diagnosis. Inherited platelet function defects are possible but are much less common than vWD. Moreover, coagulation
test abnormalities do not occur with platelet function defects. NSAIDs can contribute to bruising and menorrhagia but do
not account for prolonged APTT and low factor VIII, and are less likely to be the culprit in this setting. A factor VIII level of
35% is consistent with vWD, as von Willebrands factor (vWF) protects factor VIII from proteolysis. Quantication of vWF
and assessment of vWF multimers is the next most logical step. Hemophilia A or vWD is not an absolute contraindication
to surgery provided that an appropriate plan is in place for perioperative correction of factor deciencies.
4 A.
In the absence of bleeding, it is preferable to miss a warfarin dose and recommence at a lower dose. It is also important
to verify the reason for the unexpectedly high INR. Factors such as dietary changes and new medications should be
considered. This fall was after a known event (climbing a ladder) and is not a reason to contraindicate warfarin. The
patients risk of stroke is considerable and there is extensive evidence that warfarin will reduce the risk and that aspirin is
inadequate. Vitamin K is not indicated at an INR of 5.0 and will make re-introduction of warfarin difficult. When vitamin K is
used in the absence of bleeding, a low dose of 13mg is preferred. Prothrombin complex concentrates are only indicated
in the context of bleeding while on warfarin.
5
B.
The pre-test probability for venous thromboembolism (VTE) is high, and pulmonary embolism is the most likely and
signicant diagnosis for this patients symptoms of pleuritic chest pain. Generally, plane ights of more than 45 hours
are associated with an increased risk of VTE. In this case, metastatic cancer is the most likely precipitant. Respiratory
tract infection, pneumothorax and pulmonary metastasis are possible, but are unlikely to be the main diagnosis given the
coexistent unilateral calf pain and swelling.
6 C.
The full blood examination ndings are typical of chronic myeloid leukemia, which is conrmed by the presence of the
Philadelphia chromosome. This is a reciprocal translocation between chromosomes 9 and 22, leading to the generation
of an aberrant BCR-ABL fusion protein with dysregulated tyrosine kinase activity. Patients are treated with tyrosine kinase
inhibitors (imatinib, nilotinib, dasatinib) and monitored by quantitative polymerase chain reaction (PCR) of the BCR-ABL
mRNA using peripheral blood.
7
E.
The diagnosis is monoclonal gammopathy of undetermined signicance (MGUS). Rouleaux result from red blood cells
stacking together in the presence of elevated serum protein levels, in this case a paraprotein. The risk of progression is very
low, and monitoring of paraprotein with clinical review suffices. Normal calcium levels, preserved renal function, absence
of anemia, and bone involvement is mandatory to make a diagnosis of MGUS. Magnetic resonance imaging of the spine is
not indicated in MGUS unless the patient has symptoms. Bisphosphonate therapy is not necessary in MGUS.
453
8 A.
The pentad criteria for thrombotic thrombocytopenic purpura are present: thrombocytopenia, microangiopathic
hemolysis (indicated by anemia and schistocytes on blood lm), neurological symptoms, renal impairment and fever.
Disseminated intravascular coagulation is excluded by normal coagulation tests. IgA vasculitis is associated with arthritis,
and renal impairment may be present but without red cell fragmentation. Normal liver function tests make the HELLP
syndrome unlikely. ITP would not cause fever, anemia, renal impairment and neurological symptoms.
9 A.
The diagnosis is most likely to be autoimmune hemolytic anemia as evidenced by the presence of spherocytes and
polychromasia. A DAT will conrm the presence of immunoglobulin or complement proteins adherent on red cell
surfaces. Hereditary spherocytosis is unlikely as FBE was normal previously. Oxidative hemolysis typically shows bite
cells on blood lm. Reticulocytosis, indicated by polychromasia, is an expected nding. Malaria is unlikely if appropriate
prophylaxis was taken, and in the absence of fever. Reticulocytosis rather than reticulocytopenia is expected in the setting
of autoimmune hemolysis.
10 E.
Thrombocytopenia in HIT typically develops between 5 and 10 days after heparin exposure, but can occur earlier if there
has been prior exposure within 30 days. Pathogenic antibodies (directed against platelet factor 4 and heparin complex)
can cross-react with LMWH. Development of DVT is highly suggestive of HIT. Drug-induced thrombocytopenia is always
possible, but less likely in this setting. Immediate initiation of warfarin can cause skin necrosis. The clinical scenario of
temporal relationship to unfractionated heparin and development of DVT is a better t with HIT than ITP.
454
CHAPTER 15
ONCOLOGY
Christos S Karapetis
CHAPTER OUTLINE
WHAT IS CANCER?
DNA and genes
Essential elements of cancer diagnosis and
treatment
PREVENTION
DIAGNOSIS
Screening
Signs and symptoms
Diagnostic tests
PROGNOSIS
Cancer factors
Patient factors
TREATMENT PRINCIPLES

Adjuvant therapy
Neoadjuvant therapy
Maintenance therapy
PRINCIPLES OF CHEMOTHERAPY
PRINCIPLES OF RADIOTHERAPY
Fractionation
Radiation effects
TREATMENT RESPONSIVENESS
Potentially curable following chemotherapy
alone
Potentially curable following radiotherapy
PERSONALIZED MEDICINE
MOLECULAR TARGETED THERAPY
Monoclonal antibodies (the ABS)
Tyrosine kinase inhibitors (the IBS)
Other
FAMILIAL CANCERS AND CANCER GENETICS

ONCOLOGICAL EMERGENCIES

Febrile neutropenia
Cardiac tamponade
Addisonian crisis
Hypercalcemia
Hyponatremia
TUMOR MARKERS IN SERUM

PARANEOPLASTIC SYNDROME
CANCER WITH UNKNOWN PRIMARY (CUP)
Diagnosis
455
LUNG CANCER
Risk factors
Small-cell lung cancer (SCLC)
RENAL CANCER
Background
Treatment
Prognosis
TUMORS OF THE PELVIS, URETER AND

BLADDER
Epidemiology
Risk factors
Treatment
PROSTATE CANCER
Epidemiology
Screening
Staging
Management
TESTIS CANCER

Pathology
Diagnosis
Treatment
Relapsed disease
HEAD AND NECK CANCER

Early-stage disease
ESOPHAGEAL CANCER

Management
GASTRIC CANCER
456
Epidemiology
Diagnosis
Treatment
COLORECTAL CANCER

Management
Future directions
PANCREATIC CANCER
Key points
Epidemiology
Diagnosis
Management
HEPATOCELLULAR CARCINOMA (HCC)
Key points
Risk factors
Prognosis
Treatment
BRAIN TUMORS
oligodendroglioma)
LYMPHOMASEE CHAPTER 14
MELANOMA

Management
Future directions
SARCOMA
Diagnosis
Treatment
BREAST CANCER
Epidemiology
Risk factors
Pathology
Screening
Management
OVARIAN CANCER
Key points
Diagnosis
Management
Future directions
ENDOMETRIAL CANCER
Diagnosis
Management
Chapter 15 Oncology
Regulation of cell growth is complex, but is vital for survival. A cancer is a cell or group of cells that develops and
progresses without regard to all the physiological checkpoints and controls that regulate cell growth. This defective cell growth is usually initiated by a series of changes or
mutations in the genes of the cancer cell.
DNA and genes

All cellular processes are controlled through the DNA inside
each cell. DNA (deoxyribonucleic acid) is a self-replicating
material present in nearly all cells and is the main constituent of chromosomes. Each DNA molecule consists of two
strands coiled around each other to form a double helix. All
the genetic information of a cell is coded in this helix in the
form of chemical groups called basesthe purines adenine
and guanine, and the pyrimidines thymine and cytosine
that form specific sequences and pairs across the two adjoining strands. Adenine pairs with thymine; cytosine pairs with
guanine; in RNA, uracil replaces thymine.
Specific segments of the building blocks form discrete
genes from which proteins are produced by a process of gene
transcription and translation. DNA integrity needs to be
maintained by each cell, and this is an active process. The
DNA replication process is not always exact, and replication
errors can occur. DNA is constantly repaired; or, failing that,
the cell is set on a path of programmed cell death.
Apoptosis
In essence, all of the cells that make up the human body
have a defined function and lifespan. The death of the cell is
programmed through a process called apoptosis.
The cancer cell is one that has developed a gene mutation or multiple mutations that affect gene function, and
this subsequently has an impact on the growth and survival
characteristics of the cell. A failure of apoptotic mechanisms
develops and the cancer cells grow, form clusters, interact with the surrounding tissue environment, and develop
aberrant blood supply. The cells can migrate via lymphatic
channels and blood vessels and settle in other sites, forming
metastases. Ultimately, as the cancer grows it impacts on the
function of the regions it involves, leading to possible organ
failure. The cancer can also produce systemic adverse effects
such as anorexia, weight loss, fatigue and malaise.
Gene mutations
The genetic aberrations that lead to cancers can be inherited,
although most are acquired. Gene mutations can take the
form of gene rearrangement, translocation, deletion, insertion or amplification. Genetic damage may arise directly
from exposure to certain carcinogens (such as ionizing radiation or tobacco).

Clonalitycancers are derived from a single cell line.
Autonomycancers are not responsive to normal
physiological control mechanisms in the cell cycle.
Anaplasiacancer cells differ from normal cells in

appearance.
Invasion/metastasesmost cancer cells have the ability to
grow at sites other than the primary site, either by direct
invasion or by spread via blood or lymph. Different
cancer types have different propensities to metastasize.
Essential elements of cancer diagnosis

and treatment
Cancer survival is strongly correlated with the stage of the
cancer at diagnosis, so in most cases the earlier that a cancer
is diagnosed, the better the chance of a cure or a positive
outcome.
When a cancer cannot be cured, doctors should be able
to appropriately counsel patients, their families and carers.
Optimal measures for symptom control should be applied.
The supportive care of patients through their cancer treatments is also very important.
Figure 15-1 demonstrates the rate of growth of cancer,
which follows what is called a Gompertzian curve. It shows
that:
the cancer growth rate slows down as the cancer gets
bigger
there may be a large number of cancer cells present that
cannot be clinically detected.
Figure 15-2 (overleaf) illustrates cell kill and cell regrowth
per treatment cycle; it shows why it is important to have a
sufficient number of treatment cycles even if the cancer is no
longer clinically apparent.
PREVENTION
It has been estimated that at least one-third of all cancers are
preventable. The following strategies have been shown to be
useful preventative measures.
Cessation of smoking
Reduction or cessation of alcohol consumption
1012
Number of malignant cells
WHAT IS CANCER?
Death of patient
Lower limit of
109
clinical detection
106
Preclinical
phase
103
100
Time
Figure 15-1 Rate of growth of cancer (Gompertzian

curve)
457
Death
1012
Overt disease
Number of malignant cells
1010
108
Cells
killed
106
Remission
104
102
100
Cell regrowth
if chemotherapy
ceases prematurely
Cell
regrowth
Cycles of chemotherapy
Figure 15-2 Logarithm of cells killed (log cell kill) and

cell regrowth per treatment cycle
Healthy diet education

Weight-reduction initiatives in those who are obese or
overweight
Chemotherapy prevention:
tamoxifen or exemestane, for breast cancer
vaccines (e.g. human papillomavirus vaccine to prevent cervical cancer, hepatitis B vaccine to reduce
the risk of hepatocellular carcinoma)
aspirin to reduce colonic polyp development
Minimizing exposure to ultraviolet light (protection
from sun)
Screening for pre-cancerous conditions:
endoscopy in Barretts esophagus
Papanicolaou (Pap) testsfor cervical dysplasia
colonoscopyfor polyps
Mammographic screening for precancerous lesions
(ductal carcinoma in situ)
Surgerye.g. prophylactic mastectomy or oophorectomy in women with specific familial risk factors.
DIAGNOSIS
Screening
Screening for cancer involves the process of investigating
people who are otherwise well and have no symptoms or
signs of cancer, with the aim of detecting cancer at a preclinical stage.
Examples of positive results through screening, usually
measured as improved overall disease-specific survival rates
in the screened population, include:
breast cancer screening with bilateral mammography
from age 50
458
cervical cancer screening with Pap smears from the

onset of sexual activity
colorectal cancer screening with fecal occult blood tests
from age 50.
Other cancers where screening is being investigated but
where population reductions in mortality have not been
conclusively demonstrated include prostate cancer (prostatespecific antigen, PSA), lung cancer (low-dose computed
tomography in high-risk smokers), and ovarian cancer
(cancer-associated antigen CA125).
Signs and symptoms

The signs and symptoms of cancer are not specific, but persistence of any of the following should always raise concern
about the possibility of cancer.
Anorexialoss of appetite usually associated with
weight loss
Weight lossunexplained
Unexplained pain, including headache
Lumpse.g. breast lump, testicular lump, swollen
lymph gland
Bleeding from the bowel, bladder, vagina or lung
Difficulty swallowing
Skin rash or pigmented skin lesions
Seizures (new onset).
Specic clinical signs and syndromes

These include:
Horners syndromepartial ptosis of one eye, which
reflects infiltration of the sympathetic nerves as they
ascend through the upper mediastinum
Virchows nodean enlarged left-side supraclavicular
lymph node, which is usually firm and irregular and
may be fixed. This finding was initially described in
the context of advanced gastric cancer, but other intraabdominal malignancies can also spread to this node
Sister Mary Josephs nodea subcutaneous lymph node
in the region of the umbilicus, usually seen in intraabdominal malignancy, classically ovarian cancer
increasing fluid accumulating in body cavitiese.g.
ascites, pleural effusion, pericardial effusion
painless jaundicemay be an indication of a malignant
biliary obstruction
changing nevus or new hyperpigmented cutaneous
lesionmelanoma should be considered.
Diagnostic tests
Despite the most convincing clinical evidence, a histological
confirmation of the diagnosis is always required. This will
involve one of the following biopsy procedures:
fine-needle aspiration (FNA) cytology
core biopsy
excision biopsy.
Chapter 15 Oncology
The tissue obtained is examined with standard tissue staining (hematoxylin and eosin, H&E) enabling assessment of:
the cancer cell appearance, and
the architecture of the tissue.
Subsequent immunohistochemistry (IHC) will enable a
more detailed analysis and support a specific diagnosis,
although results are not themselves diagnostic.
Immunohistochemistry (IHC)
The following markers are useful in clinical practice:
cytokeratinscancer of epithelial origin, i.e. adenocarcinoma or squamous-cell carcinoma
CK7lung
CK20gastrointestinal tract
thyroid transcription factor (TTF)lung cancer, thyroid cancer
prostate-specific antigen (PSA)prostate (specific)
synaptophysin/chromograninneuroendocrine tumor,
small-cell carcinoma
CD117 (= c-kit)gastrointestinal stromal tumor
(GIST)
lymphocyte common antigen (LCA)lymphoma
CD20lymphoma.
PROGNOSIS
Each cancer has a unique biological behavior. The following
are factors associated with worsening prognosis.
Weight lossincreased catabolism is a poor prognostic

factor.
White cell count (WCC), including the neutrophil to
lymphocyte ratio, is a validated poor prognostic factor, and may be related to cancer-induced cytokine
production.

A prognostic factor is related to the overall outcome
of patient survival, and has an association that is independent of any treatment effects. The effect on survival
outcome is independent of intervention (therapy).
A predictive factor predicts the benefit, or lack of
benefit, related to an intervention (therapy). The predictive factor has relevance only in relation to the therapy. In the absence of intervention, the predictive factor
has no influence in the outcome.
Examples of prognostic factors:
BRAF mutation in advanced colorectal cancer
microsatellite instability (MSI) status in early-stage
bowel cancer (stages II and III)
LDH level in lymphoma.
Examples of predictive factors:
Epidermal growth factor receptor (EGFR) gene mutation and tyrosine kinase inhibitor (TKI) therapy in
advanced non-small-cell lung cancer
K-ras mutation in pre-treated advanced colon cancer.
Some biomarkers can be bothe.g. human epidermal
growth factor receptor 2 (HER2) in breast cancer.
Cancer factors
Stagethe more advanced the stage, the poorer the
prognosis.
Differentiationthe poorer the differentiation (equates
to higher grade), then the poorer the prognosis. The
caveat is that for some cancers, notably lymphoma, a
higher grade represents a poor prognostic factor without
treatment but a more responsive and potentially curable
lymphoma when treated.
Critical organ involvement.
Certain gene mutations, e.g. BRAF mutation in stage 4
colon cancer.
Patient factors
Performance statusthis is a measure of the overall fitness of patients. It takes into account mobility and the
capacity to engage in activities of daily living, including
self-care. The poorer the performance status, the worse
the prognosis.
Lactase dehydrogenase (LDH)high LDH is a marker
of increased tumor bulk, faster cell turnover, and tumor
hypoxia. A high level often indicates a poorer prognosis.
Albumina low level can be a negative acute-phase
reactant, a marker of malnutrition, and is a negative
prognostic factor.
1 Cureaccept the potential for more toxicity, consider
long-term consequences of therapies.
2 Extend survival time but not cureweigh up the benefits of therapy against toxicity, and aim to prolong life
while maintaining or improving quality of life.
3 Palliateaim to optimize symptom control and quality
of life above all else.
The six principal treatment modalities in cancer are:
1 surgery
2 radiotherapy
3 chemotherapy
4 hormonal therapy
5 molecular targeted therapy, including monoclonal
antibodies and TKIs
6 immunomodulatory therapy, including vaccines,
interferon, programmed cell death protein 1 (PD-1)
and programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T lymphocyte antigen 4 (CTLA-4)
modulators.
459
Adjuvant therapy
Adjuvant therapy is given after a treatment (usually surgery) has apparently eliminated or removed the cancer.
There is therefore no detectable cancer, and the aim of the
adjuvant therapy is to prevent a recurrence of cancer. It is
thought that the therapy can eliminate disease that may still
be present but is too small to be detected. The concept of
the cancer stem cell is also potentially important here. Such
stem cells may be cleared by the adjuvant therapy.
Postoperative adjuvant therapy has been proven to be of
benefit in increasing survival for a proportion of patients,
asoutlined below.
Postoperative adjuvant chemotherapy
Stage III colon cancer5-fluorouracil (5FU),
capecitabine, oxaliplatin + 5FU
Stage II colon cancersurvival benefit of <5%,
but should be considered in patients with high-risk
features (e.g. bowel perforation)
Early-stage breast cancer
Pancreatic cancer
Gastric cancer
Ovarian cancer
Postoperative adjuvant radiotherapy
Breast cancer
Head and neck cancer
Endometrial cancer
Brain tumors
Postoperative adjuvant monoclonal antibody
therapy
Breast cancerHER2-positive; trastuzumab
The other monoclonal antibodies have not been
associated with survival benefit as adjuvant therapies; studies investigating bevacizumab and cetuximab have been performed in early-stage colorectal
cancer, but the studies failed to demonstrate a survival advantage
Bevacizumab does not improve survival as a postoperative adjuvant therapy in stage III colon cancer
Cetuximab does not improve survival as an adjuvant therapy in stage III colon cancer
Postoperative tyrosine kinase inhibitors
Imatinib in gastrointestinal stromal tumor (GIST)
use of imatinib after the complete removal of a
GIST tumor that has intermediate or high-risk features for recurrence (these features are based on the
size of the tumor and the number of mitoses per
high-power field)
No benefit has been observed through the use of
epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors after surgery as an adjuvant therapy in lung cancer
Neoadjuvant therapy
For neoadjuvant treatment, the additional therapies are
administered before the definitive treatment (usually surgery). This usually comprises of chemotherapy with or
without radiotherapy. The advantages of giving the treatment before surgery include:
460
making the primary tumor smaller (down-staging),

which may increase the chance of complete surgical
clearance
giving the systemic treatment earlier may allow a greater
effect against micro-metastatic disease, as such disease
would be of smaller volume before as compared with
after surgery
patients may be physically fitter before the surgery and
may tolerate the chemotherapy and radiotherapy better.
Some examples of where neoadjuvant therapy is in routine
use include:
rectal cancer
esophageal cancer
breast cancer (for locally advanced disease).
It is important to consider the additional management that
patients will require to manage either the symptoms of the
cancer or the adverse effects associated with the therapies for
treating cancer.
These supportive therapies may include antiemetics,
analgesics, laxatives or antidiarrheal agents, antibiotics
and mouth rinses.
The additional contribution of allied health services can
provide a significant benefit for patients and their families. These services may include social work, dietitian
input, dental care, physiotherapy, psychology and counseling services.
Maintenance therapy
Attempts to prolong the period of cancer control through
longer administration of treatment such as chemotherapy or
monoclonal antibodies have proven to improve outcomes in
certain situations.
The use of rituximab after completion of an initial
chemotherapy + rituximab course has been proven to
prolong the time of lymphoma control (i.e. prolong
progression-free survival) for patients with low-grade
non-Hodgkin lymphoma.
Use of the cytotoxic drug pemetrexed after an initial
course of chemotherapy for non-small-cell lung cancer
has been associated with prolongation of survival.
Aside from these situations, the use of maintenance chemotherapy has not been shown to improve overall survival,
but may prolong the time to disease progression. This benefit has to be balanced against the cumulative side-effects
of therapy.
PRINCIPLES OF
CHEMOTHERAPY
In common medical parlance, chemotherapy has come to
mean treatment with agents that are classified as cytotoxic.
These drugs exert their impact principally on cells that are
actively dividing, hence their impact on cells within the
Chapter 15 Oncology
bone marrow (causing cytopenias) or lining the gastrointestinal tract (causing mouth ulceration or diarrhea).
With each dose of chemotherapy, a fixed percentage of
cells is killed (log kill) rather than an absolute number
ofcells (see Figure 15-2).
The optimal dose of chemotherapy and the frequency
of administration is determined through phase I clinical
trials, and is determined by the degree and duration of
myelosuppression and non-hematological toxicity.
The maximal tolerated dose is that dose which is tolerated
by a predefined proportion of patients without the need
for dose attenuation.
Toxicity is graded by applying international scales, such as
the National Cancer Institute Common Toxicity Criteria.
Chemotherapy is delayed if toxicity persists or significant
cytopenia is present on the day that chemotherapy is due.
Dose attenuation is also usually considered if significant toxicity develops.
When asked for their preferences, patients who already have
advanced cancer, including medical and nursing professionals, are much more likely to opt for radical treatment with
minimal chance of benefit than people who do not have
cancer.
In a study of non-small-cell lung cancer patients, 22%
stated that they would choose chemotherapy for a survival
benefit of 3 months. For a substantial reduction in symptoms
without prolonging life, 68% would choose chemotherapy.

Cytotoxic drugs often cause:
nausea and vomiting
bone marrow suppression
alopecia.
Etoposide, taxanes and anthracyclines usually cause alopecia. When used as single agents, 5FU, vinorelbine, gemcitabine, pemetrexed and carboplatin cause little hair loss.
Cytotoxics that are relatively

non-myelosuppressive
1
2
3
4
Vincristine
Bleomycin
Cisplatin
Streptozotocin
CLINICAL PEARL
Most cytotoxics that are myelosuppressive cause a
nadir at 1014 days after treatment, but some alkylating agents (e.g. busulfan, melphalan, procarbazine) can
have stem-cell toxic effects which cause severe myelosuppression with a delayed nadir 68 weeks after
therapy.
Cytotoxics that require dose reduction or

avoidance in renal disease
1 Increased toxicity systemically occurs with methotrexate, cyclophosphamide, bleomycin and bischloroethylnitrosourea (BCNU).
2 Increased renal damage occurs with cisplatin, carboplatin, mithramycin, BCNU, streptozotocin and
high-dose methotrexate.
Cytotoxics that cause prolonged azoospermia

1 Chlorambucil
2 Cyclophosphamide
3 Cisplatin
Cytotoxics that cause ovarian failure

Most combinations of cytotoxic chemotherapy will induce
ovarian failure. Women in their 40s generally do not regain
ovarian function. Younger women are more likely to
retain ovarian function and fertility. Chemotherapy particularly associated with reduced ovarian function includes:
1 Cyclophosphamide
2 Chlorambucil
3 Nitrogen-mustard
4 Mitomycin C
5 Procarbazine
Drugs which tend to increase the rate of

second cancers
Since part of the mechanism of action of cytotoxic chemotherapy is to damage DNA, there is a small risk of second
cancers with most cytotoxic drugs. Most of these are hematological malignancies due to previous exposure to alkylating agents. The drugs most often associated with secondary
leukemia are etoposide and alkylating agents.
PRINCIPLES OF RADIOTHERAPY
Radiotherapy provides localized treatment for cancer.
The main mechanism for cell death as a result of radiotherapy is damage to DNA. Malignant cells are far less
able to repair damage, so there is a differential effect
sparing normal cells.
There may also be a contribution from apoptosis (programmed cell death), release of cytokines, and the
switching on of signal transduction pathways.
Although at times cells are not killed with radiotherapy,
they may be rendered unable to replicate.
Various sources of radiotherapy are available. These include:
gamma rays from cobalt-60 decay
photons generated as X-rays or electrons in a linear
accelerator
neutrons and protons in a cyclotron.
The dose of therapy is measured in Grays (Gy). One Gy
equals one joule of energy per kilogram of tissue.
461
Fractionation
Cells are most sensitive to ionizing radiation immediately
before mitosis. Multiple exposures to radiotherapy increase
the likelihood of finding the cell in this particular part ofthe
cycle. Fractionation also serves to limit the damage to normal tissues.
Radiation effects
All normal tissues have a dose beyond which recovery will
not occur after exposure to radiation, due predominantly to
irreversible damage to the microvasculature. This defines
the maximum dose of radiotherapy.
Short-term toxicity
1 Dry and moist desquamation
2 Epilation
3 Mucosal damagegastrointestinal tract, respiratory
tract and bladder
4 Acute organ damage/failure with high-dose radiotherapy involving the lung, brain, kidney and large
volumes of bone marrow
Long-term toxicity
1 Skin fragility
2 Second malignancies
3 Direct damage to mucosal surfaces (late proctitis or
cystitis, dry mouth)
4 Scarring (small-volume bladder)
TREATMENT RESPONSIVENESS
1
2
3
4
Breast cancer (anti-estrogen)

Endometrial cancer (progesterone)
Prostate cancer (androgen blockade)
Thyroid cancer (thyroxine, which suppresses thyroidstimulating hormone [TSH])
5 Carcinoid (somatostatin)
Potentially curable following

chemotherapy alone
1
2
3
4
5
6
Germ-cell tumors (mainly testicular cancer)

Hodgkin lymphoma
Non-Hodgkin lymphoma (certain subtypes)
Acute leukemia
Wilms tumor
Ewing sarcoma and rhabdomyosarcoma (embryonal)

(v80% response rate)
1 Small-cell lung cancer
2 Non-Hodgkin lymphoma
3 Ovarian cancer
462
Potentially curable following

radiotherapy
1 Seminoma (early stage)
2 Hodgkin lymphoma (early stage)
3 Head and neck, or laryngeal cancers (early stage)
4 Cervical carcinoma (early stage)
5 Prostate cancer (early stage)
6 Bladder cancer (early stage)
Very rarely, neuroblastoma, melanoma, Kaposis sarcoma or
renal cell carcinoma can undergo spontaneous regression.
CLINICAL PEARL
Renal cell carcinoma and melanoma are relatively
resistant to cytotoxics and radiation.
PERSONALIZED MEDICINE
Recent advances in cancer therapy have focused on an individualized approach to management, focusing novel treatment on specific targets and utilizing predictive biomarkers
for optimal patient selection.
Biomarkers include immunohistochemical staining patterns, fluorescent or chromogenic in-situ hybridization
(FISH) staining patterns, or gene mutation analysis.
Pharmacogenetic biomarkers may help to predict
tumor sensitivity, but as yet have not become routine
or accepted practice nor shown improved outcomes at a
population level.
Gene expression profiling using sequence technology may
help to rapidly identify a molecular profile of a tumor that
will identify risk of recurrence and allow treatment selection.
Multiple gene panels are in commercial development,
and are currently available for risk stratification and
decision-making regarding adjuvant chemotherapy for
early-stage breast and bowel cancer. Such an approach is
not universally accepted.
MOLECULAR TARGETED
THERAPY
(The ABs and the IBs.)
The most recent advances in the medical therapy of
cancer have focused on treatments that target recently discovered or previously known molecular signals or pathways
that are critical for the survival and propagation of particular
cancers.
The new drugs have mainly comprised either monoclonal antibodies or tyrosine kinase inhibitors.
Monoclonal antibodies (the ABs)

These are large protein-based structures that inhibit
either extracellular receptors that initiate growth signals
Chapter 15 Oncology
(e.g. trastuzumab, cetuximab, panitumumab, rituximab), or the ligands of the receptors (bevacizumab).
They are usually given intravenously.
Side-effects can include hypersensitivity infusion reactions. Each antibody has its own side-effects:
cetuximabrash
trastuzumabcardiotoxicity
bevacizumabhypertension, arterial thrombotic
events, small risk of bowel perforation.
Tyrosine kinase inhibitors (the IBs)

TKIs are small molecules that inhibit either specific or
multiple tyrosine kinases (e.g. imatinib, gefitinib, erlotinib, sorafenib, sunitinib, lapatinib).
They are given orally in tablet or capsule form.
Side-effects are peculiar to each TKI, although skin
toxicity is common.
erlotinib and gefitinibrash
sunitinibfatigue, thyroid function disturbance.
Despite promising activity in tumors that often are
resistant to chemotherapy (e.g. renal cell cancer, gastrointestinal stromal tumors), with prolonged responses
and good tolerability, these treatments are not considered curative. In general, treatments are usually
continued indefinitely in cancers of advanced stage as
discontinuation has led to earlier cancer progression.
Aside from imatinib in GIST, these targeted therapies
do not have proven roles as adjuvant therapies following
surgical excision of cancer of early stages.
Other
Other potential molecular pathways targeted as part of novel
cancer therapy approaches include mTOR (in which the
inhibitor is everolimus), the hedgehog pathway (in which
the inhibitor is GDC-0449), integrins, PI3K, PARP, and
proteasomes.
FAMILIAL CANCERS AND

CANCER GENETICS
Cancers can develop in the context of a familial syndrome.
These cancers may be associated with specific gene mutations and predispose to particular cancers, sometimes occurring at a young age. Patients with such syndromes may be
at risk of multiple cancers and so should be subject to more
intensive cancer surveillance. Sometimes preventative measures should be considered, including prophylactic surgery
or pharmacotherapy.
LiFraumeni syndrome is a cancer predisposition
syndrome associated with germ-line abnormalities of
the TP53 gene. The syndrome is associated with several cancers usually occurring at an early age, including
breast cancer, sarcomas, brain tumors and adrenocortical carcinomas. The management of malignancies is the
same as for other individuals. However, in women with
breast cancer, mastectomy rather than lumpectomy plus
radiation therapy is generally indicated because of the

risk of second malignancies due to radiation-induced
tumors.
Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is an autosomal
dominant disorder with a high penetrance of cancer
in mutation carriers (approximately 80%). Lynch syndrome accounts for 3% of all colonic adenocarcinomas
and endometrial carcinoma develops in up to 60% of
women. Other cancers that develop as part of the syndrome include those of the ovary, stomach, small bowel,
hepatobiliary system, and renal pelvis or ureter.
In this context, consideration should be given to
increased frequency of cancer surveillance (Chapter 12)
This should include annual colonoscopy commencing at an age that is at least 10 years younger than
the youngest affected family member, annual urinalysis, upper gastrointestinal endoscopy, screening for endometrial cancer with endometrial biopsy
and ovarian cancer with CA-125, and transvaginal
ultrasound.
There should also be discussion about the possibility of prophylactic hysterectomy and salpingooophorectomy at the end of the childbearing years.
BRCA1 and BRCA2 gene mutations can lead to
hereditary breast and ovarian cancer (HBOC) syndrome. Men have increased risk for breast and prostate
cancer, while both men and women have other cancer
risks, such as increased risk of pancreatic cancer and
colon cancer. Effective strategies for breast and ovarian cancer risk-reduction include cancer surveillance,
risk-reducing surgery and/or chemotherapy prevention. The likelihood of this being the underlying cause
of breast cancer is higher in women who are diagnosed under the age of 40 years, although the majority of cases will not have an identifiable BRCA gene
mutation.
The familial aspects of these syndromes need to be carefully
considered. Counseling through specialized cancer genetics
services is recommended. Particular issues to contemplate
include risk quantification, cancer surveillance strategies and
preventative measures such as prophylactic surgery or preventative chemotherapy. These matters need to be handled
sensitively and professionally, as there are potential implications to family planning, insurance, body image, guilt and
family relationships.
ONCOLOGICAL EMERGENCIES
Spinal cord compression should be suspected if the
patient complains of back pain, difficulties in walking,
altered bowel habit (usually constipation, but sometimes
diarrhea with loss of anal tone), or urinary retention.
It is essential to check anal tone and check for a sensory
level.
463
CLINICAL PEARL
In the febrile neutropenic cancer patient, an empirical
antibacterial regimen should be started immediately.
The regimen should have a broad spectrum of activity (including activity against Pseudomonas aeruginosa), the ability to achieve high serum bactericidal
levels, and be effective in the absence of neutrophils
(e.g. aminoglycoside plus an anti-pseudomonal
beta-lactam such as ticarcillin-clavulanate, piperacillin, or ceftazidime).
If no infection is documented yet fever and neutropenia are still present on day 7, consideration should
be given to adding an antifungal drug.
In a patient with a central venous catheter, there
should be a low threshold for considering the addition of an antibiotic that has methicillin-resistant
Gram-positive bactericidal activity, for example
vancomycin.
Cardiac tamponade
Figure 15-3 Magnetic resonance image
demonstrating spinal cord compression
The best way to investigate is with magnetic resonance

imaging (MRI) of the spine (Figure 15-3).
Clinical judgment will be required to determine the
location of the lesion causing the symptoms, as some
patients have multiple lesions.
Treatment is with analgesia, corticosteroids and
radiotherapy.
In occasional cases, chemotherapy or surgery may be
more appropriate.
Febrile neutropenia
Patients undergoing cytotoxic chemotherapy are expected
to have a fall in their white cell count with most cytotoxic
drugs 1014 days after their administration.
If patients are unwell or febrile with this, it should be
assumed they are neutropenic until proven otherwise.
This is a medical emergency as, if untreated, overwhelming sepsis can lead to death within a very short time.
Patients may have:
fevers (>38.0C), chills, rigors
a flu-like illness
malaise without fever or signs of sepsis.
The likelihood of sepsis increases with the length of time the
absolute neutrophil count is <1.0 w 109/L. The risk increases
further if the neutrophil count is <0.5 w 109/L.
Patients are at higher risk of bacteremia/septicemia if
they have evidence of mucosal damage (mouth ulcers or
diarrhea), advancing age, or other comorbidities.
Blood cultures are often negative even in the presence of
overwhelming sepsis.
464
Clinical symptoms and signs

In the setting of malignant pericardial effusion, dyspnea
and reduced level of consciousness are symptoms suggesting an emergency due to cardiac tamponade.
Elevated jugular venous pressure, hypotension and pulsus paradoxus demonstrate hemodynamic compromise.
Heart sounds may be muffled by the fluid in the pericardial sac.
Diagnosis
Urgent echocardiogram should be obtained. This will
confirm the diagnosis and help guide pericardiocentesis,
if needed.
Other imaging techniques may also reveal the diagnosis,
for example CT scanning (Figure 15-4).
Figure 15-4 Pericardial effusion with large right

pleural effusion
Chapter 15 Oncology
Management
Supplemental oxygen should be administered as

required.
Other comorbidities should be excluded (e.g.
coagulopathy).
Pericardiocentesis may be needed urgently, or a pericardial window for longer-term management.
SVC obstruction leads to edema of the face and orbits,

facial plethora, dyspnea and orthopnea.
Examination of the neck will reveal distended veins,
with raised jugular venous pressure and loss of normal
wave forms.
Both MRI and computed tomography (CT) are effective in providing the diagnosis.
Corticosteroids and radiation therapy may relieve
obstruction and allow for specific chemotherapy to be
used if appropriate.
Addisonian crisis
(See Chapter 10.)
This can occur due to tumor involvement of the
adrenals, drugs that block the adrenal function, or withdrawal of corticosteroids that occurs too quickly.
It presents with weakness, orthostatic hypotension,
andpigmentation (if chronic).
Serum chemistry for will reveal hyponatremia and
hyperkalemia.
Treatment is with replacement of corticosteroid.

(DIC)
(See Chapter 13.)
This can occur in any malignancy, but most commonly in
carcinoma of the prostate and acute promyelocytic leukemia.
Hypercalcemia
Hypercalcemia (see Chapter 10) can be due to lytic
bone metastases, parathyroid hormone (PTH)-related
peptide production or ectopic PTH production.
It is most commonly seen in myeloma and breast, head
and neck, and lung cancers.
In the patient with cancer it can also be due to nonmalignant causes, including endocrine causes, medications (thiazides, vitamin D, lithium) and other
conditions (sarcoidosis).
Immobilization
can
precipitate
or
aggravate
hypercalcemia.
Signs and symptoms include lethargy, nausea, weakness,
dehydration and decreased reflexes.
Treatment of hypercalcemia is discussed in Chapter 10. In
some patients, hypercalcemia may be a manifestation of
advanced disease where treating it may be inappropriate.
Hyponatremia
Hyponatremia can be due to the syndrome of inappropriate antidiuretic hormone (ADH) secretion, of which smallcell lung cancer is the most common oncological cause, but
sometimes it is due to liver failure, cardiac failure, overuse
of diuretics, spurious causes (e.g. drawing blood from the
intravenous line) or medications (tricyclic antidepressants).
Investigation and treatment of hyponatremia is discussed
in Chapter 9.
CLINICAL PEARL
Superior vena cava obstruction may result from central
venous cannulation. In this circumstance, anticoagulation will be required.

Both primary and secondary intracranial malignancies
can result in raised ICP. This should be suspected if
nausea, vomiting and headache are present.
Physical examination may reveal reduced level of consciousness, cerebellar and brain stem neurological signs,
and papilledema.
MRI is a sensitive test for detecting raised ICP.
Lumbar puncture must be avoided until raised ICP
pressure is excluded.
High-dose corticosteroids will often reduce ICP while
awaiting definitive therapy.
Treatment may include intravenous mannitol, corticosteroids and urgent neurosurgical intervention.
TUMOR MARKERS IN SERUM

Tumor markers predominantly have a role in following
the course of disease rather than establishing the diagnosis. Almost all of these markers can also be raised in nonmalignant conditions.
1 Carcinoembryonic antigen (CEA). Causes of an
elevated level include:
a colonic cancer (higher levels if the tumor is more
differentiated or the cancer is at an advanced stage)
b other cancers, including lung and breast cancer
c seminoma
d cigarette smokers
e GI tract conditions: cirrhosis, inflammatory
bowel disease, rectal polyps, pancreatitis
f advanced age.
CEA is of no value in the preoperative diagnosis of
colonic cancer or as a prognostic indicator, except for
operable liver metastases where a very high level does
predict a higher risk of cancer relapse after liver resection. CEA is of value in the follow-up of resected
colonic cancer; a consistently rising titer suggests
465
metastatic disease and further diagnostic evaluation is

indicated.
Alpha fetoprotein (AFP). Causes of an elevated level
include:
a hepatocellular cancervery high titers (>500ng/
mL) or a rising titer are strongly suggestive, but
>10% of patients do not have an elevated level
b hepatic regeneration, including cirrhosis, and
alcoholic or viral hepatitis
c cancer of the stomach, colon, pancreas or lung
d teratocarcinoma or embryonal cell carcinoma
(testis, ovary, extra-gonadal)
e pregnancy
f ataxia-telangiectasia
g normal variant.
CA-19-9. Causes of an elevated level include:
a pancreatic carcinoma (80% with advanced, welldifferentiated cancer have an elevated level)
b other gastrointestinal cancers: colon, stomach,
bile duct
c other solid tumors, e.g. breast cancer, ovarian
cancer, peritoneal carcinoma
d acute or chronic pancreatitis
e chronic liver disease
f cholestasis (any benign or malignant cause)
g cholangitis.
Patients who cannot synthesize Lewis blood group
antigens (about 5% of the population) do not produce
CA-19-9 antigen.
hCG (human chorionic gonadotropin)
a non-seminomatous germ-cell tumors (50%),
pure seminoma (10%)
b choriocarcinoma (nearly 100%)
c solid tumors, e.g. lung, colon, stomach, pancreas.
Prostate-specific antigen (PSA)prostatic carcinoma or any inflammatory condition of the prostate
such as prostatitis.
CA-125raised in ovarian cancer, peritoneal carcinoma or peritoneal inflammation. CA-125 is not a
screening test, is but useful to follow disease.
CA-15/3raised in a range of solid tumors including
breast cancer, but of limited clinical use.
PARANEOPLASTIC SYNDROME
Paraneoplastic syndromes represent a group of clinical scenarios or a constellation of signs and symptoms that occur in
association with particular cancers. The cancer is the underlying driver of the syndrome, although the specific pathophysiology that underlies the syndrome may not be fully
understood.
The common paraneoplastic syndromes are:
The B symptomsanorexia, weight loss, fever.
Endocrine:
hypercalcemia secondary to parathyroid hormonerelated peptide (PTHrP), especially squamous-cell
carcinomas
466
hyponatremia due to the syndrome of inappropriate

secretion of antidiuretic hormone (SIADH)
ectopic adrenocorticotropic hormone (ACTH)
production, most often seen in small-cell carcinoma
carcinoid syndrome from neuroendocrine tumors
gynecomastia due to gonadotropin production
hypoglycemia due to secretion of insulin-like peptide from squamous-cell carcinoma or mesothelioma
hypercalcitoninemia which is usually asymptomatic.
Neuromuscular:
EatonLambert syndrome
peripheral neuropathy
subacute cerebellar degeneration
polymyositis
cortical degeneration.
Connective tissue and bone, including:
acanthosis nigricans
clubbing
hypertrophic osteoarthropathy (due to small-cell
lung carcinoma)
scleroderma (alveolar cell cancer, adenocarcinoma).
Hematological:
anemia
leukoerythroblastosis
disseminated intravascular coagulation
migrating venous thrombophlebitis.
Nephrotic syndrome due to membranous glomerulonephritis.
CANCER WITH UNKNOWN

PRIMARY (CUP)
The primary site of a cancer is not always known, and up to
5% of cancers are considered to be of unknown primary.
The most common reasons for an undefined primary site
are because the primary lesion is too small for detection, there
has been removal or elimination of the primary site with surviving metastases, or multiple sites of involvement are present
making determination of the primary site imprecise.
Diagnosis
Exhaustive diagnostic investigations, including whole-body
imaging with PET scans, are often unrewarding. Careful
evaluation of the tumor tissue is important and may provide
evidence to support a possible primary location.

It is important that potentially curable cancers or those
responsive to specific therapies are considered in formulating a treatment plan. Potentially treatable subgroups are:
1 Females with isolated axillary lymphadenopathy should
be treated as breast cancer, even with a normal mammogram and negative estrogen/progesterone receptor
status on biopsy.
2 Females with peritoneal carcinomatosis, which often
behaves like ovarian cancer, should be offered treatment with platinum-based chemotherapy.
Chapter 15 Oncology
3 Males with an elevated PSA and blastic bone lesions

should be treated as though they have metastatic prostate cancer.
4 Squamous-cell carcinoma in lymph nodes of the upper
two-thirds of the head and neck without an obvious
primary should be treated aggressively, as 5-year survival rates may then be as high as 30% in this subgroup.
5 Males who fit the classification of midline germ-cell
tumorage <50 years, mediastinal or retroperitoneal
tumors (which may not stain for AFP or beta-hCG)
may respond to platinum-based chemotherapy like that
for germ-cell tumors, with the possibility of long-term
survival.
6 Patients with neuroendocrine histology may also
respond well to platinum-based chemotherapy.
CLINICAL PEARLS
Consider treatable subsets of cancer with unknown
primary (CUP) which have better prognosis.
Most CUPs are diagnosed at an extensive stage and
have a poor outlook.
There is no standard chemotherapy regimen.

PET scandetects primary cancers in only 40% of
cases, usually lung or pancreas.
Molecular profiling may provide a signature for diagnosis of primary cancer, but currently there is no validated approach to guide therapy.

Third most common cancer overall
Most common cause of cancer death (19.5%)
The two main histological subtypes are small cell and nonsmall-cell lung cancer.

Represents 80% of lung cancers
Includes the following histologies:
squamous cell carcinoma (30% of all NSCLCs)
adenocarcinoma (45% of all NSCLCs)this
type of cancer represents a greater percentage of
NSCLCs in non-smokers and in cancer affecting
people from East Asia
large cell carcinoma (25% of all NSCLCs)usually a poorly differentiated cancer that cannot be
characterized as adenocarcinoma or squamous cell
carcinoma
Staging of NSCLC is outlined in Table 15-1.
Table 15-1 Staging of non-small-cell lung cancer
STAGE
1
Lung cancer <5cm in diameter and without

lymph node involvement
Lung cancer >5cm in diameter with

ipsilateral peribronchial or hilar lymph node
involvement
Lung cancer >7cm in diameter; or cancer

directly invading local structures including
pleura, chest wall, heart, great vessels, carina;
or cancer with mediastinal lymph node
involvement
Cancer with malignant pleural effusion,

separate tumor nodules in contralateral lobe,
or distant metastases
LUNG CANCER
Cough
Hemoptysis
Chest pain
Dyspnea
Incidental finding on a chest X-ray
Risk factors
Smoking (9095% of all cases)
Increasing age
Asbestos exposure (both carcinoma and mesothelioma);
smoking is synergistic
Radiation exposureespecially in uranium workers;
smoking is synergistic
Other occupational exposure (aromatic hydrocarbons,
arsenic, vinyl chloride, chromium, nickel, hematite,
chromate, methyl ether)
Previous lung cancer resected5% per year risk of a
second primary
Pulmonary fibrosis
DESCRIPTION
Prognosis
Figure 15-5 (overleaf) shows cumulative survival rates following treatment.
Management
Treatment of different stages is outlined in Table 15-2,
overleaf.
Treatment of stage 4 NSCLC
Chemotherapy provides a benefit for patients with advanced
lung cancer:
it improves survival
it sustains or improves the quality of life
symptomatic improvement is seen despite low objective
response rates
it delays cancer progression.
467
100
Cumulative proportion surviving
80
p < 0.001
Activating EGFR gene mutations are found in 1520%

of NSCLC cases.
These mutations are more common in females,
non-smokers and people from East Asia.
Small cell lung cancer (SCLC)

60
Stage 1
(n = 1533)
40
Stage 2
(n = 169)
Stage 3a
(n = 261)
20
Stage 3b
(n = 543)
Stage 4
(n = 635)
Represents 20% of lung cancers.

This is one of the most aggressive cancers, with a rapid
doubling time.
It has a tendency to spread early, frequently involving
the liver, bones, adrenals and brain.
It is broadly split into two stageslimited stage and
extensive stage.
Cisplatin + etoposide is the most commonly employed
chemotherapy regimen.
0
12
24
36
48
60
Months following treatment
Figure 15-5 Cumulative survival of non-small-cell

lung cancer after treatment, according to clinical
stage
Redrawn from Mountain CF. A new international staging system for
lung cancer. Chest 1966;89(4 Suppl):S225S233.
Table 15-2 Treatment of non-small-cell lung cancer
STAGE
TREATMENT
Surgery*
Surgery* + consider adjuvant chemotherapy
3a
Possible surgery chemotherapy

If inoperable, then radiotherapy and
concurrent chemotherapy
3b
Radiotherapy/chemotherapy
Chemotherapy, EGFR tyrosine kinase

inhibitor, palliative radiotherapy
* Radical radiotherapy if patient is not a surgical candidate.

EGFR, epidermal growth factor receptor.
First-line chemotherapy
Key information:
Alkylating agents have an adverse effect on survival.
Cisplatin-containing regimens confer a survival
advantage.
Cisplatin combination regimens are better than cisplatin
alone.
Epidermal growth factor receptor as a treatment
target
Epidermal growth factor receptor (EGFR) activation
initiates signal transduction that promotes tumor-cell
proliferation and survival.
468
Limited stage
Disease is limited to the thorax and encompassed within
a radiotherapy field.
Treatment is with concurrent chemotherapy and
radiotherapy.
Prophylactic cranial irradiation reduces the risk of CNS
involvement and may improve overall survival.
The aim of treatment is cure; this may be achieved
in only 1520% of patients who present with limited
disease.
Extensive stage
The disease has started to spread to other organs and is
incurable.
Without chemotherapy the prognosis is very poor, with
an expected survival of less than 3 months.
While more than 80% of patients will have tumors that
respond to chemotherapy, the majority will progress
within a short time of completing chemotherapy.
The expected survival in those who receive chemotherapy is <12 months.
Maintenance therapy
Maintenance therapy after first-line chemotherapy can prolong survival or delay the time to cancer progression. These
treatments are given after an initial course of chemotherapy, so
called first-line chemotherapy, as a means of maintaining or
sustaining the response against the cancer. In effect, that time
to cancer progression is prolonged. Pemetrexed and erlotinib
have demonstrated benefits as maintenance therapies.

Monoclonal antibodies have shown benefits in NSCLC:
Bevacizumab when combined with chemotherapy (carboplatin and paclitaxel) prolongs survival in
advanced-stage NSCLC.
Cetuximab when combined with chemotherapy
(vinorelbine and cisplatin) also prolongs survival in
advanced-stage NSCLC.
Chapter 15 Oncology
The decision to incorporate these monoclonal antibodies into first-line chemotherapy must take into
account additional toxicity, patient preference, and
cost-effectiveness.
Anaplastic lymphoma kinase (ALK) gene mutations are
found in 35% of NSCLCs, and these mutations predict
benefit associated with the TKI crizotinib. ALK mutations are associated with mucinous histology, younger
age, and non-smoking status.
Immunomodulatory approaches, particularly approaches
targeting PD-1 (programmed cell death protein 1) are
under investigation.
Screening for lung cancer in patients considered to be at
high risk has been shown to increase the rate of diagnosis at an early stage. The risk of death from lung cancer
is reduced in those who are active smokers aged over 55
with a 30 pack/year history who remain active smokers
or who have stopped smoking less than 15 years ago.
This screening practice remains under evaluation but
has been recently approved by the US Preventive Services Task Force.
Assessment of genetic biomarkers may help to guide or
select optimal molecular targeted therapies.
RENAL CANCER
Background
The typical presentation of renal cancer is with flank
pain, hematuria and abdominal mass.
75% are due to clear-cell cancers.
The VHL gene mutation is found in clear-cell
carcinoma.
Mammalian target of rapamycin (mTOR) activation
is common, and is associated with more aggressive
cancers.
The risk factors for renal cell carcinoma include:
smoking
environmental toxins such as trichloroethylene
chronic use of certain analgesic agents
genetic conditions such as von HippelLindau disease
hereditary papillary renal cell carcinoma.
A genetic predisposition may also be a factor.

CT imaging of the kidneys will often reveal characteristic features of carcinoma and help with differentiation
from simple cysts.
CLINICAL PEARL
Renal cysts that represent concern for the possibility
of renal cell carcinoma have features beyond simple
cysts, such as hairline or thick septa, irregular outlines,
thickened walls, ne or coarse calcications in the wall,
and solid elements.
A tissue diagnosis is required, and usually involves a

biopsy of either the renal lesion or a metastatic lesion if
present.
There is no reliable serum tumor marker.
CT imaging of the chest, abdomen and pelvis will assist
with staging.
A bone scan should be performed if symptoms suggest
possible bone involvement.
Much less common forms of kidney cancer include Wilms
tumor (childhood embryonic nephroblastoma) and renal
sarcoma.
Treatment
Localized disease
The aim for localized disease is complete surgical
excision.
There is no proven role for radiotherapy.
Advanced disease
There is no proven role for chemotherapy.
Regimens including immunotherapy combined with
chemotherapy have been developed, but unfortunately
toxicity concerns limit the acceptance of this approach.
There is no proven role for hormonal therapy.
VEGF-directed therapy and multi-targeted

TKIs
This is associated with 5080% tumor shrinkage and a
1020% partial response rate, but no or few complete
responses.
Sunitinib is associated with the best progression-free
survival (11 months), but an overall survival benefit has
not been demonstrated.
Pazopanib has similar efficacy to sunitinib.
mTOR-directed approach
Temsirolimus (an inhibitor of mTOR) provides a survival
benefit of 3.5 months in poor-prognosis renal cell carcinoma.
Prognosis
The 5-year survival rate for localized disease is around
90%, and about 60% of disease is diagnosed at this
stage.
Where distant metastases are detected at presentation,
representing 18% of cases, the prognosis is for approximately 11% survival at 5 years.
TUMORS OF THE PELVIS,

URETER AND BLADDER
Epidemiology
Bladder and ureteric cancer has roughly the same incidence
rate as renal cancer, at 21 per 100,000 per year. There are
469
increased rates in men compared with women, and it is

more common in individuals of Caucasian genetic origin.
The median age of presentation is 78 years of age, and the
5-year survival rate is 7080%.
Risk factors
Incidence rates and overall survival are improving with time.
However, in women, 50% of bladder cancer is now known
to be smoking-related, due to increased rates of smoking in
women. Smoking remains an important risk factor in men.
Other risk factors include the following:
Occupational exposures including to dyes (e.g. aniline dye and aromatic amines; hairdressers, machinists,
painters and truck drivers).
Schistosomiasis.
Arsenic exposure.
Chronic bladder problems, such as stones and bladder
infections, including in those with paraparesis-related
chronic urinary sepsis.
Exposure to cytotoxic drugs, especially cyclophosphamide (which is of special interest to physicians).
Cyclophosphamide is known to cause acute hemorrhagic cystitis, and lead to a significant increase
in the risk of bladder and other renal tract cancers.
Protocols related to chemotherapy use for other
cancer states include significant prophylaxis against
bladder cancer. This is achieved by administration
early in the day (not leaving a concentrated amount
of chemotherapy drug or its metabolites in the
bladder overnight), with adequate hydration, even
forced diuresis, and with the bladder protectant
Mesna (2-mercaptoethan sulfonate sodium). Mesna
detoxifies by reaction with its sulfhydryl group, and
by increasing cysteine excretion in the urine is protective against hemorrhagic cystitis.
Long-term use of compound analgesics. These gain
access to the totality of the urinary drainage system by
way of their concentration through active excretion in
the urinary tract, leading to multiple points of carcinogenesis and thereby multi-focal urethelial tumors.
Bladder cancer can take the form of:
transitional cell carcinoma (urothelial carcinoma) (90%)
squamous-cell carcinoma (34%)
adenocarcinoma (12%).
These can all occur anywhere in the urinary tract.
Bladder cancer should be suspected in those with painless
hematuria, and known risk factors. There can be dysuria,
and strangiuria in the absence of proven urinary tract infection. Other nonspecific symptoms can include frequency
and nocturia.

Early diagnosis and screening in those susceptible is best
achieved by cystoscopic examination, with retrograde
examination of the ureters.
470
Urinary cytology may be useful also in a sufficiently

concentrated sample.
Imaging modalities including intravesical ultrasound,
and abdominopelvic CT or MRI may be necessary to
determine extension beyond the bladder wall, and pelvic or retroperitoneal extension or spread.
Treatment
The mainstay of bladder cancer treatment is resection
of the tumors by endoscopic procedures; bladder and
wider pelvic resection with extended pelvic lymphadenectomy; and then consideration of either adjuvant
or rescue chemotherapy treatment.
Treatment of early or low-grade tumors is with laserinduced interstitial thermotherapy or hyperthermia, or
photodynamic therapy after using a photosensitizing
agent.

Current trials in bladder cancer include anticancer drugs
with and without bacillus CalmetteGurin (BCG)
intravesical therapy.
Maintenance and prevention of recurrence is under trial
with selenium or topical BCG.
PROSTATE CANCER
Epidemiology
The most common malignancy diagnosed in males.
While most do not die from the cancer, it still represents
the second most common cause of cancer-related death
in men.
Can be familial.
Screening
At a population level, serum PSA testing will detect
pre-clinical cases of cancer but the overall survival benefit has not been verified. There are no national population-based screening programs.
Individual management of prostate cancer risk relies on
a strong history and presentation at age <60 years.
Staging
A Incidental finding at transurethral resection.
B Palpable nodule involving one lobe of the prostate.
C Peri-prostatic tissue involved (C2 involves the seminal
vesicles).
D Metastatic disease including regional lymph nodes.
The Gleason score, a pathological grading system based on
the microscopic appearance of the cancer, informs prognosis
and may guide therapy. It is used as a pathological measure
of the biology of the cancer. A higher score usually indicates
a more aggressive (faster growing, poorer prognosis) cancer.
Chapter 15 Oncology
Management
Stages AC
Surgery and/or radical radiotherapy is the treatment of
choice.
The decision between surgery or radical radiotherapy
relies on a careful weighing of the risks of each strategy.
Usually, locally advanced disease or localized cancers
with a high PSA and a high Gleason score are managed
with radiotherapy. Those with a relatively low PSA and
Gleason score may be managed with either approach.
Risks of surgery can include erectile dysfunction
and incontinence.
Risks of radiation include radiation proctitis and
cystitis.
In men without symptoms and a low PSA/low Gleason score, a reasonable policy may be to monitor only,
as clinically significant disease may take more than 10
years to develop.
In younger men with PSA <15 ng/dL, surgery is often
recommended.
Stage D
Stage D may be treated by hormonal manipulation
when symptomatic.
LHRH agonists (e.g. goserelin or leuprorelin,
degarelix) administered by regular subcutaneous
depot injection downregulate the LHRH receptor
to cause a chemical castration. Depending on the
formulation used, these injections can be administered monthly to 3- or 4-monthly.
Anti-androgens (flutamide, bicalutamide, cyproterone acetate) block androgen receptors on tumor
cells and are used ideally in combination with medical or surgical castration (total androgen blockade).
The timing of total androgen blockade (at the time
of diagnosis or when symptoms manifest) remains
controversial.
Chemotherapy drugs that have been shown to provide
a survival benefit include docetaxel and cabazitaxel.
These drugs are usually given with prednisolone.
Strontium-89 is useful for the treatment of diffuse bone
pain from metastatic prostate cancer. A single injection can be given every 3 months. Side-effects include
transient cytopenia in about 10% of patients, and more
severe or prolonged cytopenia in about 1%.
Abiraterone is a new hormonal therapy which is well
tolerated by most patients. A randomized controlled
trial was stopped early due to a demonstrable improvement in overall survival of 3 months. Notable reductions
in PSA are frequently seen. The abiraterone mechanism
of action is mediated through inhibition of CYP17, an
enzyme critical in testosterone production both in and
outside the testes.

A prostate cancer autologous vaccine, Sipuleucel-T, is
an immune-stimulant that has been associated with a
prolongation of survival of 4.1 months in a large randomized controlled trial. This became the first FDAapproved cancer vaccine, but the expense has precluded
widespread uptake.
Enzalutamide (MV3100) is an androgen receptor inhibitor that has been demonstrated to prolong survival in
a placebo-controlled trial conducted in patients with
castrate refractory prostate cancer progressing following
chemotherapy.
New radioisotope therapeutic strategies are in
development.
TESTIS CANCER
The incidence of testis cancer has risen, having doubled
in the past 40 years.
Testis cancer represents 1% of male cancers.
It is the most common cancer in men aged 2034 years.
The lifetime risk in Caucasians is 0.2%; it is less common in people of Asian or African origin.
Risk factors
Cryptorchidism
Contralateral testicular tumor: 25% risk
Orchitis
Testicular injury
Estrogen exposure
Low sperm count
Elevated follicle-stimulating hormone (FSH)
Pathology
95% are germ cell tumors (GCTs): seminoma and
non-seminomatous germ cell tumor (NSGCT).
Carcinoma in situ (CIS) is a precursor, and if present
there is a 50% risk of developing cancer at 5 years.
NSGCT is classified into:
malignant teratoma undifferentiated (MTU)
(embryonal)
teratoma differentiated (TD) (mature teratoma)
choriocarcinoma
yolk sac tumor.
Diagnosis
Clinical features
Scrotal or testicular mass; 75% are painless

Scrotal or testicular pain
Hydrocele
Lymphadenopathy
Symptoms due to metastases
471
Investigations and staging

Testicular ultrasound is the appropriate initial investigation to assess a suspicious testicular mass.
Confirmation of the diagnosis will require orchidectomy.
CT scan is used for staging25% of cancers are, however, under-staged by CT.
Tumor markers (AFP, hCG, LDH) are an important
determinant of the presence of occult metastatic disease
after orchidectomy.
PET scan is increasingly used; note that it requires specialist interpretation and has not yet been established as
improving outcomes.
Staging according to the Union for International Cancer
Control is given in Table 15-3.
Table 15-3 UICC staging system
Clinical stage I
Pathological
stage I
Pathology conned to the testis

Tumor markers normal (or falling at
expected rate)
Radiological investigations normal
As per clinical stage I, but no evidence
of lymph-node involvement in
retroperitoneal lymph nodes following
resection
Stage II
Regional lymph-node involvement,

including retroperitoneal nodes
Stage III
Distant nodes or visceral/bone

metastases
UICC, Union for International Cancer Control.

Adapted from Sobin LH, Gospodariwicz M and Wittekind C (eds).
TNM classication of malignant tumors. UICC International
Union Against Cancer, 7th ed. Wiley-Blackwell, 2009.

Studies show that there is one consistent histological prognostic factor in this condition, which is vascular invasion
(VI).
VI is an important predictor of retroperitoneal lymphnode involvement in clinical stage 1 disease.
VI predicts the risk of relapse (usually visceral) in pathological stage I disease after retroperitoneal lymph-node
dissection.
Treatment
Sperm storage should be offered to all patients before
chemotherapy.
Radical orchidectomy
The procedure describes orchidectomy plus retroperitoneal
lymph-node dissection (RPLND).
It is part of primary treatment in the USA and Germany, but not a routine staging or therapeutic procedure in the rest of Europe or in Australia.
As imaging techniques improve, the need for RPLND
should lessen.
472
It carries a risk of causing ejaculatory dysfunction.

Routine RPLND detects metastases in 2530% of
patients, therefore 7075% are having an unnecessary
procedure.
The incidence of visceral metastases following RPLND
is 10% when lymph node is negative for tumor.
Seminoma
Stage I
Adjuvant para-aortic radiotherapy.
Single-agent chemotherapy: 1 cycle of carboplatin.
Stage II
If disease is bulky (>5 cm), treatment is with chemotherapy: bleomycin, etoposide and cisplatin (BEP), or
etoposide and cisplatin (EP).
If disease is not bulky, radiotherapy is the preferred
option.
Stage III
Treatment is with chemotherapy, either with BEP or with
EP in better prognosis disease.
NSGCT
Stage I
The choice of treatment in stage I disease is between
surveillance alone and adjuvant chemotherapy with 2
cycles of BEP.
The decision should take into account relapse risk,
prognostic histological factors, and compliance with
surveillance.
The arguments against adjuvant therapy are:
There are outstanding results in stage II/III disease, with
>90% long-term disease-free survival. So, with close
surveillance a cancer recurrence can be detected and
successful therapy implemented.
Many patients who are cured by surgery will receive
chemotherapy when they do not need it.
The arguments for adjuvant chemotherapy are:
The risk of recurrence is very low after adjuvant therapyonly 1% will develop cancer recurrence.
Close and frequent surveillance will no longer be
necessary.
The total dose (i.e. number of cycles) will be less when
giving adjuvant therapy, with less cumulative toxicity, than the chemotherapy needed to treat a cancer
recurrence.
Stages II and III
Treatment is with chemotherapy, either with BEP or with
EP in better-prognosis disease.
Intermediate- or poor-prognosis metastatic

disease
Treat with chemotherapy (3 cycles of BEP, then 1 cycle of EP).
Chapter 15 Oncology
Early-stage disease
Residual masses are commonly seen after primary chemotherapy, particularly in seminoma and differentiated teratoma, and less commonly with embryonal carcinoma.
4550% of masses are found to be lymph nodes which
contain necrotic tissue and fibrosis.
35% of teratomas are differentiated (mature teratoma).
1520% contain viable carcinoma (vital malignant
tumor).
After salvage chemotherapy for residual masses, approximately 50% of lesions will still contain carcinoma, so resection should be considered.
Small primary tumors with no nodal or distal metastases are

generally managed with single-modality treatments (either
surgery or radiation therapy).
Relapsed disease
Salvage chemotherapy for relapsed GCT
Overall, 1030% of patients with GCT will relapse.
It can be difficult to differentiate relapsed disease versus
residual mass or mature teratoma.
Patients can be cured with second-line chemotherapy,
with the long-term survival of 2030%.
Seminoma and NSGCT are treated in essentially
the same manner upon relapse following primary
chemotherapy.
Consideration should be given to surgical resection for
late relapses, as such cancers are more likely to be resistant to chemotherapy.
Most relapses occur in the first 2 years and are still curable even in those who have had prior chemotherapy.

This is usually given following conventional-dose salvage
chemotherapy or in high-risk/poor-prognosis situations,
such as:
an extragonadal primary site
progressive disease after an incomplete response to primary therapy
poor response or progression after treatment with cisplatin plus ifosfamide-containing conventional salvage
therapy.
HEAD AND NECK CANCER

A multidisciplinary approach, involving surgeons, medical oncologists and radiation oncologists as well as dentists,
dietitians, speech pathologists and rehabilitation therapists,
is generally required for treatment planning and management of patients with head and neck cancer.
Optimal therapy will depend upon tumor site and stage,
the risks of therapy, and patient performance status,
comorbidities and preference.
Patients often have a history of excessive alcohol intake
and smoking.
Human papillomavirus (HPV) is becoming increasingly
associated with oropharyngeal cancers (see below).
Advanced head and neck cancerlarge primary tumor and/
or nodal involvementis usually managed with multimodality treatments.
Options include:
primary surgery followed by either postoperative radiotherapy or concurrent chemotherapy and
radiation
induction chemotherapy (the addition of chemotherapy prior to surgery and/or radiotherapy)
concurrent chemoradiotherapy
sequential therapy (induction chemotherapy followed by concurrent chemoradiotherapy).
Palliative chemotherapy and/or supportive care is recommended for recurrent or metastatic disease.
Select patients with disease confined to the head
and neck may benefit from surgical salvage and/or
re-irradiation.
Cetuximab also provides a benefit in patients with inoperable localized disease when used in combination with
radiotherapy, particularly in patients not considered
suitable for chemotherapy.

Human papillomavirus is associated with over one-half
of all head and neck squamous-cell cancers, primarily in
the tonsils and the base of the tongue.
Younger patients without a history of excessive exposure to alcohol and tobacco are often affected.
ESOPHAGEAL CANCER
The majority of cases of esophageal cancer are either
adenocarcinoma, for which the incidence is rising, or
squamous-cell carcinoma, for which the incidence is
falling.
The male:female ratio is 4:1.
Risk factors include smoking, obesity, dry salted
foods and, most importantly, Barretts esophagus for
adenocarcinoma.
Helicobacter pylori is a protective factor for adenocarcinoma (lowers gastric acid).
Barretts esophagus is the major risk factor for
adenocarcinoma.
Tylosis (hyperkeratosis of the palms and soles; Figure 15-6, overleaf) is associated with squamous cell
carcinoma.
473
Figure 15-6 Tylosis (hyperkeratosis of the palms and soles). Diffuse yellowish hyperkeratosis (tylosis) on both
hands and feet
From Sheen Y.-S. et al. Mutation of keratin 9 (R163W) in a family with epidermolytic palmoplantar keratoderma and knuckle pads. J Dermatol
Sci 2007;45(1):635.
The three major symptoms of esophageal cancer are:
dysphagia
nausea
weight loss.
Less commonly, patients may experience chest pain or GI
tract bleeding.

Endoscopy allows for visualization of lesions and biopsy
to confirm the diagnosis.
CT imaging of the thorax and abdomen allows assessment for local spread and metastatic disease.
No survival advantage has yet been demonstrated for
population-based screening for Barretts esophagus.
Management
Early-stage disease
Multiple treatment strategies are available:
surgery alone
radiotherapy alone
chemoradiotherapy alone
surgery followed by chemoradiotherapy
chemotherapy followed by surgery
perioperative chemotherapy.
There is no evidence of the curative potential for chemotherapy alone without surgery or radiotherapy.
The most common chemotherapy regimen applied is
5FU and cisplatin in early-stage disease, and this regimen can be given concurrently with radiotherapy.
Another regimen includes ECF (epirubicin, cisplatin, 5FU) in a preoperative and postoperative contact.
Radiotherapy should not be given concurrently with
474
ECF due to the additional toxicity of radiation and

anthracyclines (epirubicin).
Metastatic disease
Metastatic disease is not curable.
Chemotherapy delivers modest survival benefit over
best supportive care, and may also help to alleviate
symptoms.
Overall, the 5-year survival rate for esophageal cancer is
20%.
GASTRIC CANCER
Epidemiology
There is a decline in incidence in Western countries of
gastric cancer, although it remains high in Southeast
Asia.
It is the second most common cause of cancer death
worldwide. Tumors of the cardia and gastroesophageal
junction are increasing.
Helicobacter pylori is the major cause; autoimmune atrophic gastritis (pernicious anemia) is less common.
Hereditary diffuse gastric cancer is autosomal dominant,
leading to early gastric cancer.
Gastric cancer often presents with locally advanced
disease.
Dyspepsia and nausea are common symptoms.
Weight loss, anorexia, early satiety, and pain are common in the advanced stages of disease.
Rarer presentations include gastrointestinal bleeding,
and prominent vomiting may be a clue to linitis plastics
or gastric outlet obstruction, where diffuse infiltration
of tumor reduces gastric distensibility.
Chapter 15 Oncology
CLINICAL PEARLS
Remember, all gastric ulcers need repeat endoscopy to ensure healing.
Early cancers are impossible to reliably distinguish
from benign ulcers on appearance alone.
Diagnosis
Endoscopy should be performed on symptomatic
patients to determine location and allow for biopsies.
Staging investigations should include abdomino-pelvic
CT.
Although PET is useful for distant metastases it may
not define peritoneal disease, for which a preoperative
laparoscopy may be of benefit.
Treatment
Surgery
Surgical resection has the greatest chance of cure.
While there is increased operative mortality for total gastrectomy, it is recommended if there is diffuse involvement of the stomach or involvement of the cardia.
Adjuvant therapy
Adjuvant chemotherapy
Meta-analyses reveal a survival benefit with the use of adjuvant chemotherapy.
Peri-operative chemotherapy (epirubicin, cisplatin and
5FU given before and after surgery) prolongs survival
in the management of operable gastric cancer compared
with surgery alone.
Following initial gastrectomy, the application of both
chemotherapy and radiotherapy may prolong survival
and lower the risk of cancer recurrence.
Chemotherapy for metastatic disease
A survival benefit has been demonstrated through the
use of chemotherapy compared with best supportive
care (BSC).
Response rates generally range from 25% to 50%.
Overall survival usually ranges from 69 months, but is
usually less than 12 months in large, randomized trials.
Trastuzumab combined with chemotherapy should be
used for patients with advanced gastroesophageal cancer that is HER2-positive on immunohistochemistry.
HER2-positive disease accounts for 20% of advanced
gastric cancers.
Combination chemotherapy is associated with palliative
benefit with acceptable toxicity.
There has been little recent change in case fatality in
Western countries, with a 5-year survival rate of 20%.
This contrasts with a 50% 5-year survival rate in Japan.

Gastric mucosa-associated lymphoid tissue (MALT)
lymphoma is a form of extranodal marginal-zone B-cell
lymphoma.
Chronic immune stimulation, most commonly from
Helicobacter pylori infection, is causative. Early lesions
often respond to H. pylori eradication, and more than
90% of patients with MALT lymphoma are infected
with H. pylori.
More advanced disease requires systemic chemotherapy.
COLORECTAL CANCER
The transformation from normal colonic epithelium to
an invasive cancer is a multi-step gene mutation process.
Adenomatous polyposis coli (APC) and hereditary
non-polyposis colon cancer (HNPCC) are driven
by single germ-line mutations.
Sporadic cancers result from the stepwise accumulation of multiple somatic mutations.
Microsatellite instability high (MSI-H) expression
is associated with HNPCC and is also observed
in approximately 1015% of sporadic colorectal
cancers.
Most cancers develop from polyps via the adenomato-carcinoma sequence.
The incidence and mortality from colorectal cancer can be reduced through population screening for
colorectal cancer, using fecal occult blood testing or
colonoscopy.
CLINICAL PEARL
2030% of cases of colorectal cancer will present with
stage IV (metastatic) disease, with the liver, lungs and
lymph nodes being the most common sites of cancer
spread.
Colorectal cancer (CRC) risk factors

Age >50
Inflammatory bowel disease
Smoking
History of adenomatous polyps
First-degree relatives with colon cancer or adenomatous
polyps
Familial polyposis (FAP) syndromes
HNPCC
Obesity, fatty and high-calorie diet and type 2 diabetes
BRCA1 mutation
Female genital or breast cancer
Acromegaly
475

Common presenting symptoms include change in
bowel habit, bleeding per rectum, abdominal bloating
or pain.
Fatigue can be a presenting feature related to irondeficiency anemia.
Colonoscopy can localize and biopsy lesions throughout
the large bowel, and polyps can be removed.
Preoperative clinical staging involves physical examination, CT scan of the abdomen and pelvis, and chest
imaging (CT or chest X-ray).
Digital rectal examination, rigid sigmoidoscopy, transrectal endoscopic ultrasound, and/or MRI are indicated
for loco-regional staging of patients with rectal cancer,
to select the surgical approach and identify those patients
who are candidates for initial radiotherapy or chemoradiotherapy rather than up-front surgery.
PET scanning is not required prior to resection of localized bowel cancer, but are performed prior to hepatic
resection for liver metastases.
Serum carcinoembryonic antigen (CEA) is not useful
in the primary diagnosis of colorectal cancer, but can
be a useful biomarker to monitor patients after initial
treatment of bowel cancer. A rising CEA level usually
indicates cancer progression or recurrence.
The optimal follow-up schedule for patients with earlystage CRC after completion of surgery and adjuvant
therapies has not been defined. The approach usually
includes periodic physical examination, CEA, colonoscopy and liver imaging (ultrasound or CT scan).
Staging of bowel cancer is outlined in Table 15-4.
CLINICAL PEARLS
Important red ags for colorectal cancer when taking
the history:
hematochezia, melena, altered bowel habits, weight
loss, iron-deciency anemia and onset of symptoms
after the age of 45 years
endocarditis or sepsis caused by either Streptococcus gallolyticus or Clostridium septicum.
Table 15-4 Staging of bowel cancer
STAGE
DESCRIPTION
Cancer restricted to the bowel wall,

extending from mucosa to submucosa and
involvement of muscularis layer but not
through to serosal surface
II
Cancer extending through the bowel wall

to the serosal surface and may even extend
beyond the serosa but not to regional
lymph nodes
III
Cancer spread to local lymph nodes
IV
Cancer spread to distant sites (metastases)
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Management
Early-stage bowel cancer
Complete surgical excision remains the curative option.
Following potentially curative resection of colon cancer, the goal of adjuvant chemotherapy is to eradicate
micro-metastases, thereby reducing the likelihood of
disease recurrence and increasing the cure rate.
The benefits of adjuvant chemotherapy have been most
clearly demonstrated in stage III (node-positive) disease.
The benefit remains contentious for stage II disease.
Stage I
No further therapy after surgery.
Stage II
The survival benefit associated with adjuvant chemotherapy is very small or absent.
Without high-risk features, observation (without
adjuvant therapy) is an acceptable approach.
If high-risk features are present, such as bowel
obstruction, bowel perforation, large tumor size,
high-grade tumor or lymphovascular invasion,
adjuvant chemotherapy may provide a survival benefit across the population.
A low number of lymph nodes examined (<12) is
also considered a potential feature associated with a
higher risk of cancer recurrence, and such patients
should be considered for adjuvant chemotherapy.
Adjuvant chemotherapy may comprise of single-agent
fluoropyrimidine (e.g. 5FU/leucovorin or capecitabine)
or FOLFOX, although combination chemotherapy has
not been demonstrated to provide a survival benefit over
single-agent fluoropyrimidine chemotherapy in stage II
disease.
Patients without high-risk features who have
MSI-H-deficient mismatch-repair tumors have a favorable prognosis and are not likely to benefit from adjuvant fluoropyrimidine-based therapy.
Stage III
Adjuvant chemotherapy provides a survival benefit,
with a relative reduction in the risk of disease recurrence
of 30% and a mortality reduction of 25%.
The most commonly used regimen is FOLFOX for 12
cycles (6 months).
Peripheral neuropathy can be a long-term complication
of oxaliplatin.
Single-agent capecitabine can also provide a survival
benefit.
There is no evidence of benefit with the addition of
bevacizumab.
No evidence has been found for improved outcomes
when cetuximab is added to chemotherapy in K-ras
wild-type stage III colon cancer.
Older patients may not benefit from oxaliplatin doublet
chemotherapy, but they do benefit from 5FU-based
adjuvant chemotherapy as much as younger patients do.
Chapter 15 Oncology
Metastatic bowel cancerstage IV

The intent of therapy is palliative in almost all people.
A subset of patients with liver, and in select cases
lung-limited, disease can undergo resection of metastases with curative intent.
Although long-term prognosis is poor for patients with
unresectable metastatic CRC, palliative chemotherapy
can relieve symptoms, improve quality of life and prolong survival.
Active drugs include the fluoropyrimidines, oxaliplatin, irinotecan, and the therapeutic monoclonal antibodies bevacizumab, cetuximab, and
panitumumab.
The optimal way to combine and sequence these
agents is not yet established. In general, exposure to
all active drugs is more important than the specific
sequence of administration.
Commonly used chemotherapy regimens include a chemotherapy doublet:
FOLFOX = folinic acid, 5FU, oxaliplatin
XELOX = Xeloda (capecitabine) and oxaliplatin
FOLFIRI = folinic acid, 5FU, irinotecan.
Long-term survival can be achieved in as many as 50%
of cases. Down-staging with neoadjuvant chemotherapy may permit successful resection in a small number
of people.
VEGF targeted therapies (bevacizumab and
aibercept)
Addition of bevacizumab to chemotherapy can prolong
survival and progression-free survival.
The benefit needs to be weighed against the acute risks,
including bowel perforation (1%), arterial thrombotic
events, hypertension and headache, wound-healing
complications and fistula formation.
Because of the risk of impaired wound healing,
bowel perforation and fistula formation, at least 1
month should elapse between major surgery and
administration of bevacizumab.
Aflibercept, another VEGF inhibitor, has also been associated with prolongation of survival when combined
with chemotherapy as part of second-line treatment of
metastatic colorectal cancer.
EGFR monoclonal antibodies (cetuximab or
panitumumab)
These antibodies have been proven to prolong survival for
patients with advanced K-ras wild-type colorectal cancer.
They have no proven role as part of adjuvant therapy in
early-stage K-ras wild-type CRC.
Rectal cancer
Neoadjuvant chemoradiotherapy (i.e. concurrent chemotherapy, in the form of 5FU infusion or capecitabine, and radiotherapy given for 56 weeks as an initial
treatment measure before surgery) is an increasingly
used strategy for patients with rectal cancer, particularly
if the tumor is locally advanced.
Preoperative chemoradiotherapy might allow some

patients to undergo sphincter-preserving low anterior
resection (LAR) rather than an abdominoperineal
resection (APR).
A short course (5 days) of high dose per fraction neoadjuvant radiotherapy is another option that is recommended by some practitioners.
Postoperative chemotherapy may also be advised after
initial neoadjuvant therapy, although the benefit has not
been quantified in randomized controlled trials.
Combining oxaliplatin with fluoropyrimidine and
radiotherapy in early-stage rectal cancer is being evaluated, but early results have revealed more toxicity without improved outcomes.
Future directions
The rationale for use of multiple biomarkers to select the
most appropriate therapy, particularly new molecular targeted therapies, remains a topic of intense investigation.
PANCREATIC CANCER
The pancreas can harbor malignancies arising from several
cell types. These can be grouped into:
exocrine pancreatic cancers
neuroendocrine pancreatic cancers (e.g. glucagonoma,
insulinoma).
Neuroendocrine pancreatic cancers are discussed in
Chapter11.
Key points
Pancreatic cancer has a poor prognosis.
When detected early, it may be cured by complete surgical resection (Whipples procedure) or by resection of
the tail of the pancreas if this is where disease is located.
Following complete surgical resection, adjuvant chemotherapy can lower the risk of cancer recurrence and provide a survival benefit.
Current treatments of advanced disease provide only
modest improvement in median survival.
Epidemiology
Pancreatic cancer occurs more commonly as age
increases.
It represents the fifth most common cause of cancerrelated death.
Prognosis is very poor, with the incidence approximating the mortality (5-year survival is 5%).
Risk factors include smoking, chronic pancreatitis,
diabetes mellitus and those with a genetic (familial)
predisposition.
At the time of diagnosis, 20% of patients will present
with localized and operable disease, 40% will have
locally advanced inoperable disease, and 40% will have
metastatic disease.
477
Diagnosis
Tumors in the pancreatic body or tail usually present
with pain and weight loss.
Tumors in the head of the pancreas typically present
with jaundice, pain, weight loss, and steatorrhea.
The most common sites of distant metastases are the
liver, peritoneum and lungs.
Contrast-enhanced multi-slice helical CT scan is the
preferred method to diagnose and stage.
Endoscopic ultrasound is another method to assess
vascular invasion, and an endoscopic ultrasonography
(EUS)-guided FNA can establish histological confirmation of the diagnosis.
CLINICAL PEARLS
New-onset diabetes mellitus in persons aged 50 years
and above with normal weight should raise suspicion
of pancreatic cancer. Also, unexplained episodes of
pancreatitis or thrombophlebitis can be manifestations
of pancreatic cancer.
Management
Complete resection will achieve the best chance of cure,
but only a minority of patients present with resectable
disease.
Even when a complete resection is achieved, the
majority of patients eventually develop recurrence.
Systemic chemotherapy (5FU or gemcitabine)
applied after R0 or R1 surgical excision can improve
outcomes.
Pancreatic cancer is often deemed unresectable due to
vascular involvement or nodal disease (locally advanced
inoperable disease), or due to the finding of metastases
at the time of diagnosis.
For recurrent or metastatic disease, treatment goals are
palliative.
Adjuvant radiotherapy, either alone or in combination
with chemotherapy, has not demonstrated improved
cure rates.
Chemotherapy can prolong survival to a modest
degree, with median survival increments of weeks to a
few months possible. Current standard chemotherapy
regimens include single-agent gemcitabine, oxaliplatin + 5FU (FOLFOX), oxaliplatin + 5FU + irinotecan
(FOLFIRINOX).
Nab-paclitaxel, when added to gemcitabine, has been
associated with prolongation of survival for patients
with advanced inoperable pancreatic cancer.
HEPATOCELLULAR
CARCINOMA (HCC)
Key points
Hepatocellular carcinoma is the third leading cause of
cancer death worldwide.
The number of deaths match the incidence, indicating a
high case fatality rate.
80% of cases develop in association with chronic hepatitis B or C infection.
There is high geographical variation, with the highest
incidence reported in eastern Asia and parts of Africa.
40% of HCC cases worldwide originate from China.
Men are between two and five times more likely to be
affected than women.
Underlying chronic liver disease or cirrhosis is common.
Risk factors
The most common etiological factor is chronic hepatitis
B or C infection.
Other causes include excessive alcohol intake, Wilsons
disease, and hemochromatosis.
Cases may be idiopathic.
Prognosis
The prognosis is best determined using the ChildsPugh
Turcotte score; prognosis is related to the score as shown
inTable 15-5.
Treatment
20% of tumors are resectable at presentation.
70% develop recurrence post-resection (90% within
3years).
Table 15-5 HCC prognosis related to ChildsPughTurcotte score (see Table 13-6)
POINTS
CLASS
1-YEAR SURVIVAL
2-YEAR SURVIVAL
56
100%
85%
79
81%
57%
1015
45%
35%
HCC, hepatocellular carcinoma.

From Pugh RN et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):6469.
478
Chapter 15 Oncology
Liver-directed strategies
This is the preferred approach where possible. Options
include:
partial hepatectomy
alcohol injection
transarterial chemotherapy embolization (TACE)
radiofrequency ablation (RFA)
cryoablation
radiotherapeutic microspheres.
Chemotherapy
Systemic chemotherapy has no proven survival benefit or
palliative role.
Molecular targeted therapy

Sorafenib, a vascular endothelial growth factor
(VEGF)-targeted TKI, may delay cancer progression
and prolong survival in a small number of cases.
Regional chemotherapy
(e.g. TACE)
Hepatocellular tumors are preferentially supplied by the
hepatic artery. Delivery of chemotherapy directly to the
tumor provides increased local drug concentration and
decreased systemic effects.
Angiography is performed with injection of a chemotherapy/lipiodol conjugate and an embolic agent
into the tumor via the hepatic artery.
Ischemia due to the embolization increases tumor
kill.
Patients may require repeated treatments.
Contraindications are:
portal vein occlusion
impairment of hepatic function
large tumor >50% of liver volume.
Toxicities from regional chemotherapy include fever
(>95%), abdominal pain (>60%), anorexia (>60%), and
deterioration in liver function.
The response rate is 5080%.
There is no consensus on appropriate drugs or technique. Usually anthracyclines or cisplatin are used.
BRAIN TUMORS
oligodendroglioma)
Key points
Almost all patients have progressive disease and will
require some form of therapy.
Surgery is usually not curative in intent.
Radiotherapy can be effective, but there are late toxicity
concerns.
The role of chemotherapy is not clearly defined.
There is little
management.
randomized
evidence
to
guide
Diagnosis
Brain tumors are diagnosed on MRI scan appearance and
biopsy.
Treatment
Surgery
Complete resection is rarely possible. Most surgeons
will biopsy if radiological appearances are consistent
with low-grade glioma.
The role of subtotal resection is debatable.
Surgery has an important role in the management of
intracranial hypertension, hydrocephalus, control of
epilepsy, and symptom palliation.
Surgery is estimated from historical series to improve or
control symptoms in about 80% of patients.
Radiotherapy
The true benefit of radiotherapy is difficult to determine
because of the heterogeneity of patient groups and many
treatment-related variables.
Retrospective reviews reveal a long-term survival
advantage for radiotherapy after surgery.
Postoperative radiotherapy for oligodendroglioma
will provide a survival benefit for a subtotally
resected tumor, but this benefit is only observed
after 5 years of follow-up.
There is no clear survival benefit from radiotherapy
if there is a true complete surgical resection.
Improvement in 5-year progression-free survival is
observed if radiotherapy is given early after surgical
biopsy rather than waiting for progression, but no
difference in 5-year overall survival.
Radiotherapy does not induce malignant transformation of low-grade glioma.
A wait and see policy can be justified in younger
patients with seizures only.
Treatment should not be delayed in patients with
focal signs, raised intracranial pressure, symptoms
or cognitive deficits.
The impact of radiotherapy on quality of life is still
uncertain.
There is no justification for radiotherapy doses above
50 Gy using the current conformal techniques, as
higher-dose radiotherapy is no more effective and
potentially more toxic, with late toxicity a particular problem.
Most progression after radiotherapy still occurs in the
radiotherapy field, suggesting that the currently used
radiation doses are inadequate for cure.
The role for intensity-modulation radiotherapy (IMRT)
and targeted dose escalation remains unclear.
479
Adjuvant treatment
Up-front chemotherapy may be indicated, especially for
patients with large tumors.

Epidemiology
The most common and most aggressive malignant primary
brain tumor, it represents 2% of all cancer-related deaths.
Diagnosis
Patients may present with neurological signs and
symptoms. Sometimes, a seizure may be the first
manifestation.
MRI imaging can provide information suggesting the
diagnosis of GBM.
A tissue sample should be obtained by neurosurgical
resection or stereotactic biopsy.
Treatment
Following the brain biopsy, treatment is usually commenced with combined chemotherapy (particularly
temozolomide) and radiotherapy. This treatment runs
for approximately 6 weeks, with the oral chemotherapy
given daily.
One month following completion of the chemoradiotherapy, patients then begin regular courses of temozolomide, given for 5 consecutive days every 4 weeks;
6cycles are usually given.
Treatment may induce imaging changes that are difficult to distinguish from progressive disease.
Bevacizumab has reduced requirements for corticosteroid therapy and has been associated with imaging
evidence of tumor response.
Despite the use of a combined modality approach, most
patients eventually relapse.
LYMPHOMA
dermis. Malignant melanocytes involve the dermal

epidermal junction in a lentiginous pattern.
3 Acral lentiginous melanomausually arises on
palmar, plantar, subungual and mucosal surfaces. Histology usually reveals large junctional nests of atypical
melanocytes with scant cytoplasm.
4 Nodular melanomavertical growth phase melanomas. They present as darkly pigmented nodules,
sometimes ulcerated. Neoplastic cells form a nodular
structure in the dermis, with no recognizable adjacent
radial growth phase. The neoplastic melanocytes are
epithelioid or spindle cells and the mitotic index is usually high.

Discolored nodule or plaque-like lesions are the hallmark feature, but they are not always dark (e.g. amelanotic melanoma).
Melanomas are diagnosed on histology; immunohistochemistry (markers S-100 and HMB-45) can be helpful
in confirming the diagnosis.
An excisional biopsy with a 12 mm rim of normalappearing tissue should be used for lesions suspected to
be a melanoma.
When an excisional biopsy is not technically feasible,
an incisional or punch biopsy can provide a definitive
diagnosis.
Staging of melanoma is described in Table 15-6.
Table 15-6 Staging of melanoma
STAGE
I
Melanoma <1mm thick and ulcerated, or

<2mm thick and not ulcerated
IIA/B
Melanoma 12mm thick and ulcerated, or

24mm thick and not ulcerated
IIC
Melanoma >4mm thick and ulcerated
III
Melanoma has spread to involve lymph

nodes
IV
Melanoma has spread to distant organs
See Chapter 13, Hematology.
MELANOMA
There are four principal histological types of melanoma,
each including an in situ form:
1 Superficial spreading melanomaplaque-type
lesions with irregular borders and variegated color.
Malignant melanocytes spread through the layers of the
epidermis, and in the vertical growth phase move to the
dermis.
2 Lentigo maligna melanomadiscolored, usually brown, macular lesions that enlarge gradually and
eventually become palpable when they invade into the
480
DESCRIPTION
Management
Once a diagnosis of melanoma has been established,
surgical excision with an adequate margin of normal tissue is required.
Lymphatic mapping and sentinel lymph-node biopsy
are indicated in the initial management of melanomas
with a thickness 1 mm, or high-risk features such as
ulceration or mitoses >1/mm2 in otherwise healthy
patients.
Postoperative treatment with high-dose interferonalpha (IFN-alpha) may reduce the risk of melanoma
recurrence in patents with resected stage III (lymph
node positive) melanoma, but the regimen is poorly
Chapter 15 Oncology
tolerated with fatigue and malaise being the most frequently observed side-effects.
Radiation therapy may also decrease the incidence of
local recurrences in carefully selected patients, although
no impact on survival has been demonstrated.
Mutations in the BRAF gene, which are present in
approximately 4060% of advanced cutaneous melanomas, may be an important driver of melanoma cell
growth.
The presence of a V600E or K mutation in the
BRAF gene predicts for responsiveness to targeted
therapies that induce BRAF inhibition, such as
vemurafenib or dabrafenib.
BRAF inhibitors significantly prolong overall survival compared with dacarbazine in patients with
metastatic melanoma that contain this BRAF
mutation.
Ipilimumab, an anti-CTLA-4 monoclonal antibody, significantly prolongs overall survival in
patients with metastatic melanoma compared with
dacarbazine, independent of the mutation status of
BRAF.
High-dose IL-2 is associated with long-term diseasefree survival in a minority of carefully selected patients.
Dacarbazine and fotemustine are chemotherapy drugs
that are used to treat metastatic melanoma but both have
limited activity, with only 15% of patients expected to
demonstrate a radiological response.
Future directions
Immunomodulatory therapies targeting PD-1 (programmed
cell death protein 1) and PD-L1 (programmed death-ligand
1) are exhibiting impressive anti-tumor activity in clinical
trials. Phase III trials are continuing.
SARCOMA
Soft-tissue sarcomas are a heterogeneous group of
tumors of mesenchymal origin. There are more than 50
different histological subtypes and each has a different
biology and clinical course.
They usually present as an enlarging, painless mass,
often well circumscribed and localized, involving the
trunk or extremities.
The presence of distant metastatic disease at the time of
initial diagnosis is more likely in large and high-grade sarcomas. About 80% of metastases are located in the lungs.
An excision or a core needle biopsy is required. Ideally,

all pathology specimens of suspected soft-tissue sarcomas should be reviewed by a pathologist who specializes
in this tumor.
CT or MRI is used to determine the stage of the
sarcoma.
Imaging of the brain with CT scanning is suggested
for patients with high-grade sarcoma or angiosarcoma,
due to the high propensity of these tumors for CNS
metastases.
In addition to tumor stage, other prognostic variables
include histological grade and subtype, tumor size, anatomical site and patient age.
Treatment
Patients should be managed in a center with multidisciplinary expertise in the management of soft-tissue sarcomas.
Surgery
Surgical resection is the principal curative treatment
modality.
Consideration must be given to the functional consequences of intervention, as surgery may require limb
amputation.
Surgical resection of limited metastatic disease can provide long-term relapse-free survival and perhaps cure in
selected patients, the majority of whom have isolated
pulmonary metastatic disease.
Preoperative (neoadjuvant) therapy

The combination of surgery and radiotherapy achieves
better outcomes than either treatment alone for nearly
all intermediate- and high-grade soft-tissue sarcomas
>5cm in the greatest dimension.
Neoadjuvant therapy can provide a benefit when used
to treat large (>10 cm), potentially resectable soft-tissue
sarcomas or if there is concern for adverse functional
outcomes from initial surgery, e.g. limb surgery.
Neoadjuvant therapy could consist of chemotherapy
alone, radiotherapy alone, or the combination either
sequentially or concurrently. There is no proven gold
standard approach.
Postoperative (adjuvant) therapy

Adjuvant chemotherapy may improve survival, but the evidence remains contentious.
Chemotherapy
Diagnosis
Pathological diagnosis is based on histological morphology, immunohistochemistry, and sometimes molecular
testing.
Referral of a patient with a suspicious soft-tissue mass
to a specialized center with a multidisciplinary sarcoma
team is recommended.
Systemic chemotherapy is a routine component of treatment for several soft-tissue sarcomas that occur predominantly in children (e.g. rhabdomyosarcoma, Ewing
sarcoma).
For asymptomatic patients with unresectable disease
and low-grade histologies, surveillance may be the preferred initial management approach.
481
Chemotherapy-sensitive histologies include synovial

sarcoma, liposarcoma, leiomyosarcoma, and high-grade
pleomorphic unclassified sarcoma.
Anthracycline or anthracycline + ifosfamide remain the
recommended first-line treatments for these patients.
Ewing sarcoma
Ewing sarcoma and peripheral primitive neuroectodermal tumors (PNETs) comprise a spectrum of neoplastic
diseases known as the Ewing sarcoma family of tumors
(EFT).
These tumors are thought to share the same cell of
origin and chromosome translocations, in particular
the 11;22 translocation involving the EWSR1 gene on
chromosome 22q12.
Although rare, these tumors represent the second most
common bone tumor in children and adolescents.
Patients with EFT require referral to centers that have
multidisciplinary teams of sarcoma specialists.
Combination chemotherapy and definitive local therapy
is usually required.
Up to 40% of patients with limited pulmonary metastatic disease who undergo intensive chemotherapy and
pulmonary resection with or without radiation therapy
may be long-term survivors.
The prognosis for other subsets of patients with advanced
disease is less favorable, but patients are treated aggressively with the aim of long-term survival or cure.
BREAST CANCER
Epidemiology
Lifetime risk1 in 12 women (some series quote as
high as 1 in 8).
1 in 33 lifetime risk of dying from breast cancer.
Incidence increases with age.
Risk factors
Long, unopposed estrogen stimulation of breast tissue
(early menarche, late menopause).
Late first pregnancy, nulliparity.
Hormone replacement therapy/oral contraceptive pill
use is associated with a small increased risk counterbalanced by benefits.
Previous radiation exposure to breast tissue, particularly
during the breast development period through puberty
or early adulthood.
Family history of breast cancer.
Pathology
Ductal carcinoma in situa pre-cancerous change, often
a field change (the in situ changes are seen in multiple
areas or can be diffuse).
Invasive ductal carcinomausually localized, palpable,
and accounts for more than 80% of breast cancers.
482
Lobular carcinomamay be multicentric, sometimes

bilateral with impalpable disease, and accounts for 10%
of breast cancer histology.
More than 50% of breast cancers are hormone-receptor
positive (estrogen and/or progesterone), and the majority of these will respond to endocrine manipulation.
HER2 receptor status is also examined, as receptor
positivity predicts benefits from treatment utilizing the
monoclonal antibody trastuzumab. 20% of breast cancers are HER2-positive. HER2 status is determined by
the evaluation of breast cancer tissue by immunohistochemistry or by in situ hybridization techniques.
Screening
The principle is based on improved prognosis when
treating breast cancer of an earlier stage (smaller tumor,
less or no lymph node involvement).
Randomized trials demonstrate a reduction in
breast-cancer-related death of 2030% with the use of
screening mammography every 23 years.
The effect is greatest in women aged 5069 years.

For early-stage breast cancer, the following investigations
are usually performed:
clinical examination of the breast
mammography
ultrasound examination of breast t guided biopsy
chest X-ray
whole-body bone scan.
The following are not performed routinely, but may be considered depending on other clinical findings and symptoms:
CT scan
PET scan.
For patients with metastatic disease, CT imaging of the
chest, abdomen and pelvis should be performed. CT of the
head may also be performed if other clinical parameters raise
concern that the brain is involved. If disease is involving the
spine and neurological symptoms are present, then an MRI
scan may be recommended.
Staging of breast cancer is given in Table 15-7.
Management
For early-stage breast cancer (disease limited to the
breast and adjacent lymph nodes), the treatment goals
are to achieve a cure.
Table 15-7 Staging of breast cancer
Stage I
Localized to breast
Stage II
Breast and lymph-node involvement
Stage III
Locally advanced or inammatory tumor
Stage IV
Metastases to distant sites
Chapter 15 Oncology
For metastatic disease, the treatment goals are to prolong survival time, alleviate symptoms, and maintain or
improve the quality of life. The treatment will not be
curative.
Surgical optionsstages I and II

1 a
Breast-conserving surgeryoffered to women

except in the setting of multi-focal breast disease
or where the tumor is large (especially in relation to
the total volume of breast tissue).
b Total mastectomy.
2 Sentinel lymph-node (SLN) biopsyif negative, axillary node clearance can be avoided. SLN positivity can
be used to predict the need for adjuvant therapy, but
subsequent axillary clearance does not improve survival
and may be avoided.
Endocrine therapyhormone-receptorpositive cancers

Ovarian ablation
This reduces the risk of cancer relapse after surgery and
improves overall survival in pre-menopausal women with
hormone-receptor-positive cancers.
It can be achieved surgically, with radiation, or with the
use of luteinizing hormone releasing hormone (LHRH)
analogues.
It is effective in both early and advanced disease.
Tamoxifen
Tamoxifen reduces the risk of breast cancer recurrence
when used after breast surgery for patients with cancer that
is hormone-receptor-positive.
The optimal duration of adjuvant therapy is 5 years.
Tamoxifen can also help reduce the size of tumors or
delay the progression of disease in patients with metastatic disease.
The benefit of tamoxifen is seen in both pre-menopausal
and post-menopausal patients.
It has an anti-estrogenic effect in breast cancer tissue but
some pro-estrogenic effects in other tissues, reducing
age-related bone loss and the risk of heart disease.
Tamoxifen is associated with an increased risk of endometrial cancer and thromboembolism.
Aromatase inhibitors (AIs)
These inhibit the conversion of androstenedione to estrone
in adipose tissue, a process that requires aromatases (enzymes
produced by the adrenal glands).
They are effective only in post-menopausal women
where estrogen production is predominantly reliant on
aromatases, and ineffective in pre-menopausal patients.
They reduce the risk of cancer recurrence after surgery
in post-menopausal women.
The optimal duration of therapy is 5 years.
Tamoxifen and AIs should not be given concurrently.
Tamoxifen and AIs can be used sequentially, for example
using tamoxifen for 23 years and then an AI for 23

years.
AIs can also be used in the management of metastatic
disease.
A principal concern with long-term AI usage is the
development of osteoporosis.
The most common reason for stopping therapy is
arthralgia.
Chemotherapy
Chemotherapy reduces the risk of cancer recurrence after
surgery and improves overall survival, but the magnitude of
benefit varies according to the stage of the cancer and the
biological characteristics of the tumor. A careful balance of
risk against benefit needs to be considered. Even patients
with small tumors (<1.0 cm) without lymph node involvement may benefit from chemotherapy, but the absolute
magnitude of benefit is less than 5%.
CLINICAL PEARL
A 2% absolute benet for overall survival means that for
every 100 women treated there will be a survival difference in 2 of them. The magnitude may be small, but
the outcome variablesurvivalis major. This small
benet may still be considered worthwhile by patients.
Active drugs include:

taxanes, e.g. docetaxel (Taxotere [T]), paclitaxel (Taxol)
anthracyclines, e.g. doxorubicin (Adriamycin [A]), epirubicin (E)
alkylating agents, e.g. cyclophosphamide (C)
antimetabolites, e.g. 5-fluorouracil (F), methotrexate
(M).
Combinations of chemotherapy are more active than single
agents. Commonly used combinations include:
CMFcyclophosphamide, methotrexate, 5-fluorouracil
ACAdriamycin (doxorubicin), cyclophosphamide
FEC5FU, epirubicin, cyclophosphamide
DCdocetaxel, cyclophosphamide
TACTaxotere (docetaxel), Adriamycin (doxorubicin), cyclophosphamide.
There are several acceptable chemotherapy regimens but no
universally accepted gold standard. Clinical trials evaluating adjuvant chemotherapy have shown that:
6 cycles of CMF improves overall survival
4 cycles of AC is equivalent to 6 cycles of CMF
6 cycles of FEC may be better than CMF
AC followed by paclitaxel is better than AC alone
4 cycles of AC is equivalent to 4 cycles of DC
TAC is better than FAC
accelerating the chemotherapy to a shorter schedule
(shorter intervals between doses) may provide a small
benefit, but this requires granulocyte growth factor
support.
483
HER2-targeted therapy
Trastuzumab
Trastuzumab, a monoclonal antibody that targets the
HER2 receptor, reduces the risk of cancer recurrence
and improves overall survival in early-stage HER2positive breast cancer.
The current recommended duration of adjuvant therapy
is 12 months.
Trastuzumab also improves survival in the management
of metastatic breast cancer, whether used as a single
agent or in combination with chemotherapy.
The principal risk associated with trastuzumab is cardiac failure, which occurs in up to 5% of patients.
Lapatinib
Lapatinib, a HER2 tyrosine kinase inhibitor, has been
demonstrated to prolong the time to cancer progression
in patients with HER2-positive metastatic breast cancer
when used alone or in combination with capecitabine.
Preliminary results from a randomized controlled trial
indicate that lapatinib is inferior to trastuzumab when
used as adjuvant therapy in early-stage breast cancer.
Skin toxicity and diarrhea are the principal toxicities.
New HER2-directed therapies
Pertuzumabthis monoclonal antibody exhibits an anti-tumor effect through inhibition of HERdimerization. Dimerization of HER receptors is
required to activate HER2 and initiate downstream signaling in the cancer cell, which is required for cancer
cell growth. The addition of pertuzumab to the combination of trastuzumab and docetaxel has been shown to
prolong progression-free survival. Pertuzumab did not
increase the risk of cardiotoxicity.
Trastuzumab emtansine (T-DM1)this is an
antibodydrug conjugate that consists of the monoclonal antibody trastuzumab with the cytotoxic agent
mertansine (DM1). Trastuzumab acts as a transporter,
enabling DM1 to enter cancer cells and inhibit tubulin. T-DM1 has been shown to prolong the survival of
patients with advanced breast cancer that is resistant to
trastuzumab alone, compared with the combination of
lapatinib and capecitabine.
Metastatic breast cancer

The most frequent sites of metastatic disease include bone,
liver, lung and brain. HER2-positive disease is particularly
prone to the development of central nervous system (CNS)
involvement. When metastatic, breast cancer is not considered curable. Measures that can improve quality of life and
prolong survival include endocrine therapies and systemic
chemotherapy. Radiotherapy is useful for local disease, in
particular to manage bone pain.
The median time to development of breast cancer recurrence in patients with hormone-receptor-negative disease is
2 years, and for hormone-receptor-positive disease 6 years.
Later recurrences do occur.
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Bisphosphonates
Bisphosphonates reduce skeletal complications associated with metastatic breast cancer involving bones,
including bone pain, malignancy-associated hypercalcemia, and skeletal fractures.
They include intravenous bisphosphonates such as zoledronic acid and pamidronate, and oral bisphosphonates
such as ibandronate and clodronate.
A particular adverse event associated with bisphosphonate use is osteonecrosis of the jaw (ONJ), with an incidence of 1% or less in most recent series, although there
are reports of ONJ rates as high as 5%. The risk of ONJ
is related to the duration of therapy and underlying dental health.
Receptor activator of nuclear factor kappa-B
(RANK)-ligand inhibitors (e.g. denosumab) may be
better at preventing skeletal complications in metastatic
breast cancer than bisphosphonates.

SLN positivity can be used to predict the need for adjuvant therapy, but subsequent axillary clearance does not
improve survival and may be avoided.
Molecular markers or signatures may be used to predict
benefit from adjuvant hormonal therapy, not just hormone receptor status.
Tamoxifen and aromatase inhibitors have been shown
to reduce the risk of breast cancer in individuals considered to be at greater risk. A careful balance of risk
vs benefit is needed when considering using such hormonal therapy as a preventive measure.
New HER2-targeted therapies may improve or prolong
response.
Bevacizumab prolongs time to cancer progression but
not overall survival.
OVARIAN CANCER
Key points
While most tumors are adenocarcinomas, the ovaries
can be affected by a wide variety of cancer pathologies.
Treatment depends on the stage, but optimal surgical clearance remains the cornerstone of successful
intervention.
For advanced-stage disease, chemotherapy after surgery
improves survival.
If recurrence of cancer occurs after initial therapy, further chemotherapy is often tried but the prognosis is
poor and goals are palliative.

Most ovarian cancers derive from epithelial cells on the
surface of the ovary, and are effectively adenocarcinomas.
Chapter 15 Oncology
Germ-line mutations in BRCA1, BRCA2 and other

genes have been implicated in some cases, but in the
majority no mutation is found.
Papillary serous histology accounts for as many as
75% of ovarian cancers. Mucinous and endometrioid tumors account for 10% each. Less than 10% of
ovarian cancers of epithelial origin are represented by
clear-cell tumors, Brenner (transitional-cell) tumors,
or undifferentiated carcinomas. Rarer cancers such
as germ-cell tumors or sex cord-stromal tumors arise
from other cell types.
Tumors of low malignant potential are called borderline
tumors and represent approximately 10% of malignant
ovarian neoplasms defined histologically by atypical epithelial proliferation without stromal invasion.
Ovarian cancer is the second most common gynecological malignancy in the developed world, but the most
common cause of death among women with gynecological cancer and the fifth leading cause of cancer death
in all women.
The lifetime risk of ovarian cancer in the general population of women is 1.4%.
Risk factors for ovarian cancer include nulligravidity, infertility, endometriosis, and hereditary ovarian cancer syndromes (BRCA mutations, Lynch
syndrome).
Protective factors include oral contraceptives, tubal
ligation, hysterectomy, and breastfeeding.
Diagnosis
Symptoms of early-stage ovarian cancer are often
ill-defined.
The majority of cases are at an advanced stage at the
time of diagnosis.
A typical presentation of ovarian cancer is a woman
with a fixed, irregular pelvic mass and an upper abdominal mass and/or ascites.
Ultrasound examination is the most useful noninvasive
diagnostic test in women with an adnexal mass and will
reveal sonographic features suggestive of malignancy.
The serum CA-125 is elevated in 80% of women with
epithelial ovarian cancer, as well as in some women with
benign and other malignant lesions.
Routine imaging following therapy has not been shown
to improve outcome, and is usually reserved to investigate symptoms or suspected recurrence rather than for
routine surveillance.
Primary peritoneal carcinoma (also known as papillary
serous carcinoma of the peritoneum) is closely associated with, but distinct from, epithelial ovarian cancer
and histologically is indistinguishable from papillary
serous ovarian carcinoma.
Management
For early-stage disease, surgery alone is usually optimal
therapy.
For all other disease, chemotherapy is recommended

after surgery.
Approximately 75% of women have disease involving the peritoneal cavity or lymph nodes, or spread
to more distant sites. A standard approach for these
women is maximal surgical cytoreduction followed
by chemotherapy. However, initial chemotherapy
may be appropriate for patients whose performance
status makes them unsuitable for a prolonged surgical
effort, or with extensive disease that precludes optimal
cytoreduction.
Optimal cytoreduction, if technically feasible,
involves removing all visible tumor and is the goal
of primary surgery.
For optimally debulked disease not extending beyond
the peritoneal cavity, chemotherapy after surgery provides a survival benefit, with up to 20% of patients
becoming long-term cancer-free survivors. Singleagent carboplatin or a combination of paclitaxel and
carboplatin are the regimens of choice, usually applied
in 6 cycles.
For disease that cannot be optimally cytoreduced (i.e.
residual tumor 1cm), there is a survival benefit associated with using a paclitaxel-platinum regimen after
surgery. Usually surgery is followed by 6 cycles of intravenous carboplatin + paclitaxel. Dose-dense (weekly
paclitaxel plus 3-weekly carboplatin) chemotherapy is
also an option.
Further chemotherapy is usually given after cancer
recurrence or progression, but the goals of second-line
therapy and beyond are palliative and survival benefit is modest. Chemotherapy agents that have activity
include topotecan, liposomal doxorubicin, etoposide
and gemcitabine.
If disease progression occurs at least 6 months after previous platinum-based chemotherapy, then the cancer
may still be platinum-sensitive and further platinumbased chemotherapy may induce a response and provide
a benefit.
CLINICAL PEARL
The role of monitoring CA-125 after surgery is controversial, as this has not been demonstrated to improve
outcomes despite allowing for earlier detection of
recurrence.
Future directions
Bevacizumab-containing chemotherapyeither firstline or following recurrencemay prolong progressionfree survival.
There is a possible role for maintenance chemotherapy,
in particular paclitaxel. The potential progression-free
survival benefit must be weighed against cumulative
toxicity.
485
ENDOMETRIAL CANCER
Endometrioid tumors account for 80% of cases and are
related to stimulation by estrogen.
Papillary serous or clear-cell tumors account for 20% of
cases and are hormone-independent.
Risk factors include estrogen exposure in the absence
of adequate exposure to progestins. High-risk situations
include tamoxifen use, obesity, type 2 diabetes, and
anovulation.
Use of oral contraceptives decreases risk.
Diagnosis
Abnormal uterine bleeding is the most common presenting symptom and occurs in 90% of cases.
486
Post-menopausal bleeding in a woman not on hormone

replacement therapy should always be investigated to
exclude endometrial cancer.
Endometrial biopsy, dilatation and curettage, or hysteroscopy with directed biopsy and curettage are the
principal diagnostic strategies.
Management
Surgery is the principal treatment modality.
Adjuvant radiotherapy will reduce the risk of recurrence
for disease that has invaded down to the muscle level
and beyond.
Adjuvant chemotherapy is also recommended in higherstage cancer.
Chemotherapy may improve symptoms and provide a
modest survival prolongation in metastatic endometrial
cancer.
Chapter 15 Oncology
1
Which of the following population-based screening programs has been proven to reduce cancer-specic mortality?
A Computed tomography (CT) scans of lungs in men aged 50 and over
B Prostate-specic antigen (PSA) screening in men aged 70 and over
C Cancer-associated antigen 125 (CA-125) measurement in all women aged 50 years
D Fecal occult blood test (FOBT) for all adults aged 50 and over
E Bronchoscopy every 5 years in smokers aged 50 and over
Which of the following statements is correct?

A A prognostic factor allows you to select the best therapy for a particular subgroup of patients.
B A predictive factor exerts an inuence on outcome that is independent of therapy.
C It is not possible for a biomarker to exert both predictive and prognostic properties.
D Predictive factors do not have any impact of the potential cost-effectiveness of a new therapy.
E A prognostic factor is related to the outcome of patient survival and has an association that is independent of any
treatment effect.
Which of the following serum tumor markers is not helpful in the clinical monitoring of patients after therapy?
A Lactase dehydrogenase (LDH) level in non-Hodgkin lymphoma
B Carcinoembryonic antigen (CEA) level in colon cancer
C Prostate-specic antigen (PSA) in prostate cancer
D Human chorionic gonadotropin (hCG) level in non-seminomatous germ-cell tumor
E Cancer-associated antigen 125 (CA-125) in the monitoring of squamous-cell carcinoma of the lung
4 In which of the following situations is treatment administered with the expectation that the majority of patients will not
be cured?
A Radical radiotherapy with concurrent chemotherapy for inoperable stage III non-small-cell lung cancer (NSCLC)
B Surgery followed by adjuvant chemotherapy for stage I breast cancer
C Chemotherapy for metastatic seminoma involving the lungs and multiple lymph nodes above and below the
diaphragm
D Nodular sclerosing Hodgkin lymphoma involving the mediastinum in a 22-year-old patient
E Surgery followed by chemotherapy in a patient with stage III colon cancer that involves 2 out of 12 lymph nodes
5
When a patient who received chemotherapy 10 days previously presents with a fever of 39C, the optimal treatment
approach is:
A Take blood cultures and check the blood count. If neutropenia is found, admit the patient for observation and
commence appropriate antibiotics based on the blood culture results and the observed antibiotic sensitivities.
B Commence Gram-positive antibiotic cover immediately, then wait for blood cultures in case further antibiotics are
needed.
C Take blood cultures and check the blood count. If neutropenia is found, then start antibiotics immediately to cover
possible Gram-negative bacteremia including Pseudomonas sepsis.
D No action is needed unless the fever persists for more than 24 hours.
E Start antibiotics only if the patients is either hypoxic or hypotensive, otherwise observe and apply supportive
measures until the fever settles.
6 Which of the following scenarios of cancer of unknown primary (CUP) may still be cured with chemotherapy?
A Well-differentiated adenocarcinoma found in the lung, bone and inguinal lymph nodes of a 42-year-old female
B Malignant ascites with carcinoma proven on cytological examination in a 77-year-old man
C Carcinoma involving multiple sites of the liver and considered inoperable
D Poorly differentiated carcinoma found in a retro-peritoneal mass in a 24-year-male
E Squamous-cell carcinoma in the supraclavicular lymph node and also involving the 5th lumbar vertebral body
7
Which of the following statements associating gene mutation with clinical implication is not correct?
A Advanced colon cancer with K-ras mutations are more likely to respond to cetuximab.
B Epidermal growth factor gene mutations have been associated with responsiveness to rst-line therapy for
advanced non-small-cell lung cancer using EGFR tyrosine kinase inhibitors.
C BRAF mutations predict a poorer prognosis in advanced colon cancer.
D The presence of V600E BRAF mutations predict responsiveness to vemurafenib in melanoma.
E ALK mutations predict responsiveness to crizotinib in non-small-cell lung cancer.
8 Chemotherapy has not been demonstrated to prolong survival for which of the following scenarios?
A First-line therapy with carboplatin and paclitaxel in advanced ovarian cancer
B Second-line chemotherapy for advanced pancreatic cancer
C Second-line chemotherapy for advanced colon cancer
D Inoperable non-small-cell lung cancer
E Combined with radiotherapy in glioblastoma multiforme
487
9 Which of the following targeted therapies does not provide a benet for the associated clinical scenario?
A Third-line therapy with cetuximab in K-ras wild-type advanced colon cancer
B Bevacizumab in the rst-line therapy of advanced colon cancer
C Adjuvant therapy with cetuximab in high-risk stage III K-ras wild-type colon cancer
D Trastuzumab in HER2-positive advanced gastric cancer
E Lapatinib in metastatic HER2-positive breast cancer
ANSWERS
1
D.
Only FOBT has been associated with improved survival. The other screening tests may enable earlier detection, but this
has not been associated with prolongation of overall survival.
E.
It is important to understand the difference between a prognostic factor (a factor associated with prognosis, independent
of a treatment effect) and a predictive factor (a factor that helps select a patient who is most likely to benet from an
intervention or therapy).
E.
CA-125 is a nonspecic tumor marker and is not a reliable indicator of disease response or prognosis in the context of lung
cancer. The other markers listed all have a role in assessing disease response and in monitoring patient status after therapy
during surveillance.
4 A.
While patients with inoperable NSCLC treated with chemoradiotherapy can achieve long-term survival, in randomized
controlled trials of selected patients only 1520% of patients become long-term survivors. The other cancers all have
expected long-term survival rates of above 50%.
5
C.
This answer relates to the optimal treatment strategy, and sequence, when patients present with presumed febrile
neutropenia. Taking blood cultures before antibiotics are commenced is important to allow the best chance of identifying
a pathogen. Antibiotics that cover Gram-negative organisms, especially Pseudomonas, are important as such an infection
can cause rapid and overwhelming sepsis.
6 D.
Consider the possibility of a retro-peritoneal germ cell tumor in such a clinical situation. Such tumors are curable with
chemotherapy.
7
A.
The predictive value of K-ras is well established in metastatic colorectal cancer. Those with K-ras mutations are less likely
to respond or benet from cetuximab. In fact, the benet is restricted to the wild-type cetuximab subgroup, and no benet
is seen in patients with tumors that harbor K-ras mutations.
8 B.
Pancreatic cancer remains a cancer associated with a poor prognosis, particularly when inoperable or metastatic. Secondline chemotherapy trials have yielded uniformly disappointing results so far.
9 C.
Monoclonal antibodies such as cetuximab have been studied in the adjuvant context, and so far the trials have been
negative. The other scenarios are all associated with a clinical benet for the molecular targeted therapies.
488
CHAPTER 16
PALLIATIVE MEDICINE
Meera Agar and Katherine Clark
CHAPTER OUTLINE
PAIN
Denition
MUCOSITIS
Denition
Interventions
FATIGUE
NAUSEA AND VOMITING
Denition
CACHEXIA AND ANOREXIA

Interventions
DYSPNEA
Denition
CONSTIPATION
Denition
DELIRIUM
Denition
INSOMNIA
Denition
Denition
489
PAIN
Denition
According to the International Association of Pain, pain is
an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms
of such damage. Pain is a complex experience, and there are
usually multiple contributing factors in any individual. It is
also important to recognize the prevalence of chronic pain,
including the more complex neuropathic pain.

Pain at cancer diagnosis occurs in 2050% of patients, and in
7590% of people with advanced cancer. Pain can be experienced at multiple anatomical sites, with varying intensity,
frequency and clinical characteristics, and is often driven by
different mechanisms.
If pain is poorly managed it can restrict function, the ability to participate in work or meaningful activities, theability
to care for oneself and ones quality of life. These adverse
effects also negatively affect caregivers quality of life. Pain
is a subjective and individual experience that may result in
fear, anxiety, depression, a sense of lack of control and/or
hopelessness if not adequately addressed.
The neurophysiology of cancer pain is complex.
Primary afferent sensory neurons transmit noxious
(C and A-delta fibers) and non-noxious (A-alpha and
A-beta fibers) stimuli (Figure 16-1). C and A-delta
fibers end within the dorsal horn of the spinal cord at
superficial levels, whereas A-alpha and A-beta fibers
Large-diameter myelinated fibers (A and A)

Proprioceptors, mechanoceptors
CIPN-induced neuropathy; paresthesias,
dysesthesias, loss of vibratory sensations,
proprioceptive deficits
Innervated peripheral
tissue, for example,
skin, bone, tendon
and viscera
Small-diameter unmyelinated fibers (C) and
thinly-myelinated fibers (A)
Nociceptors
Tumor-induced pain: ongoing, breakthrough
CIPN-induced neuropathy; mechanical and
cold allodynia
end in the deep aspect of the dorsal horn and in the dorsal column nuclei.
Sensory neurons synapse onto second-order neurons in
the spinal cord or dorsal column nuclei. These secondorder neurons then ascend to higher centers of the brain,
including the thalamus, from which projections go to
the somatosensory cortex, the anterior cingulate and the
insular cortices, all of which modulate the experience of
pain.
Peripheral sensitization (through sensitizing peripheral
afferent fibers) and central sensitization occur after prolonged exposure to C-fiber nociceptive drive, and this
is thought to be mediated via glutamate and substance
P, which alters the N-methyl-D-aspartate (NMDA)
receptor.
Long-term potentiation, possibly mediated in the hippocampus, also leads to sustained excitability of dorsal
horn pain transmission neurons.

A multidisciplinary and multidimensional assessment and
management approach is required. Thorough history and
examination, and regular reassessment are needed to adequately manage pain. A written pain management plan and
patient/caregiver education about cancer pain and its management are useful, including discussion of opioid myths
and concerns.
Non-pharmacological approaches
Psychological strategies that promote self-efficacy and
manage coexisting anxiety and depression may be helpful.
Therapeutic exercise, graded and purposeful activity, massage and soft-tissue mobilization, transcutaneous electrical
Dorsal column
nuclei
Spinothalamic
tract
DRG
Spinal cord
Figure 16-1 Primary afferent sensory nerve bers involved in generating the pain and/or neuropathy induced
by tumors and anti-tumor therapies. CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root
ganglion
From Mantyh PW. Cancer pain and its impact on diagnosis, survival and quality of life. Nature Rev Neurosci 2006; 7:797809. doi:10.1038/
nrn1914
490
Chapter 16 Palliative medicine
nerve stimulation (TENS), postural re-education and heat/

cold therapy can be helpful in some patients. Adapted activities and lifestyle adjustments may be required. Physical and
occupational therapy assessments are crucial to optimize
function.
Pharmacological approaches
Cancer pain management may require the use of opioids and
co-analgesics. Selection of the appropriate agent depends on
the severity of pain, the safety and efficacy of the agents in
the particular pain syndrome, comorbidities, patient preference, convenience, and cost.
Opioid receptors
Opioid receptors are coupled to inhibitory G-proteins.
Endogenous opioids are dynorphins, endorphins, endomorphins, nociceptin and enkephalins. The mu-opioid receptor
is the primary receptor mediating the action of opioid analgesics, including morphine, fentanyl and methadone.
Genetic variations have been identified in the human
mu-opioid receptor (MOP) gene (OPRM1) which
reduce the response to opioid analgesia.
COMT (catechol-O-methyltransferase) variants cause
up-regulation of the mu-opioid receptor, resulting in
the need for lower dosages of exogenous opioids.
P-glycoprotein efflux transporter gene (ABCB1) variants have an increased response and those with poor
metabolizer variants in the CYP2D6 gene have reduced
response to some opioids that produce metabolites
with mu-opioid receptor activity (codeine, tramadol,
oxycodone).
Table 16-1 lists opioid receptors and their respective endogenous and exogenous ligands.
CLINICAL PEARLS
Opioids remain the mainstay of cancer pain treatment.
For continuous pain, it is appropriate to give opioids
on a regular schedule and ensure that the patient has
as needed doses prescribed for breakthrough pain.
When commencing an opioid, a short-acting formulation (usually oral) or a low-dose long-acting formulation is
given and titrated to effect. A short-acting formulation (of
the same opioid where possible) should be provided on an
as needed basis for breakthrough pain.
The appropriate dose is the dose that relieves the patients
pain throughout the dosing interval, with recurrence of
pain prior to the next dose being a sign that a further
dose increase is needed.
Renal and hepatic function changes may increase a
patients propensity to adverse effects and may require
selection of an alternative opioid.
When converting between different opioids and also
between different routes of administration, it is important to be aware of the relative potency and dose equivalents to ensure that pain control is maximized. It is
Table 16-1 Opioid receptors and their ligands
OPIOID
RECEPTOR
EXOGENOUS
LIGAND
(OPIOID
MEDICATION)
ENDOGENOUS
LIGAND
Mu
Methadone
Morphine
Fentanyl, alfentanil,
sufentanil,
ramifentanil
Codeine
Tramadol (also
modulates
serotonin/
noradrenaline)
Hydromorphone
Oxycodone
Many
Beta-endorphin
Endomorphins
Kappa
Morphine
Codeine
Meperidine
(pethidine)
Oxycodone
Dynorphin A
Delta
Morphine
Codeine
Meperidine
(pethidine)
Fentanyl
Enkephalins
recommended that a dose conversion chart or calculator

is used to avoid errors.
Pharmacokinetic considerations
Accumulation of morphine metabolites can occur in
renal impairment, over a wide range of creatinine clearances, with some patients with severe renal impairment
not being affected and others with minor impairment
showing reduced clearance.
There is delayed elimination of oxycodone and its
metabolite oxymorphone (the active metabolite) in
renal failure.
Hydromorphone has several metabolites, with no evidence that they accumulate in renal failure; however,
toxicity has been reported in renal failure.
Fentanyl and alfentanil do not have active metabolites,
and have been successfully used in renal failure.
Codeine is bioactivated to morphine by cytochrome
P450 2D6, and there is evidence that codeine-6glucuronide also contributes to central nervous system
side-effects, rather than just morphine byproducts.
Opioid rotation
Opioid rotation is defined as substituting one strong opioid
with another when a satisfactory balance between pain relief
and adverse effects is not achieved with the first opioid.
491
The biological mechanisms underpinning why better pain relief and reduced adverse effects have been seen
in some clinical observations when switching from one
mu-opioid receptor agonist to another is not fully understood, but could relate to inter-individual variations in
pharmacokinetics and pharmacodynamics, such as speed of
crossing biological barriers (e.g. P-glycoprotein variants),
changes in tolerance of the mu-receptor system, or changes
in metabolism and clearance.
Co-analgesics, interventional and antineoplastic
therapies
Co-analgesics can be useful for pain associated with inflammation, nerve compression, or pain which is neuropathic in
its pathophysiology.
For pain related to inflammation, non-steroidal antiinflammatory drugs (NSAIDs) or glucocorticosteroids
can be used: the choice is related to the relative risk
of adverse effects (based on the physiological characteristics of the patient, e.g. renal function, and other
comorbidities).
Bisphosphonates can be helpful to manage bone pain, in
particular in multiple myeloma and breast cancer.
For neuropathic pain, a trial of an antidepressant such
as amitriptyline or an anticonvulsant such as pregabalin can be helpful. The choice of antineuropathic agent
should be guided by the efficacy of the agent and its toxicity profile.
Intrathecal infusions, celiac plexus blocks and nerve blockade can be extremely effective in carefully selected patients.
myelosuppression, and intrinsic genetic predisposition (e.g.

single-nucleotide polymorphisms). The current working
biological model for oral mucositis has five phases:
1 Initiation phase, due to the generation of free radicals
and DNA damage from anticancer therapies.
2 Message generation phase, in which transcription
factors (e.g. nuclear factor kappa-B [NFkB]) are activated, leading to up-regulation of pro-inflammatory
cytokines (interleukin [IL]-1-beta and tumor necrosis
factor-alpha [TNF-alpha]). These cytokines mediate
inflammation and vasodilatation, and increase the local
concentration of anticancer agents, which all lead to
tissue damage.
3 Signaling and amplification phasemicrotrauma from
speech, swallowing and mastication leads to further
ulceration. Inflammation is accelerated due to increased
signal feedback.
4 Ulcerative/bacteriological phase (during which neutropenia is common)bacterial colonization of ulcers
occurs, and the endotoxins lead to release of more IL-1
and TNF-alpha. This is likely to be the phase most
responsible for the clinical pain and morbidity associated with oral mucositis.
5 Healing phase, in which cell proliferation occurs with
re-epithelialization of ulcers, with epithelial cells
migrating and proliferating underneath the pseudomembrane (fibrin clot) of the ulcer. The direct relationship between resolution of neutropenia and oral
mucositis is uncertain.
Interventions
MUCOSITIS
Denition
Oral mucositis is inflammation and ulceration of the oral
mucosa with pseudomembrane formation. The initial presentation is erythema, followed by painful, white desquamating plaques.
Pseudomembrane formation and ulceration results from
epithelial crusting and a fibrin exudate. Similar processes
may occur anywhere along the gastrointestinal tract. With
the advent of new targeted therapies, other patterns are seen.
For example, mammalian target of rapamycin (mTOR)
inhibitors cause oral aphthous-like ulcers (mTORinhibitorassociated stomatitis).

Oral mucositis secondary to chemotherapy or radiotherapy affects more than 40% of cancer patients, resulting in
pain, and difficulty in swallowing and eating. It is a potential
source of infection, which, in extreme cases, may result in
death, particularly if accompanied by neutropenia.
The pathophysiology of mucositis involves a complex
interaction of local tissue damage, oral environment,
492
Benzydamine can assist in the prevention of radiationinduced mucositis.

Keratinocyte growth factor 1 (palifermin) is helpful in
stem cell transplantation.
Low-level HeNe laser therapy accelerates the healing of tissue; however, it is expensive and not readily
available.
Loperamide can be used to control diarrhea.
Oral sulfasalazine helps reduce radiation enteropathy when a patient is receiving pelvic external beam
radiotherapy.
Sucralfate enemas, specifically formulated in hospital,
can reduce rectal bleeding from proctitis.
Proton pump inhibitors or 5-HT3 antagonists can assist
with epigastric pain.
Amifostine can be used as a cytoprotective agent in
some settings.
Topical antiseptic and antimicrobial agents are not
helpful.
FATIGUE
Fatigue in cancer patients is invariably a result of multiple

contributing factors, as outlined in Box 16-1.
CLINICAL PEARL
Fatigue is often poorly assessed, with little consideration given as to how other symptoms may contribute,
including anemia, mood disorders and pain.
Denition
Although fatigue is common, no universally agreed definition exists. Fatigue is highly subjective, with the diagnosis
based on self-report of tiredness unrelieved by rest.
Limited data support pharmacological interventions including corticosteroids, with other agents under investigation
including modafinil, amantadine and methylphenidate.
Non-pharmacological interventions include resistive
load training and supportive counseling, with the best outcomes expected for people who have better functional status
at the time that supportive measures are instituted.
NAUSEA AND VOMITING

Approximately 70% of people with advanced cancers and
end-stage organ failure experience fatigue which is acknowledged as distressing, debilitating and negatively affecting
peoples quality of life. There are few evidence-based therapeutic options.
Denition
Nausea is defined as the unpleasant sensation of needing
tovomit. While often accompanied by vomiting, nausea and
vomiting are separate clinical entities.
Box 16-1
Contributing issues in cancer-related fatigue

Symptom burden
Pain
Anxiety
Depression
Sleep dysfunction
Obstructive sleep apnea
Restless leg syndrome
Narcolepsy
Insomnia
Nutritional imbalances
Weight changes
Changes in caloric intake
Fluid and electrolyte imbalances
Motility disorders
Physical function changes
Decreased physical activity
Decreased physical conditioning
Medical issues
Anemia (from various etiologies)
Other comorbidities
Infection
Cardiac dysfunction
Connective tissue diseases

Pulmonary dysfunction
Renal dysfunction
Hepatic dysfunction
Neurological dysfunction
Endocrine dysfunction
hypothyroidism
hypogonadism
diabetes mellitus
adrenal insufficiency
Medications
Sedating agents (hypnotics, narcotics, neuropathic
agents)
Beta-blockers
Supplements
Other (drug interactions and other medication sideeffects)
Cancer treatment effects
Chemotherapy
Radiation therapy
Surgery
Bone marrow transplantation
Biological response modiers
Hormonal treatment
From Escalante CP and Manzullo EF. Cancer-related fatigue: the approach and treatment. J Gen Int Med 2009;24(2):S412S416.
493

Nausea and vomiting secondary to
tumor-modifying treatments
Up to 80% of people treated with chemotherapy and radiotherapy are likely to experience nausea and vomiting, with
more severe problems resulting from chemotherapy. Failure to manage chemotherapy-induced nausea and vomiting
(CINV) has implications for the patients ongoing capacity
to tolerate treatment.
CINV is complex, with people at risk of immediate and
delayed presentations. Risk factors include both the chemotherapy regimen and individual factors that include female
gender, younger people and a past history of nausea and
vomiting with chemotherapy. Nausea is less likely to occur
when people have a past history of heavy alcohol use.
Nausea and vomiting secondary to

progressive disease
Quite separate to CINV is the problem of nausea and vomiting which is likely to affect 70% of patients with advanced
cancer, especially late in the course of the disease.
Nausea and vomiting secondary to tumormodifying treatmentsCINV occurs as the result of
activation of peripheral afferent nerve fibers, predominantly in the gastrointestinal tract and cerebral cortex,
as summarized in Figure 16-2.
Neuronal pathways
Emetogenic stimuli
Chemotherapy
Radiotherapy
Opioids
Chemoreceptor
trigger zone
(area postrerna)
Dopamine D2
Serotonergic 5-HT3
Histaminergic H1
Muscarinic M3
Vasopressinergic
Nausea and vomiting secondary to progressive

diseasewhile the same afferent pathways summarized in Figure 16-2 are presumed to underlie the problem of nausea and vomiting in advanced disease, there is
little objective evidence to support this.

Nausea and vomiting secondary to tumormodifying treatmentsevidence-based recommendations support the prescription of combination antiemetics. The emetogenic potential of the tumor-modifying treatment underlies the choice of antiemetics. For
the acute phase of highly emetogenic platinum-based
chemotherapy, 5-HT3 antagonists in combination with
corticosteroids and a neurokinin-1 (NK1) antagonist are
the treatment of choice.
Nausea and vomiting secondary to progressive
diseasealthough there are numerous published clinical guidelines to advise clinicians on the palliation of
nausea and vomiting, the evidence that supports the
majority of guidelines remains poor. As people approach
death, there is even less information to identify which
antiemetic is likely to be the most effective. In this situation, the choice is guided by which agent is least likely
to cause adverse effects and by ready availability. The
antiemetic that has the most robust evidence base is
metoclopramide.
Table 16-2 lists antiemetic agents and their recommended
uses.
Higher cortical
centers
Vomiting
center
(medulla)
Noxious odors
visions, tastes
Vomiting
reflex
Chemotherapy
Surgery
Radiotherapy
Peripheral afferents
Serotonergic 5-HT3
Labryinths
(inner ear)
Histaminergic H1
Muscarinic M3
Motion sickness
Labyrinthine tumors or infections
Mnires disease
Figure 16-2 The vomiting reex is triggered from multiple anatomical sites
Based on Nedivjon B and Chaudhary R. Controlling emesis: evolving challenges, novel strategies. J Supportive Oncol 2010;8(4 Suppl 2):110.
494
Table 16-2 Antiemetic drugs
ANTIEMETIC
CLASS
MECHANISM OF ACTION
RECOMMENDED USES
LEVEL OF
EVIDENCE TO
SUPPORT USE IN
CANCER-RELATED
NAUSEA AND
VOMITING
Corticosteroid:
Dexamethasone
Unknown, possibly reduced

prostaglandin activity in the brain
Treatment-related nausea and

vomiting
Nausea and vomiting secondary
to raised intracranial pressure
Vomiting secondary to bowel
obstruction
High
5-HT3 antagonist:
Granisetron
Ondansetron
Palonasetron
Dolasetron
Inhibit visceral afferents by

blocking binding of peripheral
5-HT to serotonin (type 3)
receptors along the vagus nerve
in the GI tract

vomiting
Opioid-induced nausea and
vomiting
Nausea of advanced cancer
High
NK1 antagonist:
Aprepitant
Fosaprepitant
Blockade of the binding of

substance P to NK1 receptors in
the chemotrigger zone of the
area postrema

vomiting
High
Benzodiazepine:
Lorazepam
Alprazolam
Presumably due to anxiolytic,

sedative and anterograde
amnesic effects of these
medications centrally
Especially useful in delayed or
anticipatory nausea as adjuvant
agents
Adjuvant support for the

management of treatmentrelated nausea and vomiting,
particularly when nausea
associated with anxiety
High
Atypical
antipsychotic:
Olanzapine
Antipsychotic in the
thienobenzodiazepine drug
class that blocks multiple
neurotransmitters, including:
dopamine at D1, D2, D3 and D4
brain receptors
serotonin at 5-HT2a, 5-HT2c,
5-HT3 and 5-HT6 receptors
catecholamines at alpha-1
adrenergic receptors
acetylcholine at muscarinic
receptors
histamine at H1 receptors
Adjuvant agent to manage

treatment-related nausea and
vomiting
Moderate
Antihistamine:
Diphenhydramine
Promethazine
Predominantly histamine
antagonist in vestibular nucleus
and chemotrigger zone
Central dopamine and
acetylcholine antagonist
Adjuvant, especially when

the extra-pyramidal effects
of dopamine antagonists are
considered problematic
Moderate
Butyrophenone:
Haloperidol
Droperidol
Dopaminergic (D2 subtype)

receptor antagonists
Adjuvant
Low
continues
495
Table 16-2 Antiemetic drugs continued
ANTIEMETIC
CLASS
MECHANISM OF ACTION
RECOMMENDED USES
LEVEL OF
EVIDENCE TO
SUPPORT USE IN
CANCER-RELATED
NAUSEA AND
VOMITING
Phenothiazine:
Prochlorperazine
Dopamine antagonist
Histamine antagonist
Acetylcholine antagonist
Adjuvant
High
Dopamine2antagonist:
Metoclopramide
Competitive antagonist at central

dopaminergic (D2) receptors
Weak competitive antagonist
peripherally at GI 5-HT3 receptors
(at high dose)
5-HT4 agonist
Increased lower esophageal
sphincter pressure
Enhanced rate of gastric
emptying
Adjuvant
Gastric stasis
Opioid-induced nausea and
vomiting
Nausea of advanced disease
High
5-HT, 5-hydroxytryptamine; GI, gastrointestinal; NK1, neurokinin-1.
CLINICAL PEARL
Chemotherapy-induced nausea and vomiting is best
managed pre-emptively with antiemetic medications
commenced before the initiation of treatment and routinely prescribed for 13 days post-treatment.
For highly emetogenic chemotherapy, a combination of a 5-HT3 antagonist, an NK1 antagonist and
dexamethasone minimizes the risks of nausea
andvomiting.
Moderately emetic treatments require a 5-HT3
antagonist and dexamethasone.
Low-emetic treatments require dexamethasone.
CACHEXIA AND ANOREXIA

Denition
Although often considered in tandem, anorexia and cachexia
are separate entities that often coexist.
Cancer-associated cachexia occurs as the result of an
inflammatory state leading to profound muscle wasting.
This is typically accompanied by anorexia, loss of
subcutaneous fat, increasing insulin resistance and
inflammation.
At the core of the problem is the observation that
cachexia cannot be reversed with nutritional support,
and leads to progressive weakness, weight loss and functional decline.
Although cancer-associated anorexia may be worsened by
other poorly controlled symptoms such as pain or nausea,
496
like cachexia, increasing evidence indicates that anorexia is

secondary to a profound state of cancer-induced inflammation driven by cytokines and zinc alpha2-glycoprotein.

Cachexia accompanies up to 20% of cancer patients at
the time of diagnosis, especially those with upper gastrointestinal and lung cancers. It is identified as a poor
prognostic sign, increasing the likelihood that people will
be unable to tolerate chemotherapy and other tumormodifying treatments.
The only possible treatment of cachexia requires treatment of the underlying cause.
CLINICAL PEARL
Aside from physical problems, cachexia may cause
signicant existential suffering for both the patient and
family. Contributing factors include worsening body
image, anxiety and distress.

At present there are no reliable biological markers of
cachexia, although it is increasingly recognized as a
complex inflammatory state with the key drivers being
cytokines and zinc alpha2-glycoprotein.
As with cachexia, there is no biological marker for
anorexia.
Anorexia is also presumed to be cytokine-driven, with
most attention focused on interleukin beta.
Interventions
If the etiology of cachexia is unclear, enteral or parenteral feeding should not be excluded, particularly in the
early stages of illness where cure is the therapeutic goal.
The reason that nutritional supplements should
be considered early in the disease is that the best
outcomes are achieved for people who respond to
tumor-modifying treatments, and nutritional support may help in tolerating anticancer therapies.
This situation changes with progressive disease,
especially when disease-modifying treatments are
exhausted and the risks are unlikely to outweigh
the benefits.
Up to 70% of people are likely to experience dyspnea near

the end of life. A debilitating condition, dyspnea is a poor
prognostic sign in life-limiting illness and is directly correlated with poor quality of life.
DYSPNEA
Denition
Dyspnea is a subjective experience of breathing discomfort
that may be frightening and distressing, often worsening as
life shortens.
The pathophysiology of dyspnea is complex, with multiple
afferent receptors implicated (Table 16-3).
Most recently, 3D neuroimaging studies have shown
that breathlessness causes separate areas of the cerebral cortex to be activated (anterior right insula, the cerebellar vermis, the amygdala, the anterior cingulate cortex, and the
posterior cingulate cortex). These areas of the brain are also
activated by pain. Both endogenous and exogenous opioids
may improve dyspnea by altering the central processing of
unpleasant sensations associated with dyspnea. The role of
opiods in mediating the sensation of breathlessness through
peripheral opioid receptors is not clear.
Table 16-3 Possible afferent sources for respiratory sensation
SOURCE OF SENSATION
ADEQUATE STIMULUS
Medullary respiratory corollary discharge
Drives to automatic breathing (hypercapnia, hypoxia,

exercise)
Primary motor cortex corollary discharge
Voluntary respiratory drive
Limbic motor corollary discharge
Emotions
Carotid and aortic bodies
Hypercapnia, hypoxemia, acidosis
Medullary chemoreceptors
Hypercapnia
Slowly adapting pulmonary stretch receptors
Lung ination
Rapidly adapting pulmonary stretch receptors
Airway collapse, irritant substances, large fast (sudden) lung

inations/deations
Pulmonary C-bers (J-receptors)
Pulmonary vascular congestion
Airway C-bers
Irritant substances
Upper airway ow receptors
Cooling of airway mucosa
Muscle spindles in respiratory pump muscles
Muscle length change with breathing motion
Tendon organs in respiratory pump muscles
Muscle active force with breathing motion
Metaboreceptors in respiratory pump muscles
Metabolic activity of respiratory pump
Vascular receptors (heart and lung)
Distension of vascular structures
Trigeminal skin receptors
Facial skin cooling
Chest wall joint and skin receptors
Tidal breathing motion
From Parshell MB, Schwartzstein RM, Adams L et al., ATS Committee on Dyspnea. An official American Thoracic Society statement: update
on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185(4):43552.
497

The degree of reversibility of the problem needs to be
assessed. Palliative approaches include both pharmacological
and non-pharmacological interventions.
Non-pharmacological interventions include advice
regarding positioning, including the use of walking
frames, breathing exercises, cognitive therapy and exercise programs, and moving air over the face with fans.
With regard to the pharmacological palliation of dyspnea, administration of regular, low-dose, sustainedrelease morphine has been shown to reduce the severity of the dyspnea experienced without respiratory
compromise.
CLINICAL PEARL
The administration of oxygen has not been shown to
produce signicant benets in the palliation of dyspnea
when people are not hypoxic, and thus should not be
routinely prescribed in this population. Supplemental
oxygen is unlikely to improve dyspnea when oxygen
saturations are greater than 90%.
CONSTIPATION
Denition
While there is no currently agreed definition for constipation in palliative care, it is generally accepted that changes in
usual bowel habits frequently complicate the lives of people
with advanced illness. Unlike functional constipation, no
single cause can be identified as many factors contribute to
constipation in palliative and supportive care.

The current lack of agreed diagnostic criteria makes it
difficult to assess the true prevalence of the problem of constipation in the hospice/palliative care population. Recent
observations support the notion that constipation, like some
other physical symptoms, may worsen as life shortens. It is
associated with an increased likelihood of hospitalization.
Constipation is defined as a disorder of neuromuscular function of either the colon or the pelvic floor. Opioids slow gastric emptying, and slow small bowel and colon transit times.
Other factors likely to contribute include the use of medications with anticholinergic effects, reduced performance
status and reduced oral intake.

Reversible causes should be addressed.
Assessment should include a rectal examination, which
is important to diagnose fecal impaction. A plain
abdominal radiograph is only useful to exclude a bowel
obstruction and should not be used as the basis of a diagnosis of constipation.
498
There are few data to define the optimal laxatives to use;

clinical guidelines mostly recommend either a sennabased treatment or a macrogol initially.
CLINICAL PEARL
Opioids remain the most cited risk factor for constipation; despite this, the use of peripheral opioidantagonists still requires concurrent administration of
other laxatives. If the predominant cause of the constipation is opioids, then methylnaltrexone may be added
to other agents.
DELIRIUM
Denition
Delirium is a common clinical syndrome, characterized
by disturbed consciousness and changed cognitive function that develops over a short period of time (usually hours
to days), due to the direct physiological consequences of a
medical condition.
The features of delirium can vary between individual
patients. They include: impairment in memory and
attention; disorientation to person, place and/or time;
perceptual disturbances (hallucinations, delusions); and
disturbance of the sleepwake cycle.
A diagnosis of delirium rests solely on clinical skills,
aided by the use of questionnaires that can guide clinical
assessment, as no diagnostic test exists.
There are three clinical subtypes of delirium: hyperactive
(characterized by perceptual disturbances, agitation, restlessness, psychomotor overactivity, and disorientation);
hypoactive (characterized by drowsiness, lack of interest in
the activities of living, slowed cognition, and poor initiation of movement); or mixed (where the features oscillate
between the two other subtypes).

The prevalence of delirium in oncology settings has been cited
as 1618%; however, in palliative settings it ranges from 25%
to 90% in the more advanced or terminal stages of illness.
Delirium is associated with increased mortality,
increased length of hospital stay, worse physical and cognitive recovery, and increased need for institutional care.
CLINICAL PEARLS
Delirium is associated with high morbidity and mortality, especially if detected late or missed. In people
with advanced disease, delirium is an independent
predictor of mortality.
Witnessing delirium symptoms is associated with
a markedly increased risk of generalized anxiety in
bereaved caregivers.
Delirium is a distressing experience, with more than
50% of cancer patients with delirium resolution
recalling the experience.
In a person who was previously well, a major insult would be
required to cause delirium (for example serious infection),
whereas someone with multiple risk factors can develop
delirium with a minor perturbation (change in medication,
mild hypercalcemia).
There is an average of 3 precipitants per episode of delirium. Risk factors in cancer include: advanced age; severity
of illness; prior delirium; the use of benzodiazepines, opioids
or corticosteroids; low albumin levels; bone, liver, brain or
leptomeningeal metastases; and hematological malignancies.
There are multiple neurotransmitter abnormalities in
delirium (Figure 16-3). The neurotransmitter and neurobiological pathways implicated include acetylcholine and
dopamine, serotonin, gamma-aminobutyric acid (GABA),
cortisol, cytokines, and oxygen free-radicals. There are also
emerging data supporting evidence for involvement in limbic hypothalamicpituitaryadrenal axis dysfunction, priming of microglia such that they respond more vigorously
to systemic inflammatory events in at-risk individuals, and
exaggerated inflammation-induced illness.

Effective strategies for delirium prevention include regular re-orientation, therapeutic activity, early mobilization,
management of sleep or anxiety with non-pharmacological
strategies, maintaining nutrition and hydration, and correcting vision and hearing with relevant aids (if possible).
Management of delirium relies on early identification,
and immediate assessment and treatment of precipitants.
Even in advanced cancer, delirium is reversible in at least
50% of cases. During an episode of delirium, supportive

care includes management of hypoxia, maintaining hydration and nutrition, minimizing the time spent lying in bed,
regular mobilization, and avoidance of restraints.
The role of psychotropic medications in delirium is still
to be established, with only a limited number of randomized studies to guide their use. Low-dose haloperidol is the
best-studied agent, with use recommended if a patient poses
a risk to themselves or others, or has particularly distressing
perceptual disturbance or agitation.
INSOMNIA
Denition
Insomnia is a subjective complaint by the patient of sleep
disturbance despite adequate opportunity to sleep. This
includes difficulty initiating or maintaining sleep, interrupted sleep and poor quality (non-restorative) sleep.

Sleep disturbance can lead to daytime fatigue and somnolence, and also psychological distress if time spent awake at
night is associated with negative thought patterns. Often
there is also an impact on caregivers.
The restorative function of sleep depends on well-organized and uninterrupted sleep architecture with the order
and duration of non-rapid eye movement (NREM) and
Medications
Medical illness
Surgical illness
Medications
Alcohol withdrawal
Medications
Stroke
Cholinergic
Activation
Cholinergic
Inhibition
Benzodiazepine and
alcohol withdrawal
Dopamine
Activation
Reduced
GABA Activity
Cytokine
Excess
GABA
Activation
Serotonin
Activation
Glutamate
Activation
Serotonin
Deficiency
Medications
Substance withdrawal
Benzodiazepines
Hepatic failure
Tryptophan depletion
Phenylalanine elevation
Surgical illness
Medical illness
Delirium
Cortisol
Excess
Hepatic failure
Alcohol withdrawal
Glucocorticoids
Cushings Syndrome
Surgery
Stroke
Figure 16-3 Pathophysiology of delirium. The evidence supports multiple mechanisms of delirium, which may
pertain in different clinical situations
Reproduced from Flacker JM and Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol
1999:54A(6):B239B246.
499
rapid-eye movement (REM) sleep maintained. Sleep is also

a mediating factor in pain regulation and immune function
(cytokine and natural killer cell activity). The major categories of sleep disorders are:
primary insomnia
sleep-related breathing disorders (e.g. obstructive and
central sleep apnea)
hypersomnolence (e.g. narcolepsy)
circadian rhythm disorders (e.g. shift work, jetlag).
movement disorders (e.g. restless leg syndrome)
parasomnias (e.g. night terrors, sleepwalking).
Common contributing factors to insomnia at the end of life
include anxiety and depression, delirium, direct involvement of the brain with primary or secondary cancer, fever
and sweats (especially if nocturnal), unrelieved symptoms (in particular pain, dyspnea, nausea and vomiting),
medication (stimulants, corticosteroids, bronchodilators,
activating antidepressants, and withdrawal syndromes),
restless leg syndrome (peripheral neuropathies, uremia),
and psychological factors (poor sleep habits, negative
expectations).
500

Sleep hygiene strategies can be helpful; these include:
maintaining a regular sleepwake schedule
avoiding unnecessary time in bed during the day
providing cognitive and physical stimulation during
daytime hours, in particular for bedridden patients
avoiding stimulating medication and other substances
(caffeine, nicotine) at night
minimizing noise at night
maintaining adequate pain relief through the night.
Cognitive behavioral therapy and muscle relaxation techniques may be helpful in some individuals.
Short-term use of a benzodiazepine hypnotic may be
indicated in some patients, with careful consideration of the
potential for complications and side-effects.
CLINICAL PEARL
Sleep hygiene strategies need to be tailored to individual etiologies, and sedative hypnotics considered in
selected situations for short-term use.
1
A 56-year-old woman with metastatic breast cancer presents with a new painful lytic lesion in her distal right humerus.
Plain-lm radiography suggests that the lesion is occupying less than one-third of the bony cortex, and therefore
surgical consultation is not sought. Discussions with her radiation oncologist are initiated. In the short term, what
other strategies may be useful to improve her pain control?
A Bisphosphonate infusion
B Regular opioid analgesia
C A non-steroidal anti-inammatory drug
D A neuropathic agent
E All of the above
A 71-year-old man is receiving combination cisplatin-based chemotherapy plus conventional radiotherapy for a head
and neck cancer. Despite good mouth care and regular reviews, he develops painful oropharyngeal mucositis. Which
of the following is not true?
A Mucositis is associated with increased mortality.
B Poor oral health is a risk factor for mucositis.
C Mucositis is always due to infections.
D 5-uorouracil is no longer recommended as concurrent treatment.
E Pain management is the most important aspect of treatment.
A 52-year-old man with adenocarcinoma of the pancreas has recently been diagnosed with liver metastases. In the
outpatient clinic he advises his oncologist that the main and most distressing problem he is experiencing is fatigue.
Which of the following statements is the most correct?
A There is a clearly dened association between tumor necrosis factor alpha and fatigue.
B Burst dexamethasone is strongly recommended to improve fatigue.
C Exercise programs are likely to worsen fatigue.
D Regardless of life expectancy, depression may contribute to fatigue.
E The best advice is to rest as, like tiredness, fatigue improves with rest.
4 An 80-year-old man presents with an inoperable cecal cancer which at diagnosis has already spread to the liver and
lungs. He is symptomatic with right upper quadrant pain, increasing shortness of breath, and constant nausea for
which he is unable to articulate factors that exacerbate or relieve this problem. He feels that if he could just improve
his nausea enough to eat, he would be much better. Which of the following statements is the most correct in situations
like this?
A The mechanisms that underlie nausea of progressive disease are well dened.
B Aprepitant is a useful antiemetic in this situation.
C Poorly controlled nausea is a poor prognostic sign.
D Expect that <20% of people with advanced cancer will have nausea at the end of life.
E Dexamethasone is a useful agent to trial for this man.
5
A 58-year-old woman is diagnosed with stage IIIB adenocarcinoma of the lung. At presentation, her main symptoms
are cough and weight loss. Her husband is distressed by the weight loss, constantly berating her to try harder to eat
more. He is concerned that she has just given up and is frustrated with her because of this. With regard to the cancer
cachexia, which of the following is the most correct?
A Parenteral feeding should not be considered.
B The benets of parenteral feeding usually outweigh the risks.
C Cancer cachexia is easily differentiated from other causes of weight loss in cancer.
D Cachexia may be a source of conict between patients and families.
E Dexamethasone is the most useful agent to help people gain weight.
6 A 62-year-old man with extensive small-cell cancer of the lung is referred to the palliative care consult team of the
cancer center. His main symptom is breathlessness, which he and his family are nding frightening and distressing. He
tells you he is too scared to sleep at night in case he suffocates. He is requesting home oxygen. However, you note
that his oxygen saturations are 94% on room air. What other interventions may be useful to improve palliation of his
breathlessness?
A Prescribe oxygen, as this is always useful regardless of oxygen saturations.
B Advise him to avoid morphine, as this will suppress his respiratory drive.
C Refer him to physiotherapy for advice about breathing exercises and positioning techniques.
D Advise him to rest as much as possible to avoid exacerbating his breathlessness.
E Prescribe regular nebulized 0.9% sodium chloride (NaCl) every 4 hours.
7
A patient with stage IV colon cancer presents complaining of increased abdominal distension, nausea without
vomiting, and increasingly infrequent bowel actions. At presentation, he describes a situation where he has not
experienced a bowel action for 4 days. His regular medications include sustained-release morphine 40mg daily and
501
regular sennoside 2 tablets twice daily. He notes that prior to his cancer diagnosis he had very regular bowel actions.
What is the next most appropriate step to address the fact that his bowels have not moved for 4 days?
A Organize a plain-lm radiograph to assess the degree of fecal loading.
B Organize a plain-lm radiograph to exclude a bowel obstruction.
C Undertake a rectal examination to exclude fecal impaction.
D Administer subcutaneous methylnatrexone for opioid-induced constipation.
8 A 62-year-old man with pancreatic cancer and biliary obstruction presents with increasing jaundice and disorientation.
His wife says that he has been awake all night, has displayed evidence of hallucinations and will not take his medication
as he thinks it is poison. Which of the following statements is true?
A Delirium does not affect mortality in advanced cancer.
B The cause of the presentation is most likely due to brain metastases.
C Most patients with delirium have one identied precipitant.
D Delirium is not a distressing experience as patients cannot recall it when it resolves.
E Delirium pathophysiology involves multiple neurotransmitters.
ANSWERS
1
E.
The management of bone pain requires multiple modalities to achieve analgesia. All of the suggested interventions have
been identied as useful in the management of this often distressing problem.
C.
Mucositis involves a complex interaction of local tissue damage, the oral environment, myelosuppression and intrinsic
genetic predisposition.
D.
Although a common problem in advanced cancer, the underlying etiology of fatigue remains unclear. Furthermore,
the optimal management is also unclear. However, in a void of knowledge, the best clinical practice in palliative care
recommendations are that as far as possible underlying factors are identied and reversed.
4 C.
Nausea is a common problem in advanced cancer. As life shortens, there are likely to be numerous contributing factors
occurring simultaneously. Aside from metoclopramide, the evidence base to support other antiemetics in this palliative
situation is currently limited.
5
D.
The underlying etiology of cancer cachexia is not yet clearly dened. As a result, intervention options are still being
explored. In the absence of well-dened pharmacological approaches, other work has identied this to be a source of
signicant conict between patients and families.
6 C.
Evidence suggests that non-hypoxic patients may not derive symptomatic benet from the prescription of oxygen.
More robust evidence supports the use of non-pharmacological approaches to dyspnea and the concurrent prescription
of low-dose sustained-release morphine.
7
C.
Disturbed bowel function is very common in palliative care, with numerous contributing factors including opioids and
other factors such as poor performance status, proximity to death and other medications. Fecal impaction is likely to
complicate the lives of palliative care patients, and this is most easily diagnosed with a rectal examination. Prior to the
administration of methylnaltrexone in constipation believed to be opioid-induced, a bowel obstruction must be excluded.
8 E.
Delirium in advanced cancer is an independent predictor of mortality, and multiple neurotransmitters are implicated in the
pathophysiology. Although brain metastases may be a cause, several other precipitants are also possible, and on average
patients with delirium have three or more precipitating causes for any episode of delirium. There is good evidence that
patients recall delirium after resolution and nd the experience highly distressing.
502
CHAPTER 17
IMMUNOLOGY
Brad Frankum
CHAPTER OUTLINE
KEY CONCEPTS IN IMMUNOBIOLOGY

immunodeciency
Immunity, inammation and tissue repair
ALLERGIC DISEASE
Anaphylaxis
Allergic rhinitis (AR) and allergic
conjunctivitis (AC)
Food allergy
Drug allergy
EOSINOPHILIA
MAST CELL DISORDERS


Mixed connective tissue disease (MCTD)
PRIMARY VASCULITIS
AUTOINFLAMMATORY DISORDERS
(TRAPS)
IMMUNODEFICIENCY
Secondary (acquired) immunodeciency
HIV/AIDS
Epidemiology
Pathophysiology
Management
Prognosis
SYSTEMIC AUTOIMMUNE DISEASE

503
KEY CONCEPTS IN
IMMUNOBIOLOGY
Innate and adaptive immunity are unique but heavily
interdependent entities.
Specificity and diversity are the foundation for successful adaptive immunity.
Immunological memory is the basis for immunity and
immunization.
Hypersensitivity, autoimmunity and immunodeficiency
are the key drivers of immunopathology.
Immunity, inflammation and tissue repair are essential
and interdependent components of a complex system to
maintain health.
Understanding immunobiology is the key to logical
diagnosis and treatment of infection.
Manipulation of the immune system is central to the
current, and future, treatment of a vast range of human
diseases: allergy, autoimmunity, malignancy, infection
and transplantation.

Innate and adaptive immunity are unique but heavily interdependent entities. Their key features are described in
Table17-1.
Innate immune response

Innate immunity refers to that section of the immune system
that does not require specific antigen recognition to eliminate a pathogen. It includes barrier functions such as integrity of the skin and mucous membranes, and physiological
mechanisms such as coughing, sneezing, urination, and

mucous production.
The innate immune response is rapid, first-line, and
prevents tissue invasion in most instances.
Phagocytic cells can recognize a restricted number of
cell-surface molecules on microbial pathogens, and
be directly activated. These molecules are known as
pathogen-associated molecular patterns (PAMPs).
Examples of receptors that can recognize PAMPs include
Toll-like receptors, and mannose-binding lectin (MBL).
There are also receptors in the cytoplasm of cells that
can recognize microbial products. This is obviously
important for dealing with pathogens that have evaded
defense mechanisms in the extracellular environment.
Examples include NOD-like and RIG-1-like receptors.
The innate immune system also recognizes molecules
released from damaged or infected cells. These molecules are known as DAMPs, or damage-associated
molecular patterns.
DAMPs help to activate both the innate immune
response and the inflammatory response.
Complement is a set of plasma proteins that form a cascade to ensure amplification of both innate and adaptive
immune responses.
Complement can be activated by the presence of
microbial cell surfaces, by the presence of immune
complexes, or by the binding of MBL.
Activated complement proteins have chemotactic
actions to trigger phagocytosis, as well as effector
function, resulting in cell killing through the membrane attack complex.
Activation of the innate immune response results in
recruitment of the adaptive response. This is achieved
Table 17-1 Innate versus adaptive immunity
KEY
FEATURES
INNATE IMMUNE SYSTEM
ADAPTIVE IMMUNE SYSTEM
Cells
Neutrophils, monocyte-macrophages, eosinophils,

basophils, mast cells, dendritic cells, natural killer cells
B and T lymphocytes, plasma cells
Receptors
PRRs, Toll-like receptors
B-cell receptors (immunoglobulins),

T-cell receptors
Effectors
Molecularcomplement, acute phase reactants, cytokines

Cellularphagocytes (neutrophils, monocytemacrophages), cells that produce inammatory mediators
(eosinophils, basophils, mast cells), natural killer cells
HumoralB cells, antibody

Cell-mediatedcytotoxic T cells
Specicity
Absent
Antigen-specic
Memory
Absent (does not require prior contact)
Antigen-specic (requires prior contact)
Response time
Immediate
Delayed
Response
magnitude
Not enhanced by prior contact
Enhanced by prior contact
PRR, pattern-recognition receptor.
504
Chapter 17 Immunology
predominantly via antigen presentation by dendritic cells

and macrophages to lymphocytes, but is augmented by
changes in cytokine milieu.
In turn, the adaptive immune response utilizes effector
cells of the innate system.
Box 17-1
The ve stages of the adaptive

immune response
1 Antigen capture
Adaptive immune response
2 Recognition of antigen
The three key components of the adaptive immune response

are diversity, specificity and memory.
Diversity is manifested by the deliberate generation of
many lymphocyte clones, but selecting only those that
recognize foreign but not self-antigen for survival.
Specificity refers to each lymphocyte clone having
receptors of one specificity, and responding to that
specific antigen only.
Memory is maintained by retention of antigen-specific
clones of both B and T lymphocytes, and the ongoing
production of specific antibody, in perpetuity.
A number of different cells are involved (Figure 17-1):
B cells differentiate into plasma cells to secrete antibody.
CD4+ T-helper cells direct other cells to perform
effector functions.
CD8+ cytotoxic T cells, when activated, kill cells
infected by intracellular organisms, e.g. viruses.
T-regulatory cells:
are a subset of CD4+ T cells which express high levels of CD25, and a transcription factor called FoxP3
are generated centrally in the thymus, or peripherally in secondary lymphoid tissue
are the cells which recognize self-antigen, so are
antigen-specific, but develop in such a way as to
suppress response toward self-antigen rather than
initiate it
function to maintain self-tolerance and suppress
inflammatory responses.
Adaptive
immune system
APC
T-helper
CD3, CD4
Lymphocytes
T cells
CD3
B cells
CD 19, CD20
T cytotoxic
CD3, CD8
T reg
Figure 17-1 Cells of the adaptive immune system.

APC, antigen-presenting cell; T reg = T-regulatory
cell
3 Activation of lymphocytes
4 Antigen elimination
5 Decline of immune response
The adaptive immune response proceeds through the five

stages listed in Box 17-1.
The major histocompatibility complex (MHC) is a set of
genes which encode for cell-surface proteins that represent a
critical step in presenting foreign antigen to the effector cells
of the immune system.
Cells which are able to stimulate CD8+ cytotoxic T
cells must be able to process cytosolic antigen, and present the antigen to the cell surface in conjunction with
MHC class I antigens. These are all nucleated cells.
Cells which are able to present antigen to CD4+ T-helper
cells, and stimulate them, must be able to process endocytosed antigen, and express MHC class II antigens
in conjunction with the foreign antigen on the cell surface. These are dendritic cells, monocyte-macrophages
and B lymphocytes, and are collectively referred to as
antigen-presenting cells.

Specificity and diversity are the foundation for successful
adaptive immunity.
During development in the bone marrow (B cells)
and the thymus (T cells), millions of different genetic
recombinations occur in the genes that encode for lymphocyte receptors.
Immunological specificity refers to the ability of the
immune system to possess cells that are capable of recognizing one specific antigen only. This is the function
of the lymphocyte.
B lymphocytes express cell-surface receptor (immunoglobulin) which is specific for one antigen. When
secreted, this immunoglobulin can be arranged as
a pentamer (IgM), dimer (IgA) or monomer (IgG,
IgE, IgA), but still remains specific for one antigen
only.
T lymphocytes express the T-cell receptor which is
also specific for one antigen only.
Immunological diversity refers to the capacity of the
immune system to have lymphocytes capable of recognizing every conceivable antigen. The vastness of this
repertoire is staggering.
In generating sufficient diversity amongst the lymphocyte population, the immune system needs a
system in place during the requisite genetic rearrangements that allows production of clones
505
responsive to foreign antigen, but disallows clones

that are self-reactive.
Failure to delete these autoreactive clones from
being generated, or failure to recognize and deal
with those that escape, is the basis for autoimmunity.
Immunological memory is the basis for immunity and
immunization.
Lymphocytes exist in three states: nave, effector and
memory (Table 17-2).
Nave lymphocytes
Nave lymphocytes have not encountered specific antigen, and survive for several months
only if not exposed to antigen. There is a
steady-state replacement process for these
nave cells. This may wane in older people
when immunosenescence occurs.
Nave T lymphocytes can be recognized by the
cell-surface marker CD45RA.
Nave B lymphocytes express IgM or IgD on
their surface and have low expression of the
cell-surface marker CD 27.
Nave lymphocytes circulate predominantly to
lymph nodes, and have low expression of surface molecules such as adhesion molecules that
would draw them to sites of inflammation.
Effector lymphocytes
Effector lymphocytes arise after specific antigen exposure.
They have a short half-life.
Effector T lymphocytes are either cytotoxic
Tlymphocytes or T-helper cells.
Effector B lymphocytes are plasma cells, which
secrete antibody.
Upon exposure to antigen, nave lymphocytes transform into lymphoblasts, which are larger, more metabolically active cells. Some of these lymphoblasts then
differentiate into effector cells.
Cytotoxic T cells can be recognized by the cell-surface
markers CD45, CD3 and CD8.
T-helper cells express CD45, CD3 and CD4. They
produce cytokines that stimulate B lymphocytes
and macrophages.
Both cytotoxic and T-helper cells express molecules that draw them to sites of inflammation, such
as adhesion molecules.
Activated (effector) B cells express IgG, IgA and IgE on
their surface predominantly. They have high expression
of CD27.
After resolution of the effector response to specific antigen, a population of memory lymphocytes persists in
the circulation.
These cells may survive for months or years.
Like plasma cells, memory B cells express IgG, IgA
or IgE, but can be distinguished by being small with
less cytoplasm. Memory B lymphocytes can be distinguished from nave B cells by high expression of
CD27.
Like effector T cells, memory T lymphocytes
express surface molecules that draw them to sites
of inflammation, such as adhesion molecules. They
also predominantly express CD45RO. Memory
T lymphocytes differ from effector T cells, however, by expressing high amounts of CD127.
The unique qualities of memory cells make them far more
efficient at responding to antigen challenge than nave cells.
This forms the basis of adaptive immunity. It also explains
the efficacy of vaccination:
Table 17-2 Features of nave, effector and memory lymphocytes
EFFECTOR LYMPHOCYTES
FEATURE
(B CELLS = PLASMA CELLS;

T CELLS = T-HELPER CELLS,
CYTOTOXIC T CELLS)
NIVE
LYMPHOCYTES
MEMORY
LYMPHOCYTES
Survival
Several months
Days
Months to years
B cell surface
markers
IgM, IgD
Low CD27
IgG, IgA, IgE, high CD27
IgG, IgA, IgE, high CD27
T cell surface
markers
CD45RA
T-helper cells: CD4+, CD25, CD40 ligand,

CD45RO, low CD127
Cytotoxic T cells: CD8+, CD25, CD45RO,
low CD127
CD45RO
High CD127
T cell adhesion
molecule
expression
Low
High
High
Cytoplasm size
Small
Large
Small
506
For a given antigen, there are larger numbers of memory than nave lymphocytes. This proportion increases
withage.
Memory T lymphocytes are more readily drawn to sites
of infection and inflammation.
Memory B lymphocytes have already class-switched to
express the higher-affinity cell-surface immunoglobulinsIgG, IgA and IgE.
Memory lymphocytes respond to antigen stimulation
several days faster than do nave lymphocytes.
Autoimmunity results from a combination of genetic

and environmental factors. For example, patients with
certain human leukocyte antigen (HLA) subtypes, and
with certain inherited complement component deficiencies, are more prone to SLE. When they incur tissue
damage, e.g. with exposure to ultraviolet (UV) radiation
or through infection, they are then more likely to suffer a disease flare. The cell breakdown that occurs from
the environmental factor releases more autoantigen
(in the case of SLE this is cellular nuclear material),
and the autoreactive cells then produce more antibody,
which combines with the autoantigen. The resultant
immune complexes then elicit an inflammatory response
through combination with Fc receptors on phagocytes,
and via complement activation.
Immunodeficiency can be congenital or acquired.
Most congenital (primary) immunodeficiency is genetically based. All components of the immune system
can be thus affected, although severe forms of primary
immunodeficiency are rare.
Acquired immunodeficiency can result from environmental factors such as infection (e.g. human immunodeficiency virus [HIV] infection), or malnutrition, or
from aging, or malignancy. Iatrogenic factors such as
cancer chemotherapy or immunosuppressive drugs are
also important.

immunodeciency
Hypersensitivity, autoimmunity and immunodeficiency are
the key drivers of immunopathology.
Immunological reactions that are inappropriate in intensity, inappropriately targeted or inadequately regulated
are labeled hypersensitivity disorders.
There are four classic types of hypersensitivity (see
Table 17-3).
Autoimmunity is the basis for a large amount of human
disease.
Autoimmune disease may be organ-specific, as in
Hashimotos thyroiditis and pernicious anemia; or systemic, as in systemic lupus erythematosus (SLE).
Table 17-3 Classication of hypersensitivity
TYPE
I
II
III
IV
Mechanism
Immediate
Antibody-mediated
Immune-complexmediated
T-cell-mediated
Immunopathology
IgE-mediated
Mast-cell
degranulation
Production of
prostaglandins and
leukotrienes
Antibody directed at
tissue antigens
Complement
activation
Fc-receptor-mediated
inammation
Deposition of immune
complexes in vascular
beds
Fixation of
complement
Fc-receptor-mediated
inammation
Mediated by CD4+
T-helper cells of the
TH1 or TH17 subsets,
or by cytotoxic T
lymphocytes
May be inappropriately
directed against selfantigens, or foreign
antigens (e.g. nickel
in jewelry causing
contact dermatitis)
There may be
collateral damage
in responses against
intracellular infection
(e.g. viral hepatitis)
Disease examples
Allergic rhinitis
Asthma
Food allergy
Anaphylaxis
Pernicious anemia
Myasthenia gravis
Serum sickness
Lupus nephritis
Post-streptococcal GN
Contact dermatitis
Multiple sclerosis
Type I diabetes
mellitus
GN, glomerulonephritis.
507
Immunity, inammation and tissue

repair
Immunity, inflammation and tissue repair are essential and
interdependent components of a complex system to maintain health.
Infection or tissue damage incites an inflammatory
response.
Immune system activation results in the release of a variety of cytokines (chemokines) that function to attract
effector cells.
Other cytokines are inflammatory, resulting in effects
such as vasodilatation, increased vascular permeability,
fever and pain, all of which enhance the effectiveness of
the immune response in limiting damage caused by the
injury or infection.
Clotting mechanisms are enhanced by inflammatory
cytokines. This both results in limitation of blood loss
from damaged tissue, and hinders travel of infection to
distant sites.
Yet other cytokines trigger tissue repair in order to
restore tissues once the insult has been dealt with.
For the most part, these systems function smoothly to
maintain homeostasis, and control mechanisms are in
place to curtail responses when function is restored. When
components of the systems are deficient, or control mechanisms fail to limit an excessive inflammatory response,
disease results.
Understanding immunobiology is the key to logical diagnosis and treatment of infection.
The response of the immune system to dealing with a
variety of different pathogens forms the basis of effective
treatment.
Deficiencies in components of the innate immune system, for example neutropenia, will make the individual
especially susceptible to bacterial and fungal infection,
and thus antibiotic or antifungal therapy should be considered promptly in the setting of early signs of infection.
Antibody deficiencies will similarly predispose to extracellular infection.
Cellular immune deficiency predisposes to infection
with intracellular organisms such as viruses and mycobacteria. The approach to an ill patient in this setting will
therefore differ both diagnostically and therapeutically.
At present the capacity to iatrogenically boost the
immune system is limited. Replacing immunoglobulin in those who are deficient is of proven benefit, but
the use of pooled donor immunoglobulin for infection
otherwise is not. T-cell deficiencies are even more problematic, with a very small number of congenital, severe
immunodeficiencies being managed with bone marrow
transplantation though with variable results.
Rarely, the administration of cytokines for therapy is
used. An example is the success of interferon-gamma
for chronic granulomatous disease.
508

Manipulation of the immune system is central to the current,
and future, treatment of a vast range of human disease: allergy,
autoimmunity, malignancy, infection, and transplantation.
While immunosuppression remains the mainstay of
treatment for a large number of immunologically mediated diseases, newer and more sophisticated approaches,
especially the growing use of biological agents, offer
increasing hope for more targeted and less toxic therapy.
Strategies for dealing with allergic disease include:
treatments that block the release of mediators (mastcell stabilizers) or the effect of mediators (antihistamines, leukotriene antagonists, corticosteroids)
treatments that suppress the immune system to
counteract the activity of B lymphocytes producing IgE, or effector T lymphocytes (corticosteroids,
other immunosuppressives)
treatments that manipulate and ameliorate the allergic response (immunotherapy)
specific anti-IgE therapy (omalizumab).
Autoimmune disease will predominantly require
immunosuppression to counteract the effect of pathological antibody production or autoreactive T cells.
Agents such as corticosteroids and methotrexate have
both anti-inflammatory and immunosuppressive actions,
depending on dose.
Targeted biological therapy, using monoclonal antibodies against cellular receptors or cytokines, is increasingly
being used to treat both malignancies and autoimmune
disease (Table 17-4).
Although largely unhelpful for treating infection in
immune-competent hosts, pooled human immunoglobulin can be very effective to modify immune
responses in the setting of autoimmunity (Box 17-2).
Manipulation of the immune system has enabled the
use of tissue transplantation to treat a variety of lifethreatening diseases.
Organs can now be transplanted from donors who
are less immunologically matched to the recipient
than ever before.
So successful has been immunosuppression to suppress tissue rejection, that the major risks to the transplanted patient lie in the susceptibility to infection
and the long-term threats of metabolic disease and
malignancy, rather than from organ rejection per se.
Similarly, the role of immunotherapy is likely to increase
in the treatment of malignancy in the future, both by
activating immune mechanisms directed toward cancer cells and by supporting the immune system in those
who have been immunosuppressed by the effects of chemotherapy, radiotherapy or targeted biological therapy.
Highly tissue-damaging consequences can result from
the inflammatory response induced by a variety of
infections. This is largely through the systemic effects of
pro-inflammatory cytokines.
A limited role has been defined for the use of immunotherapy that counteracts this excessive inflammatory response, but it is likely that agents will be
discovered in the future.
It is also possible that more specific and safer therapies will be developed in the future that can augment
components of the immune response to infection,
enhancing eradication of pathogens while preserving tissue integrity and function simultaneously.
ALLERGIC DISEASE
Anaphylaxis
Epidemiology
Anaphylaxis is a life-threatening disorder, with a lifetime
prevalence that is unknown but may be as high as 2%.
The incidence is increasing. Children and young adults are
Table 17-4 Biological agents with a role in
autoimmune disease
BIOLOGICAL
AGENT
ANTIBODY TARGET
Iniximab
Etanercept
Adalimumab
Golimumab
Certolizumab
TNF-alpha
Anakinra
IL-1R
Tocilizumab
IL-6
Rituximab
Ocreluzimab
Ofatumumab
CD20 (anti-B cell)
Abatacept
CD80 and CD86
Belimumab
BAFF
Natalizumab
alpha-4 integrin
Efalizumab
CD11a
affected more frequently. The diagnosis is often missed.

Fatalities due to anaphylaxis are rare, but, again, may be
under-reported. Common causes are shown in Box 17-3.
Pathophysiology
Anaphylaxis results from widespread mast-cell and/
or basophil degranulation, resulting in the immediate
release of pre-formed vasoactive and smooth-musclereactive chemicals such as histamine, and rapid production of others such as leukotrienes and prostaglandins.
This can be triggered by IgE-dependent or non-IgE
dependent mechanisms.
Non-IgE-dependent mechanisms may be IgG- or
complement-driven, or a result of direct mast-cell
activation.
Clinical features
The majority of patients with anaphylaxis have cutaneous involvement of the skin and mucous membranes, in
the form of urticaria and angioedema.
Generalized flushing can also occur.
Box 17-3
Causes of anaphylaxis
BAFF, B-cell activating factor; IL, interleukin; IL-1R, interleukin-1

receptor; TNF, tumor necrosis factor.
IgE-dependent
Foodspeanuts
and tree nuts, eggs,
crustaceans, seeds,
cows milk
Drugsbetalactam antibiotics,
neuromuscular blocking
drugs, local anesthetic
agents, insulin
Insect stings
Hymenoptera venom
(bee, yellowjacket/wasp,
hornet)
Latex, chlorhexidine
Inhalants rarelyhorse
hair, cat hair
Non-IgE-dependent
Radiocontrast media
Drugsnon-steroidal
anti-inammatories,
opioids
Physical causes
exercise, cold, heat
Idiopathic anaphylaxis
Systemic mastocytosis
Box 17-2
Evidence-based uses for high-dose immunoglobulin therapy in autoimmune disease

Neurological disease
Myasthenia gravis
CIDP (chronic inammatory
demyelinating polyneuropathy)
Guillain-Barr syndrome
Dermatomyositis
Multifocal motor neuropathy
LambertEaton syndrome
Stiff person syndrome
Hematological disease
Immune thrombocytopenic purpura
Immune neutropenia
Immune hemolytic anemia
Parvovirus B19-associated aplasia in
immunocompromised patients
Other autoimmune disease

Kawasaki disease
Vasculitis (some forms, limited
evidence)
509
Pruritus is usual.
Respiratory involvement in the form of stridor, secondary to laryngeal and upper airway edema, or wheezing,
secondary to bronchospasm, is necessary for diagnosis,
unless there is hypotension plus skin involvement.
Hypotension may result in syncope, confusion or
incontinence.
Gastrointestinal involvement in the form of nausea, abdominal cramps, vomiting and/or diarrhea is
common.
The diagnosis of anaphylaxis is clinical, but elevated
serum tryptase in a sample taken within 3 hours of the
event, or serum histamine taken within 1 hour, is usually confirmatory.
Other causes of shock need to be considered, especially
if there is no evident mucocutaneous involvement.
When anaphylaxis is suspected, it is important to
attempt to ascertain the trigger through careful history
taking, and confirmatory tests where relevant such as
allergen skin-prick tests or serum-specific IgE for foods,
drugs or venoms.
Management
The key to the management of anaphylaxis is the early
administration of epinephrine (adrenaline), and fluid resuscitation. Fluid volume expansion may need to be aggressive
to restore adequate circulation.
CLINICAL PEARL
The dose of epinephrine (adrenaline) to be used in
anaphylaxis should be 0.01 mg/kg, up to a maximum
dose of 0.5 mg. This should be given intramuscularly
(1:1000 dilution) or intravenously (1:10,000 dilution).
Intravenous epinephrine administration should only
occur in the setting of cardiac monitoring. Doses can
be repeated as needed if response is poor.
H1 antihistamines and corticosteroids are useful adjuncts

in treatment, but should never be used as an alternative
to epinephrine (adrenaline).
Any patient with anaphylaxis should be observed in
hospital for at least 4 hours, and up to 24 hours in severe
cases.
Long term, patients must be instructed to strictly avoid
identified triggers, and subsequent challenge to assess
for ongoing clinical risk should only ever be undertaken
in a hospital setting under the supervision of appropriate
specialists.
At present, the only situation in which allergen immunotherapy is appropriate to manage anaphylaxis in the
long term is with Hymenoptera venom allergy (bees,
yellowjackets/wasps, hornets). Immunotherapy for food
allergy and latex allergy is under investigation. Rarely,
rapid desensitization to antibiotics (usually beta-lactams
or cephalosporins) and insulin is conducted in an
510
inpatient setting, when no appropriate alternative drugs

can be used.
Prognosis
Death is unusual in anaphylaxis, but is probably
under-recognized.
Prognosis is worse in patients with coexisting asthma,
other respiratory disorders, and underlying cardiovascular disease.
Patients on beta-adrenoceptor blockers are at increased
risk, due to antagonism of the effect of epinephrine.
Lack of preparedness for community self-management
in those at risk, through the availability of and ability
to appropriately use an adrenaline self-injecting device,
also confers a worse prognosis.
CLINICAL PEARL
Anaphylaxis is a clinical syndrome, with no distinction
made between IgE-mediated and non-IgE-mediated
causes. The term anaphylactoid is no longer used.
Allergic rhinitis (AR) and allergic

conjunctivitis (AC)
Epidemiology
Allergic rhinitis and allergic conjunctivitis affect up to
30% of the population.
They are more common in developed countries and
temperate climates.
They frequently coexist in the same individual, but AR
is more common than AC. It is uncommon to see AC
in an individual without AR, but this can occur.
Both genders are affected equally.
AR and AC form part of the atopic phenotype, with
affected individuals more likely to suffer from asthma,
food allergy and/or atopic dermatitis.
Onset is typically in childhood after the age of about
5years until young adulthood, but can come on later in
life, especially with a change in geographical location.
Pathophysiology
Both AR and AC result from allergic sensitization to inhalant allergens.
Nasal mucosal and/or conjunctival mast cells have
surface IgE that is specific for allergen in affected
individuals.
Combination of allergen with IgE bound to the mastcell surface after inhalation into the nose, or settling on
the conjunctival surface, results in cross-linking of IgE
and triggering of the allergic reaction locally.
Common allergens implicated in AR are the house dust
mite, grass and tree pollen, and animal danders (see
Box17-4). Sufferers may be mono-sensitized, but more
commonly react to multiple allergens.
Box 17-4
Common airborne allergens

Perennial allergens
House dust mite
Dermatophagoides
pteronyssinus, D. farinae
Animal dandersdog,
cat (Fel d 1), horse hair
CockroachGerman
and American species
Moldse.g. Alternaria
tenuis, Cladosporium
herbarum
Seasonal allergens
Grass pollene.g.
perennial ryegrass,
Bermuda grass,
ragweed
Tree pollene.g. birch,
pine
CLINICAL PEARLS
The demonstration of a specic IgE to an allergen in
an individual conrms sensitization to that allergen
rather than clinical allergy.
Many individuals are sensitized to allergens that
cause no clinical symptoms.
Both in vivo (skin-prick tests) and in vitro (serumspecic IgE testing) testing are highly sensitive for
the detection of allergic sensitization. Skin-prick
testing, in expert hands, is more sensitive and specic, and allows clearer identication of individual
allergens, whereas specic IgE tests can be used
when patients have skin disease that renders skin
testing difficult, or when the patient is taking antihistamines, which will give false-negative skin-prick
testing.
Clinical features
AR is characterized by nasal congestion and blockage,
rhinorrhea (usually watery), excessive sneezing, and nasal
itch, in varying combinations. The local allergic reaction
can also result in palatal itch, or itch within the ear.
AC results in redness, excessive tearing, and itching of
the eyes.
Sufferers of AR and AC frequently complain of fatigue
and irritability.
In AR, physical examination reveals pale, swollen inferior nasal turbinates. There may be partial to complete
nasal occlusion.
In AC, conjunctivae may be injected, with variable
chemosis.
In general, symptoms will be perennial when due to
dust mite or animal danders, or seasonal with grass and
tree pollen. This, however, may vary with climatic conditions and geography.
Hayfever is a historical term that refers to the intense
rhinoconjunctivitis that occurs in the springtime in
individuals with pollen sensitization.
Diagnosis is usually not difficult, and can be confirmed by
the demonstration of specific IgE to an appropriate allergen,
either by skin-prick testing (Figure 17-2) or by the detection
of specific IgE in serum by various techniques.
Non-allergic rhinitis can cause similar symptoms to
AR, in the absence of demonstrable allergic sensitization. The etiology is unknown.
Vasomotor rhinitis is a subset of non-allergic rhinitis, and is characterized by nasal congestion and
rhinorrhea that is provoked by non-specific environmental stimuli such as rapid temperature change
and strong odors.
NARES is non-allergic rhinitis with eosinophilia,
where excess eosinophils are found on a nasal smear.
This is presumed to be due to local mucosal allergic sensitization where the culprit allergen/s is not
demonstrable systemically.
Chronic rhinosinusitis is more likely if the individual
has thick or purulent nasal discharge, sinus and/or dental pain, post-nasal drip and/or hyposmia or anosmia.
Nasal congestion can occur in the latter stages of pregnancy, and is known as pregnancy rhinitis.
Inappropriate long-term use of nasal decongestant
sprays can cause rebound nasal mucosal congestion, and
is known as rhinitis medicamentosa.
Management
Management of AR and AC is outlined in Box 17-5,
overleaf.
Prognosis
AR and AC have been shown to adversely affect quality
of life when not treated, or treated sub-optimally.
Symptoms generally persist for decades in the absence of
allergen-specific immunotherapy, only abating in most
cases in middle age.
Figure 17-2 Positive skin-prick tests

From Yu M-C et al. Allergic colitis in infants related to cows milk:
clinical characteristics, pathologic changes and immunologic
ndings. Pediatr Neonatol 2013;54(1):4955.
511
Box 17-5
Management of allergic rhinitis and allergic conjunctivitis

Allergen avoidance
May be useful for house dust mite and animal danders,
although it is difficult to achieve
Not possible for grass and tree pollens
Of limited overall efficacy
Intranasal corticosteroids
Mometasone
Fluticasone propionate
Fluticasone furoate
Budesonide
Ciclesonide
Once daily; safe for long-term use
Adherence often limits efficacy
Systemic H1 antihistamines
Cetirizine
Fexofenadine
Loratadine
Desloratadine
Safe. More effective for itching and rhinorrhea; less
effect on nasal blockage
Useful adjunct when used with other modalities
Epidemiology
Chronic rhinosinusitis (CRS) is classified as CRS without nasal polyps or CRS with nasal polyps.
The condition causes considerable morbidity.
Prevalence data suggest that CRS is common, perhaps
affecting up to 5% of the population. The type without
nasal polyps is more common.
Pathophysiology
The etiology of CRS is unknown. It occurs more frequently
in atopic than non-atopic individuals, suggesting a role for
allergic sensitization in some cases.
Humoral immunodeficiency is a risk factor for CRS,
which raises suspicion for the role of infection, as both bacteria and fungi can be isolated in many cases. Treatment with
antibiotics and antifungal agents is, however, disappointing.
This contrasts with acute bacterial sinusitis, for which antibiotics are generally efficacious.
Other risk factors for CRS include:
ciliary dyskinesia
cystic fibrosis
aspirin sensitivity
asthma.
512
Topical ocular therapy

Lubricants
Antihistamines
Mast-cell stabilizers
Multiple-action drugs
Corticosteroids
Need to be used multiple times per day. Corticosteroids
are not safe for long-term use (cataracts, infection)
Adherence is often poor
Costly
Allergen-specic immunotherapy
Subcutaneous or sublingual: single or multiple allergens,
with less evidence for efficacy for multiple allergens
Risk of anaphylaxis with subcutaneous immunotherapy,
therefore requires expert administration and specialist
supervision
Offers potential for long-term disease modication
Costly, but cost-effective in the long term
Clinical features
Chronic rhinosinusitis is generally subacute in onset, presenting with:
persistent nasal blockage (often with nocturnal snoring)
facial pain and frontal headache
post-nasal drip.
Other symptoms may include:
dental pain
hyposmia or anosmia
ear pain, fullness, or blockage
persistent cough, with or without expectoration.
Physical examination may be unremarkable, or reveal:
tenderness over the sinuses
mucopurulent secretions in the nasal passages or
pharynx
nasal obstruction.
The diagnosis of CRS can be confirmed with computed tomography (CT) or magnetic resonance imaging
(MRI) of the paranasal sinuses, and/or direct visualization with nasendoscopy.
Both persistent allergic rhinitis and non-allergic rhinitis
are less likely to cause facial pain, headache, post-nasal

drip, and alteration in the sense of smell than CRS.
ANCA-positive vasculitis should always be considered
in a patient with chronic sinus-related symptomatology,
especially if there is associated epistaxis, lower respiratory
tract symptoms, or the patient is systemically unwell.
Paranasal sinus tumors are very rare, but should be obvious on imaging.
Some patients are prone to recurrent bouts of acute
infective sinusitis. The patient should be symptomfree between episodes. The majority of cases of acute
infective sinusitis are, in fact, viral in origin, and resolve
without specific treatment.
If nasal ulceration or a saddle-nose deformity is found,
the following conditions should be considered:
granulomatosis with polyangiitis (Wegeners
granulomatosis)
midline granuloma (non-caseating granuloma
without vasculitis)
tumorcarcinoma, lymphoma
relapsing polychondritis
infectiontuberculosis, leprosy, syphilis, histoplasmosis
cocaine sniffing.
Causes of nasal blockage are listed in Box 17-6.
CLINICAL PEARL
Samters triad (aspirin-exacerbated respiratory disease,
AERD) consists of sinonasal polyposis, aspirin hypersensitivity and asthma. It should be remembered that
approximately 10% of all asthmatics will have aspirin-exacerbated asthma, but a much smaller number
have Samters triad. It is extremely important to inquire
about aspirin or non-steroidal anti-inammatory drug
(NSAID)-related symptoms in asthmatics, because anaphylaxis may occur with inadvertent use.
Aspirin desensitization (the graduated introduction of
increasing doses of aspirin, commencing with minute quantities) can be an effective treatment in Samters triad, but is dangerous due to the risk of severe
asthma or anaphylaxis and should only be performed
under strict specialist guidance. Those patients who do
tolerate the regimen often then have gastrointestinal
side-effects from the high daily doses of aspirin that are
required for maintenance of effective desensitization.
Management
CRS tends to be very corticosteroid-responsive, and
often a short course of moderate-dose prednisolone
will relieve symptoms and result in significant shrinkage of polyp size. Effects are, however, temporary and
patients can become inappropriately reliant upon ongoing steroid medication.
Intranasal steroids may benefit a minority of patients, if
used continuously.
Daily nasal lavage with saline solutions can help alleviate
symptoms.
Box 17-6
Causes of nasal blockage
Nasal mucosal conditions

Allergic rhinitis
Non-allergic rhinitis
Infective rhinitis
Chronic rhinosinusitis (with or without nasal
polyps)
Adenoidal hypertrophy
Vasculitic conditions
ANCA-positive vasculitis
Granulomatous disorders
Sarcoidosis
Mass lesions
Tumors of the nasal cavity, paranasal sinuses, or
nasopharynx
Anatomical obstruction
Nasal septal deviation
Trauma
Foreign bodies
Patients with severe and ongoing disease will often

require surgical intervention. While often effective in
the short term, disease will often recur after surgery.
Patients with concurrent allergic rhinitis should be
treated for that problem.
Leukotriene antagonists reduce symptoms in a minority
of patients.
Antibiotic therapy should be used for acute flares of the
condition. Intranasal antibiotics used long-term are of
limited benefit.
Prognosis
CRS is a chronic disease that requires ongoing management.
Few patients are symptom-free at 5 years.
Patients should be monitored for the development of
obstructive sleep apnea.
Frequent or long-term corticosteroid use will require
monitoring for the usual complications.

Atopic dermatitis is a common, chronic, pruritic skin condition which has significant adverse effects on quality of life.
The term eczema is often used synonymously, but is less
precise and is best avoided.
Epidemiology
Atopic dermatitis is estimated to affect more than 10%
of young children. The prevalence decreases with age.
AD is more common in Western industrialized nations.
The majority of patients have the atopic phenotype,
with significant risk of concurrent or future food allergy,
asthma and allergic rhinoconjunctivitis.
513
Pathophysiology
While it is clear that an abnormal Th2 response in the skin
in AD leads to the overproduction of Th2 cytokines, which
then drive excessive IgE production in response to a variety
of food and environmental allergens, it is often incorrectly
assumed that AD results solely from exposure to these allergens. Patients and parents of affected children often despair
when the strict avoidance of allergens to which they or their
children are sensitized fails to adequately control the disease.
This apparent inconsistency is explained by the other key
components of AD:
Skin dryness, resulting in poor barrier function. Patients
with genetic mutations in the gene encoding for the
structural skin protein filaggrin suffer from a particularly severe form of AD.
Chronic cutaneous bacterial colonization/infection,
especially with Staphylococcus.
Fungal colonization from puberty, especially with
Malassezia.
Pruritus, resulting in persistent scratching and further
damage to barrier function, and risk of infection.
CLINICAL PEARL
Detection of allergic sensitization by demonstration of
specic IgE by skin-prick or serum-specic IgE testing
remains important in atopic dermatitis (AD), but results
must be interpreted in the context of the individual
patient.
A child whose AD is under good control with topical treatment, and is tolerating foods such as wheat
or milk with no are in their disease after consuming
these foodseven if they have demonstrable specic IgE to these foodsshould not be advised to
remove wheat and milk from their diet.
A child who has demonstrable specic IgE to the
house dust mite may gain some benet from dust
mite reduction methods in the home, but the AD is
very unlikely to be driven by this alone, so common
sense should prevail as to the extent to which allergen avoidance measures are pursued.
Clinical features
The rash of AD:
is characterized by scaly, erythematous patches
is very pruritic
may be discoid
occurs on very dry skin.
The pattern of rash in AD (Figure 17-3) typically evolves with
increasing age, although at any point it may be generalized:
Infantscheeks, torso, nappy area
Toddlerscheeks, perioral, flexures, nappy area
Childreneyelids, behind ears, flexures, torso
Adultsflexures, limbs, hands, face, back.
Secondary infection is common, and may be manifested by
pustules, weeping, or worsening erythema.
514
Figure 17-3 Typical patterns of atopic dermatitis in

(A) an infant and (B) an adult
From: (A) Weston WL, Lane AT and Morelli JG. Color textbook
of pediatric dermatology, 4th ed. Elsevier, 2007. (B) Dr Harout
Tanielian/Science Photo Library.
Pruritic, erythematous skin rashes are common. AD is best
distinguished by the age of onset and the pattern of rash, but
may be mistaken for the following:
Allergic contact dermatitis, common causes of which
are:
nickel sulfate (jewelry)
potassium dichromate (cement, leathers, paint)
paraphenylenediamine (hair dyes, cosmetics)
para-aminobenzoic acid (sunscreen)
formaldehyde (cosmetics, shampoos)
Irritant contact dermatitis
Psoriasis
Scabies
Drug eruptions.
Biopsy of the rash is rarely necessary, with the majority of
patients displaying other atopic conditions.
CLINICAL PEARL
In a patient with a generalized erythrodermic dermatosis, a markedly elevated total serum IgE is highly suggestive of atopic dermatitis. This is one of very few situations
in which a total serum IgE is a useful diagnostic test.
Treatment
Topical treatment is the mainstay of successful management of AD.
Minimum twice-daily application of moisturizers and/or
emollients.
Adequate cleansing of the skin, while avoiding drying
soaps.
Sterilization of the skin with dilute bleach baths
23 times per week can be useful.
Liberal application of topical corticosteroids.
AD that is worse than mild should be treated with
moderate- to high-potency steroid creams or ointments (e.g. mometasone, methylprednisolone) for
as long as it takes to get the disease under control.
Mild disease, and facial AD, can be safely treated
with topical 1% hydrocortisone.
1% pimecrolimus cream can be safely used for facial
dermatitis, including eyelid dermatitis. Tacrolimus
cream may be effective in severe cases.
Wet dressings or bandages used for several hours per day
can be highly effective for moisturization.
Patients who fail to improve despite adequate topical therapy
should be considered for systemic therapy. The following
agents have been shown to be effective:
cyclosporine (ciclosporin)
azathioprine
methotrexate.
Where possible, oral corticosteroids should be avoided in
the long-term management of AD. Rebound flaring is usual
when oral steroids are withdrawn, and it is difficult to justify
the long-term side-effects of steroids in all but the most disabling cases of AD.
Treatment of superimposed infection is important.
Short courses of anti-staphylococcal antibiotics should
be used for obvious infection, or with disease flares.
Long-term low-dose antibiotics, e.g. once-daily cotrimoxazole, may be of benefit in some patients.
Intermittent application of intranasal mupirocin may
reduce staphylococcal carriage.
Prognosis
Many affected children improve with age.
Adult AD can be severe, and relatively resistant to therapy.
An explanation for the exacerbations and remissions seen

in the disease over time is not always obvious, and these
may not be only on the basis of varying allergen exposure.
Food allergy
Adverse reactions to foods can be IgE- or non-IgE-mediated,
due to immune or non-immune mechanisms. The term
allergy should be reserved for immune-mediated reactions.
Epidemiology
An epidemic of food allergy is being observed in the
developed world. The incidence of food allergy is increasing sharply, and levels of up to 10% are being observed in
preschool-aged children in the developed world.
Prevalence is much higher in children; not all children
grow out of their food allergies, so prevalence in adults
will increase over the next decades.
Adults can develop food allergy de novo.
Pathophysiology
Non-IgE-mediated food reactions tend to mainly cause
gastrointestinal symptoms, such as bloating, cramping,
and diarrhea.
This may be chemically or immunologically mediated
through non-IgE mechanisms, e.g. celiac disease.
Systemic reactions resembling anaphylaxis, or components of anaphylaxis such as generalized urticaria, can
occur through non-IgE mechanisms and can be dangerous. These can be due to a wide variety of food
components. Examples may include preservatives such
as sulfites, or food-coloring agents. In these cases, it is
presumed that release of histamine and other vasoactive
molecules through non-IgE-mediated mechanisms is
responsible.
It is increasingly recognized that food components
exacerbate symptoms of irritable bowel syndrome in
significant numbers of sufferers.
Atopic dermatitis can be exacerbated by both IgE and
non-IgE food reactions.
Allergy to a very wide variety of foods has been demonstrated in individuals, but allergy to meats, cereals and
vegetables are rare. Common causes of food allergy are
listed in Box 17-7.
Box 17-7
Common causes of food allergy

Infants
Cows milk
Soya bean milk (soy milk)
Hens eggs
Toddlers
Hens eggs
Cows milk
Peanuts
Tree nuts
Children
Hens eggs
Peanuts
Tree nuts
Seeds, e.g. sesame
Fish
Crustaceans
Fruits and some vegetables
Adults
Peanuts
Tree nuts
Seeds, e.g. sesame
Crustaceans
Fruits and some vegetables
515
Clinical features
Oral allergy syndrome (OAS)
Oral allergy syndrome results in oral and pharyngeal
tingling, itching, and sometimes swelling.
OAS uncommonly results in systemic symptoms or
airway obstruction.
It is often caused by ingestion of fruits and some raw
vegetables, and is more common in those who are sensitized to tree and grass pollen and suffer from seasonal
allergic rhinitis.
Reactions may be more common, and more severe, in
the pollen season.
Cooking will often denature the allergenic components of fruits and vegetables in OAS, and may allow
consumption.
Systemic food reactions
Angioedema of the lips, face and upper airway can result
from ingestion of culprit foods within minutes.
Gastrointestinal reactions of nausea, vomiting and diarrhea are common.
Urticaria can be generalized.
Anaphylaxis with circulatory collapse and/or airway
obstruction can result in death.
When symptoms occur immediately after food ingestion, it is usually obvious that the reaction is due to a
specific food, but young children may ingest culprit
foods when their carers are not watching them.
Food allergy almost always occurs rapidly.
Non-IgE-mediated adverse food reactions may occur
some hours after ingestion, and may result from components of several foods rather than an individual one.
Patients frequently attribute a wide range of symptoms
to food. The physician needs to take a careful history to
see if this is likely.
Testing for specific IgE with skin-prick tests or serumspecific IgE is generally sensitive for detecting foodallergen sensitization. For skin-prick testing, fresh
fruits, vegetables, seafoods and meats are more reliable
than commercially available extracts.
Emergency action plans should be in place for all foodallergy sufferers.

Epinephrine self-injecting devices must be carried at all
times by patients with food allergy who are assessed to
be at risk of anaphylaxis.
Determining the level of risk is often difficult, and
requires specialist assessment.
Food challenge testing is appropriate in individuals
when there is evidence of developing tolerance, usually evidenced by reduction in skin-prick reactivity or a
lower specific IgE value, but must be conducted in specialist clinics under strict protocols.

Urticaria (Figure 17-4) refers to raised, erythematous,
typically pruritic lesions that last for less than 24 hours.
Angioedema (Figure 17-5) is non-pitting swelling that typically involves mucous membranes but can also affect the
skin, with a predilection for face, hands and feet, and genitalia. Angioedema can affect the gut.
Acute urticaria or angioedema refers to short-lived and
self-limited episodes of disease. Causes are listed in
Box17-8.
Chronic urticaria or angioedema refers to episodes
occurring daily, or almost daily, for a minimum period
of 6 weeks.
At times the definition of the condition as either acute
or chronic can be problematic when frequent or recurrent acute episodes are occurring, but it is important to
make this judgment, given the differing pathophysiology and management approaches of the two conditions.
Around 50% of patients will have both urticaria and
angioedema simultaneously or successively, whereas
40% will have urticaria alone, and 10% exclusively
angioedema.
CLINICAL PEARL
The size of the positive skin-prick reaction to a food, or
the absolute level of serum-specic IgE to that food,
is a guide to that persons risk of an allergic reaction
occurring with ingestion but not the severity of the
reaction. The result must be used in conjunction with
the history and in comparison with the size of previous
reactions, or levels, to assess an individuals risk.
Figure 17-4 Patient with generalized urticaria
Treatment
Strict avoidance of culprit foods is essential.
516
From Callen JP and Jorrizo JL, eds. Dermatological signs of internal

disease, 4th ed. Elsevier, 2009.
Figure 17-5 Patient with lip angioedema

From James WD, Berger T and Elston D. Andrews Diseases of the
skin: clinical dermatology, 11th ed. Elsevier, 2011.
Box 17-8
Causes of acute urticaria and

angioedema
IgE-mediated
Food allergy
Insect sting allergy
Drug allergy
Aeroallergen allergy,
e.g. horse hair
Non-IgE-mediated
Adverse food reactions
Drug reactions, e.g. aspirin
sensitivity
Radiocontrast media
Physical factorscold, heat,
exercise, sun
Inherited angioedema
Idiopathic
Infection, especially in children
CLINICAL PEARLS
The patient who suffers episodes of angioedema
without any history of urticaria should be assessed
for hereditary or acquired angioedema due to complement component deciency or dysfunction. It is
inappropriate to do this if urticaria is present.
Angioedema without urticaria can also be the result
of treatment with angiotensin-converting enzyme
inhibitors.
Epidemiology
It is estimated that approximately 20% of individuals
will have an episode of acute urticaria during their life.
Chronic urticaria is less common, affecting approximately 3 people in every 1000.
Pathophysiology
Various environmental and food allergens can also cause
contact urticaria. This usually remains confined to the area
of skin or mucous membrane that the allergen directly
contacts, but can occasionally generalize. An example

might be a cutaneous reaction to a plant experienced by
a gardener.
Chronic urticaria and angioedema is not an IgEmediated disorder.
Approximately 50% of cases of chronic urticaria and
angioedema are autoimmune.
Autoimmune cases of chronic urticaria and angioedema
are characterized by IgG antibodies directed against
autologous IgE, demonstrable by a positive wheal and
flare to autologous serum on skin-prick testing.
Physical urticaria refers to urticaria and angioedema provoked by physical factors (Table 17-5, overleaf).
Regardless of the cause, the manifestations of the disease
are the result of the release of histamine and other vasoactive factors from mast cells, resulting in vasodilatation and
increased vessel permeability.
Other pruritic skin conditions can occasionally urticate, especially after extensive scratching, e.g. atopic
dermatitis.
Cellulitis is sometimes mistaken for angioedema, but
is generally painful and associated with systemic symptoms such as fever.
Serum IgE is often moderately elevated in the setting
of chronic urticaria. This should not be interpreted as
indicating an allergic cause.
Approximately 10% of those with chronic urticaria
will have demonstrable thyroid autoantibodies. Actual
thyroid dysfunction is much less common, but these
patients should remain under surveillance prospectively
for the development of hypothyroidism.
CLINICAL PEARL
Urticarial lesions that are painful or burn, last longer
than 24 hours, or leave a bruise or stain, could be
due to urticarial vasculitis. A biopsy is indicated in this
circumstance.
Hereditary angioedema (HAE)

Hereditary angioedema is a rare but important cause of
recurrent bouts of angioedema. Urticaria is absent in this
condition.
The disorder generally manifests in early childhood.
Episodes frequently affect the airway, and can be
life-threatening. Intestinal involvement is also frequent, causing severe abdominal pain and frequent
misdiagnosis.
Episodes are often precipitated by events such as minor
trauma, surgery or dental work.
It is due to a genetic defect in the complement system,
specifically in the absolute quantity of C1-esterase
inhibitor (type 1 HAE) or in its function (type II HAE).
It is an autosomal dominant disorder.
517
Table 17-5 Physical urticaria
PHYSICAL FACTOR
CLINICAL FEATURES
Dermographism
Common condition
Wheals only appear after scratching
Benign, usually self-limited condition
Heat = cholinergic urticaria
Small, transient hives directly after skin becomes hot, e.g. showering
Not associated with angioedema
Cold = cold-induced urticaria
Generally affects exposed skin

Can produce angioedema
Anaphylaxis is a risk, e.g. with immersion in cold water
Exercise = exercise-induced
urticaria
Often only occurs after moderate to strenuous exercising

Anaphylaxis can result
Water = aquagenic urticaria
Occurs with any water contact on skin, regardless of temperature

Generally does not affect mucous membranes, e.g. with drinking.
Sun exposure = solar urticaria
Presumed to be due to UV radiation
Vibration = vibratory urticaria
Occurs particularly with repetitive stimuli, e.g. using a jackhammer

Angioedema is frequent
Delayed-pressure = delayedpressure urticaria
Frequently produces angioedema

Occurs on skin subject to prolonged pressure, e.g. under tight clothes
Often antihistamine-resistant, and can be difficult to control
Food-dependent, exerciseinduced
Occurs after exercise, but only if specic food is consumed immediately beforehand
Especially occurs with wheat and seafood
Can cause anaphylaxis
Diagnosis is made by demonstrating low C4 levels, and

low C1 inhibitor levels or function.
Treatment is with transfusions of C1 inhibitor concentrate, or with one of the new medications available: icatibant, which is a bradykinin antagonist; or ecallantide, a
kallikrein inhibitor.
Prophylaxis should be administered prior to surgery,
childbirth or dental surgery.
C1-esterase inhibitor deficiency can be acquired, in
about 15% of cases. This is generally in the setting of
hematological malignancy.
Treatment of urticaria and angioedema

Acute episodes of urticaria and angioedema with an identified cause should, as much as possible, be managed longterm with avoidance of identified culprits.
Antihistamine therapy
Adequate doses of H1 antihistamines are the mainstay
of treatment for both acute and chronic urticaria, and
angioedema.
The superiority of newer, non-sedating agents such as
fexofenadine, cetirizine, loratadine, and desloratadine
over the older, sedating agents is well established. Doses
518
of up to 540 mg fexofenadine, 30 mg cetirizine and

30mg loratadine divided over 24-hour periods are safe
and may be necessary for adequate disease control.
Daily prophylactic antihistamine therapy should be used
for extended periods in the setting of chronic urticaria
and angioedema. Many patients make the mistake of
relying upon p.r.n. (as required) treatment in this setting, with disappointing results.
Prophylactic H1 antihistamines may alleviate or reduce
the severity of physical urticaria (e.g. taken prior to
exercise or cold exposure).
Addition of H2 antihistamines such as ranitidine or
famotidine may have a synergistic effect with H1 antihistamines, but are ineffective by themselves.
Alternative treatments
Acute severe urticaria or angioedema may occasionally
require a dose of subcutaneous epinephrine.
Leukotriene antagonists such as montelukast can be
tried for cases unresponsive to antihistamine.
Immunomodulatory therapy may be required for severe
or resistant cases.
Short courses of corticosteroids can alleviate acute severe
episodes.
Long-term corticosteroids should be avoided for chronic

cases, unless all other pharmacotherapy has failed.
Azathioprine, mycophenolate, cyclosporine and methotrexate should be used only under specialist supervision
and monitoring.
Prognosis
Approximately 20% of chronic urticaria patients will have
ongoing symptoms after 5 years.
Drug allergy
Adverse reactions to drugs are extremely common, and may
be predictably dose-related or idiosyncratic. The term drug
allergy should be reserved for reactions that are likely to be
immunologically mediated.
IgE-mediated drug reactions can result in anaphylaxis,
and can be fatal.
Non-IgE-mediated reactions can also be extremely
dangerous, and indeed fatal, e.g. StevensJohnson syndrome and toxic epidermal necrolysis.
Epidemiology
Allergic drug reactions are clearly under-reported, making estimation of the incidence of drug allergy very difficult. Anaphylaxis is, however, rare.
Patient self-reporting of drug allergy is unreliable. This
is particularly the case for antibiotics. Many patients (and
practitioners) mistake the viral exanthem that is exacerbated by the administration of antibiotics in childhood
for a drug allergy.
Antibiotics remain the most common cause of drug
allergy, especially those of the beta-lactam class.
Pathophysiology
Drugs can cause hypersensitivity via type I, II, III and IV
reactions, although there is likely to be overlap between
mechanisms in some instances.
Type I reactions are characterized by rapidity of onset,
due to the presence of specific IgE to that drug on the
surface of mast cells and basophils.
Type III (serum-sickness) reactions will often occur
1014 days after commencement of a drug. These reactions may last for up to 3 weeks, due to persistence of
immune complexes.
Most drug allergic reactions are likely to be T-cell mediated, and therefore fall withing the type IV hypersensitivity category. This explains the likelihood of onset of
symptoms after approximately 48 hours of drug use.
Type II reactions are less common. An example is
hemolysis resulting from treatment with penicillin. In
this instance, penicillin binds to erythrocyte membrane
proteins, resulting in antibody-directed attack against
the cell and clearance by macrophages.
Clinical features
The clinical history, with very specific noting of all drugs
taken and the timing of onset of symptoms and/or signs,
is the key to making an accurate diagnosis of drug allergy.

Supplementary testing is unavailable, or inadequate, for all
but a few drugs.
Type I reactions may result in urticaria, angioedema,
upper airway obstruction, bronchoconstriction, vomiting and diarrhea, or circulatory collapse.
Type III reactions often manifest with fever, malaise,
arthritis, maculopapular or vasculitic rash. Urinalysis
may be abnormal due to glomerulonephritis.
Cutaneous abnormalities due to drug reactions are
numerous, and include maculopapular rash, vasculitis,
urticaria, photosensitivity, erythema, erythema multiforme, cutaneous lupus, and fixed eruptions. These may
result from all types of hypersensitivity.
Table 17-6 (overleaf) outlines specific serious drug reaction
syndromes.
Any new symptoms which occur after commencing a
new drug should be considered as possibly drug-related.
Given the array of different cutaneous manifestations that
may represent drug allergy or adverse drug reactions, skin
biopsy is of limited value. However, biopsy may be useful
to confirm vasculitis or exclude other pathologies.
Peripheral eosinophilia, eosinophiluria, and acutely
abnormal liver function tests are suggestive of drug
allergic reactions.
Skin-prick and intradermal allergy testing is a validated
tool for suspected allergy to penicillin and to local and
general anesthetic agents. Cephalosporin testing is also
increasingly being performed. Positive tests have a high
positive predictive value for IgE-mediated drug allergy.
Negative testing for penicillin should be followed up
with a carefully supervised oral challenge with one of
the penicillin drugs. It is very unusual in this instance
for anaphylaxis to occur, although delayed-onset rash
may occur, confirming a non-IgE-mediated immunological reaction.
CLINICAL PEARL
Cross-reactivity between IgE-mediated penicillin and
cephalosporin allergy is relatively uncommon, with estimated rates <5%. If anaphylaxis has occurred to one of
the agents, however, it is prudent to seek specialty consultation and allergy skin testing prior to prescription of
the other class. Reactions less severe than anaphylaxis
do not require testing, but observation of the patient
upon administration of the rst dose is advisable.
Treatment
Suspected or proven drug allergy necessitates strict
avoidance of the offending drug.
Patients should be advised to wear emergency identification jewelry if anaphylaxis or other life-threatening
drug reactions have occurred.
Emergency rapid desensitization is possible to some antibiotics, e.g. penicillin, if there is no possible alternative
519
Table 17-6 Specic serious drug reaction syndromes
SYNDROME
CLINICAL FEATURES
COMMON
CULPRIT DRUGS
TREATMENT
StevensJohnson
syndrome
Maculopapular rash, which may

blister, ulcerate and necrose
Mucosal ulceration (Figure 17-6)
Fever
Usually a drug reaction, but may
follow infection or malignancy, or be
idiopathic
Allopurinol
Carbamazepine
Phenytoin
Antibiotics, esp.
sulfonamides
Medical emergency
Cease suspected culprit
medications
Hemodynamic support
Burns-style dressings and
nursing care
Corticosteroids unproven but
generally used in moderate to
high doses
Toxic epidermal
necrolysis (TEN)
Fever
Maculopapular rash
Skin ulceration and necrosis affecting
>30% of body surface area
Mucosal ulceration
Usually a drug reaction, but may
follow infection or malignancy, or be
idiopathic
Allopurinol
Carbamazepine
Phenytoin
Antibiotics, esp.
sulfonamides
Medical emergency
Cease suspected culprit
medications
Hemodynamic support
Burns-style dressings and
nursing care
Corticosteroids unproven but
generally used in moderate to
high doses, in conjunction with
high-dose IV immunoglobulin
DRESS
(drug reaction with
eosinophilia and
systemic symptoms)
Fever
Onset >10 days after commencement
of drug
Maculopapular or vasculitic rash
Eosinophilia
Abnormal LFTs
Interstitial nephritis
Pericarditis
Anticonvulsants
Allopurinol
NSAIDs
Sulfonamides
Abacavir
Withdraw offending drug

Oral corticosteroids
Erythema
multiforme
Urticaria
Target lesions
Bullae
Mucosal lesions may occur
Usually associated with infection,
esp. herpesviruses, but may be a drug
reaction
Beta-lactam
antibiotics
Allopurinol
Carbamazepine
Phenytoin
Sulfonamide
antibiotics
Cease suspected offending drug

Antihistamines if itch prominent
IV, intravenous; LFT, liver function test; NSAID, non-steroidal anti-inammatory drug.
for an inpatient with a life-threatening problem. This

procedure is high risk, and should only be performed by
allergy specialists.

Anaphylaxis to stinging insects is a life-threatening and
unpredictable form of allergic disease.
Insects of the Hymenoptera order are the usual culprits.
These are bees, yellowjackets/wasps, hornets and ants.
Anaphylaxis also can result from bites from a number of
species of fly.
Neither atopy nor family history is a risk factor for
Hymenoptera anaphylaxis, but repeated stings, e.g. in
beekeepers, does confer increased risk.
520
Figure 17-6 Oral mucosal involvement in Stevens

Johnson syndrome
From Eicheneld LF et al. (eds). Neonatal and infant dermatology.
3rd ed. Philadelphia: Elsevier, 2015.
Clinical features
Clinical reactions to Hymenoptera stings take three general
forms:
1 Typical local reactions are localized pain, erythema, and
edema. Pruritus may be prominent.
2 Large local reactions consist of extensive swelling and
erythema, contiguous with the sting site. Even if an
entire limb swells, it is classified as a local reaction if
contiguous with the sting site.
3 Systemic reactionscan range from generalized urticaria through to full-blown anaphylaxis.
It is usual for a patient to clearly have experienced the
sting, due to pain, and a stinger will often remain in situ
following a bee or wasp sting.
The patient may have trouble distinguishing the insect,
and may not recognize the species of wasp particularly.
Insect sting should be considered in any patient with
idiopathic anaphylaxis.
Skin-prick and intradermal testing to different Hymenoptera species is very sensitive to diagnose sensitization.
Treatment
The clinical history determines the appropriate course of
treatment.
H1 antihistamines, NSAIDs and oral corticosteroids can
be used for large local reactions.
All patients with systemic reactions should have an
anaphylaxis action plan and carry an epinephrine selfinjection device.
CLINICAL PEARL
Subcutaneous immunotherapy to the specic insect
venom is essential for any adult patient with a systemic allergic reaction, and for any child with a reaction worse than generalized urticaria. Immunotherapy
reduces the risk of anaphylaxis with subsequent stings
from >50% to <5%, so is highly effective. Immunotherapy is neither effective nor appropriate for local reactions, however large.
EOSINOPHILIA
Eosinophilia is classified according to the absolute level of
eosinophils in the peripheral blood:
mild eosinophilia: 0.51.5 w 109/L
moderate eosinophilia: 1.55.0 w 109/L
severe eosinophilia: >5.0 w 109/L.
Hypereosinophilia is defined as a peripheral blood eosinophil count of >1.5 w 109/L.
Eosinophils have multiple functions in innate immunity,
and inflammation:
their production is stimulated by interleukins 5 and 3,
and GM-CSF (granulocyte-monocyte colony stimulating factor)
they release a variety of cytotoxic, chemotactic and

vasoactive molecules
they are involved in tissue repair.
Causes of eosinophilia are listed in Box 17-9.
Box 17-9
Causes of eosinophilia
Common causes of eosinophilia
Allergic disease
Helminthic parasitic infection
Drug reactions
Primary eosinophilic disorders
Eosinophilic pneumonia
Organ-specic eosinophilic syndromes,
e.g. eosinophilic esophagitis
Eosinophilic fasciitis
Disorders with secondary eosinophilia
Allergic bronchopulmonary aspergillosis
Eosinophilic granulomatosis with polyangiitis (Churg
Strauss vasculitis)
Systemic mastocytosis
Malignancy, e.g. lymphoma, adenocarcinoma
Hyper-IgE syndrome
Omenn syndrome
Eosinophilic clonal disorders
Myeloproliferative hypereosinophilic syndrome
(M-HES)
Lymphoproliferative hypereosinophilic syndrome
(L-HES)
Eosinophilic leukemia (extremely rare)
Otherwise unclassied HES

HES is defined as hypereosinophilia (>1.5 w 109/L eosinophils in peripheral blood) in the absence of an identifiable secondary cause.
Patients present with a range of clinical problems including thromboembolism, pulmonary infiltrates, endomyocardial fibrosis, lymphadenopathy, splenomegaly,
and myelofibrosis.
Specific cytogenetic abnormalities are detectable in
bone marrow in some subsets, including myeloproliferative HES (M-HES) in which a tyrosine kinase mutation is present.
Corticosteroids are the mainstay of treatment for most
variants of HES.
M-HES is responsive to tyrosine kinase inhibitors, e.g.
imatinib.
Anti-IL5 monoclonal antibody therapy is increasingly
being used for all variants of HES.
521
MAST CELL DISORDERS

Cutaneous and systemic mastocytosis represent a spectrum
of malignant mast cell disorders. They are predominantly
due to mutations in the KIT-oncogene, which results in
abnormal activation of the gene with uncontrolled proliferation of mast cells.

Otherwise known as urticaria pigmentosa, CM produces a raised red, brown or purple papular rash (Figure
17-7) which can occur anywhere other than the face.
The rash urticates on scratching (Dariers sign).
It is due to the accumulation of mast cells in the skin.
Approximately 25% of those with CM will have systemic symptoms, but without demonstrable mast cell
accumulation in tissues other than the skin, most notably the bone marrow.
CM affects both children and adults. The childhood
form may regress spontaneously.
Diagnosis is made by skin biopsy.
Cytopenias may result from bone marrow infiltration.

Diagnosis is confirmed with excess mast cells seen on
bone marrow biopsy. Cytogenetics will reveal the KIT
mutation in the majority of cases.
Treatment
High-dose antihistamine therapy is the mainstay of
treatment.
UV therapy may offer some relief for urticaria
pigmentosa.
Oral sodium cromolyn should be used for gastrointestinal symptoms, and may relieve some systemic
symptoms.
Most cases of SM are resistant to tyrosine kinase
inhibitors.
Corticosteroids may relieve symptoms in some cases
of SM.
Aggressive cases of SM are usually treated with cytotoxic chemotherapy.
Patients with SM should carry an epinephrine selfinjecting device if there is a history of anaphylaxis.

Skin involvement is seen in >50% of cases of SM.
Systemic features typically manifest with pruritus, urticaria, flushing, diarrhea, abdominal pain, bronchospasm, and recurrent anaphylaxis.
Organ involvement can result in weight loss, lymphadenopathy, and hepatosplenomegaly.
Cardiac and neurological involvement is rare, but has
been described.
Bone involvement with either osteopenia or osteosclerosis is frequent.
Serum tryptase is elevated.
Figure 17-7 Typical appearance of pigmented rash in

urticaria pigmentosa, and demonstrating Dariers sign
From Skarin AT (ed). Atlas of diagnostic oncology, 4th ed.
522
SYSTEMIC AUTOIMMUNE
DISEASE
The diagnosis of one of the forms of systemic autoimmune disease is frequently devastating for a patient. This
group of diseases is chronic and incurable. Treatment is
often associated with significant short- and long-term
morbidity.
Diagnostic uncertainty is an issue in many cases, with
patients potentially displaying clinical features which
overlap between conditions, and laboratory investigations with imperfect sensitivity and specificity (see
Table 17-17 later in the chapter).
The relatively low prevalence of most systemic autoimmune diseases, combined with the heterogeneity of
clinical patterns, makes development of precise treatment protocols difficult. Clinicians will need to individualize their approach in all cases.
The following systemic autoimmune conditions will be
considered in this section:
systemic lupus erythematosus
Sjgrens syndrome
polymyositis
dermatomyositis
scleroderma
CREST syndrome
mixed connective tissue disease
primary antiphospholipid syndrome
IgG4-related disease.
Rheumatoid arthritis is covered in Chapter 18.

Systemic lupus erythematosus is a multisystem disorder of
unknown etiology, thought to affect approximately 1 in
1000 people. Females outnumber males in a ratio of 810:1.
Rare in childhood but not unheard of, onset is frequently
in the young adult years. Manifestations of the disease are
protean, and can be mild through to lethal (Box 17-10).
Pathophysiology
Systemic lupus erythematosus results from the formation
of pathogenic autoantibodies. Much of the tissue damage is
thought to result from:
the formation of immune complexes, subsequent
immune complex deposition, and initiation of inflammation via complement and Fc-receptor activation
direct antibody-directed cellular cytotoxicity

thrombus formation with resultant tissue ischemia.
Immunological abnormalities which have been demonstrated in SLE include:
abnormalities in T cell number and function
increase in the number and activity of B cells, including
autoreactive B cells
reduced number and function of natural killer cells
high levels of circulating immune complexes, and
decreased clearance by the reticuloendothelial system
abnormal cytokine profiles.
Known risk factors aside from gender include:
Inherited complement component deficiencies (C1q,
C2, C4). Complement deficiency results in reduced
Box 17-10
Clinical features of systemic lupus erythematosus (SLE)

Incidence of clinical manifestations in SLE (in
approximate descending order)
Arthralgia (or arthritis)
Fatigue
Cutaneousmalar rash (Figure 17-8), photosensitivity,
discoid lupus (Figure 17-9), alopecia, cutaneous
vasculitis, subacute sclerosing lesions
Myalgia (or uncommonly myositis)
Renalrecurrent urinary tract infection,
glomerulonephritis
Hematologicalnormocytic anemia, hemolysis,

lymphopenia, thrombocytopenia
Serositispericarditis, pleuritis
Raynauds phenomenon
Oral ulceration
Neuropsychiatriccerebritis, cerebral vasculitis,
peripheral neuropathy, psychosis, seizures
Gastrointestinalhepatitis, intestinal vasculitis
Anti-phospholipid-relatedrecurrent miscarriage,
thrombosis
Pulmonarypneumonitis, pleuritis
Cardiacpericarditis, non-infective endocarditis
Generalized lymphadenopathy
Figure 17-8 This picture displays the malar (or

buttery) rash typical of SLE. Note the sparing of
the nasolabial folds, which distinguishes it from
seborrheic dermatitis
Figure 17-9 A discoid lupus lesion on the face. Note

the predilection for the face, scaly appearance, and
lighter color in the center of the lesion, as is typical
in discoid lupus
From Wallace D and Hahn BH (eds). Dubois Lupus erythematosus

and related syndromes, 8th ed. Philadelphia: Elsevier, 2013.
From Tsokos C, Gordon C and Smolen JS (eds). Systemic lupus

erythematosus. St Louis: Elsevier, 2007.
523
ability to clear apoptotic cells, with consequent

increased exposure of cellular material on cell-surface
blebs to immunologically active cells, and the formation
of autoantibodies.
Family history. Monozygotic twins have an approximate 1 in 4 chance of disease concordance, with only
3% of dizygotic twins affected.
Certain HLA alleles. HLA subtypes A1, B8, DR2, and
DR3 show an increased frequency in SLE patients.
Certain drugs. Drug-induced lupus is associated with
multiple medications, including procainamide, carbamazepine and isoniazid, and newer biological agents
such as infliximab and etanercept.
Race. SLE is more common in Southeast Asians and
African-Americans.
Flares in disease may be associated with situations in which
there is higher than normal cell damage or turnover, such
as after exposure to UV radiation, or infection, or during

pregnancy. The disease may manifest with exacerbations
and remissions, or pursue a relentless course.
Diagnosis
Diagnosis is based on:
the totality of clinical manifestations
autoimmune serology.
tissue diagnosis where possible and appropriate; histopathology is particularly important in the setting of
renal disease (see Chapter 10), and with skin disease
where the diagnosis is not clear.
Criteria have been developed in an attempt to increase the
precision of diagnosis, and are important when attempting
to standardize patient populations for research and treatment
protocols. Those given in Box 17-11 are from the Systemic
Lupus International Collaborating Clinics (2012).
Box 17-11
SLICC classication criteria for systemic lupus erythematosus (SLE)

Requirements: v4 criteria (at least 1 clinical and 1 laboratory criterion) or biopsy-proven lupus nephritis with positive ANA or
anti-DNA. *See notes for criteria details.
Clinical criteria
1 Acute cutaneous lupus*
Immunological criteria
1 ANA
2 Chronic cutaneous lupus*
2 Anti-DNA
3 Oral or nasal ulcers*
3 Anti-Smith antibodies
4 Non-scarring alopecia
4 Antiphospholid antibodies
5 Arthritis*
5 Low complement (C3, C4, CH50)
6 Serositis*
6 Direct Coombs test (do not count in the presence of

hemolytic anemia)
7 Renal*
8 Neurological*
9 Hemolytic anemia
10 Leukopenia*
11 Thrombocytopenia (<100,000/mm3)
Notes
CLINICAL CRITERIA
1. Acute cutaneous lupus OR subacute cutaneous lupus
Acute cutaneous lupus: lupus malar rash (do not count if malar
discoid), bullous lupus, toxic epidermal necrolysis variant of
SLE, maculopapular lupus rash, photosensitive lupus rash (in
the absence of dermatomyositis)
Subacute cutaneous lupus: nonindurated psoriaform and/
or annular polycyclic lesions that resolve without scarring,
although occasionally with postinammatory dyspigmentation
or telangiectasias)
2. Chronic cutaneous lupus
Classic discoid rash localized (above the neck) or generalized
(above and below the neck), hypertrophic (verrucous)
lupus, lupus panniculitis (profundus), mucosal lupus, lupus
erythematosus tumidus, chillblains lupus, discoid lupus/lichen
planus overlap
524
3. Oral ulcers OR nasal ulcers

Oral: palate, buccal, tongue
Nasal ulcers
In the absence of other causes, such as vasculitis, Behets
disease, infection (herpesvirus), inammatory bowel disease,
reactive arthritis, and acidic foods
4. Non-scarring alopecia
Diffuse thinning or hair fragility with visible broken hairs, in the
absence of other causes such as alopecia areata, drugs, iron
deciency, and androgenic alopecia
5. Synovitis involving 2 or more joints
Characterized by swelling or effusion
OR tenderness in 2 or more joints and at least 30 minutes of
morning stiffness
6. Serositis
Typical pleurisy for more than 1 day OR pleural effusions OR
pleural rub
Typical pericardial pain (pain with recumbency improved by
sitting forward) for more than 1 day OR pericardial effusion OR
pericardial rub OR pericarditis by electrocardiography
In the absence of other causes, such as infection, uremia and
Dresslers pericarditis
7. Renal
Urine protein-to-creatinine ratio (or 24-hour urine protein)
representing 500 mg protein/24 hours OR red blood cell casts
8. Neurological
Seizures, psychosis, mononeuritis multiplex (in the absence
of other known causes such as primary vasculitis), myelitis,
peripheral or cranial neuropathy (in the absence of other
known causes such as primary vasculitis, infection and diabetes
mellitus), acute confusional state (in the absence of other
causes, including toxic/metabolic, uremia, drugs)
9. Hemolytic anemia
10. Leukopenia (<4000/mm3) OR lymphopenia (<1000/mm3)
Leukopenia at least once in the absence of other known causes
such as Feltys syndrome, drugs, and portal hypertension
Lymphopenia at least once in the absence of other known

causes such as corticosteroids, drugs, and infection
11. Thrombocytopenia (<100,000/mm3)
At least once in the absence of other known causes such as
drugs, portal hypertension, and thrombotic thrombocytopenic
purpura
IMMUNOLOGICAL CRITERIA
1. ANA level above laboratory reference range
2. Anti-dsDNA antibody level above laboratory reference range (or
2-fold the reference range if tested by ELISA)
3. Anti-Sm: presence of antibody to Sm nuclear antigen
4. Antiphospholipid antibody positivity, as determined by
Positive test for lupus anticoagulant
False-positive test result for rapid plasma reagin
Medium- or high-titer anti-cardiolipin antibody level (IgA, IgG or
IgM)
Positive test result for anti-beta-2 glycoprotein 1 (IgA, IgG or
IgM)
5. Low complement (C3,C4 orCH50)
6. Direct Coombs test (in the absence of hemolytic anemia)
ANA, antinuclear antibodies; anti-dsDNA, anti-double stranded DNA; anti-Sm, anti-Smith antibody; DNA, deoxyribonucleic acid; dsDNA,
double-stranded DNA; Ig, immunoglobulin; SLICC, Systemic Lupus International Collaborating Clinics Collaboration.
From Petri M et al. Derivation and validation of Systemic Lupus International Collaborating Clinics classication criteria for systemic lupus
erythematosus. Arthritis Rheum 2012;64(8):267786.
CLINICAL PEARL
Patients with non-specic symptoms such as fatigue
and arthralgia are often labeled as having a mild case of
lupus. They may be an adult female with a detectable
low-titer antinuclear antibody in the absence of any
objective clinical signs or specic laboratory abnormalities. Such spurious diagnostic labeling can have a
profoundly negative long-term effect on an individual,
with resultant unnecessary investigation and excessive
specialist consultation. Potentially, iatrogenic harm will
result from inappropriate use of toxic therapies. Always
consider non-immunological physical or psychological causes when faced with this type of scenario.
Autoantibodies in SLE
Demonstration of the presence of autoantibodies helps significantly with diagnosis and classification of systemic autoimmune disease. However, clinical features remain the gold
standard for diagnosis, as:
a significant minority of the population will have detectable autoantibodies in the absence of any autoimmune
disease
up to 20% of asymptomatic relatives of SLE patients will
have detectable antinuclear antibodies (ANA)
the presence of low-titer ANA increases with age, especially in women.
Conversely, SLE is very rare in the absence of ANA, so caution must be exercised when diagnosing ANA-negative
lupus.
Table 17-7 (overleaf) describes autoantibodies found in

SLE.
Neonatal lupus
Neonatal lupus results from the passage of IgG anti-SSA
(Ro) antibodies from mothers with SLE or Sjgrens
syndrome to the fetus via the placenta.
Clinical features in the newborn include complete heart
block, which is frequently irreversible and may be associated with congestive heart failure if the heart block
develops sufficiently early before delivery; skin rash; and
hematological abnormalities including hemolytic anemia and thrombocytopenia.
Severity of maternal illness does not correlate with the
risk of development of neonatal lupus, but the risk is
significant if previous pregnancies were affected.
All but the cardiac lesions resolve by 3 months of age
(commensurate with the half-life of maternal IgG).
Monitoring of disease activity

Clinical history and physical examination will provide
the most accurate gauge of disease activity, but laboratory
investigations are a useful supplement. A patient with active
inflammatory disease will characteristically demonstrate evidence of an acute-phase response and active consumption of
complement.
A disease flare may be accompanied by:
a rising titer of anti-ds-DNA antibodies
an elevated erythrocyte sedimentation rate (ESR)
525
Table 17-7 Autoantibodies found in systemic lupus erythematosus (SLE)
AUTOANTIBODY
SENSITIVITY
COMMENT
Antinuclear antibodies (ANA)
>95%
More specic with increasing titer

Titers <1:320 not considered signicant in most laboratories
Homogeneous pattern more specic for SLE
No relationship with disease activity
Double-stranded DNA (dsDNA)
~50%
Good specicity for SLE, which increases with higher titer

Titer may reect disease activity
Risk factor for renal disease
SS-A (Ro)
3050%
Also found in Sjgrens syndrome

Associated with subacute cutaneous disease
2% of babies born to SS-A-positive mothers develop congenital
heart block
SS-B (La)
10%
More sensitive and specic for SS
Anti-Sm (Smith)
2030%
Highly specic for SLE
Anti-histone
High for drug-induced

lupus
Not found in association with anti-TNF-therapy-associated

drug-induced lupus (iniximab, etanercept)
Anti-cardiolipin antibodies
(including lupus inhibitor)
25%
May be associated with anti-phospholipid syndrome, or

asymptomatic
TNF, tumor necrosis factor.
normochromic, normocytic anemia

active urinary sediment
reduced levels of complement components C3 and C4,
and total hemolytic complement.
CLINICAL PEARL
C-reactive protein (CRP) is often not elevated in the
setting of systemic lupus erythematosus. A rise in CRP
in a lupus patient with a previously normal CRP should
raise the prospect of concurrent infection.
Treatment and prognosis

In general terms, treatment for SLE is symptomatic for
manifestations that are non-organ- or non-life-threatening,
but immunosuppressive for the more serious complications.
Non-steroidal anti-inflammatory drugs (NSAIDs) may
be helpful for arthralgia and myalgia, and sometimes for
pericarditis.
Hydroxychloroquine has important disease-modifying
actions, and should be considered for use in most cases
of SLE in a dose of 200400 mg daily.
Corticosteroids are used widely in this condition, both
for their anti-inflammatory and their immunosuppressive actions. Low-dose therapy may help with cutaneous and articular disease. Higher doses will be required,
often as initial, urgent therapy, for manifestations such as
nephritis, neuropsychiatric disease or severe cytopenias.
Intravenous (IV) high-dose methylprednisolone is the
most rapidly-acting immunosuppressive agent available,
526
but does carry the risk of causing avascular osteonecrosis, particularly of the femoral head.
For severe forms of lupus nephritis and for neuropsychiatric disease, or severe cases of lupus affecting other
organs (e.g. pneumonitis), cyclophosphamide has been
the mainstay of treatment. This alkylating agent is usually used as pulsed IV therapy in this setting. Newer regimens use lower doses on a fortnightly basis.
The search continues for less-toxic, equally efficacious
therapies.
Mycophenolate has been demonstrated to be a viable
alternative in some clinical situations, including for
most forms of renal disease.
Biological agents such as rituximab, and anti-TNF
(tumor necrosis factor) monoclonal antibodies, are only
supported by anecdotal evidence at this stage. There
is preliminary evidence that a monoclonal antibody
against BAFF (B-cell activating factor of the TNF family), a TNF-like molecule that, amongst other things,
activates B cells, has some benefit in SLE.
Table 17-8 summarizes the mechanism of action and major
toxicities of drugs used to treat SLE. Given the chronic
nature of SLE, much of the long-term morbidity is due
to the effects of treatment, particularly corticosteroids.
Table 17-9 (overleaf) provides a guide that may be useful
in systematic monitoring of patients on long-term steroids
and/or immunosuppressants.
Patients with SLE have a 5-year survival rate of >90%.
Given the heterogeneity of the condition, prognostication is
difficult, and clearly is worse in those with significant renal,
neurological or pulmonary disease. The major long-term
Table 17-8 Mechanism of action and major toxicities of drugs commonly used to treat SLE
DRUG
MECHANISM OF ACTION
MAJOR TOXICITIES
Hydroxychloroquine
Possible action via reduction of IL-1 production,

inhibition of neutrophil chemotaxis, decreased
production of toxic oxygen metabolites from
phagocytes
Retinal toxicity
Prednisolone
Inhibits leukocyte migration

Reduces cytokine production
Suppresses antibody production
Weight gain, osteoporosis, glucose

intolerance/diabetes mellitus, hypertension,
Cushings syndrome, poor wound
healing, avascular osteonecrosis,
immunosuppression
Azathioprine
Inhibits DNA synthesis in dividing cells, therefore is

cytotoxic to lymphocytes
Blocks CD28 co-stimulation, so prevents activation
of nave lymphocytes
Hepatitis, GI intolerance, myelosuppression,

skin malignancy, immunosuppression
Methotrexate
Inhibits enzyme dihydrofolate reductase, which

leads to impairment of thymidylate synthesis, and
impairment of DNA synthesis
The anti-inammatory effect results from the
impairment of leukocyte function
GI tract disturbance, mucositis,

myelosuppression, hepatic brosis,
pulmonary brosis, immunosuppression
Cyclosporine
(ciclosporin)
Inhibits production of IL-2 by T lymphocytes, thus

reducing induction of cytotoxic T cells and T-celldependent B cell responses
Renal impairment, hypertension, glucose

intolerance, gum hypertrophy, hirsutism,
immunosuppression, skin malignancy
Cyclophosphamide
Alkylating agent which cross-links DNA

Has a pronounced effect on reducing the function
of lymphocytes
Myelosuppression, especially neutropenia,

hemorrhagic cystitis, nausea and
vomiting, bladder cancer, skin malignancy,
immunosuppression, pulmonary brosis
Mycophenolate
Inhibits purine synthesis, resulting in reduced

guanine nucleotides especially in lymphocytes,
resulting in reduced function
GI tract disturbance, anemia,

immunosuppression
GI, gastrointestinal; IL, interleukin; SLE, systemic lupus erythematosus.
risk to health is likely to be due to medication toxicity,

through increased risk of:
malignancy
infection
metabolic disease.
There is some evidence that SLE is an independent risk factor for atherosclerotic vascular disease, presumably due to
the atherogenic consequences of chronic inflammation.

Primary Sjgrens syndrome is a chronic, relentless, systemic
autoimmune disease characterized by autoimmune destruction of exocrine glands, and sometimes accompanied by vasculitis. The classic clinical features of SS are:
dry eyes due to keratoconjunctivitis sicca, secondary to
destruction of the lacrimal glands
dry mouth (xerostomia), due to destruction of the
salivary glands.
The disease is generally not life-threatening, but serious
complications such as nephritis and pneumonitis can occur
It should be kept in mind that patients have a significantly increased risk of lymphoma.
When xerophthalmia or xerostomia occurs in association with other systemic autoimmune disease, such as
rheumatoid arthritis or SLE, this is known as secondary
Sjgrens syndrome.
Pathophysiology
The etiology of SS is unknown.
It is predominantly a disease of middle-aged women.
It is likely that by the time of diagnosis, most of the damage to the exocrine glands has been done. This explains
the lack of efficacy of immunosuppressive medication
in this condition, which is generally contraindicated
except when vasculitis occurs.
Histopathology reveals intense lymphocytic infiltration
of involved structures in SS.
The tissue damage is likely a result of type IV (cellmediated) immune hypersensitivity.
The autoantigen is unknown.
527
Table 17-9 Monitoring of patients on long-term immunosuppressants
DRUG
EVERY 3 MONTHS
EVERY 6 MONTHS
ANNUALLY
Corticosteroids
Blood sugar levels

Blood pressure monitoring
Lipid monitoring
Bone densitometry
Cyclophosphamide
Full blood count (more frequently

depending on protocol being
used)
Urinalysis, for
hematuria; cystoscopy
if positive
Skin examination (for pre-malignant

and malignant change)
Papanicolaou (Pap) tests (females)
Azathioprine

Full blood count

Pap tests (females)
Methotrexate

Full blood count (more frequently
in initiation of treatment phase)
Clinical screening for cough
or dyspnea (risk of pulmonary
brosis)

Pap tests (females)
Cyclosporine
(ciclosporin)
Blood sugar levels

Blood pressure monitoring
Renal function and electrolytes
Oral examination (for gum
hypertrophy)
Mycophenolate
Full blood count
Lipid monitoring

Pap tests (females)
Biannual renal DTPA scans
Pap tests (females)
DTPA, diethylene triamine pentaacetic acid.
Table 17-10 Major clinical manifestations of Sjgrens syndrome
MANIFESTATION
CAUSE
Keratoconjunctivitis sicca
Destruction of lacrimal glands
Xerostomia
Destruction of salivary glands
Dry skin
Destruction of sebaceous glands
Dry cough
Due to lack of respiratory tract mucous
Dental caries/gingivitis/periodontitis
Due to lack of saliva
Parotitis
May have recurrent painful episodes, or chronic inammation with gradual

parotidomegaly
Be aware of possibility of malignant transformation
Pancreatitis
Rare
Pneumonitis
May lead to shrinking lung syndrome
Cerebral vasculitis
Likely to result in focal neurological signs, or organic brain syndrome
Interstitial nephritis
Renal tubular acidosis a likely outcome. Can progress to renal failure
Glomerulonephritis
May progress to end-stage renal disease
Cutaneous vasculitis
Often affects lower limbs, and tends to be recurrent
Fatigue
Lymphoma
528
Most often in parotid glands
Diagnosis
The diagnosis is primarily clinical, but is supported by serological testing. In rare cases, tissue biopsy is required.
The classic autoimmune serology found in SS consists of:
high-titer antinuclear antibody (ANA) in speckled
pattern.
positive SS-A and SS-B (Ro and La) antibodies
positive rheumatoid factor.
It is typical to find:
significant polyclonal hypergammaglobulinemia
markedly elevated erythrocyte sedimentation rate (ESR).
The Schirmers test can be used to document reduction in
tear production, and rose bengal staining of the ocular surface will demonstrate keratoconjunctivitis sicca.
It is advisable for the physician to involve an ophthalmologist in the long-term care of the SS patient.
Treatment
Treatment is largely symptomatic.
Lubricant eyedrops such as methylcellulose are important both for comfort and to prevent scarring of the eye
surface. They should be applied every couple of hours
during the day.
Lubricant ocular gel can be applied prior to bed.
CLINICAL PEARL
Cyclosporine (ciclosporin) eyedrops can be quite successful at restoring some tear production and reducing
the severity of keratoconjunctivitis sicca, which is interesting given the lack of efficacy of systemic immunosuppression in SS.
Dry mouth is difficult to treat.

Patients may benefit from using an atomizer to spray
water into the mouth if frequent water-sipping
causes polyuria.
Pilocarpine mouth washes may help stimulate residual salivary gland function.
Regular dental care is essential to attempt to avoid
progressive tooth damage.
Patients should be regularly monitored for development of
complications such as interstitial nephritis or glomerulonephritis, although unfortunately immunosuppression is frequently ineffective at altering disease course. Lymphoma
needs to be kept in mind as a long-term risk.
elevated creatine kinase in the vast majority of cases

characteristic electromyographic changes of fibrillations
and positive sharp waves.
These diseases are approximately twice as common in
women as men. The etiology is unknown, although there
are associations with certain HLA alleles. Onset is more
common in middle age, but can occur in childhood.
CLINICAL PEARL
There is a subgroup of patients in whom the inammatory myopathies are a paraneoplastic syndrome,
thought to be approximately 20% of all cases.
Polymyositis (PM)
Polymyositis is a rare autoimmune inflammatory disease of
muscle.
The target antigens are skeletal muscle intracellular
proteins.
The process is predominantly B-cell driven.
The anti-synthetase syndrome occurs in a subset of
about 30% of PM patients. In most cases this is associated with the anti-Jo-1 antibody, although other
anti-synthetase antibodies have been described. These
patients have interstitial lung disease, non-erosive
arthritis, and a characteristic hyperkeratotic dermatosis
known as mechanics hands (Figure 17-10). Raynauds
phenomenon may be prominent, and fever may occur.
Dermatomyositis (DM)
Clinical presentation in DM is similar to PM, but is
accompanied by characteristic skin changes as outlined in
Table 17-11 (overleaf). Histopathological and immunopathological studies reveal subtle differences in the muscle
of biopsies taken from these patients, suggesting that the
conditions are part of a disease spectrum.
The autoimmune inflammatory myopathies, polymyositis
and dermatomyositis, present with:
progressive symmetrical, usually proximal, weakness of
skeletal muscle
muscle aching or pain, although this is variable
cutaneous changes in the case of dermatomyositis
Figure 17-10 The hyperkeratosis and ssuring known

as mechanics hands
529
Table 17-11 Polymyositis versus dermatomyositis
POLYMYOSITIS
DERMATOMYOSITIS
No skin
involvement, other
than mechanics
hands in the
anti-synthetase
syndrome
Pathognomonic cutaneous signs:

Violaceous (heliotrope) rash
on and around top eyelids
(Figure 17-11)
Gottrons nodules/papules over
extensor surfaces of hands
(Figure 17-12)
Non-pathognomonic cutaneous
signs:
Facial erythema
Poikiloderma (Figure 17-13)
Progressive
symmetrical muscle
pain and weakness
Progressive symmetrical muscle

pain and weakness
Muscle biopsy
shows perifascicular
muscle atrophy
and regeneration;
inltration with
CD4+ T cells
Muscle biopsy shows muscle ber

inltration by cytotoxic (CD8+)
T cells, and macrophages
Anti-synthetase
antibodies more
common
Anti-synthetase antibodies
uncommon
Increased risk of
malignancy, but
less so than in
dermatomysitis
Signicantly increased risk of

malignancy compared with
general population
Figure 17-12 Gottrons papules overlying the

metacarpophalangeal, proximal interphalangeal, and
distal interphalangeal joints
From Paller AS and Mancini AJ. Hurwitz Clinical paediatric
dermatology, 4th ed. Philadelphia: Elsevier, 2011.
Figure 17-11 Heliotrope rash around the eyes in a

patient with dermatomyositis
From Paller AS and Mancini AJ. Hurwitz Clinical paediatric
dermatology, 4th ed. Philadelphia: Elsevier, 2011.
Figure 17-13 Poikiloderma, as may be found in

dermatomyositis. Note the combination of
hyper- and hypo-pigmentation, and erythema
From Bolognia JL et al. Dermatology, 2nd ed. St Louis: Elsevier, 2008.
Diagnosis
The diagnosis can be established to a satisfactory degree of
certainty with the combination of:
clinical features
elevated creatine kinase levels
characteristic electromyographic features
positive autoimmune serology in the form of antisynthetase antibodies and/or ANA. Unfortunately,
autoantibodies lack sensitivity in this situation
rheumatoid factor positivity in approximately 50% of
patients
muscle biopsy. This will also help distinguish other
myopathies such as inclusion-body myositis.
530
Treatment
Corticosteroids are the mainstay of treatment and are
generally effective, but often at unacceptably high doses
with excessive toxicity.
High-dose IV immunoglobulin is a treatment for which
there is an evidence base. It does not result in immunosuppression, so is highly desirable if effective.
Cyclosporine (ciclosporin), azathioprine and mycophenolate as steroid-sparing agents are supported by anecdotal evidence only, but will frequently be required.
Newer biological agents such as rituximab show great
promise in limited case series.
Box 17-12
CLINICAL PEARL
Steroid-sparing immunosuppressive agents will frequently be required in the setting of systemic autoimmune disease, given that these diseases are chronic and
often life-threatening. The rarity, and heterogeneity, of
systemic autoimmune disease makes evidence-based
treatment guidelines impossible for many clinical scenarios, unlike in common diseases such as hypertension or ischemic heart disease. The skill in managing
systemic autoimmune disease lies therefore in striking
a balance between the issues of efficacy, short- and
long-term toxicity, patient adherence to treatment,
drug cost and availability, and individual patient factors.
For example, a young female with dermatomyositis
who has become Cushingoid with doses of prednisolone high enough to control the disease may be best
started on azathioprine rather than cyclosporine (ciclosporin) or mycophenolate, because:
there is concern that she may not be fully adherent
with contraception as she has expressed a desire
to have a baby before too long (mycophenolate is
highly teratogenic, azathioprine is better established
as safer in pregnancy than cyclosporine)
her blood pressure is 125/85 mmHg (cyclosporine is
likely to make this worse)
there is a strong family history of type 2 diabetes
mellitus (cyclosporine predisposes to glucose intolerance).
An important role for the treating physician when caring
for patients with systemic autoimmune disease will be
to advocate to funding and approval bodies on behalf
of their patients to obtain access to expensive therapy.
Skin changes in scleroderma
Thickening and edema of digits (sclerodactyly)

(Figure 17-14)
Prominent telangiectasia, especially on digits and face
Skin tightening on face, resulting in reduction in oral
aperture, and beaking of nose
Calcinotic nodules and/or ulcers, especially on digits
Pulp atrophy of digits
Thickening and edema of skin on trunk
Figure 17-14 The typical swollen and shiny

appearance of hands due to sclerodactyly. Note
also the xed exion position of the ngers
From Marks JG and Miller JJ. Lookingbill & Marks Principles
of dermatology, 4th ed. Philadelphia: Elsevier, 2006.
Box 17-13

Otherwise known as diffuse and limited systemic sclerosis,
this is a disease spectrum involving autoimmune inflammation with vascular involvement and connective tissue scarring in the skin and multiple other organs. It is thought to
have an incidence of around 1 in 10,000.
Clinical manifestations
Diffuse scleroderma nearly always involves the skin both
below and above the elbows and knees, including the
face and trunk (Box 17-12), and will variably involve
pulmonary, gastrointestinal, renal and cardiac systems
(Box 17-13).
In limited scleroderma, skin involvement is usually
confined to the distal limbs, although facial changes
can occur. The label CREST syndrome is often given,
due to the prominence of Calcinosis, Raynauds phenomenon, Esophageal dysfunction, Sclerodactyly and
Telangiectases.
CREST patients will often have digital ulcers, and are at
risk of pulmonary arterial hypertension.
Nail-fold capillaroscopy will reveal abnormalities in
most patients with both limited and diffuse disease.
Changes include reduction in numbers of capillaries,
with those remaining forming giant loops.
Organ involvement in scleroderma

Pulmonary
Interstitial brosis
Pulmonary arterial hypertension
Pleural effusion
Gastrointestinal
Reux esophagitis
Dysphagia due to strictures
Intestinal brosis leading to dysmotility and absorptive
abnormalities
Renal
Accelerated hypertension
Rapidly progressive renal failure due to renal
vasculopathy
Cardiac
Pericarditis
Myocarditis
Cardiac failure
Raynauds phenomenon is often an early manifestation,

occurs almost invariably, and reflects the vascular abnormality with propensity to vasospasm. This contributes
to digital ulceration in around half of cases, and can be
further complicated by digital gangrene, infection with
osteomyelitis, and autoamputation.
Digital ulceration is extremely painful, and disabling.
531
The etiology of scleroderma is not known and the pathogenesis is complex, with abnormalities demonstrable in the
function of endothelium, epithelium, fibroblasts and lymphocytes. The end result is accumulation of abnormal and
excessive extracellular matrix, which gradually fibroses and
causes tissue dysfunction. A variety of autoantibodies are
detectable in this condition, the pattern of which can be
helpful in distinguishing subtypes.
Diagnosis
The diagnosis of scleroderma is made on clinical
grounds, with the appearance of the hands being of
greatest utility.
Tissue biopsy is rarely indicated.
Autoantibodies are detectable in the majority of cases,
with a nucleolar-pattern ANA present in 7090% of
cases.
Anti-centromere antibodies have sensitivity of >50% for
limited scleroderma, with a small percentage of patients
with diffuse disease also positive.
The opposite is true for the anti-Scl-70 antibody, whose
target is DNA topoisomerase 1.
Pulmonary fibrosis can be detected on high-resolution
CT scanning and with pulmonary function tests
(PFTs).
PFTs are the most useful tool for monitoring the
progression of lung disease, along with the 6-minute
walk test.
Echocardiography is generally used for screening for
pulmonary arterial hypertension.
Endoscopy will detect the presence of esophagitis.
Differential diagnosis of skin findings is outlined in
Box17-14.
CLINICAL PEARL
Despite popular concern about the safety of silicone
breast implants, there is no epidemiological evidence
to support a link between silicone prostheses and
scleroderma.
Treatment
Lung disease, and particularly pulmonary fibrosis, is the
major cause of mortality in scleroderma.
Interstitial lung disease is the only indication for
immunosuppression in the form of high-dose corticosteroids and other agents such as cyclophosphamide, but results are disappointing.
Early detection of pulmonary arterial hypertension in
scleroderma patients is critical, with evidence that commencement of endothelin-receptor antagonists such as
bosentan, and possibly phosphodiesterase-5 inhibitors
such as sildenafil, can delay progression and improve
prognosis.
Autologous human stem-cell transplantation should be
considered in a patient with progressive skin and/or lung
disease in the presence of normal cardiac function.
532
Box 17-14
Differential diagnosis of thickened

and tethered skin
CREST syndrome, scleroderma, or mixed connective

tissue disease
Eosinophilic fasciitis
Localized morpheasmall areas of sclerosis
Chemicalsvinyl chloride, pentazocine, bleomycin,
toxic oil syndrome
Pseudosclerodermasecondary to porphyria cutanea
tarda, acromegaly, carcinoid syndrome
Scleredemadiabetics develop thick skin over the
shoulders and upper back
Graft-versus-host disease
Silicosis
Scleroderma renal crisis is uncommon, at around 5%

of cases. It is characterized by marked hyper-reninemia,
so early detection of hypertension and institution of
angiotensin-converting enzyme inhibitor (ACEI) therapy is vital.
Raynauds phenomenon and digital ulceration may be
improved with the use of calcium-channel antagonists
such as felodipine or nifedipine, via vasodilatation.
Acute digit- or limb-threatening ischemia can be treated
with IV prostacyclin.
Patients with scleroderma frequently face great challenges
with activities of daily living, chronic pain, and depression.
Treatment aimed at providing physical and psychological
support, and palliative care when appropriate, needs to be
part of the overall approach to management.
Mixed connective tissue disease

(MCTD)
This rare condition is characterized by features of SLE, polymyositis, scleroderma and rheumatoid arthritis, in the presence of autoantibodies against ribonucleoprotein (RNP).
The RNP antigen is actually a complex of polypeptides, a
number of which can act as the epitope. The ANA is usually
markedly elevated in a speckled pattern.
Patients present with a variety of symptoms. Common
symptoms are:
Raynauds phenomenon
sclerodactyly
hand swelling
esophageal reflux
myositis.
Less common symptoms are:
pulmonary arterial hypertension
glomerulonephritis
Sjgrens syndrome
skin changes
hematological abnormalities.
MCTD is more common in women. It can occur, rarely, in

childhood.
Treatment is dictated by the nature of the organ involvement in the individual patient, along the lines that would be
used for the separate disease entities.

Antiphospholipid syndrome is characterized by:
recurrent fetal loss, and/or
recurrent venous or arterial thrombosis (Box17-15).
For diagnosis, persistent antibodies (>12 weeks) against
phospholipid must be detectable in the form of:
anti-cardiolipin antibodies
anti G2-Glycoprotein1 antibodies, or
lupus inhibitor.
APS occurs frequently in patients with SLE, with
2550% demonstrating autoantibodies but an estimated 1015% developing the clinical syndrome.
Conversely, only 510% of individuals with APS also
have lupus.
The etiology of the condition is unknown, but APS is
more common in females.
A rapidly progressive form of the disease in which multiple organs are affected by infarction, including the liver
and kidneys, resulting in multi-organ failure, is known
as catastrophic APS.
The antiphospholipid antibodies bind to phospholipids
or phospholipid-binding proteins on cell surfaces. This
triggers thrombus formation within vessels, via a number of mechanisms.
Binding of phospholipid on platelet surfaces activates platelets, and activated platelets stimulate the
increased expression of adhesion molecules as well
as inflammatory and prothrombotic cytokines.
Phospholipid-binding proteins are anticoagulants,
so binding of these by antibody results in inhibition
of their function, and favors thrombosis.
Box 17-15
Clinical manifestations of APS
Venous thrombosis
Arterial thrombosis
Pre-term birth due to eclampsia or preeclampsia
(prior to 34 weeks of gestation, fetus normal); or
Fetal death beyond 10 weeks of gestation; or
3 or more consecutive spontaneous abortions at
<10 weeks of gestation
Thrombocytopenia
Livedo reticularis
Hemolysis
Stroke
Neurological diseasechorea; migraine
Possible pulmonary hypertension
Possible renal artery stenosis
Laboratory considerations
It should be noted that the presence of antiphospholipid
antibodies in a serum sample interferes with the activated
partial thromboplastin time (APTT) in the laboratory,
leading to prolongation. This, paradoxically, gives an in
vitro elevated APTT in the setting of an invivo propensity to thrombosis. It also renders the APTT essentially
invalid for use to monitor therapy with unfractionated
heparin. The prolonged APTT will not be correctable with mixing with normal serum in the laboratory,
demonstrating the presence of an inhibitor.
Demonstration of lupus inhibitor confers an adverse
prognosis to the patient, with increased likelihood of
both fetal loss and thrombosis.
Most laboratories measure both IgG and IgM anticardiolipin antibodies, but the IgG form is more predictive of development of the clinical syndrome.
Thrombocytopenia is found in up to 25% of cases.
Treatment
Lifelong anticoagulation is usually required for patients
with thrombotic complications of APS, with warfarin
the first choice of drug.
Treatment of pregnant patients with APS is dealt with in
Chapter 26.
There are no clear evidence-based guidelines for the
patient who is found to have antiphospholipid antibodies but is asymptomatic. Use of long-term anti-platelet
therapy needs to be balanced against the increased risk
of intracerebral hemorrhage in this situation.
It has recently been recognized that a cluster of rare conditions, characterized pathologically by fibroinflammatory
changes in organs, occurs in the context of IgG4 plasma cell
infiltration of the affected organs, and elevated serum IgG4
in most cases.
Conditions now recognized to form part of this spectrum include:
autoimmune pancreatitis
Mikuliczs syndrome
retroperitoneal fibrosis
Riedels thyroiditis
Kuttners tumor
periaortitis and periarteritis
mediastinal fibrosis
inflammatory pseudotumor
eosinophilic angiocentric fibrosis
multifocal fibrosclerosis
inflammatory aortic aneurysm
idiopathic hypocomplementemic tubulointerstitial
nephritis with extensive tubulointerstitial deposits.
Organs known to be potentially involved in this process
include the pancreas, periorbits, biliary tract, thyroid,
salivary glands, retroperitoneum, lung, breast, skin,
meninges, pericardium, prostate, aorta, lymph nodes,
kidneys, and mediastinum.
533
The etiology of this condition is unknown, but is presumed to be autoimmune. It is more common in elderly
males.
Tissue biopsy is required to make the diagnosis. At
times, tissue can be replaced by tumefactive masses,
making IgG4-related disease a differential diagnosis for
malignancy.
When recognized, the patient should be screened for
potential disease in other target organs.
Treatment requires immunosuppression.
Corticosteroids are the mainstay of initial treatment.
Second-line agents such as azathioprine are often
required for steroid-sparing effect.
PRIMARY VASCULITIS
Vasculitis can be a localized problem, or part of a systemic process.
Vasculitic disease may be primary, or occur as part of a
systemic disorder such as SLE or rheumatoid arthritis.
Systemic vasculitic illnesses are generally autoimmune in
basis and life-threatening, requiring aggressive immunosuppressive therapy.
The following section will focus on the primary systemic
vasculitides.
Classification of the vasculitides is confusing. Some
authors classify according to the size of the vessels involved,
while others recommend groupings based on association
with anti-neutrophil cytoplasmic antibodies (ANCAs).
Box 17-16 groups the illnesses taking both features into
account.
More recently, a revised, more comprehensive classification system has been recommended (Box 17-17).
This system will be used to discuss the diseases addressed
below.
Box 17-16
Classication of vasculitides
Large-vessel, non-ANCA-associated
Giant-cell arteritis/Polymyalgia rheumatica
Takayasu arteritis
Medium-vessel, non-ANCA-associated
Polyarteritis nodosa
Kawasaki disease
Small-vessel, ANCA-associated
Wegeners granulomatosis
ChurgStrauss vasculitis
Microscopic polyarteritis
Small-vessel, non-ANCA-associated
Leukocytoclastic vasculitis
Essential cryoglobulinemia (see Chapter 10)
HenochSchnlein purpura
534
Polymyalgia rheumatica (PMR)
Clinical characteristics
Polymyalgia rheumatica is a disease of unknown etiology, characterized by stiffness and aching in the limb
girdle, particularly in the mornings.
Incidence increases progressively in people over the
age of 50 years, and is more than twice as common in
females as males.
The pain centers around the shoulders in up to 95%
of patients, the neck and hips in the majority, and the
lower back in some.
PMR causes systemic symptoms in approximately half
of those affected, in the form of malaise and fatigue, and
can cause fevers and night sweats.
Peripheral arthritis can occur.
Pathophysiology
There is some evidence that the pathological lesion is a
low-grade synovitis, rich in CD4-positive T lymphocytes, and macrophages.
Vasculitis is not a feature, but PMR forms part of a
disease spectrum with giant-cell arteritis (GCA), with
approximately 20% of PMR patients developing GCA
and around 50% of GCA patients also suffering PMR.
Diagnosis
PMR is invariably accompanied by an acute phase
response, resulting in elevated ESR, CRP, and at times
abnormal liver function tests and a normocytic anemia,
although there are cases described with a normal ESR.
MRI or bone scanning may demonstrate synovitis in
proximal joints.
The diagnosis is clinical.
Treatment
Failure of symptoms to resolve with low-dose corticosteroids, usually with a starting dose of 15 mg/day,
should prompt reconsideration of the diagnosis.
Patients may need long-term treatment, or the disease
may eventually spontaneously remit.
Patients should be counseled to seek urgent review if
they develop symptoms suggestive of GCA, such as
headache or visual disturbance.
Giant-cell arteritis (GCA)

GCA is a life-threatening vasculitis involving large and
medium-sized muscular arteries, especially those of
theexternal carotid system. GCA typically involves the
temporal arterieshence its alternative, but less accurate, name temporal arteritis.
Patients are usually elderly.
Atherosclerosis, heavy smoking, and the HLA-DRB1
haplotype are risk factors.
Box 17-17
Names for vasculitides adopted by the 2012 International Chapel Hill Consensus
Conference on the Nomenclature of Vasculitides
Large-vessel vasculitis (LVV)
Takayasu arteritis (TAK)
Giant-cell arteritis (GCA)
Medium-vessel vasculitis (MVV)
Polyarteritis nodosa (PAN)
Kawasaki disease (KD)
Small-vessel vasculitis (SVV)
Anti-neutrophil cytoplasmic antibody (ANCA)associated
vasculitis (AAV)
Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (Wegeners) (GPA)
Eosinophilic granulomatosis with polyangiitis
(ChurgStrauss syndrome) (EGPA)
Immune complex SVV
Antiglomerular basement membrane (anti-GBM)
disease
Cryoglobulinemic vasculitis (CV)
IgA vasculitis (HenochSchnlein) (IgAV)
Hypocomplementemic urticarial vasculitis (HUV)
(anti-C1q vasculitis)
Single-organ vasculitis (SOV)

Cutaneous leukocytoclastic angiitis
Cutaneous arteritis
Primary central nervous system vasculitis
Isolated aortitis
Others
Vasculitis associated with systemic disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis associated with probable etiology
Hepatitis C virusassociated cryoglobulinemic vasculitis
Hepatitis B virusassociated vasculitis
Syphilis-associated aortitis
Drug-associated immune complex vasculitis
Drug-associated ANCA-associated vasculitis
Cancer-associated vasculitis
Others
Variable-vessel vasculitis (VVV)

Behets disease (BD)
Cogans syndrome (CS)
Jennette JC et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheumatism
2013;65(1):111.
Patients present with severe headache, scalp tenderness,

malaise, fevers, and weight loss.
Focal neurological symptoms can occur, depending on
pattern of vessel involvement.
Jaw claudication with chewing, and tongue claudication
are not pathognomonic, but have a high positive predictive value for this condition.
Aortic arch syndrome and neuropathy occur in a
minority.
Physical examination will usually reveal fever, and
marked tenderness over the scalp with thickened, tender
temporal arteries which may have lost their pulse.
Visual symptoms are a medical emergency, as they
indicate embolization or vasculitis of the ophthalmic
artery, which is a branch of the external carotid. Sudden
blindness may result.
Investigations
Laboratory investigations reveal markedly elevated ESR
and CRP, and often a normocytic anemia, thrombocytosis, and abnormalities on liver function tests.
Diagnosis is established by temporal artery biopsy

revealing granulomatous inflammation of the full thickness of the arterial wall, with infiltration by multinucleated giant cells, lymphocytes and fibroblasts. The intima
is often markedly hyperplastic, with stenosis and occlusion of the vessel. It is recommended that biopsies take
at least 1 cm of the length of the vessel, to avoid falsenegatives due to skip lesions, and are taken within
1week of the commencement of corticosteroids.
Imaging techniques of the temporal arteries such as with
ultrasound or MRI do not yet have a defined role.
Treatment
High-dose corticosteroids need to be administered
immediately upon suspicion of the diagnosis of GCA,
either orally (1 mg/kg/day of prednisolone) or intravenously (methylprednisolone 500 mg daily for 3 days
followed by high-dose oral prednisolone).
Once clinical and serological parameters return to normal, gradual dosage tapering can occur with careful
monitoring.
535
If unacceptably high doses of steroids are required for

disease control, a second immunosuppressive agent
such as cyclophosphamide or methotrexate may be
required.
There is insufficient evidence to support the use of biological agents such as infliximab at this stage.
Many patients will go into apparent long-term remission
after a period of immunosuppression, but approximately
50% of patients suffer a flare with steroid reduction.
Takayasu arteritis
Takayasu arteritis is a disease that almost exclusively affects
young females from East Asia.
It is a granulomatous vasculitis of the proximal aorta and
its major branches.
Fibroproliferative changes are found in the intima of the
affected vessels, resulting in variable stenosis, thrombosis, and aneurysmal dilatation
Clinical presentation is invariably with ischemia of the
affected region. It is often referred to as pulseless disease.
Patients may present with:
transient ischemic attacks
strokes
limb claudication
visceral ischemia
hypertension that can result from renal artery stenosis
constitutional symptoms of fever, malaise, and weight
loss (frequent)
serological evidence of an acute-phase response
absent peripheral pulses
vascular bruits
aortic regurgitation due to dilatation of the aortic root.
Imaging is a mainstay in the diagnosis of the disease. MRI
and CT angiography are safer, and of similar utility, to contrast angiography.
Treatment consists of:
Immunosuppression for the vasculitis.
Corticosteroids in high doses are used for initial remission induction.
Second agents such as methotrexate, cyclophosphamide or mycophenolate may be needed for remission
maintenance.
Surgical methods to restore blood flow in occluded vessels where possible.
Surgical approaches depend on the location and
severity of lesions, and range from percutaneous
angioplasty through to stenting and bypass.
Polyarteritis nodosa (PAN)
Polyarteritis nodosa is a rare vasculitis of unknown etiology affecting medium to small arteries. The disease has
a propensity for mesenteric, renal and coronary arteries.
536
Approximately 50% of sufferers will be hepatitis B

surface-antigen positive; it is important to identify
patients with active hepatitis B infection, as the treatment will differ despite the disease being identical.
PAN has also been associated with other infections such
as HIV and cytomegalovirus (CMV), with autoimmune
disease such as rheumatoid arthritis, and with malignancy
e.g. Hodgkins lymphoma and hairy-cell leukemia.
PAN is more common in men.
Most patients have marked constitutional symptoms of
fever, night sweats, weight loss, fatigue, and malaise. More
specific symptoms and signs (Box 17-18) will generally be
due to organ ischemia.
There is no specific diagnostic test for PAN, other than
demonstration of necrotizing vasculitis on tissue biopsy.
Testicular biopsy is relatively safe, and has quite high
sensitivity in patients with testicular symptoms.
Imaging may demonstrate irregularities of vessels such
as stenosis or aneurysm formation.
Treatment is with immunosuppression, generally commencing with high-dose corticosteroids and then with a
second agent such as cyclophosphamide.
Patients with hepatitis B should be treated with antiviral
medication.
Kawasaki disease
Kawasaki disease is a disease almost exclusively of childhood that commences with high fever and causes systemic vasculitis of medium-sized arteries.
The acute phase of the illness is characterized by high
fever which lasts for upward of a week. The more
prolonged the fever, the greater the risk of cardiac
complications.
Kawasaki disease is common in Japan and Korea, but
much less common elsewhere. The etiology is unknown.
Box 17-18
Clinical features in patients with

polyarteritis nodosa
Angina pectoris
Myocardial infarction
Mesenteric angina
Intestinal infarction
Mononeuritis multiplex
Stroke
Cutaneous vasculitis
Asymmetric polyarthritis
Testicular pain
Splenic infarction
Hypertension
Renal infarction
Box 17-19
Clinical manifestations of
Kawasaki disease
Common
Prolonged fever
Cervical
lymphadenopathy
Mucocutaneous
lesions: conjunctivitis,
diffuse maculopapular
rash, strawberry
tongue, inamed lips,
pharyngitis, edema of
the palms and soles,
desquamation of the
ngers
Less common
Arthralgia
Arthritis
Diarrhea
Myocarditis/pericarditis
Aseptic meningitis
Pneumonia
Hepatitis
The clinical abnormalities (Box 17-19) are due to vasculitis, and this is also responsible for the feared complication of aneurysmal dilatation of arteries, especially the
coronary arteries. This in turn can lead to rupture or
thrombosis of the vessel, leading to myocardial ischemia
or infarction. Aneurysm formation generally occurs
between 2 and 12 weeks of disease onset.
There is no specific diagnostic test for Kawasaki disease,
so clinical features are key.
A high index of suspicion is necessary, given the importance of instituting treatment promptly to lessen the risk
of aneurysm formation.
Most patients display an acute phase response.
High-dose IV immunoglobulin should be administered
as soon as the diagnosis is made. If fever does not resolve
promptly, a second dose should be given.
Aspirin also improves prognosis and is used in low doses
to reduce the risk of thrombosis.
CLINICAL PEARL
Aspirin is contraindicated in children because of the
risk of Reyes syndrome. Kawasaki disease is one of the
rare exceptions to this rule, as benet outweighs risk
in this case.
Granulomatosis with polyangiitis (GPA)/
Wegeners granulomatosis (WG)
Granulomatosis with polyangiitis is a systemic vasculitis
with a propensity to involve the respiratory system and
the kidneys.
It is one of the ANCA-associated vasculitides, with up
to 90% of sufferers ANCA-positive, especially those
with systemic rather than localized disease.
GPA can be a fulminant, life-threatening disease, and

lung involvement is frequently misdiagnosed as infection in the first instance, resulting in considerable peril
for the patient.
CLINICAL PEARL
Granulomatosis with polyangiitis should be a differential diagnosis in any patient with a pulmonaryrenal
syndrome, hemoptysis, or respiratory tract symptoms
that fail to respond to antibiotics. Delays in diagnosis
signicantly worsen both the pulmonary and the renal
prognosis.
Box 17-20 lists the clinical manifestations of GPA.

The majority of patients present with upper respiratory
tract symptoms of variable duration and severity, prior
to the development of systemic constitutional features
and those related to involvement of various organs.
Cavitating lung lesions are typical, with or without
interstitial changes.
The renal lesion is a pauci-immune, focal necrotizing
glomerulonephritis.
Development of renal failure can be rapid.
Diagnosis
The detection of a c-ANCA (cytoplasmic pattern
ANCA) with anti-PR3 (proteinase 3) antibodies in a
patient with consistent clinical features is diagnostic of
GPA.
Rarely, p-ANCA (perinuclear pattern ANCA)
is found in patients with the more typical clinical
phenotype of GPA than microscopic polyangiitis
(which is described below).
In ANCA-negative patients, tissue diagnosis will
be required. This will usually be in the setting of
sinonasal disease, so biopsy of the nasal mucosa may
reveal vasculitis.
Box 17-20
Clinical manifestations of GPA

Rhinosinusitis
Epistaxis
Cough
Dyspnea
Dysphonia
Hemoptysis
Respiratory failure
Fever
Renal failure
Hypertension
Arthralgia
Headache
Focal neurological symptoms
537
While tissue biopsy will reveal granulomatous necrotizing vasculitis, this may not always be possible in the
setting of an acutely unwell patient. Treatment needs
to be instituted immediately when respiratory, renal or
neurological involvement is present.
There is usually serological evidence of an acute phase
reaction.
Microscopic urine examination, determination of renal
function, and lung imaging is essential in all patients.
It is worthwhile to obtain CT imaging of the paranasal
sinuses.
Baseline testing of pulmonary function should be
performed.
Treatment
Without aggressive immunosuppression, the prognosis
of GPA is dismal.
The use of cyclophosphamide has resulted in a 5-year
survival rate of >90%, although progression to endstage kidney disease remains a risk.
High-dose IV corticosteroids should be instituted
immediately for any patient with lung or kidney disease,
concurrently with cyclophosphamide. Evidence is best
for oral cyclophosphamide.
Some patients may be able to be maintained on
methotrexate or mycophenolate, given the significant long-term toxicity associated with cumulative
doses of cyclophosphamide of more than 10 g.
It is recommended that patients on long-term
immunosuppression be treated with prophylaxis
for Pneumocystis jirovecii in the form of low-dose oral
trimethoprim-sulfamethoxazole.
The aim of treatment is to achieve remission. This can
be assessed by clearing of respiratory tract lesions, and
normalization or stabilization of renal function.
The titer of c-ANCA and PR3 antibodies may be a
guide to disease activity, and can be used for long-term
monitoring of patients.
Occasionally, fulminant disease requires plasma
exchange.
The role of newer biological agents is yet to be defined.
Microscopic polyangiitis (MPA)

Similar to GPA, MPA is a small-vessel vasculitis associated
with ANCA.
Patients with MPA generally present with constitutional
symptoms, and renal impairment with active urinary
sediment.
Lung disease will often cause hemoptysis secondary
topulmonary vasculitis.
Upper airway involvement is not usual, in contrast to
GPA.
Skin, joint, and neurological complications affect a
minority.
538
The ratio of lung:renal involvement is reversed compared with GPA, whereby renal involvement in MPA is
present in 90% of patients.
MPA is characterized by p-ANCA (perinuclear ANCA)
and the presence of antibodies to MPO (myeloperoxidase) in about 80% of cases.
Occasionally, c-ANCA is detected in patients who
behave clinically more like MPA than GPA.
The presence of a positive p-ANCA and MPO antibodies has high positive predictive value for the diagnosis
of MPA. Renal biopsy is desirable, however, for both
definitive diagnosis and prognostic reasons.
Determination of renal and pulmonary function at baseline is essential, as is lung imaging.
The treatment approach is similar to that described for GPA.
Eosinophilic granulomatosis with polyangiitis

(EGPA)/ChurgStrauss syndrome (CSS)
Eosinophilic granulomatosis with polyangiitis is a rare
eosinophilic vasculitis of small vessels that arises in
patients with a history of atopic disease. Most patients
will have a history, often for many years, of allergic
rhinosinusitis and asthma.
When vasculitis develops, patients present with a combination of blood eosinophilia and pulmonary infiltrates, sometimes with hemoptysis, vasculitic skin
rash, and neurological disorder in the form of either
symmetrical peripheral neuropathy or mononeuritis
multiplex.
Diagnosis
Around half of patients are p-ANCA-positive.
Tissue biopsy of skin or sural nerve may be helpful for
diagnosis if cutaneous or neurological disease is present.
An eosinophilic vasculitis is diagnostic.
Lung biopsy is generally not needed when characteristic
radiological abnormalities are present in an atopic patient.
Bronchoalveloar lavage will reveal eosinophil-rich fluid
if performed.
Treatment
As is typical for most eosinophilic disorders, corticosteroids
are effective. Some patients, however, require ongoing therapy with unacceptably high doses. In this circumstance, a
second agent such as methotrexate or mycophenolate may
be required.
IgA vasculitis (IgAV)/Henoch-Schnlein

purpura (HSP)
IgA vasculitis is a systemic vasculitis which is much more
common in children than adults. The disease results from
deposition of IgA-containing immune complexes in vessel
walls, stimulating an inflammatory response.
Palpable purpura of the lower extremities is invariable,
very often extending up to the buttocks (Figure 17-15).
Joint involvement and abdominal pain occur in the
majority of cases.
The arthritis mainly affects the joints of the lower
limbs.
The abdominal pain may be accompanied by bloody
diarrhea.
Around 40% of sufferers will have microscopic
hematuria.
Renal impairment is rare, but a small number of
patients, usually adults, will progress to end-stage renal
disease.
IgAV usually follows on from infection, mostly of the
upper respiratory tract. Both Streptococcus and Staphylococcus have been implicated in some case series.
Diagnosis
Diagnosis is generally obvious when faced with the
combination of the lower extremity purpura, and joint,
GI tract or renal disease.
Renal biopsy changes are identical to IgA nephropathy
when the kidneys are involved.
Treatment
Most episodes resolve without treatment within 3
weeks.
Severe episodes, and those with renal impairment or

evidence of organ failure, require treatment with systemic corticosteroids and possibly second-line agents
such as cyclophosphamide or mycophenolate.
Cutaneous leukocytoclastic angiitis
This may occur in isolation, or in association with a systemic
vasculitis or autoimmune disease (Box 17-21).
Drug reactions are the common cause when there is no
associated systemic illness.
Reactions to vaccines or foods are also a possibility.
Sometimes the disease appears to be idiopathic.
Systemic diseases include SLE, SS, IgAV, rheumatoid
arthritis (RA), and cryoglobulinemia, with the pathogenetic mechanism being immune-complex deposition.
Clinically, patients have tender, non-blanching purpuric or
petechial lesions which nearly always start on the distal lower
limbs, but may spread proximally. Biopsy reveals perivascular neutrophils with fibrinoid necrosis (leukocytoclasis;
Figure 17-16, overleaf).
The rash is self-limited once the inciting antigen (e.g.
antibiotic) is withdrawn.
When associated with systemic disease, treatment is
according to the usual protocols for that disease.
Behets disease
Behets disease is a rare disorder characterized by painful oral (Figure 17-17, overleaf) and genital aphthous
ulceration, uveitis, and vasculitis that can affect multiple
organs, including the central nervous system, retina and
skin.
Box 17-21
Differential diagnosis of palpable

purpura
Leukocytoclastic vasculitis (angiitis)
Idiopathic
Cryoglobulinemia
Malignancy
IgA vasculitis (Henoch-Schnlein purpura)
Malignancy
Systemic autoimmune diseasesystemic lupus
erythematosus, Sjgrens syndrome, rheumatoid
arthritis
Cutaneous emboli
Figure 17-15 The typical palpable purpura seen in

Henoch-Schnlein purpura (IgA vasculitis)
From Habif TB. Clinical dermatology, 5th ed. St Louis: Elsevier, 2009.
Infection
Meningococcus
Gonococcus
Rickettsia (e.g. Rocky Mountain spotted fever)
539
Vasculitic complications require immunosuppression

with corticosteroids and often second-line agents.
Ocular disease especially needs an aggressive approach,
with anti-TNF monoclonal therapy gaining favor in
this situation.
AUTOINFLAMMATORY
DISORDERS
These are a group of monogenic inflammatory syndromes
characterized by fever, rash, and serositis. Mostly very rare,
there are now a large number of identified syndromes, but
familial Mediterranean fever and TNF-receptor-associated
periodic syndrome are the most prevalent of these.
Figure 17-16 This photomicrograph shows
leukocytoclasis, with evidence of brinoid necrosis and
polymorphonuclear cells surrounding the blood vessel
From Elston D et al. Dermatopathology. Philadelphia: Elsevier, 2008.
Figure 17-17 Oral ulcer in Behets disease

From Krachmer JH, Mannis MJ and Holland EH. Cornea, 3rd ed.
St Louis: Elsevier, 2010.
An oligoarthritis, recurrent abdominal pain, and pulmonary vasculitis rarely may occur.
More common in women, there is a striking racial disposition with Behets mainly affecting those from Iran,
Turkey and East Asia.
Behets does not result in autoantibody formation,
but will usually be accompanied by an acute phase
response.
The skin of most patients with Behets displays pathergypuncturing the skin with a needle results in the
formation of a pustule after 2448 hours.
Treatment
Recurrent ulceration may be ameliorated with treatment with colchicine.
Both dapsone and thalidomide have been reported to
display efficacy.
540
This most common of the autoinflammatory syndromes

affects predominantly those of ethnicity from the populations located around the Mediterranean Sea. FMF results
from a mutation in the MEFV gene, and is autosomal
recessive.
Most patients present in childhood or adolescence.
The disease is characterized by recurrent acute attacks
of peritonitis, high fever, and joint pain due to arthritis
that is typically a large-joint monoarthritis.
Pleuritis, pericarditis, and testicular pain can also occur,
as can an intensely erythematous rash that mainly affects
the lower limbs.
Attacks occur at variable frequency. In severe cases they
may be weekly.
Many patients undergo abdominal surgery due to
uncertainty regarding the cause of peritonitis.
Those with frequent attacks over a prolonged period are
at risk of the development of secondary amyloidosis as a
result of prolonged elevation in levels of the acute phase
reactant serum amyloid A protein. Renal amyloidosis is
the most common site.
Diagnosis
Inflammatory markers are raised during an attack. ESR,
CRP, white cell count, and platelets are usually elevated, often markedly so.
These parameters usually normalize between attacks.
The definitive test is demonstration of the abnormal
MEFV gene.
Treatment
Long-term administration of colchicine at a dose of
0.51.5 mg daily reduces the number and severity
ofattacks, and the risk of amyloidosis, in the majority
of patients.
Interleukin-1 (IL-1) inhibition with monoclonal antibody therapy (anakinra, rilonacept, canakinumab) may
have a role in the treatment of FMF in those unresponsive to or intolerant of colchicine.

Selective serotonin reuptake inhibitors (SSRIs) may
reduce the frequency and severity of attacks.
TNF-receptor-associated periodic
syndrome (TRAPS)
Less common than FMF, TRAPS is an autosomal dominant condition resulting from a mutation in the TNFRFS
1A gene which encodes the TNF (tumor necrosis factor)
receptor.
Onset is generally in early childhood (<10 years) but can
be delayed until adulthood.
Fever often lasts for 1014 days.
Abdominal pain is typical, and often severe.
Myalgia and arthralgia occur frequently, along with
headache, pleuritis, a variety of skin rashes, and ocular
inflammation in the form of conjunctivitis or uveitis.
Secondary amyloidosis can be a chronic complication.
Table 17-12 Primary and secondary

immunodeciency
TYPE
EXAMPLE(S)
Predominant antibody
deciencies
Common variable
immunodeciency
Combined T and B
cell deciencies
Severe combined
immunodeciency
Phagocyte defects
Chronic granulomatous disease
T-cell deciency
DiGeorge syndrome
Secondary immunodeciency
Environmental
Malnutrition
Infection
Human immunodeciency virus
Disease-related
Malignancy; protein-losing
enteropathy; burns; widespread
skin disease
Iatrogenic
Cancer chemotherapy;
Immunosuppressive drugs
Diagnosis
Inflammatory markers are raised during an attack. ESR,
CRP, white cell count, and platelets are usually elevated, often markedly so. These do not always return to
normal between attacks.
Definitive diagnosis depends on detection of the abnormal TNFRFS 1A gene.
CLINICAL PEARL
Immunodeciency should be suspected in the setting of:
recurrent or chronic infection
infection with low-virulence organisms
evidence of end-organ damage, e.g. bronchiectasis
poor response to standard antimicrobial therapy
recurrent infection with the same organism.
Treatment
Blockade of TNF with etanercept is the mainstay of
treatment in this disorder.
Patients with an unsatisfactory response to etanercept
may benefit from IL-1 blockade.
IMMUNODEFICIENCY
Deficiencies of the immune system are common, and can
be divided into primary (congenital) and secondary (acquired).
Primary immunodeficiency refers to a defective component, or components, of the immune system due to a
genetic mutation.
Secondary immunodeficiency occurs as a result of a
wide array of diseases, and their treatments.
Table 17-12 gives examples of deficiencies of each type.
For the clinician, the challenge will often be:
to recognize when a patient with infection is immunodeficient, and thus be in a position to adapt treatment
appropriately
to look at ways to protect the patient from future risk,
for example through prophylaxis and immunization.
The true incidence of primary immunodeficiency is
unknown, but is relatively common if selective IgA deficiency is taken into account. Approximately 65% of cases
are antibody deficiencies. Unfortunately, many cases are
missed in both developed and developing countries.
Diagnosis is frequently delayed for an average of around
5 years.
Given that earlier diagnosis improves prognosis, many
patients will have developed complications by the time
their underlying immunodeficiency is recognized.
Consanguinity is the major risk factor for primary
immunodeficiency.
Box 17-22 (overleaf) outlines clinical clues to diagnosis at
different ages.
CLINICAL PEARL
Infection is the major complication of immunodeciency,
but it is important to remember that immunodeciency
is also associated with immune dysregulation. Some
patients will develop autoimmunity, allergy and malignancy as a result of their immunodeciency.
541
Box 17-22
When to consider a diagnosis of primary immunodeciency

Infancy
Failure to thrive
Family history of primary
immunodeciency
Omphalitis
Congenital defects
Consanguinous parents
Childhood
8 or more infections in 1 year,
especially ear infections
Persistent candidiasis
Recurrent skin infection
Recurrent abscesses
Primary antibody defects

Antibody defects generally manifest with recurrent sinopulmonary infection in the form of otitis media, sinusitis and
pneumonia (Table 17-13). Frequent, recurrent, and chronic
infection should raise suspicion.
Investigating antibody deciency

The initial investigation of a patient with suspected primary
antibody deficiency should be with:
full blood count
serum immunoglobulins
specific antibody responses following vaccination with
protein antigens (tetanus, pertussis), and polysaccharide
antigens (Pneumococcus).
If these are normal:
investigate for complement deficiency: CH50, AH50,
C2, C4, C3.
If there is evidence of lymphopenia and/or hypogammaglobulinemia, follow-up testing should be sought with:
lymphocyte subsets
specific gene testing.
CLINICAL PEARL
Differential diagnosis in recurrent sinopulmonary infection:
primary or secondary immunodeciency
allergic rhinosinusitis
chronic rhinosinusitis with or without polyposis
cystic brosis
ciliary dyskinesia
anatomical sinonasal obstruction.
Any age
Opportunistic infection, e.g. with
Pneumocystis jirovecii
Recurrent pneumonia or sinusitis
Evidence of end-organ damage,
e.g. bronchiectasis
Failure of response to standard
antibiotics
Autoimmune disease
paranasal sinus imaging should be performed if patients

are symptomatic
patients are unlikely to have an adequate response to
most immunization
hyperimmune globulin should be used where available if
exposure to a relevant infection is reasonably suspected.
Combined antibody and cellular

immunodeciencies
Congenital T-cell deficiency has a profound effect on the
development and function of B cells also, and hence patients
present with problems related to both cell-mediated and
humoral immunodeficiency.
Patients generally present as infants, and without treatment do not survive.
Severe combined immunodeciency

Rare; approximately 1:65,000.
Consanguinity is a major risk factor.
Infants present with sepsis, failure to thrive, and opportunistic infections.
Multiple gene defects have been identified, e.g. adenosine deaminase deficiency, JAK3 deficiency, Omenn
syndrome.
Treatment involves stem-cell transplantation or gene
therapy.
Phagocyte deciency
Phagocyte deficiency accounts for approximately 10% of
primary immunodeficiency. Most deficiency in phagocyte
number or function is acquired, secondary to infection,
medication, nutrition or malignancy, with the primary
forms being due to rare genetic defects.
Long-term management of antibody

deciency
Chronic granulomatous disease (CGD)
Patients who are on long-term immunoglobulin replacement therapy should be kept in regular review:
IgG levels should be monitored to ensure adequate
replacement
lung function testing and imaging should be performed
at regular intervals to screen for bronchiectasis
This is a rare condition with an incidence of approximately 1:250,000.

Patients with CGD tend to present with recurrent deepseated infections due to Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia spp. and Aspergillus
spp. Hepatic and pulmonary infections are frequent.
542
Table 17-13 Primary antibody deciencies
PRIMARY
IMMUNODEFICIENCY
INCIDENCE
GENETIC
DEFECT
CLINICAL
FEATURES
DIAGNOSIS
TREATMENT
Selective IgA
deciency
Common;
1:500 to 1:700
Unknown
80% asymptomatic
Recurrent
sinopulmonary
infection
Celiac disease
Autoimmune disease
No measurable
IgA
Antibiotic therapy
as required
Common variable
immunodeciency
(CVID)
1:25000 to
1:50000
Mutations
dened in
about 15%;
includes TACI,
ICOS genes
Onset may be delayed

until teenage years or
young adulthood
Recurrent bacterial
infection, especially
sinopulmonary;
septicemia, abscesses
Bronchiectasis
Autoimmune disease
Low IgG
Low IgM and IgA
is usual
Poor or absent
specic antibody
response to
vaccination
Regular
replacement
therapy with
pooled donor
immunoglobulin
Specic antibody
deciency
Unknown
Unknown
Recurrent bacterial
infection, especially
sinopulmonary; otitis
media
Absent or subnormal response

to vaccination
(e.g. pneumococcal, tetanus)
Regular
replacement
therapy with
pooled donor
immunoglobulin
IgG sub-class
deciency
Unknown
Unknown
Clinical signicance
unclear
No longer
recommended
in screening for
immunodeciency
Low levels of
one or more
IgG sub-classes
in presence of
normal total IgG
Nil
X-linked agammaglobulinemia
1:70000 to
1:400000
BTK gene
Almost exclusively
seen in boys; presents
in childhood with
recurrent bacterial
infection
Absent B cells
Low or absent
IgG, IgM, IgA
BTK gene
abnormality
Regular
replacement with
pooled donor
immunoglobulin
BTK, Brutons tyrosine kinase; ICOS, inducible co-stimulator; TACI, transmembrane activator and calcium-modulator and cyclophilin-ligand
interactor.
CGD is caused by mutation in one of the five genes that

encode the nicotinamide adenine dinucleotide phosphate (NADPH) phagocyte oxidase complex (Phox)
which is responsible for the respiratory burst that kills
phagocytosed bacteria in neutrophils.
Diagnosis is by demonstration of reduced phagocyte
oxidase activity, either by a negative NBT (nitroblue
tetrazolium) test by or a reduction in the dihydrorhodamine 123 assay.
Treatment is with long-term administration of gammainterferon, prophylactic antibiotics (trimethoprimsulfamethoxazole) and antifungals (itraconazole).
Primary neutropenia
Cyclic neutropenia and severe congenital neutropenia are
rare conditions with defined genetic mutations.
T-cell deciencies
Primary T-cell deficiencies are outlined in Table 17-14
(overleaf).
CLINICAL PEARL
Relatively few pathology tests need to be employed in
the initial screening of a patient with suspected primary
immunodeciency:
full blood count and lm
serum immunoglobulins
complement levels
specic antibody responses.
If all of these are normal, primary immunodeciency
is unlikely. If the lymphocyte count is low, specic Band T-cell subsets should be measured. If HowellJolly
bodies are present on blood lm, asplenia is likely.
543
Table 17-14 Examples of primary T-cell deciencies
T-CELL IMMUNODEFICIENCY
INCIDENCE
GENE
DEFECT
CLINICAL FEATURES
DIAGNOSIS
DiGeorge syndrome
1:4000
Deletion of
chromosome
22q11.2
Typical facies
(Figure 17-18)
Recurrent infections
Hypocalcemia due to
parathyroid hypoplasia
Schizophrenia
Developmental delay
Thymic hypoplasia
Cardiac anomalies
Reduction in T-cell
numbers
Ataxia-telangiectasia
1:100,000
ATM
Progressive ataxia
Ocular and cutaneous
telangiectasia from age
35 years
Recurrent bacterial
infections
Low Ig levels
Lymphopenia
Poor antibody responses
Elevated alpha-fetoprotein
WiskottAldrich
syndrome
1:100,0001:1,000,000
WASP
X-linked recessive
Severe eczema; recurrent

bacterial infection,
frequently staphylococcal
Thrombocytopenia with
small platelets
Hyper-IgE
1:100,000
STAT3
Eczema; skin abscesses

(Figure 17-19)
Recurrent staphylococcal
infection
Pneumatoceles
Candidiasis
Typical facies
Retention of primary
teeth (Figure 17-19)
Very high total serum IgE

Eosinophilia
Ig, immunoglobulin.
Vaccination in PID
Live viral and bacterial vaccines should not be given.
Specifically, oral polio vaccine, bacille CalmetteGurin (BCG), measles-mumps-rubella (MMR)
vaccine, yellow fever, live typhoid, varicella vaccine,
live influenza vaccine, and live oral rotavirus vaccine
should be avoided.
Inactivated and sub-unit vaccines are safe, but may be
ineffective; antibody response should be measured to
check efficacy.
Passive immunization should be considered where
appropriate, e.g. VZV (varicella zoster virus)
immunoglobulin.
Secondary (acquired)
immunodeciency
The majority of cases of secondary immunodeficiency
globally result from poor nutrition and chronic infection
544
secondary to poor living conditions, or communicable disease. In the developed world, aging of the population with
the accompanying immunosenescence accounts for a substantial proportion of the increased susceptibility to infection, along with immunosuppressive treatments used in the
treatment of a variety of malignant and autoimmune conditions, and in the management of transplanted organs.
HIV/AIDS
The human immunodeficiency virus (HIV) pandemic has
presented unique global challenges both clinically and ethically. The acquired immune deficiency syndrome (AIDS)
has affected all nations and all sections of society. There
have been deep insights into the understanding of both the
intact and the disordered immune system as a result of this
disease. A previously nearly universally fatal condition has
turned into a chronic, treatable condition due to the advent
of effective antiretroviral therapy.
Figure 17-18 Patients with typical facies for DiGeorge

syndrome
From Fung WLA et al. Extracardiac features predicting 22q11.2
deletion syndrome in adult congenital heart disease. Int J Cardiol
2007;131(1):5158.
Figure 17-19 Patient with hyper-IgE syndrome,

demonstrating severe atopic dermatitis (above) and
retention of primary teeth (below)
From Esposito L et al. Hyper-IgE syndrome: dental implications. Oral
Surg Oral Med Oral Pathol Oral Radiol 2012;114(2):14753.
Epidemiology
UNAIDS, the Joint United Nations Programme on HIV/
AIDS, estimates that:
34 million people are infected with HIV globally (2011)
women make up approximately 55% of infected adults
1.7 million people died of the disease in 2011
2.5 million people were newly infected in 2011
sub-Saharan Africa accounts for 69% of people living
with the infection
high rates of infection are found in the Caribbean,
Central Asia and Eastern Europe
5 million people are infected in Asia.

Heterosexual transmission remains the predominant
mode of acquisition of the virus globally.
Male-to-male sex carries the highest risk in developed Western countries and is an important risk factor
elsewhere.
Other key risk groups include:
children, through perinatal transmissionUNAIDS
estimates that there were 330,000 new infections in
children in 2011
people who inject drugs
sex workers.
Other risk factors include:

concurrent genital infection
uncircumcised males
transfusion of infected blood products
exposure from medical or dental procedures.
Pathophysiology
HIV is transmitted through body fluids.
HIV gains entry to cells through the CD4 molecule
found on the surface of CD4+ cells, T-helper lymphocytes, monocyte-macrophages, and dendritic cells.
The CD4 molecule acts as the receptor for an HIV
envelope protein known as gp120.
For successful entry into the cell, HIV gp120 must
also bind a co-receptor, which is usually a protein in
a class known as chemokine receptors.
The two major chemokine receptors used by HIV
for cell entry are CCR5 and/or CXCR4. Differences in gp120 protein structure determine tropism
for either of these co-receptors. CCR5 blockade is
one therapeutic target in HIV treatment.
To enter the cell, the virus undergoes fusion with
the membrane, a step that can be blocked by fusion
inhibitors.
HIV is a single-stranded RNA retrovirus that requires
reverse transcription in the cell cytoplasm, through the
545
action of the enzyme reverse transcriptase, to form singlestranded and then double-stranded DNA. This step can
be blocked by reverse transcriptase inhibitors.
For the newly formed HIV DNA to be copied, it must
next be integrated into the host cell genome via the
action of the enzyme integrase. This is the next target
for therapeutic blocking of the process, with the use of
integrase inhibitors.
Following successful transcription, the newly formed
viral polypeptides are spliced by the enzyme protease
into their functional forms, a step susceptible to the
action of protease inhibitors.
The viral particles and structural proteins are then
assembled in the cytoplasm into mature virus which is
ready for release.
Most individuals mount a prompt and vigorous immune
response to acute HIV infection, via formation of antibody
and the action of cytotoxic T cells and natural killer cells.
A high viral load and a sudden drop in CD4+ T-cell numbers during the acute infection phase is typically seen, followed by restoration as the immune response kicks in.
The virus is directly cytopathic to CD4+ T cells. In
addition, infected cells are targeted by cytotoxic T lymphocytes, and by antibody. It is less cytopathic toward
macrophages and dendritic cells.
Viral replication continues in lymphoid tissue at varying
rates, and a steady decline is seen in CD4+ lymphocyte
numbers and immune function over years, with consequent increase in plasma viral load unless effective treatment is instigated.
As immune function declines, patients become susceptible to a range of infective, autoimmune and neoplastic
complications.
It is unclear whether the use of antiretroviral medication

for the acute infection confers benefit in the long term,
although a severe acute illness with high levels of viremia is poorly prognostic.
The demonstration of antibodies to HIV remains the
mainstay of diagnosis. Enzyme immunoassays are used
as screening tests, but confirmation of HIV infection
requires a positive Western blot test. Recommended
baseline investigations are outlined in Box 17-24.
The formation of HIV antibodies signals the end of the
seroconversion phase, but antibodiesalthough detectable at 3 months in the vast majoritymay occasionally
take up to 6 months or even longer to be detectable in
serum. For this reason, rapid diagnosis depends on the
detection of viral antigen in the serum, with p24 antigen
testing or nucleic acid amplification testing.
Chronic HIV infection

Untreated, the majority of patients decline physically
and immunologically after a variable-length clinically
latent period.
Autoimmune phenomena may be seen prior to
the development of significant immunodeficiency
(Box 17-25). This is often associated with a CD8+ lymphocytosis, and affected organs may also demonstrate
infiltration with cytotoxic T cells. Generalized lymphadenopathy may persist during this phase.
Box 17-24
Recommended baseline
investigations for the newly
diagnosed HIV patient

Acute HIV infection
More than 50%, and possibly up to 90%, of patients
will suffer an acute illness from 3 to 6 weeks after being
infected with the virus. Clinical features are outlined in
Box 17-23.
Box 17-23
Clinical features of acute HIV

infection
Common
Fever
Generalized
lymphadenopathy
Maculopapular rash
Headache
Pharyngitis
Myalgia
Constitutional
symptoms
546
Less common
Oral candidiasis
Splenomegaly
Diarrhea
Arthralgia
Night sweats
Productive cough
Meningitis
CD4+ T cell count

HIV viral load
HIV resistance assay (genotypic/phenotypic,
depending on local availability)
Full blood count
Electrolytes, urea, creatinine
Fasting lipids and glucose
Urinalysis
Hepatitis B and C serology
Toxoplasma serology
CMV serology
Screening for other STIs (syphilis, chlamydia,
gonorrhea)
HIV tropism assay
HLAB*5701 (to detect risk of abacavir hypersensitivity)
CMV, cytomegalovirus; HIV, human immunodeciency virus; STI,

sexually transmitted infection.
Adapted from: http://aidsinfo.nih.gov/contentles/AdultARV_GL_
Table3.jpg
Box 17-25
Autoimmune diseases seen in HIV

infection
Immune thrombocytopenic purpura
Polymyositis
Lymphoid interstitial pneumonitis
Bells palsy
Sjgrens syndrome
Autoimmune thyroid disease
GuillainBarr syndrome
As immunodeficiency progresses, opportunistic infection

begins to appear. Early such infections include:
recurrent or persistent herpes simplex
herpes zoster
oral hairy leukoplakia
oropharyngeal candidiasis.
When immunodeficiency becomes profound, generally
coinciding with a CD4+ T lymphocyte count of <200/m3,
life-threatening infections such as pneumocystis pneumonia
(Figure 17-20) and malignancies such as Kaposis sarcoma
(Figure 17-21) become frequent.
Management
Comprehensive management of the HIV-infected patient
requires attention to the psychological, environmental,
socioeconomic, sexual and physical factors affecting each
individual. Access to medical treatment, specifically antiretroviral therapy, is obviously a key consideration.
The complexities of such management are beyond the
scope of this text. The principles of pharmacotherapy, however, are key to the successful treatment of the disease, as
outlined in Table 17-15 (overleaf).
Figure 17-20 Chest X-rays and corresponding CT

scans of pneumocystis pneumonia in chronic HIV
infection; note the interstitial changes progressing to
ground-glass appearance
Antiretroviral therapy (ART)

Aims of therapy
Control viral replication.
Maintain or restore immune function (specifically
CD4+ T cells).
Prevent emergence of resistance (at least three antiviral
agents aimed at two molecular targets).
It should also be noted that ART is used for both
pre-exposure prophylaxis (PrEP), and post-exposure
prophylaxis (PEP).
When to initiate therapy
Current guidelines are:
CD4+ T cells 350/mm3. This T-cell level usually correlates with a viral load of 10,000100,000 copies per
mL.
Commence with three drugs.
Evidence is accumulating that the earlier ART is initiated after infection, the better the prognosis. This does,
Figure 17-21 Cutaneous Kaposis sarcoma in an AIDS

patient.
From Hoffman R et al. Hematology, basic principles and practice,
5th ed. Philadelphia: Elsevier, 2009.
547
Table 17-15 AIDS-dening conditions and their treatment
CONDITION
Infections
Esophageal, bronchial, tracheal or pulmonary
candidiasis
Azole antifungals
Pneumocystis jirovecii pneumonia
High dose oral or IV co-trimoxazole, or IV pentamidine, plus

prednisolone 1 mg/kg/day for 21 days if PaO2 < 70 mmHg on
room air
Cerebral toxoplasmosis
Pyrimethamine, plus sulfadiazine or clindamycin
Cytomegalovirus retinitis
IV ganciclovir or foscarnet, or oral valganciclovir
Cytomegalovirus disease elsewhere
IV ganciclovir or foscarnet, or oral valganciclovir
Cryptosporidiosis
Restoration of immune function essential; paromomycin,

azithromycin not proven to be effective
Coccidioidomycosis, disseminated or extrapulmonary
Amphotericin-B or azole antifungals
Cryptococcosis, extrapulmonary
IV amphotericin-B with ucytosine, followed by oral uconazole
Herpes simplex bronchitis, pneumonitis, esophagitis,

or ulcer lasting >1 month
Acyclovir (aciclovir), valacyclovir or famciclovir
Histoplasmosis, disseminated or extrapulmonary
Amphotericin-B or azole antifungals
Chronic intestinal isosporiasis
Co-trimoxazole
Mycobacterium tuberculosis infection
Standard four-drug therapy as rst-line: rifamycin, isoniazid,

pyrazinamide, ethambutol
Multi-drug resistance is found in many parts of the world,
necessitating local protocols
Interactions with ARVs are complex and must be considered
Mycobacterium avium complex or

M. kansasii
Clarithromycin, ethambutol, rifabutin
Recurrent salmonella septicemia
As per standard treatment guidelines
Recurrent bacterial pneumonia
Progressive multifocal leukoencephalopathy
Combination ART
Malignancy
Kaposis sarcoma
Control of HIV infection with ART; radiotherapy or combination

chemotherapy in rare instances
Cerebral lymphoma
Burkitts lymphoma
Immunoblastic lymphoma
Invasive cervical cancer
Other
CD4+ T lymphocyte count <200/mm3
HIV-associated wasting (>10% body weight plus
diarrhea, weakness and fever)
Control of HIV infection with ART
HIV-associated dementia
Control of HIV infection with ART
ART, antiretroviral therapy; ARV, antiretroviral drug; HIV, human immunodeciency virus.
548
however, need to be weighed against the patients willingness to commit to lifelong adherence and the risk of
drug toxicity.
The use of ART in HIV-infected individuals also
reduces transmission of the disease.
CLINICAL PEARL
The institution of antiretroviral therapy (ART) carries the
risk of triggering immune reconstitution disease (IRD).
The risk is higher in patients who are more immunosuppressed at initiation of ART (lower CD4 count),
and those who have existing opportunistic infection,
even if treated. In IRD, the recovering immune system
triggers a dysregulated, often exuberant, inammatory response to the existing opportunistic infection.
This can result in clinical ares of disease that carry a
high risk of mortality, especially with cryptococcal and
mycobacterial infections. A range of autoimmune phenomena can also occur. Patients with IRD may require
corticosteroid therapy.
Factors impairing efficacy of therapy

Non-adherence.
Poor tolerability.
Drug interactions between antivirals, or other medications, that reduce effective drug levels.
Toxicities of antitretroviral drugs (ARVs) are outlined in
Table 17-16 (overleaf).
Drug resistance
Drug resistance has been documented in:
therapy-nive patients who have been infected with
resistant virus
patients who have experienced treatment failure; nonadherence is a major risk factor for this
all classes of ARV.
It should be tested for in:
therapy-nive patients
patients who have experienced treatment failure, to
guide treatment changes.
In the virally-suppressed patient on long-term HIV treatment, it is important to screen for and manage potential
comorbidities:
hyperlipidemia
hypertension
glucose intolerance and diabetes mellitus
lipodystrophy
proteinuria
osteoporosis.
Prognosis
Prognosis has improved dramatically in all areas of the
world where treatment with ARVs is available.
Prognosis is adversely affected by socioeconomic factors, and concurrent morbidities especially pulmonary
tuberculosis in the developing world.
Long-term morbidity is increasingly a problem in
patients on long-term ARVs, due to increased cardiovascular risk from metabolic abnormalities such as
lipodystrophy.
The challenge will be to develop less-toxic antiviral
medication for long-term use, and eventually curative
therapy.
549
Table 17-16 Antiretroviral drugs
DRUG TARGET
DRUG EXAMPLES
CLASS TOXICITIES
IMPORTANT SPECIFIC
DRUG TOXICITIES
Preventing viral entry

chemokine receptor
antagonists
Maraviroc
Hepatotoxicity
Rash
Pyrexia
Upper respiratory tract infection
Cough
GI intolerance
Preventing viral entry

fusion inhibitors; prevent
gp41from achieving fusionactive conformation
Enfuvirtide (T20)
Injection site reactions

GI intolerance
Fatigue
Preventing reverse
transcriptionnucleoside
reverse transcriptase
inhibitors; analogues
of native nucleoside
substrates
Zidovudine
Didanosine
Lamivudine
Abacavir
Emtricitabine
Stavudine
Zalcitabine
Lipodystrophy
Lactic acidosis
Hepatic steatosis
Abacavirhypersensitivity
reaction in those with
HLA-B*5701; rash
Stavudineperipheral
neuropathy
Zidovudinebone-marrow
suppression
Didanosinepancreatitis
Preventing reverse
transcriptionnucleotide
reverse transcriptase
inhibitors
Tenofovir
Lipodystrophy
Lactic acidosis
Hepatic steatosis
Renal impairment
Preventing reverse
transcriptionnonnucleoside reverse
transcriptase inhibitors
binding to reverse
transcriptase, preventing its
action
Etravirine
Delavirdine
Efavirenz
Nevirapine
Rilpivirine
Rash
Hepatotoxicity
Efavirenzneuropsychiatric
changes; nightmares;
teratogenic
Nevirapinerash; hepatotoxicity
Preventing integration of
HIV into host cell genome
integrase inhibitors
Elvitegravir
Raltegravir
Nausea
Headache
Diarrhea
Myositis
Rash
Preventing viral polypeptide

splicingprotease inhibitors
Atazanavir
Fosamprenavir
Darunavir
Indinavir
Saquinavir
Ritonavir (used to inhibit
metabolism and enhance
blood levels of other protease
inhibitors)
Lopinavir
Nelnavir
Tipranavir
Amprenavir
Lipodystrophy
Hyperlipidemia
Hepatotoxicity
GI intolerance
GI, gastrointestinal.
550
Atazanavirhyperbilirubinemia;
prolonged PR interval;
nephrolithiasis
Fosamprenavirrash
Lopinavirdiabetes
1
A 16-year-old male has perennial symptoms of nasal blockage, excessive sneezing and ocular itch. Which of the
following statements is most likely to be TRUE for this patient?
A Skin-prick allergy tests will be strongly positive for birch and ryegrass.
B Allergen avoidance has no role in the management of his condition.
C A cows-milk-free diet may improve his symptoms.
D Positive serum-specic IgE for Dermatophagoides pteronyssinus probably explains the cause of his problem.
E Effective treatment of this problem is unlikely to improve the management of his coexistent bronchial asthma.
A 44-year-old female presents with daily episodes of urticaria for approximately 6 months. The urticarial lesions are
occurring in a generalized distribution. There have also been four episodes of moderately severe angioedema, affecting
the lips and periorbital tissues. The patient has not noted any physical factors that provoke the problem. Which of the
following actions would be most appropriate in this circumstance?
A Organize for skin-prick allergy tests to a broad range of foods and aeroallergens.
B Prescribe fexofenadine 180 mg twice daily for a minimum period of 2 months.
C Prescribe a short course of prednisolone 50 mg daily to achieve control of the problem.
D Place the patient on a modied diet that excludes common allergenic foods.
E Order testing for complement components C4 and C1q to exclude hereditary or acquired angioedema.
A 50-year-old man suffers acute hypotension during an operation to remove his gallbladder under general anesthesia.
The anesthetist notes some urticarial lesions on the torso and increased airway pressures, and treats the patient
with epinephrine and uid volume expansion with good effect. Which two of the following actions would constitute
appropriate follow-up?
A Take blood immediately for serum tryptase measurement.
B Organize for skin-prick and intradermal testing to the anesthetic drugs used during the procedure as an outpatient.
C Strictly avoid all drugs used during the procedure in future.
D Prescribe the patient an epinephrine self-injecting device.
E Perform a skin test with the agents being used for future anesthesia in the anesthetic bay prior to any further
anesthesia, to ensure no new allergies have developed.
4 A 25-year-old male presents with central chest pain of subacute onset, made worse by inspiration and somewhat
relieved by leaning forward. He has noticed a rash over his cheeks in recent weeks, and has been feeling fatigued.
His wrists and ngers have been aching, especially in the mornings. Physical examination reveals a malar rash with
sparing of the nasolabial folds. There are no abnormal cardiac signs, and no obvious joint swelling. Dipstick urinalysis
is negative for blood and protein. Laboratory investigations reveal erythrocyte sedimentation rate 45 mm/h (reference
range [RR] 135 mm/h), C-reactive protein 4.8 mg/L (RR 0.05.0 mg/L), antinuclear antibodies 1:640 (homogeneous
pattern), double-stranded DNA antibody negative, and microscopic urine examination normal. Which of the following
statements is correct in this case?
A The patient should be commenced on prednisolone at a dose of 1 mg/kg/day.
B The chest pain is unlikely to be related to the other symptoms.
C Hydroxychloroquine at a dose of 200 mg twice daily should relieve the symptoms within 48 hours.
D Lack of a pericardial rub makes pericarditis unlikely.
E An electrocardiogram, full blood count and extractable nuclear antigen (ENA) test would be appropriate in this
situation.
5
A 75-year-old female with a 50-year history of smoking 30 cigarettes per day presents with severe headaches for
2weeks. She has been taking prednisolone 5 mg daily for 4 months for the diagnosis of polymyalgia rheumatica (PMR).
She denies ocular symptoms or night sweats. She has recently lost several kilograms in weight. She has a longstanding
cough with morning sputum production, which has worsened over the past few months. Physical examination reveals
a thin woman with a temperature of 37.8C. There is mild bilateral scalp tenderness but no obvious thickening of the
temporal arteries. Which of the following approaches would be appropriate in this situation?
A Arrange for chest radiograph and head computed tomography (CT) for the presumptive diagnosis of lung cancer
with cerebral metastases.
B Organize an urgent temporal artery biopsy to exclude giant-cell arteritis (GCA).
C Increase the prednisolone dose to 50 mg daily and organize an urgent temporal artery biopsy.
D Arrange urgent ophthalmological review to exclude ophthalmic artery vasculitis.
E Arrange for urgent erythrocyte sedimentation rate (ESR) and full blood count, and only increase the steroid dose if
these have shown substantial change from previous levels.
Questions continue overleaf.
551
6 A 60-year-old female patient develops pallor and pain of the right hand while camping in cold weather, which last
for about an hour. She subsequently develops a persistent dry cough, mild dyspnea on exertion, and feels weak.
Physical examination reveals bilateral basal inspiratory lung crackles, no signs of pulmonary hypertension, and marked
symmetrical weakness of proximal muscle groups. Which combination of abnormal laboratory results is most likely to
correspond to this clinical situation?
A Antinuclear antibodies positive 1:1280, anti-Jo-1 antibodies positive, CK (creatine kinase) 853 U/L (reference range
[RR] 26140 U/L)
B Antinuclear antibodies positive 1:320, anti-RNP antibodies positive, CK 299 U/L (RR 26140 U/L)
C Antinuclear antibodies positive 1:2560, anti-SS-A antibodies positive, anti-SS-B antibodies positive, rheumatoid
factor 42 IU/mL (RR 014 IU/ml), CK 130 U/L (RR 26140 U/L)
D Antinuclear antibodies negative, rheumatoid factor 102 (RR 014 IU/mL), CK 53 U/L (RR 26140 U/L)
E Antinuclear antibodies positive 1:2560, anti-ds-DNA 27 IU/mL (RR 06 IU/mL), anti-Sm antibodies positive, CK 330
U/L (RR 26140 U/L)
7
A 52-year-old non-smoking male presents with a left-hemisphere ischemic stroke. Subsequent investigations reveal:
Activated partial thromboplastin time (APTT)
37 seconds
Reference range (RR) 2539 seconds
Patient DRVVT
40 seconds
RR 3242 seconds
DRVVT + phospholipid
36 seconds
DRVVT (normalized) ratio
1.0 seconds
<1.2 = negative
1.2 1.5 = weak positive
1.62.0 = moderate positive
>2.0 = strong positive
Kaolin ratio
1.1
(RR <1.2)
Cardiolipin IgG antibodies
75 GPL
(RR <5 GPL)
Cardiolipin IgM Abs
45 MPL
(RR <5 MPL)
Beta-2-glycoprotein 1 Abs
33 SGU
(RR <20 SGU)
Dilute Russell viper venom time (DRVVT) and

phospholipid neutralization:
GPL, unit equivalent to 1 microg of immunoglobulin G; MPL, unit equivalent to 1 microg of immunoglobulin M; SGU,
standard IgG anti-beta glycoprotein 2 international units.
Which of the following management approaches would be most appropriate in this situation?
A Aspirin 100 mg daily long-term.
B Subcutaneous therapeutic-dose enoxaparin for 3 months, then recheck cardiolipin antibody levels. If levels remain
positive, institute lifelong warfarin therapy.
C Therapeutic-dose intravenous unfractionated heparin until warfarin therapy has been instituted to therapeutic
levels. Continue warfarin therapy lifelong.
D Standard therapy for stroke. Recheck cardiolipin antibodies in 3 months. If the IgG cardiolipin antibody level
remains positive, institute lifelong warfarin therapy.
E Immediately commence aspirin, intravenous heparin, and warfarin. Once therapeutically warfarinized, discontinue
heparin but continue aspirin and warfarin
8 A 21-year-old woman has had ve signicant episodes of sinusitis and three of bronchitis, in the previous 12 months.
Which of the following pathology results would be consistent with the most likely diagnosis in this case?
A Normal total IgG levels, but reduced IgG2 and IgG4
B Reduced total hemolytic complement level
C Persistent reduction in the absolute neutrophil count
D Reduced levels of blood CD4+ lymphocytes on ow cytometry
E TACI mutation
9 A 35-year-old man with stable human immunodeciency (HIV) infection for 5 years on treatment with two nucleoside
reverse transcriptase inhibitors and efavirenz is found to have detectable HIV viremia (at a low level) for the rst time
since commencing antiretroviral therapy. Which of the following would be the most appropriate course of action?
A Perform antiretroviral resistance testing, and add a protease inhibitor.
B Suspend antiretroviral therapy while waiting for antiretroviral resistance testing and CD4+ T-cell numbers.
C Perform antiretroviral resistance testing and change to a different three-drug regimen.
D Perform antiretroviral resistance testing, CD4+ T-cell numbers, and maintain the current regimen pending the results.
552
ANSWERS
1
D.
This is a typical case of persistent allergic rhinoconjunctivitis, which is usually caused by exposure to perennial allergens
such as house dust mite or animal danders. The demonstration of specic IgE to Dermatophagoides pteronyssinus
strongly suggests that the house dust mite is the cause. Specic house dust mite reduction measures, particularly in the
bedroom, may help alleviate symptoms, and should be employed in addition to other therapy. Cows milk does not cause
persistent allergic rhinoconjunctivitis. Birch or ryegrass allergy causes seasonal (spring and summer) symptoms rather than
perennial ones. There is evidence that improved control of allergic rhinitis symptoms results in improved asthma control.
B.
Of the options given, prescription of a prolonged course of adequate-dose non-sedating H1 antihistamines is the
appropriate course of action in chronic idiopathic urticaria and angioedema (CIU/A). CIU/A is not an allergic or diet-related
condition, so allergy testing and elimination diets are not appropriate. Corticosteroids should be avoided in CIU/A if at all
possible, as this is a chronic problem, and reliance on steroids is likely to cause signicant morbidity. The exception would
be if a severe bout of angioedema was present. Angioedema secondary to a complement deciency is not associated
with urticaria.
A and B.
This is a typical history of anaphylaxis to general anesthesia. Measuring serum tryptase promptly will help conrm the
diagnosis of anaphylaxis. Formal skin testing in a specialized clinic for allergy to the agents usedand generally to a
standard panel of anesthetic drugsis essential to identify the culprit. This will also allow the patient to have access to
the drugs which were not the cause of the reaction in the future. It may be very difficult to avoid all of the drugs which
were administered on this occasion in the future if the patient requires further surgery. The patient does not need an
epinephrine self-injecting device if his only anaphylaxis risk is general anesthesia! Non-standardized skin testing is not a
safe way to diagnose drug allergy.
4 E.
This patient most likely has acute pericarditis in the setting of systemic lupus erythematosus (SLE). A combination of malar
rash, arthralgia and positive antinuclear antibody in a young male has a high positive predictive value for the disease.
Elevated erythocyte sediment rate (ESR) with normal C-reactive protein is typical of SLE. Pericardial rub is an insensitive
sign for pericarditis, so an electrocardiogram and echocardiogram should be performed. The presence of anti-Sm, antiSS-A, or anti-SS-B on ENA testing would be strong evidence of SLE, although sensitivity is low. Evidence of a lymphopenia
or normochromic, normocytic anemia would also be consistent with SLE. Treatment in this situation would be appropriate
with non-steroidal anti-inammatories, and possibly low-dose corticosteroids. There is no apparent indication for highdose steroids. Hydroxychloroquine is a good choice for ongoing therapy, but its effect is not rapid so other treatment is
needed in the short term.
5
C.
Approximately 20% of patients with PMR will go on to develop GCA. Being on low-dose corticosteroids may disguise
some of the symptoms and signs of GCA, so the lack of visual symptoms or palpable temporal arteries should not reassure
the clinician that GCA has not developed. Similarly, the lack of serological evidence of an acute phase response, while
being unusual, does not exclude GCA altogether. Headache is the most common symptom of GCA. To miss the diagnosis
of GCA and not treat it, only to have a patient go blind or have a stroke, is a disaster. The approach should always be to
treat the patient for GCA while organizing diagnostic tests. While involvement of an ophthalmologist in the case may be
important, they will not usually be able to diagnose changes due to GCA in the absence of ocular symptoms.
6 A.
The combination of Raynauds phenomenon, myopathy and probable interstitial lung disease is a classic presentation
of the anti-synthetase variant of polymyositis. The presence of antinuclear antibodies and anti-Jo-1 antibodies would be
consistent with this, and the markedly elevated CK level would indicate signicant myositis. Answer B would be more
consistent with mixed connective tissue disease, where pulmonary brosis would be unlikely. Answer C is likely to be
Sjgrens syndrome. The ndings in answer D could be present in rheumatoid arthritis, where one would not expect
a myopathy. Answer E is consistent with systemic lupus erythematosus, where myopathy to this degree and rapidly
developing pulmonary brosis would be unusual.
Table 17-17 summarizes disease associations with autoantibodies.
553
Table 17-17 Autoantibodies and disease associations
DISEASE
Systemic lupus
erythematosus (SLE)
PREVALENCE/COMMENT
ANA
>95%; homogeneous pattern more specic
ds-DNA
~50%; high specicity; risk factor for renal disease
SS-A
3050%; also found in Sjgrens syndrome
SS-B
10%; also found in Sjgrens syndrome
Sm
2030%; high specicity
Drug-induced lupus
Histone
>70% specicity; not associated with drug-induced lupus

due to anti-TNF (tumor necrosis factor) therapy (iniximab,
etanercept)
Sjgrens syndrome
ANA
Up to 80%; speckled pattern associated with SS-A and SS-B
SS-A (Ro)
6095%; responsible for neonatal lupus (only about 2% of

SS-A-positive women will have babies with neonatal lupus)
SS-B (La)
4090%
ANA
6090%; variable pattern
Myositis-specic antibodies:
Anti-synthetase including Jo-1
20%; associated with anti-synthetase syndrome; more

common in PM than DM
Anti-signal recognition
Not routinely measured
Anti-Mi-2
Myositis-associated
antibodies: includes anti-PMScl, anti-U1RNP, anti-Ku
ANA
Up to 90%; nucleolar pattern reasonably specic
Scl-70
~50%
Centromere
~10%
ANA
Up to 90%; nucleolar pattern reasonably specic
Centromere
~80%
Scl-70
<10%
Mixed connective
tissue disease
ANA
>90%
RNP
Approaches 100% sensitivity; also found in SLE and

scleroderma
Antiphospholipid
syndrome (APS)
Cardiolipin
Lupus inhibitor
Beta2-GP-1
Demonstration of one of these antiphospholipid antibodies

necessary for diagnosis of APS; 25% of SLE patients are
antibody-positive
Granulomatosis with
polyangiitis (Wegeners
granulomatosis)
c-ANCA (proteinase 3)
>90%
p-ANCA (myeloperoxidase)
Occasional
Microscopic
polyangiitis
80%
Occasional
Eosinophilic
granulomatosis with
polyangiitis (Churg
Strauss syndrome)
50%
Occasional
Polymyositis (PM)/
dermatomyositis (DM)
Scleroderma
CREST syndrome
554
AUTOANTIBODY
C.
The results show strongly positive anti-cardiolipin and beta-2-glycoprotein 1 antibodies, consistent with the antiphospholipid syndrome (APS), and very likely to have caused a thromboembolic stroke. The lupus inhibitor is not present,
as evidenced by the normal DRVVT and phospholipid neutralization, and normal APTT.
Russell viper venom (RVV) contains a coagulant that activates factor X, which in turn converts prothrombin into thrombin
in the presence of phospholipid and factor V. The DRVVT will therefore be prolonged in the case of either the presence
of an inhibitor of phospholipid or a deciency of factor V or prothrombin. In the laboratory, a standard sample of RVV and
phospholipid is used that will give a clotting time within a range when combined with normal serum. Abnormal serum that
contains some types of antiphospholipid antibody will result in a prolonged time. The lupus inhibitor prolongs the DRVVT,
whereas most other anti-cardiolipin and beta-2-glycoprotein 1 antibodies do not.
Without anti-coagulation, this patient is at high risk of further thrombosis. Antiplatelet therapy is not adequate therapy, and
there is no evidence that both anticoagulation and antiplatelet therapy need to be used concurrently in APS. Technically,
the presence of the anti-cardiolipin antibodies needs to be documented on two occasions 12 weeks apart for the
diagnosis of APS, but there is no reason to use enoxaparin for 3 months rather than warfarin.
In the unlikely event that the anti-cardiolipin antibody levels are no longer elevated when checked at 3 months, and if
no other predisposing factors to stroke have been identied in this patient, it would still be advisable to continue lifelong
anticoagulation.
8 E.
A mutation in TACI is found in a small number of patients with common variable immunodeciency (CVID). This case
history is typical of CVID, which tends to come on in teenagers or young adults, and classically results in recurrent
respiratory tract infection. IgG subclass deciency has not been shown to signicantly increase the risk of recurrent
infection. Complement deciencies usually present with invasive infection due to encapsulated organisms, such as
Neisseria meningitides or Streptococcus pneumoniae. Neutropenic disorders are more likely to present with abscesses,
septicemia, and oral mucosal infections. Reduced levels of T cells are associated with opportunistic viral and fungal
infections.
9 D.
In this situation, the most likely explanation for the loss of viremic control is non-adherence to therapy. There are multiple
possible explanations for this: adverse drug reactions, concern over long-term medication use, psychosocial factors, or
simple difficulty with remembering to take daily medication. It is important to explore these issues with the patient and use
this opportunity to reinforce the importance of adherence. Drug resistance is very possible if adherence has been patchy,
and a change of therapy may be required once the results of resistance therapy are available. Any change, however, is best
made with knowledge of the resistance pattern. It is advisable to check the T-cell count at this point, especially if a change
in therapy is likely.
555
CHAPTER 18
MUSCULOSKELETAL MEDICINE
Kevin Pile
CHAPTER OUTLINE
AN APPROACH TO A PATIENT WITH
PAINFUL JOINTS
History
Examination
Investigations
RHEUMATOID ARTHRITIS (RA)
Genetics and environmental contribution to RA

Pathology
Diagnosis
Investigations
Treatment
Conclusions
SPONDYLOARTHROPATHIES

CRYSTAL ARTHROPATHIES
Gout
Pseudogout
RELAPSING POLYCHONDRITIS (RP)

OSTEOARTHRITIS (OA)
Clinical features
Investigations
Treatment
GENETIC CONNECTIVE TISSUE DISORDERS

PAINFUL SHOULDERS
Clinical assessment
Examination
TENNIS ELBOW AND GOLFERS ELBOW

PLANTAR FASCIITIS
FIBROMYALGIA
Investigations
Prognosis, differential diagnosis and treatment
SEPTIC ARTHRITIS
Investigations
Treatment
ACUTE LOW BACK PAIN

Specic pathology leading to acute low back pain
Management
Outcome
CHRONIC LOW BACK PAIN

Clinical assessment
Invasive treatment
557
Musculoskeletal disease and/or injury is an almost universal

human experience. Multiple branches of medicine deal with
varying aspects of the musculoskeletal system, but it is the
internist who will often be required to make the more difficult diagnoses, and institute and supervise an increasingly
sophisticated array of available treatments, particularly for
chronic conditions.
AN APPROACH TO A PATIENT
WITH PAINFUL JOINTS
History
You should assess the following:
Are the symptoms related to a musculoskeletal problem,
and which part?
Was there an identified trigger or precipitant?
Why has the patient presented at this time?
What has been the pattern or progression of symptoms?
Are there features of a systemic illness or inflammatory
symptoms?
Has anything helped the problem?
Pain and loss of function are primary presenting symptoms,
and while usually coexistent this is not always the case.
Is the pain in a joint; in a related joint structure such as
tendon, ligament or bursa; or in a bone?
What is the nature of the pain; when does it occur; and
what is the effect of movement? The red flag for malignant pain is a dull, deep ache within a bone that occurs
at night or when resting. Similar symptoms may occur
with Pagets disease or with a fracture.
The cardinal features of the joint pain will often help distinguish inflammatory from mechanical etiologies (Box
18-1).
Onset of symptoms following specific trauma selfevidently supports mechanical disruption of a joint, its
surrounding capsule and ligaments, or a bone fracture.
Box 18-1
Differentiators of joint pain

Inammatory
musculoskeletal pain
Pain and stiffness
predominant in the
morning and the end of
the day
Stiffness for >30 minutes
Symptoms lessen with
activity
Pain does not improve
with rest
Localized erythema,
swelling, tenderness
Systemic features
fatigue, weight loss
Non-inammatory/
mechanical pain
Short-lived joint
stiffness
Pain worsens with
activity
Pain improves with rest
Less obvious triggers to explore are infectious exposures

(Box 18-2), which should include vaccinations (rubella)
and recent travel (Lyme disease after tick bites).
The Togaviridae family of viruses, which include the
arthropod-borne alphavirus, and rubella virus are a
significant cause of arthritis worldwide.
Viruses such as Ross River, chikungunya, onyongnyong, Barmah Forest, Mayaro and Sindbis are
associated with outbreaks of viral arthritis in South
America, Europe, Africa, Asia and Australia.
Several infections may not be overtly symptomatic (e.g.
a rash may not be seen or may be quite mild in Ross
River or Barmah Forest virus infection), or the site of
infection may produce no symptoms (e.g. chlamydial
urethritis/cervicitis with resultant reactive arthritis).
The connection between genitourinary symptoms and
arthritis will not be self-evident to patients.
The majority of viral arthropathies resolve within
68 weeks, and can be excluded from the differential
diagnosis of chronic arthropathies.
Box 18-2
Common infections associated with arthritis

Viral*
Hepatitis B, hepatitis C
Rubella
Parvovirus
Arbovirus
Coxsackievirus
Cytomegalovirus
Varicella
*
Gastrointestinal
Salmonella typhimurium
Shigella exneri
Yersinia enterocolitica
Campylobacter jejuni
Serology should be tested according to exposure.
558
Genitourinary
Chlamydia trachomatis
Gonococcus spp.
Chapter 18 Musculoskeletal medicine
A comprehensive family history is a key part of each and

every history.
A familial pattern of a specific diagnosis such as rheumatoid arthritis, ankylosing spondylitis or systemic lupus
erythematosus (SLE) highlights that particular diagnosis
and may also raise related diagnoses that are particularly
relevant for seronegative spondyloarthritides, such as
psoriasis or inflammatory bowel disease in first-degree
relatives.
A family history of other, non-musculoskeletal autoimmunity such as thyroid disease or type 1 diabetes
mellitus is also a risk factor for autoimmune arthritis.
Examination
The examination of a patient with arthritis identifies the
pattern and number of joints involved and whether extraarticular features are present, as detailed in Table 18-1. The
cardinal features of inflammation are sought:
systemic featurestemperature, pulse and blood pressure
joint featureslocalized erythema and warmth, tenderness to touch, soft boggy inflammation obscuring the
joint margins, and reduced function.
Due to its prevalence, coexisting osteoarthritis is common,
and hence the patient may well have the hard bony swelling
of osteophytes in the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints of the hands, in addition to
the inflammatory findings.
Examination will reveal:

how many joints are involved, separating monoarthritis from oligoarthritis (4 joints) and polyarthritis
(>4 joints)
whether these joints are large or small
whether there is spinal (particularly sacroiliac) involvement.
Distal to the wrist and ankle there are at least 56 joints, so
that as the number of joints increases in the hands and feet,
the pattern becomes increasingly symmetrical.
As well as a joint focus, the fingernails are assessed for
pitting or onycholysis suggestive of psoriasis, and the scalp,
umbilicus, natal cleft and extensor surfaces of the knee and
elbow should be inspected. The presence of a malar rash or
photosensitive rash in a young woman who has additional
constitutional features would elevate SLE in the differential
diagnosis.
CLINICAL PEARL
Parvovirus B-19 may cause an acute symmetric polyarthritis and aplastic anemia with a positive rheumatoid
factor.
Table 18-1 Patterns of arthritis
PATTERN
MONOARTHRITIS
INFLAMMATORY
SPINAL DISEASE
SACROILIITIS
ASYMMETRICAL
LARGE JOINT
ARTHRITIS
SYMMETRICAL
SMALL JOINT
ARTHRITIS
(MCP, PIP, MTP)
DIP HANDS
Differential
diagnosis
Trauma
Hemophilia
Septic
Gout
Pseudogout
Ankylosing
spondylitis
Psoriatic arthritis
IBD
Psoriatic arthritis
Reactive arthritis
IBD
RA
SLE
Psoriatic arthritis
Inammatory OA
(if involves PIP and
1st CMC)
Psoriatic arthritis
Further
investigations
X-ray
Aspirate for
crystals and
culture
Review personal
and family history
HLA-B27
X-ray lumbar spine
and SI joints
Review personal
and family history
Examine scalp
and buttocks for
psoriasis
Examine for
conjunctivitis and
urethritis
Infection screen
Examine for
rheumatoid
nodules, skin
rashes, serositis or
mucositis
Urinalysis
RF, CCP
antibodies, ANA
X-ray hands and
feet
X-ray hands
ANA, anti-nuclear antibodies; CCP, cyclic citrullinated peptides; CMC, carpometacarpophalangeal; DIP, distal interphalangeal; HLA, human
leukocyte antigen; IBD, inammatory bowel disease; MCP, metacarpophalangeal; MTP, metatarsophalangeal; OA, osteoarthritis; PIP,
proximal interphalangeal; RA, rheumatoid arthritis; RF, rheumatoid factor; SI, sacroiliac; SLE, systemic lupus erythematosus.
559
Investigations
Investigations serve four purposes:
1 to confirm or refute a diagnosis
2 to monitor for known complications of the disease or
the treatment
3 to identify a parameter that changes with disease activity or treatment
4 to contextualize the presenting problem, e.g. are there
coexisting medical conditions in the patient which may
have an impact on the diagnostic or therapeutic process?
The last includes the non-specific inflammatory markers
ESR (erythrocyte sedimentation rate) and CRP (C-reactive
protein). If a persons joints are hot and swollen upon examination, the ESR or CRP result is not diagnostic but it is a
parameter to monitor.
CLINICAL PEARLS
Whenever the possibility of a septic joint is considered, aspiration of the joint is mandatory. Aspirated
uid should be sent to the laboratory for crystal
microscopy, cell count and differential, Gram staining, culture and sensitivities. Specic tests for tuberculosis and fungal infection may be indicated.
On a joint aspiration, 5000/mm3 white cells suggests rheumatoid arthritis, spondyloarthopathies,
gout or pseudogout; 5000 white cells/mm3 is
likely to be septic arthritis.
RHEUMATOID ARTHRITIS (RA)

Rheumatoid arthritis is a chronic inflammatory disease
affecting the synovium, and leading to joint damage and
absorption of adjacent bone.
The overall incidence of RA is 2050 per 100,000 per
year, and the prevalence ranges from 0.31.1%.
Age of onset peaks in the 5th decade, and females are 23
times more likely to be affected than males, although
the sex distribution becomes less apparent with increasing age.
Apart from the suffering and disability caused by the
disease, it also has a significant impact on life expectancy, with RA patients living on average 310 years less
than unaffected patients in the background population.
Risk of RA is associated with human leukocyte antigen

(HLA) DR4 and DR1 alleles, which have similar betachain sequences, potentially affecting the selection and
presentation of arthritogenic peptides to CD4+ T cells.
The HLA component accounts for only 30% of the
genetic risk of RA, and other genes associated with RA
include tumor necrosis factor alpha (TNF-alpha); peptidyl arginine deaminases (PADIs) that catalyze the citrullination of arginine residues and, therefore, determine
the level of citrullinated peptides; and PTNP22 (tyrosine phosphate non-receptor type 22) that has also been
linked with type 1 diabetes and autoimmune thyroid disease, due to reduced deletion of autoreactive T cells.
Smoking is the most potent environmental trigger, with
smokers at two- to fourfold increased risk of RA and heavy
smokers being at higher risk than light smokers.
Smoking is associated with citrullination of alveolar
proteins throughout the body, with citrullinated antigens binding with more affinity to HLA-DR4.
More severe rheumatoid disease is seen in smokers with
erosive arthropathy, rheumatoid nodules, and vasculitis.
The increased risk of RA persists for up to 20 years after
cessation of smoking.
Susceptibility
Subclinical
Environmental:
Smoking
Infections (e.g. EBV)
Low UV (vitamin D)
Periodontal disease
Silica exposure
Dietprotective:
Omega 3
Mediterranean diet
Fruit
Vitamin C
Occupation:
Agriculture
Postal and print
Mineral oil exposure
Disease onset
Genetics and environmental

contribution to RA
The etiology of RA is complex, involving interplay between
genetic and environmental factors (see Figure 18-1).
The prevalence of RA in first-degree relatives of RA
sufferers is approximately 10 times that of the background population.
The major susceptibility gene for RA (HLA-DRB1)
is located in the class II histocompatibility region on
chromosome 6p.
560
Genetic:
Family history
Other autoimmune disease
HLA-DR4/DR1
Female gender
PTPN22 gene
Smoking
Aging
Estrogen withdrawal
Decreased androgen levels
Socioeconomic status
Manual work
Progression
and impact
Figure 18-1 Development of rheumatoid arthritis.

EBV, EpsteinBarr virus; HLA, human leukocyte
antigen; PTPN22, protein tyrosine phosphatase
non-receptor type 22
Workers exposed to silica dust (drilling or crushing rock) are

at up to a threefold risk of RA.
It is not clear why the prevalence of RA is so much
higher in women compared with men. Estrogen exposure
in women has a protective effect, with a decreased incidence
of RA noted among users of oral contraceptive pills. This is
consistent with increased risk of the disease after the menopause, and the slight protective effect of using hormone
replacement therapy.
The strongest evidence of an infectious trigger for RA is
with EpsteinBarr virus (EBV), the glycoprotein of which
has cross-reactivity with the HLA-DRB1 shared epitope.
Increased incidence and levels of EBV DNA have been
reported in peripheral blood mononuclear cells and synovial
fluid of RA patients, and the virus is well described to have
immunomodulatory properties.
One of the more interesting infectious links brings together
the long-described association of periodontitis with RA, and
the more recent anti-cyclic citrullinated peptide antibodies
(anti-CCP antibody; sensitivity 76%; specificity 96%).
Pathology
The underlying pathology of RA transforms the synovium
into a chronically inflamed tissue.
The normally thin synovial layer thickens dramatically
due to accumulation of macrophage-like and fibroblastlike synoviocytes.
The sub-synovial layer becomes edematous, hypervascular, and hypercellular with the accumulation of
macrophages, mast cells, CD4+ T cells, CD8+ T cells,
natural killer (NK) cells, B cells and plasma cells.
The increased number of cells in the synovium in RA
is believed to result from recruitment of blood-derived
leukocytes, as well as increased proliferation and reduced
apoptosis.
Neutrophils are abundant in rheumatoid synovial fluid
but are sparse within the synovium.
In concert with this inflammatory process, the inflamed
synovium invades adjacent cartilage and bone.
Cartilage injury is caused by the generation of degradative enzymes including matrix metalloproteinases, and
aggrecanases.
Cytokines released from synovial tissue affect distant
chondrocyte production in the extracellular matrix.
Bone injury is separately mediated by a process of
osteoclast activation. Osteoclast activation occurs via a
receptor known as RANK (receptor activator of nuclear
factor kappa-B). The ligand system for this receptor,
RANKL, is a member of the TNF superfamily. It is
produced in the inflammatory setting by osteoclasts
after stimulation by cytokines released from macrophages and/or fibroblasts.
CLINICAL PEARL
Rheumatoid arthritis involves the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints,
but not the distal interphalangeal (DIP) joints.
Box 18-3
1987 ACR criteria for RA

1 Morning stiffness of greater than 1 hours duration.
2 Objective evidence of joint inammation such as
soft-tissue swelling or uid in 3 of 14 dened joint
areas (being right or left PIP, MCP, wrist, elbow, knee,
ankle, and MTP joints).
3 At least one of the joint areas demonstrating
inammation must be in the hands.
4 Simultaneous involvement of the same joint area
bilaterally in at least one pair.
5 Rheumatoid nodules.
6 A positive rheumatoid factor using a method that is
positive in <5% of normal subjects.
7 Typical changes of RA in hand and wrist X-rays, which
must include erosions or unequivocal periarticular
osteopenia.
ACR, American College of Rheumatology; MCP,
metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal
interphalangeal; RA, rheumatoid arthritis.
Diagnosis
The American College of Rheumatology (ACR) has developed criteria for the epidemiological classification of RA
(requires a patient to meet four of seven criteria; Box 18-3).
Clinical features should have been present for at least 6weeks.
The newer 2010 ACR criteria (Table 18-2, overleaf)
allow the diagnosis of RA to be made earlier, but include
a greater percentage of persons who subsequently go into
remission and may not have had classical RA. Definite RA
requires a score of 6 or greater.
CLINICAL PEARL
The American College of Rheumatology scoring system
reinforces the mental picture of rheumatoid arthritis (RA)
as one of peripheral small joint polyarthritis of greater
than 6 weeks duration, with laboratory evidence of
acute inammation and serology suggestive of RA.

Rheumatoid arthritis is a systemic disease with predominant
articular manifestations, but also includes myriad extraarticular disease encompassing most systems.
Synovitis manifests as tender, hot and functionally
restricted joints, and in RA has a predilection for the
PIP, MCP, wrist and MTP joints.
More proximal joints such as ankle, knee, shoulder,
cervical spine and temperomandibular joint can also
be involved.
Synovial tissue also surrounds many tendons, with
resultant swelling and pain.
As disease progresses, the synovial inflammation secondarily destabilizes the supporting joint ligaments and
tendon pulleys, allowing subluxation.
561
Table 18-2 2010 ACR criteria for RA
SCORE
A. Joint involvement
The classical deformities of RA are volar subluxation of the hand at the wrist with ulnar deviation,
and subluxation of the fingers at the MCP joints
with ulnar deviation.
The fingers themselves may develop either swanneck deformity (hyperextension of the PIP joint,
with flexion of the DIP joint) or boutonniere
deformity (flexion of PIP joint, with hyperextension of the DIP joint)and both may occur within
the same person. See Figure 18-2.
1 large joint (shoulder, elbow, hip, knee,

ankle)
210 large joints
13 small joints (MCP, MTP, PIP, wrist)
410 small joints
CLINICAL PEARL
>10 joints (at least 1 small joint)
While the presenting complaint may relate to the hands,

an examination and palpation of the metatarsophalangeal joints is essential and will often reveal unrecognized synovitis, which often begins in the 4th joint.
Later dorsal subluxation at this joint leads to severe pain
due to weightbearing on the metatarsal heads, callous
formation on the soles of the feet, and abrasions on
the subluxed toes from rubbing on footwear.
B. Serology (at least one result needed)

Negative RF and negative CCP antibodies
Low positive RF or low positive CCP (13 w

upper limit of normal [ULN])
High positive RF or high positive CCP
C. Acute-phase reactants (at least one needed)

Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
D. Duration
<6 weeks
6 weeks
ACR, American College of Rheumatology; CCP, cyclic

citrullinated peptides; CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate; MCP, metacarpophalangeal; MTP,
metatarsophalangeal; PIP, proximal interphalangeal; RA,
rheumatoid arthritis, RF, rheumatoid factor.
Extra-articular manifestations should be considered. They

include:
scleritis and corneal thinning leading to rupture
pleural effusions
pulmonary fibrosis
pericarditis
vasculitic ulcersparticularly nailfold infarcts, leg ulcers
rheumatoid nodulesskin and lungs
mononeuritis multiplex
atlanto-axial subluxation with spinal cord compression
(C1C8 dermatomes and any paresthesiae or hyperreflexia should be checked for)
Feltys syndrome (splenomegaly, neutropenia)
A
Figure 18-2 (A) Hyperextension of the proximal interphalangeal (PIP) joints and hyperexion of the distal
interphalangeal (DIP) joints in the right hand, demonstrating the swan neck deformity. (B) Hyperexion of the
PIP and hyperextension of the DIP joints, which is the boutonniere deformity
From: (A) Sebastin SD and Chung KC. Reconstruction of digital deformities in rheumatoid arthritis. Hand Clinics 2011;27(1):87104.
(B) Canale ST and Beaty JH (eds). Campbells Operative orthopaedics, 12th ed. Philadelphia: Elsevier, 2013.
562
large granular lymphocyte (LGL) syndrome (splenomegaly, neutropenia, infections, risk of leukemia)
Raynauds phenomenon
cricoarytenoiditis (if an RA patient has neck pain, sore
throat or hoarseness, cricoarytenoiditis must be ruled
out before intubating because of the risk of airway
collapse)
pyoderma
secondary Sjgrens syndrome
anemia
thrombocytosis
peripheral neuropathy.
Investigations
There are no specific tests to confirm the diagnosis of RA.
Investigations are undertaken to:
support the differential diagnosis
clarify the impact and severity of the diagnosis at that
time
detect physiological changes that will affect management.
Rheumatoid factor (RF) is a polyclonal antibody predominantly of the IgM and IgG (immunoglobulin) classes, which
targets the Fc region of IgG.
While commonly thought to have diagnostic significance by both doctors and patients, it has a very poor
predictive value, being present in only 70% of RA
cohorts and also present in at least 5% of the normal
population. The resulting lack of specificity for RA can
lead to confusion, and unnecessary treatment.
RF positivity increases with age, and is positive in any
circumstance with prolonged antigen stimulation such
as malaria, bronchiectasis, and tuberculosis.
Anti-cyclic citrullinated peptide (anti-CCP) antibody is a
useful diagnostic test for RA. The sensitivity is of the same
order as RF. The specificity improves when anti-CCP antibodies and RF are present concurrently.
CLINICAL PEARLS
Rheumatoid nodules and rheumatoid factor (RF)
positivity are linked pathologies, with the presence
of nodules almost guaranteeing the presence of RF,
but not vice versa. RF positivity is associated with
increased joint erosions, and vasculitis.
The patient with a swollen calf and RA or osteoarthritis (OA) may have ruptured a Bakers cyst
examine the posterior knee for a cyst.
X-ray changes in RA mirror the joints clinically involved,

primarily affecting the hands, the PIP and MCP joints, and
the wrists. Soft tissue swelling occurs early, with periarticular osteopenia noted, and subsequently symmetrical joint
space narrowing. Erosions, when they occur, begin at the
site of synovial lining of the joint capsule, reflecting onto
the cartilage/periosteum junctions so that they occur slightly
distant from the joint surface.
The inflammatory process affects other investigations

nonspecifically, with no findings unique to RA.
Erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP) will both be raised in accordance with
the inflammatory process, and will act as a monitor of
therapy with the goal being their normalization.
CRP is the first to rise and fall after an inflammatory
stimulus, and is the preferred measurement for monitoring success in suppressing joint inflammation, particularly in RA.
CLINICAL PEARL
Despite lack of specicity, C-reactive protein will be the
rst inammatory marker to rise and fall, and is the preferred way to monitor joint inammation.
The blood film commonly will show:

inflammatory thrombocytosis
normochromic normocytic anemia
hypochromic microcytic anemia due to iron deficiency,
which can occur after prolonged inflammation due to
the inflammatory process blocking the utilization of the
bodys iron stores; concomitant therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs) may cause
genuine iron deficiency via gastrointestinal blood loss
often, a neutrophil leukocytosis induced by corticosteroids.
The standard clinical examination should include urinalysis,
with the presence of proteinuria or leukocytes warranting
further microscopy and evaluation.
Investigations should also include:
electrolytes, urea and creatinine
liver function tests (potential hepatotoxicity with some
treatments).
Treatment
To minimize the morbidity of RA, long-term management of patients is required, based on drug treatment, nonpharmacological approaches including physiotherapy, and
psychosocial support. As yet there are no reliably curative
or disease-remitting therapies, although considerable gains
have been made recently with the advent of biological therapies for this condition.
Traditional disease-modifying anti-rheumatic

drugs (DMARDs)
There is no way of predicting who will respond to a particular therapy, either a conventional DMARD or a biological
DMARD, and therefore a decision pathway must be used. A
pathway for treating RA is shown in Figure 18-3 (overleaf),
with adjunct therapy of oral steroids, joint injections, and
hydroxychloroquine used as required.
Intra-articular and/or low-dose oral corticosteroids are
frequently administered as bridging therapy until the
effect of DMARDs is fully established.
563
In some patients they are used long-term with

DMARDs, in order to satisfactorily suppress the disease.
Corticosteroids may also be used alone in the elderly for
disease control, if this can be achieved with a daily dose
equivalent to 7.5mg prednisolone or less.
Methotrexate underpins current treatment regimens, and
may be commenced alone or in combination with leflunomide or sulfasalazine. If disease remission cannot be achieved
using these agents within 69 months, then consideration of
biological agents should be made.
Methotrexate is currently the gold standard DMARD,
with doses accelerated to achieve 2025 mg/week
within 68 weeks of commencement, with folic acid
supplementation of 5mg/week.
Objective outcomes need to be recorded, including:
swollen and tender joint counts
inflammatory markers (ESR, CRP)
a quality of life/functional index.
The principal side-effects of methotrexate include:
bone marrow suppression (note that trimethoprim is an
anti-folate and must be avoided because this can induce
cytopenia)
pneumonitis (not dose-related)
liver fibrosis
hepatitis
nausea
mouth ulcers.
Failure to achieve remission of disease activity after a maximum of 34 months of methotrexate therapy should result in
an escalation to combination therapy, or switching of therapy.
Leflunomide is administered at 20mg daily, and sulfasalazine is commenced at 500mg daily and increased at
500mg/week to 2g daily, and occasionally to 3g daily.
Biological agents targeting specific cytokines such as

TNF (adalimumab, golimumab, infliximab, etanercept, certolizumab), and interleukin-6 (tocilizumab),
or that block cell-to-cell signaling such as that through
CTLA4-Ig (abatacept) are becoming increasingly used
in those who do not respond quickly to standard therapy, and may become standard or first-line therapy as
cost reduction alters their costbenefit profile.
CLINICAL PEARLS
Despite the development of biological agents,
methotrexate remains the anchor drug (alone or in
combination) for the majority of patients with rheumatoid arthritis.
Anti-tumor necrosis factor therapy should not be
utilized in patients with any demyelinating disorder,
or severe congestive heart failure.
Omega-3 oil supplementation

Inflammation is characterized by the production of
arachidonic-acid-derived
eicosanoids
(prostaglandins,
thromboxanes, leukotrienes). Long-chain omega-3 fatty
acids, eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) have anti-inflammatory properties when taken
in doses greater than 2.7 g daily, and are of proven benefit in RAincluding reduced morning stiffness, decreased
tender joint count, and a lessened need for treatment with
NSAIDs.
Monitoring of DMARD and biological therapies

All RA patients requiring immunosuppressive therapy
should be screened for hepatitis B and C and for tuberculosis, according to local guidelines.
Table 18-3 describes a guide for monitoring antirheumatic therapy.
Joint injection
Oral steroids
Hydroxychloroquine
Methotrexate
Leflunomide
Abatacept
Sulfasalazine
Tocilizumab
Etanercept
Adalimumab
Golimumab
Infliximab
Certolizumab
Figure 18-3 Schema of rheumatoid arthritis therapy

564
Table 18-3 Monitoring of anti-rheumatic therapy
THERAPY
BASELINE MONITORING
PERIODIC MONITORING
NSAIDs
BP, edema, K+, creatinine
K+ and creatinine at 1 week

BP and edema at each clinical visit
Annual FBC
Methotrexate
Chest X-ray, hepatitis B and C serology, FBC,

LFT
FBC, LFT at 46 weekly intervals

Chest auscultation at each clinical visit
Sulfasalazine
FBC, LFT
FBC, LFT monthly w 3, then 3-monthly
Leunomide
Chest X-ray, hepatitis B and C serology,

FBC, LFT
FBC, LFT at 46 weekly intervals; extend to

12-weekly when stable
Chest auscultation at each clinical visit
Anti-TNF therapy
Chest X-ray, hepatitis B and C serology

Screen for latent TB, as per local guidelines
As clinically indicated
BP, blood pressure; K+, serum potassium; FBC, full blood count/screen; LFT liver function tests; NSAIDs, non-steroidal anti-inammatory
drugs; TB, tuberculosis; TNF, tumor necrosis factor.
Conclusions
Early recognition of RA and undifferentiated poor-prognosis
arthritis, and prompt disease suppression with DMARDs
and prednisolone, are key to the initial improvement of the
patients quality of life and to minimizing subsequent progressive joint damage.
Methotrexate retains its key role in the treatment of
RA and, while there remains controversy over unequivocal demonstration of the superiority of combination therapy, several studies do support the concept. Some of the best
evidence in support of combination therapy is that of TNF
blockers when combined with methotrexate, in which the
combination is significantly superior to monotherapy with
either agent with respect to clinical, functional and radiographical outcome.
Reactive
arthritis
Ankylosing
spondylitis
Psoriatic
arthritis
Spondyloarthropathies
Synovitis and enthesitis
RF negative
Young male preponderance
Family history
HLA-B27 linked
Mucocutaneous features
Spinal inflammation
Sacroiliitis
IBD-associated
arthritis
SPONDYLOARTHROPATHIES
The spondyloarthropathies are a group of disorders characterized by inflammation of the spine and sacroiliac joints,
and may include an oligoarthritis with a preference for
hipand shoulder joints. Ankylosing spondylitis (AS) is the
prototypic disease, and as a group they share several common factors, as depicted in Figure 18-4.
The principal diagnoses are AS, psoriatic arthritis (PsA),
reactive arthritis (ReA), and inflammatory bowel disease
(IBD)-associated arthritis. Common to many classifications is
an undifferentiated spondyloarthropathy and a juvenile-onset
chronic arthritis. Despite the separate diagnoses and mucocutaneous manifestations, there is significant overlap, with:
subtle colitis and terminal ileitis in AS
the palmar lesions of reactive arthritis being histologically indistinguishable from pustular psoriasis
the presence of high bacterial populations in psoriatic
plaques possibly inciting a reactive component.
The key and unique pathology of spondyloarthropathies is
enthesitis/enthesial inflammation (inflammation of tendon
Figure 18-4 Relationships within

spondyloarthropathies. HLA, human leukocyte
antigen; IBD, inammatory bowel disease; RF,
rheumatoid factor
and ligament insertions into bone), which occurs at sites of

physical stress.
Easily identified sites of enthesitis are plantar fasciitis, or
Achilles tendinitis.
The same pathology occurs within the axial skeleton,
where inflammation of the spinal longitudinal ligament
and intervertebral disc insertions causes pain on movement and ultimately calcification and fusion.
This fibrotic response at sites of inflammation also links
the spondyloarthropathies with:
ascending aortitis
anterior uveitis
apical lung fibrosis.
565
Synovitis varies between different group members, but is

usually an asymmetric small- and large-joint lower-limb
arthritis that may represent an extension of enthesitis
from the surrounding joint capsule into the synovium.
The spondyloarthropathies present a clinical spectrum, with
AS as a strongly HLA-B27 related spinal/sacroiliac disorder,
ReA as a predominantly lower-limb asymmetric arthropathy only moderately associated with HLA-B27, and PsA in
between (see Figure 18-5).

Ankylosing spondylitis is a chronic progressive inflammatory
disorder predominantly affecting the sacroiliac joints and
spine (spondylitis), leading to fusion of vertebrae (ankylosis).
Affecting 0.11.4% of the population, its prevalence
is underestimated due to misdiagnosis of degenerative
back disease.
The typical age of onset is between 17 and 35 years,
with a male predominance of 3:1.
With an over 90% genetic contribution there is a strong
family history to be elicited, and the HLA-B27 association explains 2050% of genetics, possibly via dysregulated immunity to gut bacteria.
Sacroiliac (SI) inflammation causes pain localized over the
SI joints, with pain extending into the buttocks that may
radiate to the thighs but not below the knee. The presenting symptoms are of insidious low-back pain persistent for
at least 3 months, worsened by inactivity and improved by
exercise.
CLINICAL PEARL
Features strongly indicative of an inammatory basis
of back pain are insidious onset at age <40 years,
improvement with exercise and no improvement with
rest, with pain at night (particularly the early morning).
Ankylosing spondylitis
Predominantly
spinal/sacroiliac and large
proximal joints, i.e.
shoulders and hips
HLA-B27 95%
Reactive arthritis (RA)

Predominantly asymmetrical
large joint arthritis of lower
limbs
HLA-B27 40%
Psoriatic arthritis
Mixed spinal/sacroiliac and peripheral large and
small joint involvement
Spinal and sacroiliac
disease
HLA-B27 5060%
Peripheral large and small

joints less association with
HLA-B27; HLA-DR4 related,
similar to RA
Overall HLA-B27 3540%
Figure 18-5 Relationship of the

spondyloarthropathies to HLA-B27
566
The consequence of enthesial inflammation of the spine

is progressive spinal pain, and restriction of movement in all
directions that is clinically evident first in the lumbar region
and progresses to involve the whole spine.
Over time the classical AS posture (Figure 18-6) develops:
forward thrust and flexed neck
increased abdominal girth
loss of lumbar lordosis
flexed hips and knees.
Objective documentation of spinal disease includes:
occiput to wall distance
degree of cervical rotation and lateral flexion
reduced chest expansion (supplemented by pulmonary
function testing)
lumbar flexion measured as Schobers indexthe
Schobers test is a clinical measurement of lumbar spine
mobility, and a reduction of the index is likely in AS
lumbar lateral flexion measured as fingertip to floor
distance.
The ability to touch your toes is a composite of lumbar
flexion, hip movement and hamstring stretch, and is unreliable in AS.
CLINICAL PEARLS
Ankylosing spondylitis restricts spinal movement in
all directions. Degenerative spinal disease is predominantly in one plane.
Dactylitis (or a sausage-shaped digit) is caused by
both synovitis and enthesitis in more than one digit,
and is a key sign of a spondyloarthropathy.
Nonspecific constitutional features of inflammation,

such as fatigue, anorexia and weight loss, are present proportional to disease activity, although profound weight loss
warrants investigation for IBD.
Ankylosis of the spine, in addition to restricting a range
of daily activities, increases the risk of spinal fracture from
minor trauma, with potential spinal cord injury or cauda
equina syndrome.
Additional extra-articular complications are
uveitis
aortitis with aortic insufficiency
cardiac conduction defects
restrictive lung disease secondary to pulmonary fibrosis
restricted thoracic wall movement; this may lead to reliance on diaphragmatic breathing, with marked abdominal wall excursion
Achilles tendinitis.
Diagnosis
The ASAS (Assessment of SpondyloArthritis International
Society) classification criteria for ankylosing spondylitis in
a person aged <45 years, with back pain for >3 months, are:
sacroiliitis on X-ray or magnetic resonance imaging
(which will detect earlier features) plus one or more
additional feature
Treatment
A key platform of therapy is exercise to maintain the
spine in an erect and normal position, with maintenance
of a normal range of spinal movements, and spinal muscle strength.
NSAIDs assist in reducing symptoms to allow exercise
to be undertaken, with participation in group activities
aiding adherence.
Regular NSAID use may slow X-ray progression, but
has to be balanced against gastrointestinal and renal
toxicity.
Sulfasalazine, and methotrexate and other DMARDs,
have no proven benefit in axial arthritis but may be useful in peripheral joint disease.
Anti-TNF agents have made a large difference to the
management of AS. They significantly improve patientreported outcomes of disease activity, pain and fatigue,
along with reduced acute phase reactants and spinal
movement scores. Retardation of radiological progression is yet to be demonstrated.
Figure 18-6 Typical posture of patient with
ankylosing spondylitis; note the exed neck,
protruberant abdomen, and loss of lumbar lordosis
or
the presence of HLA-B27 and two features from:
inflammatory back pain
arthritis
enthesitis
uveitis
dactylitis
family history of spondyloarthritis
psoriasis
raised CRP
inflammatory bowel disease
NSAID-responsive.
CLINICAL PEARL
Sacroiliitis is not always present on plain X-rays. Reliance on the presence of unequivocal sacroiliitis on
plain X-rays delays both the diagnosis and the management, and in 510% of cases will prevent the diagnosis
being made at all.
Laboratory testing
Before testing HLA-B27, you need to consider the family
history and your clinical confidence.
AS has a 95% association with HLA-B27, so if AS is
present in a first-degree relative then there is 50% random chance of finding a positive result.
810% of the normal population carry HLA-B27, so
a positive result with an uncertain clinical presentation
is unlikely to help, although the absence of HLA-B27
would make you rethink the diagnosis.

Skin disease
Psoriasis is characterized by red, scaly, raised silvery
plaques within a well-demarcated patch, typically
occurring on the scalp, elbows and knees.
Pitting of the nails is a strong clue that a rash may be
psoriatic. Psoriasis is common in Caucasians, with a
prevalence of around 2%. It is much less common in
Asians.
There is a family history of psoriasis in one-third of
patients.
Joint disease
Arthritis occurs in 1040% of cases. A clinical clue is
sausage-shaped digits.
Compared with AS there is a more equal sex distribution.
85% of patients have developed skin lesions in the
510 years before the onset of joint disease.
Around 10% develop psoriasis and PsA contemporaneously.
5% have a pattern of PsA with psoriasis developing
later.
As illustrated in Figure 18-5 above, the spectrum of PsA is
broad and may mimic any form of inflammatory arthritis.
Table 18-4 (overleaf) compares PsA with RA.
CLINICAL PEARL
40% of patients with psoriatic arthritis will have only
spinal and sacroiliac disease resembling ankylosing
spondylitis, with the most common pattern an oligoarthritis of large and small joints.
567
Table 18-4 Comparison of psoriatic arthritis and

rheumatoid arthritis
PSORIATIC
ARTHRITIS
RHEUMATOID
ARTHRITIS
Small-joint
involvement
++
+++
DIP involvement
+++
Spine, sacroiliac
involvement
++
C-spine late
Enthesitis
+++
Synovitis
++
+++
Subcutaneous
nodules
++
Skin lesions
+++
RF-positive
+++
Anti-CCP
antibodies
+++
Inammatory
markers
++
+++
Family history
+++
CCP, cyclic citrullinated peptide; C-spine, cervical spine; DIP,

distal interphalangeal. RF, rheumatoid factor.
Less common in PsA is the small joint peripheral polyarthritis which resembles RA; the DIP-only pattern;
and the <5% pattern of arthritis mutilans in which
destruction of the PIP and DIP joints leads to operaglass fingers.
When assessing a patient for PsA, in addition to a confirmed personal or family history of psoriasis, examination of the scalp, natal cleft, umbilicus and extensor
surfaces for unrecognized psoriasis is required.
Psoriatic nail changes of pitting, transverse ridging and
onycholysis should be carefully sought.
There is no relationship between the extent of psoriatic skin
disease and the prevalence or severity of PsA.
CLINICAL PEARLS
Useful clues to psoriatic arthritis are distal interphalangeal inammatory disease, synovitis of interphalangeal (IP) joints in the toes, and sausage
digitsrepresenting synovitis of proximal and distal
IP joints with tenosynovitis and periostitis.
Sausage-shaped digits occur commonly in psoriatic
arthritis and reactive arthritis.
568
Treatment
As with all inflammatory joint disease, a program that maintains joint mobility and the strength of the supporting muscles is required. PsA can have an insidious pattern of joint
involvement so that at any one time the disease burden is
low, but it progressively damages and restrict joints and
function, particularly in the hands.
Physiotherapy and splintage assist with joint protection,
and single or small numbers of inflamed joints can be
injected with corticosteroids.
Care is required with the use of oral corticosteroids as
they may cause rebound skin lesions if rapidly reduced.
In patients with predominant synovitis the management
is similar to RA, with methotrexate used to treat both
skin and joint lesions. Sulfasalazine and leflunomide
may also be used.
Anti-TNF agents have been successfully used, and there
is interest in the use of the IL-12/23 antagonist ustekinumab for both psoriasis and PsA.

Reactive arthritis is an aseptic joint inflammation that occurs
distant in both time and place from an inciting infection that
is usually of gastrointestinal or genitourinary origin.
Typically it affects young adults, with a very slight overall male predominance.
Onset is usually 721 days after the trigger.
HLA-B27 positivity is present in 6595% of cases.
Less than 5% of exposed persons will develop ReA.
The most common genitourinary trigger is Chlamydia
trachomatis, which can be detected by polymerase chain
reaction (PCR) analysis of a morning urine sample.
Chlamydial infection is commonly asymptomatic in
women, and should be tested in a woman presenting
with knee monoarthritis.
Gastrointestinal triggers are common food poisoning organisms, which will be evident on personal and
household contact history. PCR is replacing stool culture, and will allow detection of Salmonella typhimurium,
Shigella flexneri, Yersinia enterocolitica and Campylobacter
jejuni.
Rarer triggers include post-streptococcal ReA, and
Neisseria spp.
There is a high prevalence of human immunodeficiency
virus (HIV) infection in people with reactive arthritis,
and it may occur in the setting of acute infection.
The joint disease in ReA is an asymmetrical oligoarthritis,
or monoarthritis, usually of the lower limb. Most commonly there is involvement of the knee, ankle and hip, and
less often the shoulder and wrist. Enthesitis of the plantar
fascia and Achilles tendon are common.
The mucocutaneous manifestations of ReA are a sterile urethritis, balanitis, cervicitis, and conjunctivitis/uveitis.
An infrequent skin involvement is keratoderma blennorrhagica on the palms and soles, which is a pustular variant
of psoriasis.
Treatment
If the inciting trigger is identified, then this should be treated
and if possible avoided in the future. Most cases resolve
within 3 months, and require only simple management
involving analgesia, NSAIDs and intra-articular steroids.
However, a significant minority have disease severe enough
to require DMARDs. The morbidity from eye disease can
be severe, and necessitates specialist intervention.
CLINICAL PEARL
A small percentage of patients with reactive arthritis
develop a chronic destructive arthropathy requiring
the full range of disease-modifying agents (DMARDs),
initially with sulfasalazine, and at times progressing to
biological therapies.
An AS-type spondyloarthropathy is found in 220% of
patients with ulcerative colitis or Crohns disease, and
up to 60% of patients with AS are found to have subclinical inflammatory bowel disease (IBD) if the colon
and terminal ileum is examined and biopsied.
The HLA-B27 allele associates with the presence of
sacroiliitis, which may be asymmetrical compared with
the symmetry of AS.
Peripheral arthritis is not HLA-B27-associated and is
an asymmetrical oligoarthritis, often monoarthritis,
involving knees, ankles and MTP joints.
Treatment of the IBD generally also reduces the joint
disease.
Hyperuricemia is the primary risk factor for gout, with a

risk that increases exponentially with the serum uric acid
(UA) level.
The prevalence of hyperuricemia is 1020% in some
populations, although the majority of patients with
hyperuricemia do not develop gout.
Currently, asymptomatic hyperuricemia does not warrant treatment, but this is likely to require review with
increasing evidence of a relationship between hyperuricemia and hypertension, renal disease, metabolic syndrome, diabetes, and cardiovascular disease.
Serum UA levels are determined principally by genetic
polymorphisms of renal urate transporters and glucokinase regulatory proteins.
Genetically predisposed people may subsequently
develop gout if they are exposed to other risk factors
such as a high purine diet, obesity, increased alcohol
consumption, or diuretic use.
Etiology
Uric acid is the end-product of purine metabolism in
humans (Figure 18-7), due to the absence of uricase
activity.
This lack of uricase activity, combined with kidneys
that efficiently reabsorb 90% of filtered UA, and eating habits that create high amounts of purine, result
in a UA normal range of 0.360.42 mmol/L, which is
very close to or above the 0.41 mmol/L saturation concentration of many tissues and exceeds that of cooler
peripheries. This contributes to UA crystallization
within the joints and to the creation of tophi (Figure
18-8, overleaf).
Box 18-4 (overleaf) lists secondary factors to be considered.

Clinically this presents with polyarthritis, fever and a
salmon-pink rash, but it is uncommon. Very elevated serum
ferritin levels are typically found. There may be hepatitis.
Aggressive immunosuppression is usually required, with
biological therapy worth considering.
CRYSTAL ARTHROPATHIES
Hypoxanthine
Inosine
Xanthine
oxidase
Adenosine
Xanthine
Gout
Gout is an intensely painful acute inflammatory response to
monosodium urate crystals within the joint.
More than 1% of adult men in Western countries have
gout, with significant increases in prevalence occurring
secondary to obesity, insulin resistance, low-dose aspirin, diuretics for hypertension, and longevity.
Gout affects men four times more than women, and
most often develops after the age of 45 years, although
earlier gout occurs particularly in men with a family history of gout or a history of heavy alcohol consumption.
In women estrogen has a uricosuric effect, so gout is
most often of postmenopausal onset.
Guanosine
Xanthine
oxidase
Urate
Uricase
Allantoin
CO2 / H2O2
Figure 18-7 Purine pathway producing urate

569
Diets high in low-fat dairy products are associated with

reduced risk.
Fructose-rich fruits (apples, oranges) are associated with
a modestly increased risk of gout.
Coffee consumption reduces the risk of gout.
In prospective studies, beer has the greatest effect on gout
risk, then spirits, whereas wine has no increased risk.
CLINICAL PEARL
An elevated uric acid level does not indicate that the
diagnosis is goutit only indicates an increased risk
ofgout.
Diet and alcohol

The relative risk of gout is higher in people who eat a
diet high in red meat.
Diets high in purine-rich vegetables (peas, beans, lentils,
mushrooms and asparagus) do not increase the risk.
Stages of gout
The first stage is asymptomatic hyperuricemia, a
common physiological abnormality which in most
people is not associated with the development of gout.
Figure 18-8 Tophaceous gout
Box 18-4
Causes of hyperuricemia
A. Increased uric acid production (10%)
Obesity
Myeloproliferative disease
Pagets disease
Alcohol
Psoriasis
Hemolysis
Rhabdomyolysis
Glycogen storage diseases (types III, V, and VII)
Inborn errors of metabolism (including hypoxanthine
guanine phosphoribosyltransferase [HPRT] deciency)
570
B. Decreased uric acid excretion (90%)

Renal impairment
Starvation
Polycystic kidney disease
Acidosis (ketoacidosis, lactic acidosis)
Toxemia of pregnancy
Hypothyroidism
Hyperparathyroidism
Bartter syndrome
Diabetes insipidus
Down syndrome
Sarcoidosis
Lead poisoning
Drugs:
aspirin
diuretics
ethambutol
L-dopa (levodopa)
pyrazinamide
Asymptomatic hyperuricemia does not need to be

treated.
The second stage is characterized by periodic attacks
of acute gout with asymptomatic interludes. The frequency, duration and severity of the acute gout tends to
increase over time. Patients develop a marked systemic
illness with fevers, chills and intense pain that escalates
over 612 hours.
Finally, chronic gout may develop with the development of tophaceous deposits and a chronic arthropathy
overlaid with intermittent flares.
Acute gout
Acute gout attacks can be triggered by direct trauma to the
joint, dehydration, acidosis, alcohol intake, administration
of chemotherapy, or rapid weight loss. A common trigger
is intercurrent illness, or surgery, that causes an acute phase
response, causing an increased urinary excretion of UA,
subsequent lowering of serum UA levels with partial crystal
dissolution, and encouragement of crystal shedding into the
joint fluid.
The vast majority of first attacks affect only a single
joint, typically the great toe MTP joint (podagra), but
oligoarticular and polyarticular gout can occur, especially in the elderly.
Distal and cooler joints are characteristically targeted,
possibly due to the reduced solubility of UA in these
joints: midfoot, ankle, finger joints, wrists, and knees.
Attacks commonly start in the early morning, awakening the patient from sleep with rapid development of
severe pain and tenderness over 624 hours.
One of the characteristic features of acute gout attacks
is that they are self-limiting, and resolve spontaneously
regardless of treatment within several to 14 days.
Diagnosing gout
The purist approach is to establish the presence of negatively birefringent intracellular UA crystals in the joint
fluid of an inflamed joint (Figure 18-9). In reality, the
classically inflamed podagra/1st MTP joint is a difficult
joint to aspirate.
A practical diagnosis can be made using a typical presentation such as podagra with a current or recent history of
hyperuricemia.
Strong supporting evidence is the presence of tophi, or
documented joint crystals during an inter-critical (clinically quiescent) period.
CLINICAL PEARL
If septic arthritis is suspected, or if a larger joint is
involved, then joint aspiration for Gram staining and
culture in addition to crystal identication is required.
Figure 18-9 Needle-shaped urate crystals (yellow

and blue) under polarizing microscopy (crystal color
depends on orientation relative to the polarizer; the
blue crystals are at 90 to the yellow)
CLINICAL PEARL
Remember the joint aspiration changes in gout and
pseudogout:
Goutnegative birefringence, yellow needles
Pseudogoutweakly positive birefringence, blue
rhomboids
Acute gout management

Acute gout will spontaneously get better, so the goal of therapy is provision of pain relief and reduction in the duration
of acute inflammation. NSAIDs and colchicine are the most
widely prescribed agents, with corticosteroids (oral, intramuscular, intra-articular) also of value.
NSAIDs are effective in reducing pain if used in full
doses; options include indomethacin 50mg three times
daily, diclofenac 50 mg three times daily, celecoxib
100 mg twice daily, and etoricoxib 120 mg daily. All
of these agents work quickly but should be limited to
7days duration.
Colchicine use for the management of acute gout
should be restricted to when NSAIDs and corticosteroids are contraindicated, ineffective or cause unacceptable side-effects. Start with two 0.5mg tablets followed
by 0.5mg one hour later, and then 0.5mg twice daily
for 24 days maximum.
Colchicine adverse effects of nausea, vomiting
and diarrhea occur in 2575% of patients prescribed 1.54.5mg daily, and occur in all patients
on higher doses. Severe adverse effects include
bone marrow suppression, neuromyopathy and
rhabdomyolysis.
CLINICAL PEARL
Gout and septic arthritis can coexist, and joint aspiration
can also identify the calcium pyrophosphate dihydrate
(CPPD) crystals of pseudogout.
Colchicine should not be prescribed to be taken until

diarrhea develops.
571
Oral corticosteroids are useful in patients in whom

NSAIDs or colchicine are contraindicated due to
comorbid factors.
Prednisolone or prednisone 2550mg daily is often
needed to ensure adequate control of acute gout.
Comparative studies equate prednisolone 3035mg/
day to indomethacin 50 mg three times daily and
naproxen 500 mg twice daily respectively, with
equal efficacy in reduction of pain, and similar
adverse events.
In those in whom you wish to avoid oral steroids, intraarticular steroid injection can be undertaken.
Chronic gout management/urate-lowering

options
In a patient with recurring attacks of acute gout, the goal
is to reduce the frequency and severity of acute attacks
over the next 1218 months, so that they eventually
disappear.
The initiation of therapy may induce mobilization
flares of gout, and a plan of managing these acute attacks
needs to be in place.
In addition to medical therapy, a dietary review should
take place, and patients should be advised to maintain a
high water intake to assist with urate excretion.
CLINICAL PEARL
Urate-lowering agents need to be used long-term, and
currently lifelong therapies should be commenced
when gout is severe, as indicated by:
recurrent ares (particularly polyarticular)
deforming and destructive tophaceous deposits
the presence of renal calculi.
of patients. It occurs 26 weeks after treatment is

started, with features of toxic epidermal necrolysis,
exfoliative dermatitis, fever, eosinophilia, liver and renal
dysfunction, vasculitis, and bone-marrow suppression.
Allopurinol should never be re-tried in such situations.
Extreme caution is required with the co-administration
of allopurinol, azathioprine, or mercaptopurine.
The co-prescription of ampicillin/amoxicillin with
allopurinol should also be avoided due to an increased
frequency of skin rash.
CLINICAL PEARL
Urate-lowering agents such as allopurinol or probenecid should not be initiated, ceased or adjusted during
an acute attack of gout. The unstable serum uric acid
level will cause additional crystal shedding and worsen
the attack.
Probenecid
Probenecid blocks the proximal tubular reabsorption of uric
acid.
Its starting dose is 250mg daily for 1 week, increasing to
250mg twice daily, and then very gradually the dose is
titrated against serum UA up to a maximum of 1000mg
twice daily.
The net effect of probenecid is increased urinary excretion of UA, and it is contraindicated in patients with
coexisting renal stones.
Probenecid may potentiate the toxicity of methotrexate,
and aspirin should be avoided as at any dose it antagonizes the action of probenecid.
Pseudogout
The goal of therapy is to achieve a serum urate level of
0.300.36 mmol/L, and therapy is stepwise escalated until
this target is reached. Treatment is initiated slowly and at
low levels during a quiescent phase of gout, although in
some patients with frequent attacks it can be initiated when
the acute attack is controlled and while the NSAID or
corticosteroid is being continued.
Allopurinol
Allopurinol blocks the metabolic conversion of hypoxanthine to uric acid (Figure 18-7), and can cause a rapid reduction in serum UA, resulting in mobilization flares.
Allopurinol should be commenced at 50 mg/day for
2 weeks, prior to increasing to 100mg/day.
Subsequently, serum UA should be measured 34
weeks after the dose increase, and stepwise increases
of 100 mg continued until the target serum UA of
0.30 mmol/L is achieved.
Minor self-limiting drug reactions are relatively common, affecting 210% of patients, and include itching,
rash and gastrointestinal problems.
The more serious and potentially fatal allopurinol hypersensitivity is far less common, estimated at 0.0020.4%
572
The most frequent manifestation of CPPD-deposition disease is chondrocalcinosis, the asymptomatic radiographical
finding of calcification of articular or fibro-cartilage.
Up to 5% of the worlds population show radiographical
evidence of chondrocalcinosis, with the incidence rising with age to 1540% of those >60 years of age, and
3060% of those >85 years old.
The acute symptomatic presentation of chondrocalcinosis is termed pseudogout, on the basis of its similarity to
gout in terms of acute and painful joint inflammation.
A less common chronic arthropathy is most common in
elderly women; while usually mild, it can lead to quite
severe and rapidly destructive arthritis. The 2nd and 3rd
MCP joints are most commonly those severely affected.
The presentation of pseudogout is of an inflammatory
arthropathy with loss of function, early-morning stiffness and improvement with activity. Other manifestations
include: atypical forms of OA; severe destruction mimicking neuropathic arthropathy; a symmetrical synovitis similar to RA; and calcification of the intervertebral discs and
longitudinal spinal ligaments leading to restricted spinal
mobility, and hence resembling ankylosing spondylitis but
without sacroiliitis.
Box 18-5
Conditions associated with calcium

pyrophosphate dihydrate (CPPD)deposition disease
Secondary to underlying medical conditions
Hyperparathyroidism
Hypophosphatasia
Hemochromatosis
Hypomagnesemia
Familial hypocalciuric hypercalcemia
Possibly hypothyroidism
Chronic gout
Secondary to underlying cartilage alterations
Aging and possibly osteoarthritis
Postmeniscectomy
Epiphyseal dysplasia
iron
ATP
AMP
pyrophosphatase
activity
Human ANKH
mutation
CLINICAL PEARL
extracellular
pyrophosphate
iron, Fe3+ > Fe2+
A systemic response to pseudogout is noted in half of

patients with fever, neutrophil leukocytosis, and raised
inammatory markers.
crystal nucleation
A definitive diagnosis of CPPD-deposition disease requires

unequivocal identification of weakly positively birefringent
rhomboid or rod-shaped CPPD crystals in joint fluid or
articular cartilage.
Aspirated fluid is often turbid or bloodstained, with
reduced viscosity and a marked neutrophil leukocytosis.
Articular cartilage at any site may demonstrate chondrocalcinosis, with the classical sites being the triangular ligament of the wrist, the pubic symphysis, and the
menisci of the knee.
It has been proposed that the presence of CPPD crystals in synovial fluid combined with radiographically
observed calcification of the cartilage would make a
definitive diagnosis and either one would make a probable diagnosis. The absence of chondrocalcinosis does
not exclude the diagnosis of CPPD.
Although many metabolic and endocrine diseases are
reported to predispose to CPPD deposition, the better
evidence for an association lies with hyperparathyroidism, hemochromatosis, hypophosphatasia, and hypomagnesemia (see Box 18-5 and Figure 18-10). The
presence of a CPPD arthropathy in a patient younger
than 50 years, or in those with florid polyarticular
Hypophosphatasia
Alkaline
phosphatase
Hypomagnesemia
CPPD deposition is associated with acute attacks of

pseudogout, characterized by joint effusions with marked
neutrophilia.
The release of CPPD crystals into a joint space is followed by neutrophilic phagocytosis, with subsequent
release of potent chemoattractant and inflammatory
mediators.
Pseudogout most commonly involves the knees, followed by the wrists, metacarpophalangeal joints, hips,
shoulders, elbows, and ankles.
The joint distribution may provide a clue to CPPD
disease, as primary OA rarely involves the MCP joint,
wrist, elbow, shoulder or ankle. CPPD crystals, however, may also be found in the synovial fluids of primary
OA, either alone or in association with basic calcium
phosphate crystals.
Tenosynovitis is also reported, and is associated with
tendon rupture.
Soft tissue CPPD deposits may present as tumor-like
masses.
Acute attacks of pseudogout may be precipitated by local
events that induce crystal shedding from cartilage into the
synovial fluid, such as trauma, arthroscopy or intra-articular
injection of high-molecular-weight hyaluronic acid as a
viscosupplement. Systemic changes affecting calcium concentration, such as rapid changes in fluid balance, medical
illness, commencement of thyroxine replacement, or parathyroid surgery, can also induce an acute attack.
Hypercalcemia
Hypomagnesemia
CPPD disease
Figure 18-10 Metabolic factors predisposing to

calcium pyrophosphate dihydrate (CPPD)-deposition
disease. AMP, adenosine monophosphate; ANKH,
inorganic pyrophosphate transport regulator; ATP,
adenosine triphosphate
chondrocalcinosis, should lead to a complete investigation for an underlying metabolic disorder.
Treatment
The therapeutic options for pseudogout are more limited
than for gout. Symptomatic therapy with NSAIDs, colchicine, joint aspirations, intra-articular steroids, and nonpharmacological support are the main approaches to acute
management of the acutely inflamed joint. There is currently no specific treatment to slow or prevent the gradual
joint deterioration due to chondrocalcinosis, or the progression of the crystal deposition itself, other than treatment of
any underlying biochemical or metabolic disorders.
573
RELAPSING POLYCHONDRITIS
(RP)
Relapsing polychondritis is a rare condition of unknown
etiology characterized by repeated inflammation of cartilaginous structures. An autoimmune, cell-mediated
response to type II collagen leads to inflammation of the
elastic cartilage of ears and nose, the hyaline cartilage of
peripheral joints, vertebral fibro-cartilage, and tracheobronchial cartilage.
The classical presentation is of acute painful inflammation of the cartilaginous pinna of the ear, with sparing
of the ear lobule. Often misdiagnosed as infection, the
sparing of the non-cartilaginous lobe is a clue, and often
the attacks become bilateral.
Nasal chondritis and inflammation of eyelids occurs,
with saddle-nose deformity (Figure 18-11) a complication of distal septal inflammation.
Arthritis is the second most common presentation, with
involvement of the small joints of the hands, knees and
ankles.
Recurrent involvement of the trachea can lead to
tracheomalacia and obstruction.
During the course of the illness, nearly half the patients
will experience deafness due to involvement of Eustachian tube inflammation, and vestibulo-cochlear nerve
inflammation.
Less commonly, aortitis and aortic regurgitation can
develop, along with large vessel and leukocytoclastic
vasculitis.
RP has been described in association with major vasculitides, and connective tissue disorders such as RA and systemic
lupus erythematosus. There are no specific investigations,
with diagnosis being made on clinical grounds.
Figure 18-11 Saddle-nose deformity

From Bennett HS and Reilly PG. Restylanea temporary alternative
for saddle nose deformity in nasal Wegeners granulomatosis: how
we do it. Br J Oral Maxillofacial Surg 2011;49(4):e3e5.
574
RP is a relapsing disorder, and the treatment depends on

the severity of disease and the end organs involved.
Mild symptoms may only require analgesics and
NSAIDs, with colchicine and dapsone used for more
persistent symptoms.
Severe manifestations require pulse and oral prednisolone, with additional therapy as per vasculitis and renal
involvement utilizing methotrexate, cyclophosphamide
and mycophenolate.
CLINICAL PEARL
Saddle-nose deformity (nasal septal collapse) occurs
in granulomatosis with polyangiitis and relapsing polychondritis.
OSTEOARTHRITIS (OA)
The global impact of osteoarthritis on the health system
is enormous, particularly in an aging population with its
associated obesity and metabolic disorders. It is crucial to
identify and promptly provide effective treatment to these
patients to reduce pain, improve quality of life, and avoid
potentially painful and crippling sequelae of the disease.
Individual therapeutic strategies continue to provide suboptimal management, and future research directions will
include new therapies and combine multiple therapies.
Osteoarthritis can be subdivided into primary or secondary
types, as described below.
1 Primary or idiopathic osteoarthritis can be subclassified
into localized or generalized, with commonly affected sites
including the hands, feet, knees, hips and spine. Generalized osteoarthritis usually affects three or morejoints.
2 Conditions that alter the balance of cartilage wear or
damage, and repair processes, may contribute to the
development of secondary osteoarthritis. These conditions or diseases include:
a joint inflammation, e.g. RA, that induces enzymatic destruction of the collagen matrix and
aggrecan molecules which are integral to cartilage
b direct trauma to cartilage or its vascular supply, and secondary biomechanical derangement,
increasing local wear
c congenital and acquired disorders of joint morphometry, which leads to local wear
d obesity with increased mechanical load, and concomitant decreased mobility
e obesity-associated metabolic syndrome with
insulin resistance, which causes elevated inflammatory cytokines secondary to the accumulation,
and activation of proinflammatory cells within the
adipose tissue, particularly the abdomen
f certain occupations (e.g. farmers), and repetitive
high-impact sports
g other diseases such as diabetes mellitus, acromegaly, hypothyroidism
h neuropathic (Charcot) arthropathy.
Clinical features
CLINICAL PEARL
Pain is the predominant symptom in patients with
osteoarthritis, which is typically worse with activity and
relieved by rest. Pain occurring at rest and at night signies more advanced disease. Evening stiffness is the
hallmark of osteoarthritis, while morning stiffness lasting longer than 30 minutes is more suggestive of an
inammatory arthropathy.
Signs of osteoarthritis include the following:

Altered gait from hip, knee, ankle or foot involvement.
Joint tenderness on palpation, which is easily elicited on
superficial peripheral joints such as the hands, knees and
feet, and is not necessarily accompanied by joint swelling.
Crepitus or creaking from the joints, which may be
both felt and heard by the patient, and can be elicited
by placing a palm on the joint and objectively feeling for
disrupted joint movements.
Osteophytes, which may be palpable as bony protrusions along the edge of the joint, and are easily seen and
felt at the DIP joints of the hand.
Joint effusions which, if present, are usually cool to the
touch.
Analysis of synovial fluid shows mild inflammation
(white cell count of less than 2000 cells/mm3), and
slightly elevated protein levels. It should be negative for
culture and crystals.
CPPD-deposition disease may mimic the clinical course of
osteoarthritis or cause secondary osteoarthritis, which may
be evident radiographically.
Psoriatic arthritis is the great mimic, and can present
in many forms, including only DIP joint disease. Marked
inflammation of the DIP joints, without palpable osteophytes, and with concomitant evidence of psoriasis in the
nails or skin, is suggestive of PsA. Synovitis of the interphalangeal joints of the toes is also a helpful clue which points to
psoriatic arthritis rather than osteoarthritis.

Hands
The hands are commonly involved in OA, with bony
osteophytic changes known as Heberdens nodes
(Figure 18-12) and Bouchards nodes affecting the distal
and proximal interphalangeal joints, respectively.
The first carpometacarpal joint can also be affected, giving the physical appearance of a squared hand due to
subluxation of the thumb under the palm.
Figure 18-12 Heberdens nodes of the distal

interphalangeal joints
From Abishek A and Doherty M. Diagnosis and clinical presentation
of osteoarthritis. Rheum Dis Clin North Am 2013;39(1):4566.
Figure 18-13 Hallux valgus

From Coughlin MJ, Saltzman CL and Anderson RB (eds). Manns
Surgery of the foot and ankle, 9th ed. Philadelphia: Elsevier, 2014.
Ankle disease of the talonavicular and subtalar joints is

often secondary to trauma and ligamentous instability.
Knees
Physical findings on examination of the knees may
underestimate the degree of knee involvement.
Malalignment of the knees may occur in advanced
disease, giving the physical appearance of genu varum
(bowed legs) or genu valgum (knocked knees), and is
associated with more rapid progression of OA of the
knees.
Bakers cyst, a fluctuant swelling in the posterior aspect
of the knees, may also be elicited.
Feet
Varying degrees of foot involvement can occur.
The first metatarsophalangeal joint can cause a bunion (hallux valgus) deformity (Figure 18-13) or hallux
rigidus.
Hips
OA of the hip is typically associated with pain and limited range of motion, and the development of a limp
aimed at reducing pain.
575
It is important to distinguish referred pain to the hip

(from the lumbosacral spine or knee) from greater trochanteric bursitis, which is felt laterally with a normal
range of passive motion.
Pain worsens with weightbearing and is usually localized to the groin or medial thigh.
Spine
OA of the spine typically occurs in the areas of greatest
spinal flexibility, at levels C5 to C7 and L3 to L5, with
relative sparing of the thoracic spine.
It is important to recognize that cervical and lumbar
spondylosis may occur due to osteophytes originating
from the diarthrodial facet joints, combined with intervertebral disc narrowing and hypertrophic vertebral spur
formation, which impinges on the spinal canal or exiting nerve root, potentially causing neurological deficits.
Paraspinal muscle spasm is a common clinical finding.
In severe OA, spondylolisthesis (forward slipping of a
vertebral body) can be seen. It is usually demonstrated
at levels L4 to L5.
Shoulders
Glenohumeral joint involvement typically causes
chronic anterior shoulder pain, made worse on movement, particularly abduction.
Acromioclavicular joint involvement may cause diffuse
shoulder pain, or pain in the anterior shoulder, and may
not be immediately evident as OA of the shoulder.
Investigations
Uncomplicated OA with typical clinical characteristics rarely
warrants further investigation. However, further laboratory
testing and imaging may be carried out in patients with:
isolated knee or hip symptoms, without other evidence
of OA
atypical joint involvement (e.g. shoulder, elbow, wrist
and ankle)
sudden onset of severe joint pain.

This is to ensure that important inflammatory and infective
causes are not missed.
Septic arthritis should always be considered in a systemically unwell patient, and requires joint aspiration and
culture even in joints classically affected by OA.
Radiographical severity may not correlate with clinical severity, and early findings are often nonspecific.
X-ray distinctions between OA and RA are shown in
Table18-5.
Treatment
In general, therapeutic options are non-pharmacological,
pharmacological and surgical (Figure 18-14). Factors to
consider when managing a patient with OA include:
prior perception and knowledge of OA, including its
treatment
treatment efficacy and adverse effects
cost, availability and logistics of treatment modality
the presence of comorbid disease
functional activity, including work and recreational
aspirations
Non-pharmacological options
Non-pharmacological therapy should always be part of a
patients management strategy, because it may significantly
reduce pain and disability and may reduce or negate the
need for pharmacological treatment.
Exercise and activity should be prescribed to all patients
with large joint involvement, regardless of their age. It
provides a distraction as part of a cognitivebehavioral
approach to pain management, utilizes endorphin
release, and provides psychological benefit from
improved overall wellbeing and control of pain.
Some patients may benefit from physiotherapy sessions.
Aerobic exercise improves wellbeing, and benefits
patients with obesity and hypertension.
Table 18-5 Comparison of radiographical features of osteoarthritis and rheumatoid arthritis
RADIOGRAPHICAL
FEATURE
OSTEOARTHRITIS
RHEUMATOID ARTHRITIS
Clinical pattern
Distal interphalangeal and 1st

carpometacarpal joints, and less often
proximal interphalangeal joints
Proximal interphalangeal and

metacarpophalangeal joints, and wrist,
plus deformities
Joint-space narrowing
Localized to one side, or compartment

of joint
Diffusely throughout joint
Periarticular erosions
Absent
Present
Subchondral bony change
Sclerosis
Osteopenia
Subchondral cysts
Present
Absent
Osteophytes
Present
Absent
576
Assess non-pharmacological interventions for all patients according to

individual needs at all stages of OA (e.g. weight loss, exercise)
How severe is the pain?
Management of mild to moderate persistent symptoms

zSimple analgesiaacetaminophen (paracetamol)
zTrial short-term topical NSAIDs or capsaicin
zTrial short-term oral NSAIDs
Management of moderate to severe persistent symptoms

zContinue acetaminophen (paracetamol)
zContinue oral NSAIDs (with caution)
zOpioid therapy for severe symptoms where surgery
is contraindicated or not yet available
Management of acute flare of symptoms

zStep up/add therapy as needed
zConsider intra-articular corticosteroid
injection
Consider referral for orthopedic assessment

zIn cases of severe osteoarthritis and if
patients fail to respond to conservative
therapy
Figure 18-14 Recommended therapeutic approach to hip and knee osteoarthritis (OA). NSAIDs, non-steroidal
anti-inammatory drugs
Local neuromuscular training increases muscle strength,
and range of joint motion.
There is clear evidence that even modest weight loss
improves function and reduces pain in overweight
patients with OA, especially of the hip and knee.
Appropriate footwear (e.g. thick, soft soles; insoles),
walking aids, braces and slings are available, and may
improve symptoms of osteoarthritis significantly.
Transcutaneous electrical nerve stimulation (TENS)
and thermotherapy are safe and effective adjunct therapies in most patients with OA.
Tai chi and acupuncture may be of benefit by improving muscle tone and balance, especially if patients are at
risk or have a fear of falling.
Pharmacological options
Acetaminophen (paracetamol) is recommended as a
first-line option for patients with OA. It is inexpensive,
effective and well tolerated.
Doses of up to 1 g four times daily may be used;
however, under-dosing is common mainly due to
patients perceptions of its safety and the number
of tablets involved. Slow-release formulations allow
dosing three times daily.
Acetaminophen is thought to work via inhibition of
COX-3, and has little prostaglandin inhibition and
therefore no gastrointestinal, cardiovascular or renal
toxicity.
Topical NSAIDs are a popular option with patients and
are safer than oral NSAIDs (achieving systemic levels
15% that of orally taken NSAIDs).
Topical capsaicin is also a viable alternative.
Oral NSAIDs may be an option in patients unresponsive to acetaminophen or topical NSAIDs.
They may be used in combination with other

agents; however, potential side-effects include gastrointestinal, liver, renal and cardiovascular toxicity, especially in the elderly. NSAIDs should be
used at the lowest effective dose for the shortest
time possible.
If a patient has a history of peptic ulcer disease,
the use of antiulcer prophylaxis or a selective
COX-2 inhibitor should be considered. NSAIDs
should also be used with caution in patients taking
concomitant warfarin, because of the increased
risk of bleeding via NSAID-induced platelet
dysfunction.
There has been increasing global withdrawal of
COX-2 inhibitors from the market because of
increased adverse cardiovascular events in users.
COX-2 inhibitors may be an option for patients
at low cardiovascular risk, who have a history of
intolerance to COX-1 NSAIDs, or peptic ulcer
disease.
Mild to moderate opioids may be used in combination
with acetaminophen, although the need to use higher
dosages should alert the physician to the need for specialist referral and consideration for surgery, or the use
of a regional nerve block.
Low-dose amitriptyline (2550mg daily taken 2 hours
before bedtime) should be considered in patients with
refractory pain and poor sleep.
Depression is a common comorbidity, and should not
be overlooked.
Intra-articular glucocorticoids may be useful in patients
with mono- or oligo-articular involvement, and with
persistent symptoms despite the use of regular acetaminophen and/or NSAIDs. They may be utilized every
3months.
577
Surgery
Arthroplasty should be considered in patients with
severe and disabling hip or knee OA because it provides
the potential for pain control, restoration of function,
and improvement in quality of life.
Referral should be made before severe protracted pain
and functional limitation set in, because this may affect
the outcome negatively.
An aging yet active obese population affects the timing
of joint replacement surgery. The early and immediate
gain in quality of life needs to be balanced against the
increasing number of patients requiring revision of their
joint replacements later in life, with its currently poorer
outcome and increased perioperative morbidity and
mortality.
GENETIC CONNECTIVE TISSUE

DISORDERS
A number of inherited disorders of connective tissue, specifically mutations in genes encoding for collagen and elastin,
result in significant musculoskeletal abnormalities in addition to other organ defects. Three of the important diseases
are outlined in Table 18-6.
PAINFUL SHOULDERS
Shoulder pain is an almost unavoidable life experience, with
7% of an adult population reporting at least 1 month of shoulder pain in the previous year, and a quarter of 85-year-olds
suffering from chronic shoulder pain and restriction.
The peak annual incidence of shoulder disorders is in
the 4th and 5th decades, at a rate of 0.25%, with roughly
an equal sex incidence.
Up to 20% of patients with chronic shoulder pain, and

65% of all diagnoses, relate to lesions of the rotator cuff.
CLINICAL PEARLS
The localization of pain may be diagnostically helpful.
The pain-sensitive structures of the shoulder are
mainly innervated by the 5th cervical segment (C5),
so that pain from these structures is referred to the
C5 dermatome, creating the sensation of pain over
the anterior arm, especially the deltoid insertion.
The acromioclavicular joint is innervated by the C4
segment, so that pain arising here is felt at the joint
itself, and radiates over the top of the shoulder into
the trapezius muscle and up to the side of the neck.
Clinical assessment
In the elderly a history of trauma, marked night pain, and
weakness on resisted abduction, strongly suggests a rotator
cuff tear. The sleeping position that induces night pain is an
important clue in the history.
Shoulder pain that results in awakening when not lying
on the affected shoulder is found in frozen shoulder
(adhesive capsulitis) and inflammatory arthritis.
Pain when lying on the affected shoulder is seen in acromioclavicular joint disease and rotator cuff disease.
Prior shoulder problems suggest rotator cuff disease with
chronic impingement or calcific tendinitis.
A history of marked shoulder joint swelling suggests an
inflammatory arthropathy, with the presence of an anterior bulge in the shoulder usually secondary to a subacromial bursa effusion.
Glenohumeral OA is characterized by morning stiffness, pain with use, and chronicity of symptoms. OA
Table 18-6 Genetic connective tissue disorders
EHLERSDANLOS
SYNDROME
OSTEOGENESIS
IMPERFECTA
MARFAN SYNDROME
Genetics
1:5000 births
Abnormality in structure of
collagen due to 1 of 3 types of
mutation in the collagen gene,
affecting types I, III, and V collagen
1:10000 births
Abnormality in type I collagen
gene
1:4000 births
Abnormality in elastin due to
brillin gene mutation
Clinical
features
Joint hypermobility
Hyperextensible skin
Easy bruising
Delayed wound healing
Blood vessel abnormalities
Brittle bones with multiple

pathological fractures
Blue sclerae
Abnormal dentition
Overgrowth of long bones

High arched palate
Dislocated ocular lenses
Mitral valve disease
Aortic root aneurysms with aortic
incompetence
Diagnosis
Clinical; genetic testing may be

available
Skin biopsyabnormal collagen

production by broblasts
Clinical grounds
Treatment
Supportive
Bisphosphonates
Individual complications are

treated as they arise
578
is, however, significantly less common than rotator cuff

dysfunction.
Causes and characteristics of shoulder pain are outlined in
Table 18-7.
Examination
The contours of the shoulder are examined for wasting,
asymmetry and muscle fasciculations.
Palpation should proceed from the sternoclavicular
joint along the clavicle to the acromioclavicular joint, to
the tip of the acromion, and the humeral head beneath
theacromion.
The shoulder range of movement should be examined
both actively and passively, with muscle strength and
pain on resistance assessed. There are essentially three
movements to test in the shoulder:
abduction due to supraspinatus contraction
external rotation as a result of infraspinatus and teres
minor movement
internal rotation due to subscapularis movement.
the cuff between the proximal humerus and the acromioclavicular arch occurring from anomalies of the
coracoacromial arch (structural impingement), and
from instability due to joint hyperlaxity or weak rotator
cuff muscles (functional impingement).
Acquired impingement occurs secondary to osteophytes
growing from the acromioclavicular joint, or calcification of the acromioclavicular ligament.
Painful arc of abduction
acromioclavicular joint
180
Painful arc of
abduction in
rotator cuff
120
70

The glenohumeral joint is, by virtue of its anatomical
shape, reliant for its stability on the tendons and ligaments of the rotator cuff as well as the rotator cuff muscles (supraspinatus, infraspinatus, subscapularis, teres
minor) for additional stability.
The rotator cuff becomes compressed in the subacromial space as the arm is elevated, with impingement of
Figure 18-15 Painful arc. The patient slowly abducts

the arm as high as possible, describing symptoms
asthe arm rises
Table 18-7 Causes and clinical characteristics of shoulder pain
CATEGORY
CAUSE
CLINICAL FEATURES
Extracapsular
lesions
Rotator cuff, and subacromial bursae.g.

impingement syndromes, calcic tendinitis,
cuff tears, bursitis
Painful arc of abduction (Figure 18-15)

Pain on resisted cuff muscle movements, with
intact passive movement (allowing for pain and
guarding)
Pain on impingement maneuvers as the inamed
rotator cuff tendons impinge on the inferior surface
of the acromion, and coracoacromial arch
Intracapsular
lesions
Glenohumeral jointinammatory arthritis,

i.e. rheumatoid arthritis, spondyloarthritis,
pseudogout
Joint capsuleadhesive capsulitis
Bone diseasePagets disease, metastases
Loss of both active and passive movement

Reduced glenohumeral range
Night pain
Muscle strength, allowing for pain, is intact
Referred pain
Cervical spinefacet joint root impingement,

discitis
Brachial plexusbrachial amyotrophy
ThoraxPancoasts tumor
Thoracic outlet syndrome
Suprascapular nerve entrapment
Subdiaphragmaticabscess, blood, hepatic
lesions
Arm and hand pain with paresthesia

Marked muscle weakness and wasting
Neck pain and stiffness
Herpes zoster rash
Systemic features with weight loss
579
Complications of impingement include a frozen shoulder, rupture of the rotator cuff tendons, or rupture of
the long head of biceps.
CLINICAL PEARL
Three positive clinical tests (supraspinatus weakness,
weakness of external rotation, and impingement), or
two positive results for a patient older than 60 years,
are highly predictive of a rotator cuff tear.
Treatment
Treatment depends on the mechanism of impingement.
Patients with functional impingement are treated with
a resting sling for 2436 hours, pendular exercises, and
full-dose NSAIDs.
Structural impingement is treated similarly, but the
surgical options of arthroscopic surgery to remove
osteophytes or trim the acromion are available, after an
adequate trial of conservative therapy.
Corticosteroid injection to the subacromial space can be
combined with an initial 47 days of pendulum exercises and avoidance of abduction, prior to a program of
shoulder-strengthening exercises.

This common disorder (2% cumulative risk in an at-risk
population annually) is frequently misdiagnosed, and is
characterized by painful restriction of all shoulder movements, both active and passive, with characteristic restriction in the glenohumeral range.
There is marked reduction, or absence, of shoulder
external rotation at 0 abduction, reduction of both
internal and external rotation at 90 abduction, as well
as prominent restriction of placing the hand behind the
back on internal rotation.
Frozen shoulder is characterized pathologically by
fibrosis and retraction affecting predominantly the anterior and inferior structures of the glenohumeral joint
capsule.
Patients usually present in the 6th decade of life, and
onset before the age of 40 is very uncommon.
Box 18-6 lists the diseases associated with frozen shoulder, diabetes being the most significant. Diabetes, particularly longstanding type 1 diabetes mellitus, is associated
with glycosylation of subcutaneous collagen and the development of soft-tissue contractionso-called diabetic
cheiroarthropathy.
CLINICAL PEARL
When a diabetic patient presents with adhesive capsulitis, other diabetic complications, especially retinopathy
and nephropathy, are seen more frequently and should
be searched for.
580
Box 18-6
Common disorders associated with

frozen shoulder
Acute shoulder trauma, and shoulder immobilization

Diabetes mellitus
Thyroid disease (both hyper- and hypothyroidism)
Cardiac disease, particularly after cardiac surgery
Neurological disease with loss of consciousness, or
hemiplegia
Pulmonary diseasetuberculosis, carcinoma
Rotator cuff disease, especially cuff tear
Acute glenohumeral joint inammation
Three phases of frozen shoulder are recognized.

1 Painful inflammatory phase: beginning insidiously
with often only a minor injury being recalled, nocturnal awakening pain develops. The pain may be constant, and prevents the patient lying on the shoulder.
Studies suggest that this phase lasts 29 months.
2 Frozen shoulder: with time, the night and rest pain
eases but the shoulder remains frozen. Mean duration
is 412 months.
3 Recovery phase: after a mean delay of 526 months,
in the majority of patients shoulder limitation slowly
recovers toward normal range (usually a 1030% loss of
motion which is often undetected by the patient). The
total duration of symptoms lasts 1242 months, with
mean disease duration of 30 months.
Interestingly, 1020% of patients develop a contralateral frozen shoulder, usually milder than the first, while the original
shoulder is thawing.
Management
It is important to educate patients that the condition
will spontaneously resolve and the stiffness will greatly
reduce.
NSAIDs and analgesics can be used.
Exercise within the limits of pain achieves a better longterm outcome than intensive physiotherapy.
Patients who receive an intra-articular injection earlier
in the course of the disease recover more quickly compared with placebo.
For those unable to tolerate the pain and disability of a
frozen shoulder, manipulation under anesthesia (MUA)
is a reliable way to improve the range of movement.
Itis particularly indicated when disability persists after
6 months of non-operative therapy. Other surgical
approaches include arthroscopic release of adhesions,
and hydrodilatation.
Oral corticosteroid initially improves a frozen shoulder
with a modest benefit on pain and disability, and ability
to move the shoulder, but the effect does not last beyond
6 weeks.
TENNIS ELBOW AND GOLFERS

ELBOW
A small number of patients have recalcitrant lateral epicondylitis, and are considered for operative interventionopen,
arthroscopic, and percutaneous.
Tennis elbow, or lateral epicondylitis, is considered to be

an overload injury, which occurs after minor or unrecognized microtrauma to the proximal insertion of the extensor
muscles of the forearmparticularly extensor carpi radialis
brevis.
It is the most frequently diagnosed elbow condition,
occurring most commonly in middle life (3555 years
of age), and has an incidence in general practice of
47 cases per 1000 patients.
Despite its common name, most cases occur in nontennis players, and it is frequently a work-related
enthesopathy affecting up to 15% of workers in at-risk
industries which are characterized by highly repetitive
activities.
Both traction injury and ischemia appear to play a role in
the development of this lesion.
The clue to the diagnosis is exquisite tenderness distal to, or
anterior to, the lateral epicondyle. Resisted movement that
tightens the fascial origin of the extensor carpi radialis brevis, i.e. resisted wrist dorsiflexion and resisted finger extension, worsens the pain.
Golfers elbow, or medial epicondylitis, is the mirror image

of tennis elbow and is thought also to relate to repetitive
traction stress, and to microtears at the insertion of the forearm flexors (flexor carpi radialis) and pronator teres into the
medial epicondyle.
It occurs in both professional and amateur sports players, as well as manual workers such as bricklayers.
It is much less common than tennis elbow, being
approximately one twentieth as common.
Similarly to tennis elbow the diagnosis is clinical, with
localized tenderness which worsens on resisted wrist
flexion and forearm pronation.
CLINICAL PEARL
Diagnosis of tennis elbow:
Lateral elbow pain with tenderness on palpation just
distal to the lateral epicondyle
Worsening pain localizing to the lateral epicondyle
on resisted wrist dorsiexion
Treatment
It is usually a self-limiting condition, with the average
duration of a typical episode being 6 months to 2 years,
with 90% recovering within 1 year.
Various conservative interventions exist for the treatment of this condition, including pain-relieving medications, corticosteroid injections, physiotherapy, elbow
supports, acupuncture, surgery, and shockwave therapy.
Most important in treatment is activities modification;
both the frequency and the method of performance. In
the work setting a review by an occupational therapist
is recommended, focusing particularly on pronation/
supination movements and grip size.
A physiotherapy program that includes strengthening
exercises for the entire upper limb, and a graded resistive
program for wrist dorsiflexors, is recommended.
Injection of corticosteroid with local anesthetic into the
inflamed tendon may give short-term relief, but may be
offset by a poorer long-term outcome.
There may be a role for injection of platelet-rich plasma
into the tendon.
CLINICAL PEARL
Golfers elbow:
Elbow pain at the medial epicondyle
Increasing symptoms on resisted wrist exion, and
resisted forearm pronation
Treatment includes modication of activities, upper
limb exercises, and analgesics
PLANTAR FASCIITIS
Plantar fasciitis commonly causes inferior heel pain, and has
been reported to occur in up to 10% of the US population.
It affects both active and sedentary adults of all ages,
but is more likely to occur in those who are obese, who
spend most of the day on their feet, or who have limited
ankle dorsiflexion.
Plantar fasciitis is a musculoskeletal disorder primarily
affecting the fascial enthesis. Although poorly understood, the development of plantar fasciitis is thought to
have a mechanical origin.
The diagnosis is based on the history and physical examination (Box 18-7, overleaf).
Unaccustomed walking in the sedentary, or prolonged
running in the athlete, may induce fatigue tears of the
plantar fascia, and avulsion fracture may cause pain
at the medial calcaneal tuberosity. The same area is
involved in spondyloarthropathy (ankylosing spondylitis, psoriatic arthritis and reactive arthritis) as plantar
fascia enthesitis.
50% of patients with plantar fasciitis and 20% of persons without plantar fasciitis have heel spurs. The presence or absence of heel spurs is not helpful in diagnosing
plantar fasciitis.
Most patients with plantar fasciitis eventually improve,
although slowly, with 80% of patients treated conservatively in complete remission at 4 years. A variety of therapies
are utilized in the treatment of plantar fasciitis, including
581
Box 18-7
Diagnosis of plantar fasciitis
Chronic inferior heel pain on weightbearing:

throbbing, searing, piercing in character
Pain worst with the rst steps in the morning, or after
rest
Pain reduces after mobilization, to recur with
continued activity
Walking barefoot, on toes, or upstairs exacerbates pain
Tenderness around medial calcaneal tuberosity at the
plantar aponeurosis
Bilateral plantar fasciitis is highly suggestive of a
spondyloarthropathy
exercise, and the key recommendations are summarized in

Box 18-8.
Limited evidence supports the use of corticosteroid
injections to manage plantar fasciitis; the benefit is shortlived, and may be associated with serious adverse effects such
as fascial rupture.
FIBROMYALGIA
Fibromyalgia syndrome (FMS) is a soft-tissue musculoskeletal condition with many features in common with chronic
fatigue syndrome (CFS), the major difference being the
predominance of musculoskeletal features in FMS. Clinical
features of FMS are:
pain on both sides of the body
pain above and below the waist
pain in an axial distribution
increased tenderness on palpation, although a specific
number of trigger points is no longer required for
diagnosis.
FMS diagnosis is based on a composite Widespread Pain
Index (019) and Symptom Severity Score (012), with a
score 13 consistent with fibromyalgia (Figure 18-16). The
pain is often defined as aching or burning, and may vary
in intensity and location from day to day. Almost all people
Box 18-8
Therapeutic recommendations for

treating plantar fasciitis
582
Off-the-shelf (non-magnetic) insoles

Plantar fascia stretching is more effective than calf
stretching, and should be recommended to all patients
Corticosteroid iontophoresis should be considered for
short-term relief if initial therapy fails
Custom-made night splints
Walking casts in those who have failed conservative
therapy
Open or endoscopic surgery for those who have failed
all conservative measures
with FMS will describe muscular pain, fatigue, insomnia,

joint pain and headache, half having memory impairment,
poor concentration and paresthesiae, and one-third to onefifth experiencing anxiety and depression.
Musculoskeletal pain is, by definition, the most consistent feature of FMS.
Fatigue, for some patients, can be almost as debilitating.
Disordered sleep is also a very frequent feature, and
clearly contributes to the general feeling of fatigue
and to the mood disturbances. Sleep abnormalities are
strongly correlated with the alpha-EEG abnormality on
an electroencephalogram, and with movement disorders
including the periodic jerking of arms and legs, teeth
grinding (bruxism), and restless legs.
Gastroesophageal reflux disease (GERD) occurs with
high frequency, as does irritable bowel syndrome.
Headaches are a major feature in at least 60%, and may
be of the migraine or tension type.
Facial pain is also relatively common, including discomfort related to temperomandibular joint dysfunction.
Psychological and psychiatric morbidity is also increased
in patients with FMS. This may range from minor mood
disturbance to major depression. There is also a very high
prevalence of anxiety disorders, including obsessive compulsive disorder and post-traumatic stress disorder.

An estimated prevalence of FMS is 14%, and it is 26 times
more likely to occur in women than men. The incidence in
the female population has been estimated at 11.3 per 1000
person years. Although it can occur at any age, the condition
becomes more common with advancing years.
It is highly unlikely a single underlying cause for FMS
will be found, with a strong interplay between physical and
psychological factors.
The onset of illness may be triggered by physical illness,
including intercurrent infection; or by trauma, including surgery.
There is some suggestion that heredity may play a part,
with components of the serotonergic and dopaminergic
systems being candidate genes.
Some of the symptomatology around the trigger points
may be due to increased acetylcholine at the motor endplate, causing contraction and shortening of the sarcomere. This may lead to increased energy consumption
and increased local blood supply, with resulting local
tenderness.
A number of local and systemic mediators have been
implicated in the pathogenesis. These include bradykinin, calcitonin gene-related peptide (CGRP),
substance P, TNF-alpha, interleukin-1 (IL-1), noradrenaline, and serotonin.
Investigations
Routine investigations including full blood count, biochemistry, ESR, CRP and other inflammatory markers
are all within the normal range.
Widespread Pain Index

(1 point per check box; score range 019 points)
Symptom Severity
(score range 012 points)
1 Please indicate if you have had pain or tenderness during

the past 7 days in the areas shown below.
Check the boxes in the diagram for each area in which you
have had pain or tenderness.
2 For each symptom listed below, use the following scale to indicate the
severity of the symptom during the past 7 days.
No problem
Slight or mild problem: generally mild or intermittent
Moderate problem: considerable problems; often present and/or at a
moderate level
Severe problem: continuous, life-disturbing problems.
No
Slight or Moderate Severe
problem
mild
problem problem
problem
RLeft jaw
Right jaw R
RNeck
Right shoulder R
Right upper arm R
RChest or
breast
Left shoulder R
Left upper arm R
RUpper
back
RAbdomen
Right lower arm R
RLower
back
Left lower arm R

RRight hip or
buttocks
Right upper leg R
Points
A. Fatigue
R
R
R
B. Trouble thinking or remembering
R
R
R
C. Waking up tired (unrefreshed)
R
R
R
3 During the past 6 months have you had any of the following symptoms?
Points
RLeft hip or
buttocks
Left upper leg R
A. Pain or cramps in lower abdomen R No
R Yes
B. Depression
R No
R Yes
C. Headache
R No
R Yes
Additional criteria (no score)

Right lower leg R
Left lower leg R
4 Have the symptoms in questions 2 and 3 and widespread pain been

present at a similar level for at least 3 months?
R No
R Yes
5 Do you have a disorder that would otherwise explain the pain?

R No
R Yes
Figure 18-16 Criteria worksheet for bromyalgia

From Wolfe FI et al. The American College of Rheumatology preliminary diagnostic criteria for bromyalgia and measurement of symptom
severity. Arthritis Care Res 2010;62(5)60010.
X-rays, CT and MRI are likewise generally normal, and

there are no specific abnormalities on muscle biopsy,
electromyography (EMG) or nerve conduction studies
(NCS).
Electroencephalography (EEG) for more formal sleep
studies may be requested in patients who have marked
sleep disturbance. This may reveal abnormalities including periodic limb movement disorder, rapid eye movement (REM) sleep disorder, or sleep apnea.
The diagnosis of FMS is basically one of exclusion, and is
made clinically.
Prognosis, differential diagnosis

and treatment
The outlook for a patient with classic FMS is very variable, and the condition tends to become chronic.
More widespread understanding and a clearer definition
of the syndrome, along with a more highly developed
treatment flow, is beginning to streamline management
and improve the outlook for a proportion of patients.
There is no specific treatment. Therapeutic measures

depend upon the precise complaints of the patient, and
should take into account other aspects of the patients
health.
Treatment measures include the following.
Appropriate investigation and making a clear
diagnosis. Educating the patient as to the nature of the
diagnosis, and reassuring them about the prognosis and
treatment. Liaison with support organizations for education, and self-help groups.
Attention to psychological and social factors, and
encouraging the patient to have a normal sleep pattern
and to engage in physical activity consistent with the
state of health and preferences.
Pain relief. This may range from simple analgesics
such as acetaminophen (paracetamol), to more powerful
agents. Inappropriate use of powerful opioid analgesics should be avoided, as this may lead to dependence
and seldom alleviates the symptoms in the long term.
NSAIDs have marginal benefits over simple analgesics.
Tramadol is a weak opioid, with some action to inhibit
583
the uptake of serotonin; this agent sometimes proves to

be of great benefit.
Antidepressants. Either tricyclic antidepressants or
selective serotonin reuptake inhibitors (SSRIs) are of
benefit in many cases. Some patients benefit from these
agents even when there is no major evidence of depression. Dual inhibitors of both noradrenaline and serotonin uptake, such as duloxetine, may be of particular
benefit. Duloxetine is FDA-approved for the treatment
of fibromyalgia.
Alpha2-adrenergic agonists such as clonidine or tizanidine are of benefit to some patients, and may act by
inhibiting the action of neurotransmitters such as glutamate or substance P within the central nervous system.
Anticonvulsants may contribute to pain relief. There
is increasing experience with agents such as pregabalin
and gabapentin, which reduce the release of the central
pain transmitters glutamate and substance P, resulting
in improvement in pain and quality of sleep.
Trigger point injection. This may be undertaken
with local anesthetic, steroid or botulinum toxin. Botulinum may be more effective than steroid injection,
and may act by diminishing acetylcholine release, thus
decreasing muscle activity and local ischemia.
Postural training, exercise, and ergonomic adjustments (particularly in the workplace) may all help
patients to adapt to disability associated with FMS.
Stress reduction may be achieved with a variety of
techniques, including cognitivebehavioral therapy,
relaxation techniques and biofeedback methods.
Physical therapies such as acupuncture, massage,
transcutaneous electrical nerve stimulation (TENS),
and ultrasound may all be helpful. Hydrotherapy is
strongly recommended for all fibromyalgia patients.
SEPTIC ARTHRITIS
An acutely swollen knee is one of the most common presentations of a monoarthritis; and fortunately, due to the
ease of aspirating this joint, it is also a monoarthritis with a
good chance of a diagnosis being made. Although redness
may occur in any acute arthritis regardless of the etiology, its
presence evokes a more limited diagnosis. The differential
diagnosis of monoarthritis is listed in Box 18-9.
Elevated temperature suggests infection, and questioning should cover the systemic aspects of infection as well
as questioning and examination for local and more distal
sites of infection.
Septic arthritis is usually exquisitely tender to examination, with resistance to joint movement.
Staphylococcus is the most common cause of musculoskeletal sepsis, accounting for 80% of infections, with
the prevalence of both streptococcal and mycobacterial
infection increasing.
With staphylococci, streptococci, Gram-negative bacteria and anaerobes, only one joint is usually involved.
584
Box 18-9
Differential diagnosis of
monoarthritis
Traumameniscal or ligamentous tears with or

without hemarthrosis
Sepsisgonococcal arthritis, Staphylococcus aureus,
penetrating injury, or foreign body
Reactive arthritispost gastrointestinal or genitourinary
infection
Hemophilia
Crystal arthritisgout or pseudogout
Inammatorya single joint presentation of an
ultimately polyarthritic process, e.g. rheumatoid,
psoriatic or reactive arthritis
Polyarticular involvement is more likely in the elderly

or the immunosuppressed, with infection by Haemophilus influenzae, meningococcus, and Neisseria gonorrhoeae
tending to be polyarticular.
Lyme disease can present with knee involvement,
although the diagnosis can be quickly excluded if there
has been no exposure to the tick vector of Borrelia
burgdorferi.
H. influenzae is the most common organism in children
under 5 years who have not been immunized.
A particular clinical situation is suspected septic arthritis
in a postoperative shoulder, in which Propionibacterium
acnes should be considered.
If septic arthritis is clinically suspected, prompt evaluation of
the synovial fluid is mandatory prior to the administration
of antibiotics. Accompanying clinical features may include
fever and acute onset of symptoms. The presence of risk
factors should be looked for, and these include:
age >80 years
diabetes mellitus
rheumatoid arthritis and other joint disease
prosthetic joint
recent joint surgery
skin infection, cutaneous ulcers
intravenous drug use, alcoholism
previous intra-articular corticosteroid injection.
Gonococcal septic arthritis will not have systemic or cutaneous manifestations in 50% of cases. This diagnosis should
be considered in all sexually active patients. In young adults,
gonococcal arthritis is a common cause of non-traumatic
acute monoarthritis, and questioning regarding either a
change in sexual partners or genitourinary symptoms needs
to be undertaken.
In addition to the often polyarticular arthritis, tenosynovitis and a pustular rash of the extremities should be
examined for.
Gonococcal arthritis is 34 times more common in
women, who often develop the arthritis in the perimenstrual period.
Men will often experience a urethritis as dysuria and

may notice a morning discharge, whereas women may
be asymptomatic.
Adequate analgesics, antipyretics and rest should be

employed, with the joint aspiration or lavage itself often
affording considerable pain relief.
Investigations
The key investigation of a suspected septic joint is aspiration
of the joint. A relatively small volume of only 12 ml of fluid
is sufficient to complete all investigations; however, the joint
should be aspirated of as much fluid as can be obtained without increasing the trauma of the procedure.
Substantial pain relief is achieved by aspirating a tense
effusion, and while re-accumulation will occur, it buys
some time while the preliminary results are received
from the laboratory.
Note should be taken of the color, viscosity and turbidity of the aspirate. Normal synovial fluid is similar to egg
white, and is both viscous and acellular.
As the degree of inflammation increases, from the negligible amount found in OA to the mid-range of RA and
the extreme of septic arthritis, the viscosity decreases
and the cellularity and turbidity increase.
CLINICAL PEARL
Blood-colored effusions are suggestive of either
trauma or calcium pyrophosphate arthropathy.
Comparisons of synovial fluid analysis are shown in

Table18-8.
Tests requested should include an urgent Gram stain, cell
count and differential, crystal examination using polarized
light microscopy, and culture.
ACUTE LOW BACK PAIN

Low back pain (LBP) is a common human experience with
an annual incidence of 25%, and 7090% of the general
population experiencing an episode of LBP at some point
in their lives, with a peak prevalence at 65 years. Fortunately, 90% of individuals with acute LBP improve within
48 weeks, and only 5% of patients develop persistent or
chronic LBP lasting >3 months. Risk factors for low back
pain are shown in Table 18-9.
The cause of the vast majority of LBP is unknown, with
no pathological cause for the pain found in at least 80% of
cases (Box 18-10, overleaf). Based on the history and physical examination, LBP is classified as:
nonspecific LBP or simple backache
nerve-root or spinal-nerve compromise
potentially serious spinal pathology (including infection,
cancer, fracture, inflammatory back pain, and cauda
equina syndrome).
Table 18-9 Risk factors for low back pain
Strongest risk
factor
Previous history of back pain
Strong risk
factors
Poor job satisfaction

Emotional distress
Treatment
Manual laborer, involving heavy lifting
The presence of bacteria on Gram staining, or subsequent bacterial growth, requires specialist medical and
orthopedic review, to combine antibiotic therapy with
joint lavage.
Empirical therapy for septic arthritis using intravenous
antibiotics covering S. aureus and N. gonorrhoeae should
be commenced after the synovial fluid aspirate has been
obtained.
Prolonged sitting or standing

Moderate risk
factors
Vibration-tool use
Smoking
Obesity
Poor physical tness
Table 18-8 Synovial uid characteristics in health and disease
NORMAL
NONINFLAMMATORY
INFLAMMATORY
SEPTIC
Color
Clear
Straw yellow
Yellow
Variable
Clarity
Transparent
Transparent
Hazy opaque
Opaque
Viscosity
High
High
Low
Lowthick
WBC count (per mm3)
0200
2002000
200075,000
>75,000
Neutrophils
<25%
<25%
2550%
>75%
WBC, white blood cell.
585
Box 18-10
Causes of acute low back pain (LBP)

97% mechanical LBP
80%: idiopathic
20%:
prolapsed intervertebral disc
lumbar spondylosis
spondylolisthesis
spinal stenosis
fracture
Scheuermanns disease
1% non-mechanical spinal pain
Inammatory spondyloarthritis
12% visceral disease
Infection
Neoplasia
Serious pathology as a cause of back pain is uncommon,

<5% having compression fractures, and <1% cancer, infection, inflammatory disorders, or cauda equina syndrome.
Red flags of suspicion are listed in Box 18-11.
CLINICAL PEARL
Indicators of nerve root problems:
Unilateral leg pain > low back pain
Radiates to foot or toes
Numbness and paresthesia in same distribution
Straight leg raising induces more leg pain
Neurological decit conned to one nerve root distribution
Simple backache does not benefit from extensive investigation, which may even be harmful if leading to the
management of benign abnormalities such as disc bulge
on imaging, despite these being rarely related to LBP.
In those few cases where further diagnostic investigation is required, it should be aimed at confirming a specific pathological lesion that would explain the patients
symptoms or findings.
Box 18-11
Red ags of low back pain

Weight loss, fever, night sweats
Nocturnal pain
History of malignancy
Recent or current infection
Acute onset <20 or >55 years
Constant or progressive pain
Bilateral or alternating symptoms
Neurological or sphincter disturbance
Morning stiffness
Claudication or peripheral ischemia
586
Cauda equina syndrome should be suspected when leg

pain that includes several spinal nerve levels is accompanied by widespread motor and/or sensory weakness, and
importantly when there is associated bladder or bowel
dysfunction.
Specic pathology leading to acute

low back pain
The spine is commonly described as a three-joint complex,
consisting of the intervertebral disc anteriorly and the two
facet joints posterolaterally. These border the triangularshaped spinal canal, as depicted diagrammatically in
Figure18-17.
Deformity of the three-joint complex, anterior or posterior subluxation (spondylolisthesis) of a vertebral
body, as well as deformity of the posterior longitudinal
ligament and ligamentum flavum, can lead to nerveroot impingement in the lower spine or to spinal cord
compression at higher levels.
The spinal cord ends at approximately the level of
L1L2, so that neurological manifestations in LBP syndromes are lower motor neuron lesions affecting the
peripheral nerve roots.
The most common site of disc prolapse is the L4 or
L5 disc, and at that level a posterolateral protrusion
impinges on the L5 nerve root. A centrally placed bulge
may affect multiple lower nerve roots in a bilateral fashion, causing a cauda equina syndrome.
The combined pathologies of facet joint hypertrophy/
osteophyte formation, disc bulges, and deformity of the
long ligaments effectively stenoses the spinal canal and
is a common spinal disorder in the elderly, presenting
with pseudoclaudication, sciatica, and dysfunction of
the cauda equina.
Abnormalities in X-ray and MRI are poorly associated with
the occurrence of nonspecific LBP.
Abnormalities found when imaging people without
back pain are just as prevalent as those found in patients
with LBP, and it needs to be remembered that radiological abnormalities of degeneration and spondylosis have
been reported in 4050% in people without LBP.
Many people with LBP show no abnormalities, which
has led to the recommendations to be restrictive in
imaging unless red flags are present.
CT and MRI are equally effective in diagnosing lumbar
disc herniation and stenosis, but are only meaningful if
compatible with the clinical findings.
MRI is the modality of choice for suspected infection
or malignancy, although these are relatively rare causes
ofLBP.
Prolapsed intervertebral disc

The intervertebral disc is composed of the inner nucleus
pulposus and the outer annulus fibrosus. The outer third
of the annulus is innervated such that mechanoreceptors respond to distortion. Prolapsed disc is a result of the
nucleus pulposus protruding through a defect in the annulus
Intervertebral
disc
Normal intervertebral
disc, facet joints and
exiting nerve root
Central disc bulge and posterolateral

bulge with ligamentum
flavum hypertrophy
Facet joint hypertrophy
Figure 18-17 Nerve root pain

fibrosus, usually a tear in the posterolateral portion. While
this is generally due to degeneration in the annulus fibrosus,
it can result from mechanical forces, e.g. heavy lifting. The
tear results in a local inflammatory response.
Spinal fracture
The older patient, particularly female, who presents with
sudden-onset localized back pain after minor or inconsequential trauma should be suspected to have an osteoporotic
compression fracture, particularly in the presence of additional underlying risk factors for osteoporosis.
Cancer
Features predictive of malignancy as a cause of LBP are:
1 previous history of cancer
2 age 50years or older
3 failure of conservative therapy
4 weight loss >4.5 kg.
Using these indicators, patients with a past history of cancer
should undergo MRI investigation; with any other indicator, a CT scan or plain-film radiograph is ordered.
Infection
A history of immunosuppression, or risk factors for breaches
in the normal barriers to bacteremia, should be elicited
from the patient and coupled with an examination looking
for septic foci. In 40% of cases of spinal osteomyelitis there
is a hematogenous spread from an identifiable extraosseous
source, most commonly genitourinary, skin or respiratory.
The most commonly identified organism is Staphylococcus aureus, with Gram-negative organisms in the elderly or
intravenous drug users.
Management
Treatment guidelines are summarized in Box 18-12.
Box 18-12
Summary of treatment guidelines

for acute low back pain
Reassure patient of favorable prognosis

Advise patient to remain active, and discourage bed
rest
Do not prescribe specic back exercises
Prescribe regular medication consisting of
acetaminophen (paracetamol)
non-steroidal anti-inammatory drugs
Consider net benet of muscle relaxants
Recurrences of LBP are common, with an estimated

three-quarters having a recurrence within a 1-year period.
The severity, however, is usually less, and does not always
lead to a new visit to the physician.
CHRONIC LOW BACK PAIN

In patients with chronic LBP the terms nonspecific or
mechanical low back pain are used with an implication that
an anatomical or pathological basis is understood as the cause
of the patients symptoms. In reality, the etiology remains
unknown for the majority of such patients.
Clinical assessment
Observation is used to determine alteration in posture,
muscle wasting, changes in the physiological lordoses,
and the effects of movement on the alignment of the
spine.
Palpation can be undertaken to assist in evaluating
movement at a segmental level, and also to identify local
tenderness.
Outcome
Most guidelines for the management of acute LBP identify the following as poor prognostic factors: fear avoidance behavior, leg pain, and low job satisfaction. Overall,
however, it is consistently reported that more than 90% of
patients improve by 612 weeks.
Strong evidence supports the use of exercise and intensive multidisciplinary pain-treatment programs for
chronic LBP.
Cognitivebehavioral therapy, analgesics, antidepressants, NSAIDs, back schools, and spinal manipulation
are supported only by weak evidence.
587
Regrettably, however, for most effective treatments the

effects are usually only small and short-term.
No evidence supports using interventions such as steroid
injections, lumbar supports, and traction.
Treatment guidelines are outlined in Box 18-13.
Box 18-13
Recommended guidelines for the

treatment of chronic low back pain
Invasive treatment
The efficacy of invasive interventions in the form of facet
joint, epidural, trigger point and sclerosant injections have
clearly been shown to be ineffective for the treatment of LBP
and sciatica.
No sound evidence is available for the efficacy of spinal
stenosis surgery, although surgical discectomy may be considered in those with sciatica due to lumbar disc prolapse,
who have failed to respond to conservative management.
588
Recommend cognitivebehavioral therapy,

supervised exercise, brief educational interventions,
multidisciplinary (biopsychosocial) treatments
Advise patient to remain active
Short-term use of non-steroidal anti-inammatory
drugs and weak opioids
Consider the net benet of muscle relaxants, back
schools, anti-depressants, and manipulation
Avoid passive treatment such as ultrasound and
shortwave
Invasive treatments such as facet joint injections are
generally not recommended
1
A 28-year-old woman presents with an 8-week history of pain and swelling in her left knee. She is afebrile, has
moderate effusion of the left knee, mild left quadriceps wasting, and a sausage digit of the right 3rd toe. Her
erythrocyte sedimentation rate (ESR) is 58 mm/h (normal <18) and C-reactive protein (CRP) 45 mg/dL (normal <5).
Which of the following statements is correct in this case?
A The absence of psoriasis on examination excludes psoriatic arthritis as a likely diagnosis.
B Quadriceps wasting and an 8-week history indicate a chronic arthritis that is not part of the post-infectious arthritis
spectrum.
C Investigation should include an early morning urine for Chlamydia trachomatis polymerase chain reaction (PCR)
testing.
D Her anti-nuclear antibodies (ANA) will be positive with a homogeneous pattern and titer >1:1280, with anti-doublestranded DNA antibodies elevated above the reference level.
E The prominent inammatory marker elevation indicates sepsis, and intravenous ucloxacillin should be
administered pending further investigation.
A 54-year-old bricklayer has had progressive pain and swelling in his hands over the past 46 months. He nds it
hard to dress himself in the morning, with pain under his feet when rst standing. He can only begin carrying bricks
when he has warmed up in the sun, around 10 a.m. A local family physician commenced him on prednisolone
7.5mg daily for the past 2 weeks, and he feels much better. When examined, he winces when shaking hands, and
has palpable synovial swelling of his metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. His
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are normal, rheumatoid factor (RF) testing is
negative, and anti-cyclic citrullinated peptide (CCP) antibody strongly positive. Which of the following approaches
is most appropriate?
A No additional therapy is needed, as his normal inammatory markers will soon be matched by resolution of his
clinical ndings, and the prednisolone will then be able to be withdrawn.
B The absence of RF indicates a seronegative disease, such as psoriatic arthritis. Initiation of anti-interleukin 12/23
therapy will treat both the arthritis and his psoriasis.
C A chest X-ray is not required.
D Information and prescriptions for hydroxychloroquine, methotrexate, folic acid and omega-3 oil supplementation
should be provided.
E Bricklaying will accelerate his joint destruction and he should cease employment and seek an occupation that does
not require manual labor.
You have been managing an overweight patient with gout for some time. He presents after a week of pain and swelling
in the right knee and more recently his left midfoot. Both joints are warm, pink and tender. Which of the following is
correct regarding this presentation?
A His acute gout should be managed with non-steroidal anti-inammatory drugs (NSAIDs) or corticosteroids before
prescribing colchicine.
B He should cease his allopurinol during the acute attack and recommence when his joints have been quiet for at
least 2 weeks.
C Todays serum urate, 0.38 mmol/L, is within the normal range (0.360.42 mmol/L), making acute gout very
unlikely.
D He has continued to have attacks of gout despite reliably taking his allopurinol 300mg tablet daily, and has failed
this therapy. It should be ceased and an alternative agent trialed.
E He has been losing weight rapidly, using a diet which includes peas, beans, mushrooms and asparagus. These are
rich in purines, and will have brought on this attack of gout.
4 Vera is a 64-year-old book-keeper who now nds it hard to operate her computer and to pick up objects. The pain
in her hands has worsened over the past few years, and she has had to stop her hobby of needlework. She has had
psoriasis of the scalp for most of her life. Examination is of square hands, with swelling of all distal interphalangeal
(DIP) joints and most of her proximal interphalangeal (PIP) joints. Blood tests showed a rheumatoid factor (RF) of 16 IU
(normal <14) and C-reactive protein (CRP) of 7 (normal <5). Which of the following is correct?
A Symmetrical interphalangeal swelling combined with a positive RF indicates a diagnosis of rheumatoid arthritis.
B Careful examination of the joints is needed to differentiate hard bony swelling from soft boggy swelling.
C An X-ray of the hands is needed to conrm the diagnosis.
D Topical non-steroidal anti-inammatory drugs (NSAIDs) are less efficacious than oral agents.
E The presence of elevated inammatory markers warrants the addition of an anti-rheumatic agent such as
methotrexate.
589
ANSWERS
1
C.
An oligoarthritis with dactylitis (synovitis of both interphalangeal joints and tenosynovitis) is highly suggestive of a
seronegative spondyloarthritis, the differential diagnosis for which includes psoriatic arthritis. Diagnostic criteria for
psoriatic arthritis are weighted toward current psoriasis on examination, but previous psoriasis or a family history
of psoriasis can be considered. In up to 10% of cases the psoriatic skin rash will develop after the arthritis.
Gastrointestinal and genitourinary infections can be associated with a longer-lasting reactive arthritis, and symptoms of
infection should be sought. Chlamydia trachomatis infection is often asymptomatic and a missed infection may adversely
affect future fertility, hence the importance of PCR testing in this case. If there has been travel through areas prone to
arthropod-borne viruses, this can cause an arthritis that is often of short duration, but there are exceptions with some
patients having chronic symptoms.
Systemic lupus erythematosus is often associated with arthralgia or a symmetrical small-joint arthritis, and in the absence
of other systemic features is lower on the differential diagnosis. A screening ANA test may be undertaken, with subsequent
testing dependent on the result; extractable nuclear antigen testing if a speckled ANA pattern is found, and anti-dsDNA
antibodies if a rim or homogeneous pattern is found.
Septic arthritis is a diagnosis not to be missed; however, in an afebrile, immunocompetent patient with a long history,
bacterial infection is unlikely. Positive culture results from synovial uid aspiration are well below 100%, but synovial
aspirate for Gram stain, cell count and differential, and culture should be undertaken prior to antibiotic commencement.
D.
Prednisolone may have ameliorated the cytokine-driven ESR and CRP response, but the presence of synovitis in the MCP
and PIP joints indicates a joint count of at least 20, which is severe disease. The treatment target will be undetectable
clinical synovitis, in addition to normalization of his inammatory markers.
Psoriatic arthritis is the great mimic and can present with any pattern of joint inammation; a symmetrical rheumatoid
arthritis (RA)-like picture occurring in 10% of psoriatic arthritis. While approximately 70% of RA patients are RF-positive, the
absence does not exclude RA (nor does the presence prove RA). Absence of RF would not dissuade you from a diagnosis
of RA, particularly in the presence of anti-CCP antibodies, which are most specic for RA and are present in some of the
RF-negative RA patients. Anti-CCP antibodies are a poor prognostic factor, correlating with increased joint damage and
extra-articular manifestations.
The available information fullls points 2, 3 and 4 of the 1987 American College of Rheumatology criteria for RA which did
not include anti-citrullinated peptide status. Using the newer 2010 criteria, this man has denite RA on the basis of joint
count (5 points), high positive anti-CCP antibodies (3 points), and duration >6 weeks (1 point). Low-dose prednisolone can
quickly ameliorate disease, and should be combined with methotrexate and folic acid. Methotrexate is slow-acting over
68 weeks, after which the prednisolone can be withdrawn. Hydroxychloroquine is synergistic with methotrexate therapy.
As most patients are interested in diet and natural therapies, constructive guidance on the use of 2.7 g daily of EPA/DHA
long-chain omega-3 fatty acids to reduce symptoms and lessen the need for therapy with non-steroidal anti-inammatory
agents with associated side-effects will be well received.
A chest X-ray is indicated due to smoking being one of the strongest environmental triggers for RA, and pulmonary
brosis can occur as part of the disease process and as a reaction to medications such as methotrexate and leunomide.
A baseline for comparison is a handy reference, and it is also part of the screen for tuberculosis, which is recommended,
along with hepatitis serology, in patients likely to receive long-term immunosuppression.
RA reduces life expectancy; up to 50% of RA patients will no longer be in employment at 10 years, and this is more
likely in a manual worker. However, this is not inevitable, and the array of treatment options has meant remission is an
achievable target. Each clinic visit should amend therapy to minimize objective measures of disease impact on joint count,
inammatory markers, and patient quality of life.
A.
Untreated gout will progress from intermittent acute monoarthritis to increasingly frequent and severe attacks that will
involve more proximal joints, and become polyarticular. Once commenced, allopurinol should only be ceased for an
allergic reaction or adverse event. Ceasing or commencing a urate-lowering therapy during an acute attack creates friable
uric acid crystals within the joint, and will worsen and prolong the attack, and patients are likely to abandon the therapy as
it makes their gout worse.
Up to 30% of patients will have a normal urate level during an acute attack, particularly if measured a few days into the
attack. This is falsely low due to the acute phase response and does not exclude the diagnosis of gout. Once uratelowering therapy is commenced, treatment is adjusted until a urate level of 0.300.36 mmol/L is reached. In this example,
his normal urate is still above target and his allopurinol should be increased to 400mg after the acute attack has settled.
One 300mg tablet is insufficient therapy in the majority of patients, and allopurinol should not be abandoned but instead
slowly titrated to achieve the target at lowest possible dose, with doses up to 900mg daily approved.
Vegetable-derived purines have no negative effect on gout and can be safely incorporated into diets aimed at reducing
meat and seafood intake, while increasing low-fat dairy intake. His rapid weight-loss diet may have induced a ketotic/
starvation state leading to reduced renal excretion of urate, and may have precipitated his gout.
590
Increasing awareness of the toxicity of colchicine has meant that it should only be used in acute attacks if NSAIDs and
corticosteroids are ineffective or contraindicated, which is a rare event. If used, the dose needs to be strictly monitored
and used for no longer than 4 days, with a 2- to 3-day gap between courses.
4 B.
Osteoarthritis is the most common form of arthritis, and typically involves the DIP joints, leading to osteophytic expansion
of the joint line, known as Heberdens nodes. The 1st carpometacarpal joint is involved similarly, leading to subluxation
of the joint which moves the thumb toward the palm of the hand to give a square appearance to the hand in the prone
position. Osteophytes of the PIP joint (Bouchards nodes) are less common than Heberdens nodes. A low-level RF occurs
in at least 5% of the healthy population, and needs to be interpreted in the clinical context. Osteoarthritis is relatively
non-inammatory compared, for example, with gout or rheumatoid arthritis, but can cause mild elevation of markers as
seen in this case. Methotrexate is not indicated in osteoarthritis.
Psoriatic arthritis occurs in 2533% of patients with psoriasis. Clinical examination to differentiate hard bony swelling from
soft boggy swelling distinguishes osteoarthritis from psoriatic arthritis. Clinical examination provides the pattern of joint
involvement, and will differentiate inammatory synovitis from degenerative osteophytes; an X-ray will not provide more
information in these circumstances.
Effective therapy for osteoarthritis remains problematic, with many studies showing large placebo effects. In comparative
studies, topical NSAIDs have a larger effect size than oral agents.
591
CHAPTER 19
NEUROLOGY
Christopher Levi, Thomas Wellings and Brad Frankum
CHAPTER OUTLINE
DISORDERS OF CONSCIOUSNESS
Denitions
Causes of coma
Assessment of the patient with impaired
consciousness
HEADACHE
Secondary headache
STROKE

Thrombolysis
INTRACEREBRAL HEMORRHAGE
Medical treatment
Surgical management
SUBARACHNOID HEMORRHAGE (SAH)

aneurysmal SAH
Surgical versus endovascular management of SAH
TRANSIENT ISCHEMIC ATTACK (TIA)

Denition
Differential diagnosis of transient neurological
disturbances
Pathophysiology
Investigation
DEMENTIA
Diagnosis
Diagnostic work-up of the dementia patient
SEIZURES AND THE EPILEPSIES
Seizure types
The epilepsies
Status epilepticus
BALANCE, DIZZINESS AND VERTIGO
Hemodynamic dizziness or lightheadedness

Vertigo
Central pathologies
MOVEMENT DISORDERS
Tremor
593
Dystonia
NMDA encephalitis
MULTIPLE SCLEROSIS AND CNS

INFLAMMATION
Neuromyelitis optica (NMO; Devics disease)
Acute disseminated encephalomyelitis (ADEM)
and transverse myelitis (TM)
Neurological manifestations of sarcoidosis and
Behets disease
DISORDERS OF
CONSCIOUSNESS
Denitions
Consciousness is the state of responsiveness of an individual to the environment.
The most severe form of impairment of consciousness
is coma, a state of unresponsiveness where the person is
unable to be aroused.
The ascending reticular formation (reticular activating
system, RAS) is the central neuroanatomical structure
responsible for maintaining consciousness. It comprises
a network of neurons extending from the medulla to the
thalamus, receiving projections from all major sensory
pathways and sending projections diffusely to the cerebral cortex.
Normal consciousnessalert wakefulness with orientation, and prompt and appropriate response to stimuli.
Confusion and deliriumclouding of consciousness with
impaired attention, concentration and capacity for clear
thought and understanding. There is often slowed or
inappropriate response to stimuli, progressing to disorientation, distractability, agitation, and restlessness. In
severe forms, anxiety, behavioral disturbance and hallucinations are seen.
Stupor and obtundationdrowsiness, progressing to
absence of spontaneous motor activity, and responsiveness only evident to vigorous stimulation or pain.
Comaunrousability, where no appropriate response
can be elicited by external stimuli.
Causes of coma
Coma is the result of either dysfunction of the RAS or diffuse processes affecting both cerebral hemispheres.
It is important to note that structural lesions in the
brainstem and the cerebral hemisphere will not necessarily cause impairment of consciousness.
594
NEUROMUSCULAR DISEASE
Myopathy
Genetic muscle disorders
Disorders of the neuromuscular junction
Motor neuron disease (MND)/amyotrophic lateral
sclerosis
Demyelinating neuropathy and Guillain-Barr
syndrome (GBS)
Focal brainstem lesions need to be strategic, with

the location directly damaging the RAS in the
ventral medulla and peri-aqueductal region of the
ventral pons and midbrain.
Hemispheric lesions need to be causing significant
mass effect with lateral and/or downward displacement, and secondary mass effect on the diencephalic
structures containing the upper extent of the RAS.
The most common cause of coma is diffuse (Box 19-1)
and widespread disturbance of brain function secondary
to factors such as neurotropic drugs, and toxic, metabolic and electrical disturbances of brain function.
Box 19-1
Causes of coma
Structural or focal brain pathology (approx. 30%)
(Supratentorial 15%, infratentorial 15%)
Stroke
Meningitis
Encephalitis
Cerebral abscess
Brain tumor
Head injury
Diffuse disturbances of brain function (approx. 70%)
Metabolic:
Hypoxia
Hyponatremia
Hypercalcemia
Uremia
Hypoglycemia
Hepatic encephalopathy
Toxic substances:
Hypnosedative drugs
Narcotics
Seizure-related:
Post-ictal coma
Persistent subclinical seizure activity
Psychogenic (rare)
Chapter 19 Neurology
Table 19-1 Glasgow Coma Scale
SCORE
1
Eyes
Does not open

eyes
Eyes open to pain
Eyes open to
command
Eyes open
spontaneously
Verbal
Makes no sound
Incomprehensible
sounds, groans
Inappropriate
words
Confused,
disorientated
Alert and
converses
normally
Motor
No movement
Extension to pain
(decerebrate
response)
Abnormal
exion to pain
(decorticate
response)
Flexion or
withdrawal to
painful stimuli
Localizes to
pain
Obeys
commands
Note that the scale goes from a total of 3 to 15. A score less than 3 is not possible.
CLINICAL PEARL
Relatively common and serious but potentially reversible causes of sudden-onset coma include:
acute basilar artery occlusion with brainstem stroke
fulminating meningitis
generalized seizure with ongoing non-convulsive
seizure activity
hypnosedative drug overdose.
Assessment of the patient with

impaired consciousness
A detailed immediate, recent and past history is essential
in formulating the differential diagnosis in a patient with
stupor or coma.
It is particularly important to interview family
members and reliable witnesses to gain insight into
antecedent events, recent health status, past medical problems, evidence of recent behavioral change,
seizures, and alcohol or drug abuse.
It is also essential to obtain a detailed medication
history, and to consider the possibility of a drug
overdose.
Thorough physical examination is essential (see below).
Structural brain imaging with computed tomography
(CT) or magnetic resonance imaging (MRI) will reveal
structural pathology in approximately 30% of patients.
Cerebrospinal fluid (CSF) analysis will assist to identify
meningitis and encephalitis.
Electroencephalography (EEG) will identify patients
with ongoing seizure activity.
Physical examination can often provide important diagnostic clues. General examination should include:
assessment of temperature
careful inspection of the skin for rashes, and for needle marks which would provide evidence of intravenous
drug use or insulin-requiring diabetes
Table 19-2 Key pupillary abnormalities in the patient

with impaired consciousness
PUPILLARY
ABNORMALITY
LIKELY
PATHOLOGY
Dilatation of one pupil with poor

or no response to light
Ipsilateral 3rd nerve

palsy
Non-reactive, sometimes
irregular mid-position pupils
Midbrain pathology
Pinpoint pupils
Pontine pathology or
narcotic excess
Small, reactive pupils
Toxic/metabolic
encephalopathy
Fixed, dilated pupils
Major brainstem
damage
observation of respiratory patternsabnormal patterns

can be seen in brainstem pathology and with metabolic
disturbances
cardiorespiratory examination, particularly looking for
evidence of heart valve or lung infection, or circulatory
failure.
Neurological examination should include an initial assessment of the level of consciousness using the Glasgow Coma
Scale (Table 19-1).
A structured neurological examination should then be
conducted to examine a hierarchy of brainstem function.
Examination should include the following components:
Pupil size and reactivity (Table 19-2).
Eye position and movements (Table 19-3, overleaf).
Corneal reflexesthese may be absent in light coma
due to toxic or metabolic causes, but are usually retained
until severe levels of coma develop. Their absence generally suggests a poor prognosis.
Oculocephalic reflexesthe so-called dolls-eye
maneuver examines the vestibulo-ocular reflexes
(VORs) and is induced by lateral rotation of the head:
595
Table 19-3 Eye movement abnormalities in the patient with impaired consciousness
EYE MOVEMENT ABNORMALITY
LIKELY PATHOLOGY
Lateral conjugate gaze deviation away from side of lesion
Lateral pontine structural pathology
Lateral conjugate gaze deviation toward side of lesion
Frontal hemispheric structural pathology
Forced lateral gaze deviation
Active fronto-temporal seizure foci
Skew deviation and ocular bobbing (a rhythmic downward

jerking of both eyes)
Low pontine or ponto-medullary pathology
Major dyscongugate eye positioning
Generally suggests either 3rd nerve palsy, 6th nerve palsy

(nuclear or infranuclear for either) or an internuclear
ophthalmoplegia. Pathology could be either pontine or
midbrain
Conjugate depression of both eyes or eyes jerking back into

the orbits (refractory nystagmus)
Suggests midbrain pathology
Roving eye movements or minor dysconjugate movements
Commonly seen in coma and are of no adverse prognostic

signicance
Ping-pong gaze (rhythmic lateral conjugate eye

movements)
These are poorly localized brainstem phenomena
lateral rotation with intact brainstem vestibular

nuclei results in conjugate movements of the eyes in
the opposite direction to head movement
the loss of brainstem VOR results in the eyes
remaining fixed, looking in the direction of movement, and with no conjugate shift.
Caloric reflexesthis test also examines the VORs, and
is performed by irrigating the external auditory canal
with ice-cold water:
an intact VOR results in the eyes deviating tonically toward the irrigated side and suggests the possibility that the cause of the coma is pathology above
the pons
an absent or dysconjugate caloric response suggests
brainstem pathology.
A general neurological examination should then be completed, with assessment of character and symmetry of tone,
reflexes, plantar responses and fundoscopy.
HEADACHE
Headache is thought to arise from a number of pathophysiological mechanisms:
irritation of pain-sensitive structures within the cranium, such as the blood vessels and meninges
release of chemical mediators activating central pain
pathways, such as in migraine
stimulation of extracranial nociceptive pathways by
muscle contraction, such as in tension headache.
Less commonly, extracranial pathologies may lead to
headache:
damage to or inflammation of extracranial blood vessels
596
structural/inflammatory pathology in paranasal sinuses

referred pain from cervical spine pathology.
A systematic approach to assessment and management of
headache is illustrated in Figure 19-1.

Migraine
Migraine is one of the commonest neurological disorders,
affecting 1 in 5 people.
The condition causes considerable burden in terms of
quality of life and societal economic impact.
It is a complex multifactorial illness with pathophysiology that is incompletely understood.
There are defined links to the phenomenon of cortical
spreading depression, and also to activation of the trigeminovascular system, inducing inflammatory changes
in intracranial vessels and the dura.
Figures 19-2 and 19-3 (overleaf) describe the cortical, subcortical and upper cervical cord pathways linking to the
dura, and blood vessel innervation via the trigeminovascular
system.
Presentation
Migraines typically present with recurrent severe headache associated with autonomic symptoms.
1015% of migraine sufferers experience migraines
with aura.
The severity of the pain, duration of the headache,
and frequency of attacks is variable, and migraine
lasting longer than 72 hours is often termed status
migrainosus.
HEADACHE SYNDROMES
CLASSIFIED BY TIME COURSE
AND SEVERITY
Severe, sudden
Instant thunderclap
IMMEDIATE
REFERRALCALL
AMBULANCE
Subarachnoid
hemorrhage unless
proven otherwise
Subacute severe over

hours to days
Severe over minutes

to hours
Focal
neurological
signs
IMMEDIATE
REFERRALCALL
AMBULANCE
Possible causes:
Meningitis*
Craniocervical artery
dissection
Venous sinus
thrombosis
Stroke
hemorrhagic
Unilateral eye pain
High-risk headache syndromes.

These presentations carry high
potential risk of serious underlying
pathology and acute major
neurological morbidity
* Prehospital antibiotics if
suspected meningococcal
disease
Recurrent or chronic
persistent or daily
Tender
temporal artery
Family physician
management
Routine referral if
needed
>50, unilateral
tenderness over
temporal artery,
high CRP/ESR
? Giant cell arteritis
Possible causes:
Tension
Migraine
Medication overuse
Cough
Exertional
Sexual
Chronic post
traumatic
Cluster
Cervicogenic
No focal
neurological
signs
Cerebral imaging
CT brain contrast
or MRI depending on
clinical scenario.
(May need to discuss
with neurologist)
Early neurological
referral or advice re
workup
High-dose
cocorticosteroids.
Immediate referral
to neurologist/
ophthalmologist
Possible causes:
Tumor
Cerebral abscess
Accelerated intracranial hypertension
ldiopathic intracranial hypertension
Intracranial hemorrhagesubdural
Post-traumatic
Venous sinus thrombosis
Intermediate-risk headaches.
These presentations can carry a high
risk of major neurological morbidity if
a definitive diagnosis and specific
management is not promptly instituted
Low-risk headache.
Generally these headaches align
with a pre-existing and often
longstanding history of relapsing
intermittent chronic daily or acute
relapsing-on-chronic headache.
Rarely signify serious underlying
pathology and rarely carry a risk
of major morbidity
Figure 19-1 Headache assessment and management algorithm developed by Levi, Magin and Sales. CT, computed
tomography; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging
The described phases of a migraine attack are:

1 prodromewhich occurs hours or days before the
headache
2 auragenerally immediately precedes the headache
but can occur in association with it
3 headache phase
4 postdromal period.
Prodromal symptoms occur in approximately 50% of
migraine sufferers.
This phase may consist of altered mood, fatigue, sleepiness, and a variety of nonspecific symptoms.
These symptoms usually precede the headache phase of
the migraine attack by several hours or days.
Aura (most commonly visual, but also somatosensory, dysphasic or vertiginous) comprises focal neurological phenomena that precede or accompany the attack.
Aura appear gradually over 520 minutes and generally
last less than 60 minutes, and mirror the cortical spreading depression phenomenon.
Visual aura is the most common of the neurological

accompaniments, and most often consists of unformed
flashes of white and/or black, or rarely of multicolored
lights (photopsia) or formations of dazzling zigzag lines.
Some patients complain of blurred or shimmering or
cloudy vision, as though they are looking at an area
above a heated surface, or looking through stained glass.
The visual aura is commonly associated with an area of
visual losseither scotomatous or at times hemianopic.
The headache phase of the migraine attack usually begins
within 60 minutes of the end of the aura phase.
The typical migraine headache is unilateral, throbbing,
and moderate to severe, and can be aggravated by physical activity.
The pain may be bilateral at the onset, or start on one side
and become generalized, and may occur primarily on one
side or alternate sides from one attack to the next.
The onset is usually gradual. The pain peaks and then
subsides and usually lasts 272 hours in adults and
148 hours in children.
597
TNC
Brainstem
Glutamate NMDA
receptors
C1
and C2
Second-order
brainstem TNC
neurons
TGVS
neuron
CGRP receptors
Figure 19-3 Pain pathways in headache. CGRP,

calcitonin gene-related peptide; NMDA, N-methylD-aspartate; TGVS, trigeminovascular system; TNC,
trigeminal nucleus caudalis
Based on Goadsby PJ and Bartsch T. On the functional
neuroanatomy of neck pain. Cephalalgia 2008; 28 (Suppl 1):17.
Figure 19-2 Proposed pain pathways in migraine.

In this scenario, the trigger is a wave of cortical
depression (1) which sensitizes and stimulates
the trigeminal pathway in either direction (2, 3).
This results in stimulation of the trigeminocervical
complex (TCC) (3) in the brainstem; onward
stimulation of the thalamus and other areas can
cause pain and nausea. Other reex pathways from
the brainstem via the superior salivatory nucleus to
the dural blood vessels, which result in vasodilatation,
can also be activated at this stage. The stimulation
of trigeminal nerves innervating the dural blood
vessels (2, 4) results in the release of mediators
such as calcitonin gene-related peptide (CGRP),
substance P (SP) and neurokinin A (NKA), which cause
vasodilatation and participate in inammation. CGRP
and possibly other mediators are able to stimulate
nociceptors in the trigeminal nerve endings, resulting
in further activation of the pathways to the TCC and
thalamus (5) and consequently further pain. The
control of vascular tone in the dural blood vessels
is complex, with sympathetic, parasympathetic and
serotonergic systems contributing to the migraine
process. Vasoconstrictor innervation of these vessels
is by sympathetic nerves and vasodilatation occurs by
parasympathetic innervation. Serotonergic pathways
produce vasoconstriction by stimulation of 5-HT1B
receptors and vasodilation via 5-HT2 receptors. TG,
trigeminal ganglion
From Waller DG et al. Medical pharmacology and therapeutics,
4thed. Saunders, 2014.
598
The frequency of attacks is extremely variable, from a

few in a lifetime to several per week; the average sufferer
experiences 13 headaches a month.
The head pain varies greatly in intensity, and can be
very severe.
The pain of migraine is invariably accompanied by
autonomic features, particularly nausea, which occurs
in almost 90% of patients, with vomiting occurring in
about one-third. There may be localized edema of the
scalp or face, scalp tenderness (migranous hygroma),
prominence of a vein or artery in the temple, or stiffness
and tenderness of the neck.
The effects of migraine may persist for some days after the
main headache has ended (postdrome period). Many sufferers report feeling tired or washed out with impaired
concentration for a few days after the headache has passed.
The International Classification of Headache Disorders
published by the Headache Classification Subcommittee
of the International Headache Society in 2004 classifies
migraine as follows:
Migraine without aura, or common migraine, involves
migraine headaches that are not accompanied by an aura.
Migraine with aura, or classic migraine, usually involves
migraine headaches accompanied by an aura. Less commonly, an aura can occur without a headache, or with a
non-migraine headache.
Two other varieties are familial hemiplegic migraine and sporadic hemiplegic migraine, in which a patient has migraines
with aura, and with accompanying motor weakness. If
a close relative has had the same condition, it is called
familial; otherwise it is called sporadic.
Another variety is basilar-type migraine, where a headache
and aura are accompanied by difficulty speaking, vertigo,
ringing in the ears or a number of other brainstemrelated symptoms, but not motor weakness.
Childhood periodic syndromes that are commonly precursors of

migraine include cyclical vomiting (occasional intense
periods of vomiting), abdominal migraine (abdominal
pain, usually accompanied by nausea), and benign paroxysmal vertigo of childhood (occasional attacks of vertigo).
Retinal migraine involves migraine headaches accompanied by visual disturbances, or even temporary blindness
in one eye.
Complicated migraine includes migraine headaches and/or
auras that are unusually long or unusually frequent, or
are associated with a seizure or brain lesion.
Probable migraine describes conditions that have some
characteristics of migraine, but where there is not enough
evidence to diagnose it as a migraine with certainty (in
the presence of concurrent medication overuse).
Migraine management
The general approach to management depends on the characteristics, frequency and severity of attacks.
Infrequent, relatively mild attacks may need little more
therapy than prompt simple analgesics or non-steroidal
anti-inflammatory medication.
More severe and refractory migraine may require the
use of tryptan medication.
If attacks occur frequently, generally twice or more per
month, then it is reasonable to use prophylactic agents.
Acute-phase treatment
Non-steroidal anti-inflammatory drugs (NSAIDS)
NSAIDs with evidence from randomized, placebocontrolled trials include single-dose aspirin (650
1000 mg), ibuprofen (4001200 mg), naproxen
(7501250 mg) and diclofenac (50100 mg).
Some of these studies are limited by varying outcome measures and definitions of migraine, but all
NSAIDs may be beneficial in patients who have
migraine, with or without aura.
Indomethacin as acute-phase treatment for
migraine, including the suppository form for nauseated patients, can also be effective.
There are no studies comparing the relative efficacy
of different NSAIDs; in general, if one NSAID is
ineffective then a different drug may be tried.
Triptans
The serotonin 1B/1D agonists (triptans) are specific therapies for acute migraine, working to
dampen activity in the trigeminovascular system
by inhibiting release of vasoactive neurotransmitted peptides such as calcitonin gene-related peptide
(CGRP). Oral triptans include sumatriptan, zolmitriptan, naratriptan, rizatriptan and eletriptan.
Sumatriptan can also be given as a subcutaneous
injection and as a nasal spray for patients with vomiting. Randomized, controlled trials and systematic
reviews have found all of the triptans to be effective
for the treatment of acute migraine.
Prophylactic treatment
Beta-blockers
Numerous placebo-controlled trials show evidence
that propranolol (in doses of 40160 mg daily) is
significantly more effective than placebo for reducing

migraine frequency. Other beta-blockers may also be
used for migraine prophylaxis but have less evidence.
Beta-blockers should be avoided in patients with
erectile dysfunction, peripheral vascular disease,
baseline bradycardia or low blood pressure, and used
cautiously in elderly patients, asthmatics, diabetics,
and patients with cardiac conduction disturbances.
Pizotifen
Placebo-controlled trials demonstrate that pizotifen
(in three divided doses starting at 1.5 mg daily, dosage range 1.53 mg daily) is superior to placebo for
migraine prophylaxis.
Weight gain and sedation are the most common
adverse events.
Calcium-channel blockers are widely used for migraine
prophylaxis. However, the data supporting the efficacy
of calcium-channel blockers are relatively weak.
Antidepressants
Amitriptyline (starting dose 10 mg nocte, dosage
range 2050 mg) was effective in randomized trials for migraine prophylaxis in four trials. Anecdotal
evidence suggests that amitriptyline is most effective in migraine associated with sleep disturbance
and mild affective symptoms. Other tricyclic antidepressants have no proven benefit.
Side-effects of tricyclic antidepressants include sedation, dry mouth, constipation, tachycardia, palpitations, orthostatic hypotension, weight gain, blurred
vision, and urinary retention. Confusion can occur,
particularly in the elderly.
The serotonin/norepinephrine reuptake inhibitor venlafaxine (starting at 37.5 mg once a day, dosage range
75150 mg once a day) can also be effective as prophylaxis for migraine.
Anticonvulsantssodium valproate, gabapentin and
topiramate are all more effective than placebo for reducing the frequency of migraine attacks.
Other prophylactic agents:
Botulinum toxinseveral randomized placebocontrolled trials have found no consistent, statistically significant benefits for botulinum toxin
injection in the treatment of episodic migraine
headache; however, there is evidence to support its
use in chronic migraine/tension headache.
Methysergidean ergot derivative and a specific
serotonin receptor antagonist (primarily 5HT2),
has been demonstrated in open-label and controlled
studies to be effective in migraine prophylaxis. Longterm use is associated with a low risk of retroperitoneal, pleural and heart valve fibrosis, and therapy
duration of >4 months is not recommended. The use
of triptans in combination for acute attacks is also not
recommended, due to risk of vasospasm.
Non-pharmacological therapies
Cognitivebehavioral therapy is as effective as drug therapy in preventing migraine, and is useful in all age groups
including children and adolescents. Relaxation exercises,
599
stress-management training, acupuncture and reduction in

caffeine intake are also beneficial. They may be more effective when combined with preventive drug therapy.
Menstrual migraine
Migraine can be sensitive to changes in estrogen concentrations. When estrogen levels are stable (e.g. during pregnancy or after menopause), women are often relatively free
of migraine attacks. Estrogen concentrations fall immediately before menstruation and can trigger a migraine attack.
Cluster headache
Cluster headache is rare, and is mainly seen in males with
attacks of severe, generally periorbital headache typically
accompanied by unilateral rhinorrhea, lacrimation, or conjunctival congestion. Attacks typically last from 15 minutes to
3 hours, recurring in separate bouts, often nocturnally, with
18 attacks per day for several weeks or months. Prevention of
further attacks is the main focus of cluster headache treatment.
Preventive treatment options
Verapamil sustained-release 160 or 180 mg orally, once
daily, up to 360 mg daily.
Methysergide 1 mg orally, once daily, up to 3 mg twice
daily.
Lithium 250 mg orally, twice daily, titrated according
to clinical response and tolerance, and guided by serum
concentration levels.
Preventive treatment is continued until attacks have ceased
for 1 week or more. The same preventive drug is usually
effective if attacks recur. In some cases, multiple preventive
drugs may need to be used in combination.
Bridging treatment with corticosteroids can be used while
prophylaxis is taking effect:
prednisolone 50 mg orally, daily in the morning for
710 days, then tapered off over 3 weeks.
Acute treatment
High-flow oxygen100% by inhalation, for up to
15 minutes at 10 L/min using a tight-fitting, nonrebreathing mask is effective in relieving cluster headache in a large proportion of patients.
Sumatriptan 6 mg subcutaneously, sumatriptan 20 mg
intranasally, dihydroergotamine 1 mg intramuscularly,
or lignocaine 4% solution instilled into the nose on the
side of the pain can all be effective for acute attacks.
Tension headache
Tension headache is the most common form of headache.
It is usually characterized by bilateral, dull ache,
described as a feeling of tightness or pressure that may
extend like a band around the head and down the neck.
Affective symptoms are more common in this group, as
are environmental stressors.
Stress is a common trigger for exacerbations.
The term chronic daily headache is sometimes used
to describe frequent attacks or constant (chronic unremitting) tension headache, which usually evolves from
infrequent tension headache over many years.
600
Non-pharmacological management
Massage, stretching, heat and postural correction can
relieve pain.
Cognitivebehavioral therapy is as effective as drug
therapy in episodic and constant tension headache.
Relaxation exercises, stress-management training, and
reduction in caffeine intake are also beneficial.
Pharmacological management
Simple analgesics are effective for short-lived attacks
of tension headache; however, medication-overuse
(rebound) headache may develop if analgesics are used
regularly for more than 23 days in a week.
Frequent attacks or chronic tension headaches are best
treated with a combination of non-pharmacological
approaches and preventive medication in the form of
amitriptyline 5075 mg daily. If amitriptyline produces
unacceptable adverse effects, nortriptyline or dothiepin
can be used.
Preventive medications may take several weeks to act, and
their effect may be blocked by frequent analgesic consumption and then development of medication-rebound
headache. Preventive medication should be continued for a
minimum of 36 months, and then tapered off and ceased.
Secondary headache
Headache is present in a wide range of pathologies, from
intracerebral hemorrhage and stroke to malignant hypertension and even intracranial infection. Most of these conditions are discussed in their relevant chapters. There are,
however, a few disorders presenting primarily with headache that should be specifically discussed.
Headaches with increased intracranial pressure

Venous sinus thrombosis (VST)
A disorder requiring a high threshold of suspicion, VST may
present at any age, but often occurs in young patients with a
history of venous thrombosis.
It presents with a headache often described as a pressure inside the head, sometimes with pulsation. Due
to raised intracranial pressure, it is usually worse when
lying flat or with coughing or straining.
With time papilledema develops, though in very acute
VST this may be absent.
It can be associated with venous stasis, and venous
infarction of superficial cerebral cortex.
Seizures often occur.
Small-convexity subarachnoid bleeds may be seen,
distant to any typical sites of aneurysms.
Diagnosis
Diagnosis is with dedicated cerebral imaging with CT
venography or MRI venography (Figure 19-4).
Treatment
Even in patients with subarachnoid bleeds, urgent anticoagulation is the mainstay of treatment. Investigation for
thrombophilia should be routine in these patients.
assessment including biochemistry, cell count and cytology to exclude other abnormality within the meninges
resulting in raised intracranial pressures.
Figure 19-4 A reconstructed MR venogram of a

patient with extensive venous sinus thrombosis. Note
obliteration of the superior sagittal sinus
Idiopathic intracranial hypertension (IIH)
Previously termed benign intracranial hypertension, IIH is
most certainly not benign.
It commonly affects overweight young women, and is a
disease on the rise.
It presents with insidious onset of headache, with similar
features to VST although less acute in onset. It is worse
with lying and better upright. It is worse with coughing
or straining.
Risk factors apart from weight, age and gender include
the use of tetracyclic antibiotics (tetracycline, doxycycline), and retinoids for acne.
IIH is frequently associated with visual symptoms,
including transient visual obscurations with bending,
coughing or straining (when a brief rise in intracranial
pressure impairs retinal perfusion), and at times blurring
of vision.
A scotoma consistent with an increased blind spot may
be noted.
Diplopia may occur, commonly due to abducens palsy
(or bilateral palsies) due to compression from intracranial pressure.
Patients usually present with florid papilledema and are
referred for urgent investigation and management.
Diagnosis
Urgent imaging of the brain should be performed to
exclude venous sinus thrombosis or mass lesion.
IIH is typically diagnosed on the basis of appropriate
history, examination, and absence of thrombosis on
imaging.
It can be confirmed and treated by performing a lumbar puncture in a left lateral position. Normal opening pressure in this position is less than 20 cmH2O,
while in patients with IIH the pressure is usually well
over 25cmH2O. A minimum of 30mL of CSF should
be removed as a therapeutic procedure, and sent for
Management
Weight loss is the cornerstone of IIH management, and
10% weight loss can result in substantial improvements
in symptoms.
In patients with morbid obesity, early intervention
should be considered if weight loss does not occur
while undergoing supportive management.
When present, retinoids and tetracyclic antibiotics must
be ceased.
Medical management involves the use of acetazolamide
at doses of 250750mg twice daily to reduce CSF production. A carbonic anhydrase inhibitor, acetazolamide
induces a mild metabolic acidosis and may cause acral
paresthesiae, and increases the risk of kidney stones. It
causes carbonated beverages to taste unpleasant.
Topiramate may be used to augment this effect,
with the additional benefits of appetite suppression
and headache reduction.
Serial lumbar punctures may be used to treat recurrent
headache.
In patients poorly responsive to medication or with
vision-threatening ocular symptoms, more invasive procedures may be required.
Optic nerve sheath fenestration may be performed to
reduce pressure on the optic nerve head if vision is
threatened. Other symptoms of IIH are not treated.
Shunting is occasionally performed, though placement
of shunts is often difficult and shunts commonly fail.
In patients with significant stenosis of venous outflow,
venous stenting is also considered when medical intervention has failed.
Headaches with low pressure

Spontaneous low-pressure headache is rare. It is seen far
more commonly following lumbar puncture (LP), especially
when a large-gauge cutting needle is used.
The headache occurs due to low CSF pressure, and
occurs with an upright posture. It improves dramatically
with a return to a supine position.
Low-pressure headache following LP is typically treated
by pushing oral fluids, giving caffeine (which increases
CSF production) and restricting the patient to strict bed
rest in a supine position for 2448 hours.
If this fails to work, blood patch may be performed.
The rare presentation of spontaneous low-pressure headache can be diagnosed through the combination of a typical
clinical presentation and MRI imaging demonstrating an
increased CSF space, often with gadolinium enhancement.
Specialized imaging (MRI or nuclear scintigraphy) can
isolate the source of the leak, and treatment is with largevolume or targeted blood patch.
601
STROKE
Stroke is a heterogeneous collection of pathological entities,
but may be divided into broad pathogenic subgroups: 85%
ischemic, 10% intracerebral hemorrhage, 5% subarachnoid
hemorrhage.
An understanding of stroke pathophysiology is important in determining the most appropriate acute therapy
and preventive treatment.
Brain imaging with CT or MRI is required to accurately differentiate ischemic from hemorrhagic stroke.
Clinical features and brain imaging findings should be
used to determine the affected brain topography (e.g.
anterior or posterior circulation, cortical or subcortical).
This can give some clues to the underlying etiology and
help guide further investigation. For example, subcortical syndromes such as lacunar stroke are often due to
small vessel disease, while cortical syndromes should
prompt a search for cardiac emboli or carotid stenosis.
Although traditionally included as a type of stroke, subarachnoid hemorrhage is a distinct clinical entity with acute
onset of severe headache or sudden loss of consciousness,
and is diagnosed by acute CT scan. All cases of suspected
subarachnoid hemorrhage require immediate evaluation in
hospital.
Stroke may be classified as described in Box 19-2. The
incidence of different causes of ischemic stroke are given in
Table 19-4.
Box 19-2
The TOAST stroke classication system

The TOAST (Trial of Org 10172 in Acute Stroke Treatment)
classication is based on clinical symptoms as well as the
results of further investigations. Based on this, a stroke is
classied as being due to:
1 Thrombosis or embolism due to atherosclerosis of a
large artery
2 Embolism of cardiac origin
3 Occlusion of a small blood vessel
4 Other determined cause
5 Undetermined cause:
a two possible causes
b no cause identied
c incomplete investigation.
Determination of the subtype is important for:
classifying patients for therapeutic decision-making in
daily practice
describing patients characteristics in a clinical trial
grouping patients in an epidemiological study
careful phenotyping of patients in a genetic study.
From Adams HP Jr, et al. Classication of subtype of acute
ischemic stroke. Denitions for use in a multicenter clinical trial.
TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke
1993;24:3541.
CLINICAL PEARL
Atrial brillation accounts for 85% of thromboembolic
stroke and 36% of ischemic stroke.

Any patient with sudden onset of focal neurological
symptoms or signs should be considered to have an
acute stroke, and should be urgently evaluated in hospital with transport to hospital by ambulance.
Ideally, health systems should have pre-hospital stroke
assessment and triage protocols to facilitate rapid access
for stroke sufferers to hospital, and thereby maximize
potential eligibility for time-limited acute therapy.
Clinical assessment remains the cornerstone of diagnosis of
acute stroke.
The clinician must rule out a stroke mimic, determine
the severity of the neurological deficit (ideally using
a validated stroke scale such as the National Institutes
of Health Stroke Scale score), and arrange immediate
investigations.
In a patient presenting acutely, immediate brain imaging is required to determine the pathology and exclude a
stroke mimic. CT scanning (Figure 19-5) is used acutely
to exclude hemorrhage and may show evidence of
infarction, but MRIparticularly diffusion-weighted
imagingis much more sensitive for detection of
ischemia.
602
Table 19-4 Causes of ischemic stroke
CAUSE
% OF CASES
Cardioembolic
42
Large artery atherosclerosis
16
Small vessel disease
11
Undetermined
25
Other causes
Advanced CT and MRI techniques may help guide

immediate therapy decisions, and can potentially define
brain tissue that may be salvaged by reperfusion therapies, possibly beyond the conventional time window
for treatment (Figures 19-6 and 19-7). This is currently
being studied in trials, and is not recommended in routine clinical practice.
Clinical and radiological assessment can also suggest the
subtype of ischemic stroke (e.g. lacunar stroke), but this
is not always accurate.
In almost all patients, the clinician should search for a
cardiac or carotid (where appropriate, as in an anterior
circulation territory stroke) source of embolus.
The best stroke care involves admission to a dedicated
stroke unit; the evidence in support of stroke unit care is
Figure 19-5 CT scan of infarction in the distribution of

the frontoparietal branch of the middle cerebral artery
From Perkin DG et al. Atlas of Clinical Neurology, 3rd ed.
Core
Penumbra
Figure 19-7 Imaging the ischemic penumbra. The

ischemic penumbra can be imaged with magnetic
resonance imaging and advanced perfusion
computed tomography (CT). Penumbral imaging with
advanced CT is now a validated technique and can be
used to identify those patients most likely to respond
to reperfusion therapies. The penumbral signature
is tissue that has marker delay in contrast transit (see
MTT [mean transit time] map above) in the setting of
relatively preserved cerebral blood ow and volume.
CBF, cerebral blood ow; CBV, cerebral blood
volume; CTA, CT angiogram; DWI, diffusion weighted
image; MRA, magnetic resonance angiogram; MTT,
mean transit time; NCCT, non-contrast CT; tPA =
tissue plasminogen activator.
From Parsons MW et al. Perfusion computed tomography:
prediction of nal infarct extent and stroke outcome. Ann Neurol
2006;59:726.
Clot
Figure 19-6 The ischemic penumbra. The ischemic

penumbra is the region of critically under-perfused
tissue at risk of progressing to infarction if reperfusion
does not occur promptly. The penumbra is
maintained by collateral ow and varies in extent
and duration across individual patients with similar
vessel occlusions at similar points in time from stroke
onset. The ischemic penumbra can now be imaged
with advanced magnetic resonance and computed
tomography perfusion methods
overwhelming. Organized care in a stroke unit reduces mortality and dependency by approximately 20%, increases the
likelihood of discharge to home, and does not increase the
length of hospital stay. The benefits are seen regardless of
age, gender or severity of stroke. Key components of a stroke
unit include specialized staff, a coordinated multidisciplinary
team, location in a geographically discrete unit, and early
mobilization.
Thrombolysis
CLINICAL PEARL
The time between onset of brain ischemia and commencement of reperfusion is one of the critical factors
determining the outcome of thrombolysis. Every minute saved can make a difference to clinical outcome.
Intravenous alteplase (a recombinant tissue-plasminogen

activator) is an effective treatment for selected patients with
nonhemorrhagic stroke.
When administered within 4.5 hours of symptom onset,
alteplase (0.9 mg/kg up to 90 mg intravenously [IV] over
1 hour, with 10% of the dose given as an initial bolus)
increases the likelihood of independence (discharge to
home) by 30%.
Delivery of treatment within 90 minutes from stroke
onset is associated with a number needed to treat for
rapid complete recovery of 3. The absolute benefit
reduces with time between onset and alteplase delivery.
603
The major complication of alteplase is symptomatic

intracranial hemorrhage, which occurs in around 6% of
patients.
At present, use of alteplase beyond 4.5 hours is not
guideline-recommended in some countries, and clinical trials are exploring the efficacy and safety of different
types of thrombolytic drug up to 9 hours after stroke
onset, some using advanced brain-imaging techniques.
CLINICAL PEARL
If pre-hospital and hospital systems of care are well
organized, stroke units should be aiming to treat
approximately 20% of their ischemic stroke patients
with alteplase.
Thrombolysis must be given in a setting with expert

staff, and close monitoring of blood pressure and neurological status is required for 24 hours following alteplase
infusion.
Hypertension should be treated promptly if blood
pressure exceeds 185/110 mm Hg, aiming to maintain blood pressure below this level.
Neurointerventional therapy, with intra-arterial thrombolysis or clot retrieval, is possible in a few highly
specialized stroke centers.
Intra-arterial approaches may be considered for
patients with proximal middle cerebral artery, distal internal carotid artery, and basilar occlusions, as
these respond poorly to intravenous thrombolysis.
Evidence supports intra-arterial thrombolysis
within 4.5 hours of ischemic stroke onset, but the
data for clot retrieval are currently limited.
In the setting of extensive hemispheric infarction (typically
complete distal carotid or middle cerebral artery occlusion),
cerebral edema results in mortality rates of above 80%.
In such patients, neurosurgical hemicraniectomy can be
performed to reduce intracranial pressure and improve
cerebral perfusion. Randomized controlled trials show
that this treatment reduces the mortality rate by 50%.
However, most survivors are left with some degree of
disability.
Hemicraniectomy should be considered within
48 hours of stroke onset for patients aged between 18
and 60 years. The decision-making process should
involve experienced stroke specialists and neurosurgeons working in highly specialized stroke units.
Cerebellar hemorrhages and large cerebellar infarcts are
associated with a mortality of >80%. Ventricular drainage,
to relieve acute hydrocephalus, and posterior fossa decompression are the treatments of choice for space-occupying
cerebellar hemorrhages and infarcts.

Multidisciplinary stroke care involves screening and assessment of swallowing ability, management of fluid balance
604
Box 19-3
Exclusion criteria and relative

exclusion criteria for thrombolytic
therapy in stroke
Exclusion criteria
Head trauma or prior stroke in previous 3 months
Symptoms suggest subarachnoid hemorrhage
Arterial puncture at non-compressible site in previous
7 days
History of previous intracranial hemorrhage
Elevated blood pressure (systolic >185 mmHg or
diastolic >110 mmHg)
Acute bleeding diathesis, including but not limited to:
Platelet count <100,000/mm3
Heparin received within 48 hours, resulting in
APTT > upper limit of normal
Current use of anticoagulant with INR >1.7 or
PT >15 seconds
Blood glucose concentration <50 mg/dL (2.7 mmol/L)
CT demonstrates multilobar infarction (hypodensity >
1
/3 cerebral hemisphere)
Relative exclusion criteria
Recent experience suggests that under some
circumstanceswith careful consideration and weighing
of risk to benetsome patients may receive brinolytic
therapy despite 1 or more relative contraindications.
Consider risk to benet of recombinant tissue
plasminogen activator (rtPA/alteplase) administration
carefully if any of these relative contraindications is
present:
Only minor or rapidly improving stroke symptoms

(clearing spontaneously)
Seizure at onset with post-ictal residual neurological
impairments
Major surgery or serious trauma within previous
14 days
Recent gastrointestinal or urinary tract hemorrhage
(within previous 21 days)
Recent acute myocardial infarction (within previous
3 months)
APTT, activated partial thromboplastin time; CT, computed

tomography; INR, international normalized ratio; PT, prothrombin
time.
From Levi CR et al. The implementation of intravenous tissue
plasminogen activator in acute ischaemic strokea scientic
position statement from the National Stroke Foundation and the
Stroke Society of Australasia. Int Med J 2009;39:31724.
and nutrition, guideline-based management of physiological

variables such as blood sugar, temperature and blood pressure,
and early mobilization and physical therapies for weak limbs
including adequate management of shoulder positioning.
Blood pressure is often elevated after an acute ischemic
stroke; in most instances this settles spontaneously.
Ingeneral, blood pressure lowering should be avoided in
the acute phase of stroke (first 48 hours); exceptions may

include patients with malignant hypertension, hypertensive encephalopathy or those receiving alteplase.
Patients who are hypoxic should be given supplemental
oxygen, but routine use is not supported.
Fever should be lowered with acetaminophen
(paracetamol).
Hyperglycemia is associated with worse outcomes
after stroke, and IV fluids containing glucose should be
avoided. Around 20% of patients admitted with acute
stroke are found to have unrecognized diabetes. Blood
glucose levels should be monitored, with action taken to
maintain euglycemia, but intense and aggressive management of blood glucose is not recommended.
Early mobilization, adequate hydration and antiplatelet therapy can help to prevent deep vein thrombosis in
all patients with ischemic stroke. Patients immobilized
by the ischemic stroke should receive low-molecular-weight heparin. The use of graduated compression
stockings is not recommended.

Most recurrent ischemic events occur within the initial few
weeks of the primary event. Prompt introduction of pathophysiologically tailored secondary prevention is critical.
Antiplatelet therapy
Aspirin reduces the risk of subsequent stroke by approximately 13% and all vascular events by 20%. There is no
discernible difference in efficacy between the different
doses of aspirin down to 30 mg daily. Low doses are
associated with less risk of hemorrhagic complications.
Both men and women benefit from aspirin.
Several studies and meta-analyses found that the combination of dipyridamole plus aspirin was marginally
more effective than aspirin alone. Dipyridamole plus
aspirin is preferred in patients with moderate or greater
absolute risk of recurrent stroke events. It should also
be considered in patients with recurrent stroke events
despite aspirin therapy, but has more adverse effects.
Headache is the most frequent adverse effect and may
be overcome by initiating treatment with smaller
doses.
Clopidogrel is modestly more effective than aspirin in
the prevention of serious high-risk vascular outcomes
(stroke, myocardial infarction, vascular death). Clopidogrel is mainly used as second-line therapy in patients
who are either intolerant of aspirin or have developed
recurrent cerebral ischemic events while on aspirin.
The combination of clopidogrel plus aspirin has been
the subject of several randomized controlled trials.
There is no benefit to this combination because a reduction in ischemic events is offset by an increase in serious
bleeding. The combination is not recommended for
long-term stroke prevention; however, it is often used
as short-term therapy. It may be continued, with care, if
there are clear cardiac indications.
Warfarin
The recurrent stroke risk in patients with atrial fibrillation can be as high as 1520% per year on no antithrombotic therapy. There is strong evidence that
anticoagulation is better than antiplatelet therapy for
long-term secondary prevention of ischemic stroke in
patients with atrial fibrillation, reducing the incidence
of further events by approximately 66% per year.
In patients without atrial fibrillation or another clear
source of cardiogenic embolism (e.g. mural thrombus),
there is no benefit of warfarin over antiplatelet therapy.
With careful control of the international normalized
ratio (INR), the risk of serious intracranial bleeding is
0.5% and extracranial bleeding is 2.5% per year.
The best time to commence warfarin after stroke is not
known. Guidelines generally suggest delaying treatment
for a week or two after acute stroke and using an antiplatelet agent in the interim.
In patients with atrial fibrillation who are unable to take
warfarin, the combination of aspirin and clopidogrel
reduces the rate of stroke compared with aspirin alone,
but with a higher risk of major bleeding complications.
New oral anticoagulants (NOACs)

Dabigatran, a direct thrombin inhibitor, shows superior
ischemic stroke protection compared with warfarin.
Factor Xa inhibitors (rivaroxiban, apixiban) have
recently been demonstrated to show non-inferior stroke
protection.
All the new agents have significantly lower rates of
major bleeding, and in particular intracranial bleeding,
in comparison to warfarin.
Blood pressure lowering

Hypertension is the major reversible risk factor for first and
recurrent stroke.
For secondary prevention of stroke, the importance of
blood pressure lowering has been shown in a meta-analysis
of 10 randomized controlled trials of antihypertensive therapy. Both recurrent strokes and cardiovascular events were
reduced by around 30% per year. The reduction of blood
pressure was often modest and the initial blood pressure
of many patients was in the normal range, yet all experienced benefit. The data are primarily from studies that used
angiotensin-converting enzyme inhibitors (ACEIs) alone or
in combination with a diuretic, but almost all antihypertensive agents are effective.
Cholesterol lowering
Studies consistently show that cholesterol lowering with
an HMG-CoA reductase inhibitor (statin) reduces the
risk of further strokes.
Overall, statins reduce the risk of stroke by 12% (a 20%
reduction in ischemic stroke was offset by an increase
in risk of hemorrhagic stroke), and all serious vascular
events by 25%.
605
Cholesterol lowering with a statin should be considered

in most patients following ischemic stroke, regardless of
their initial cholesterol levels.
CSF drainage devices (to reduce the risk of secondary

deterioration due to hydrocephalus caused by obstruction of the fourth ventricle) can be an effective adjunctive therapy to decompression.
Management of carotid stenosis

Carotid endarterectomy (CEA) is effective in secondary
prevention after minor stroke or TIA (transient ischemic attack). The benefit is greatest when the stenosis
is severe (more than 70%), the stroke event was recent,
and the patient is male or over 75 years of age. The benefit is marginal for patients with 5069% symptomatic
stenosis, or if the surgery is delayed beyond 3 months.
The success of the procedure is critically dependent on
the skill of the surgeon, who must have a perioperative
complication rate of less than 3%.
Percutaneous transluminal cerebrovascular angioplasty
and stenting (PTCAS) is less effective than CEA, largely
because of significant greater early periprocedural hazard. PTCAS is not routinely recommended for management of carotid stenosis. It may be considered in
circumstances where CEA is not feasible, or risk of surgery excessive.
INTRACEREBRAL
HEMORRHAGE
Medical treatment
Blood pressure lowering in acute intracerebral hemorrhage
may reduce hematoma expansion, and a recent large randomized trial (INTERACT2) suggested that aiming for
a blood pressure target of 140/90 mmHg showed a strong
trend to better long-term functional outcome.
Current consensus guidelines recommend urgent blood
pressure lowering if above 180/110 mmHg, aiming for a
target systolic blood pressure of 160 mmHg or possibly
now 140 mmHg.
Warfarin-related intracerebral hemorrhage can be
treated by urgent reversal with a combination of prothrombin complex concentrate, fresh frozen plasma
(FFP) and vitamin K; however, this therapy is generally
not effective and prognosis is generally very poor.
In patients immobilized by their intracerebral hemorrhage
and requiring prophylaxis for deep vein thrombosis, it is
common practice to commence low-molecular-weight
heparin 48 hours after the hemorrhage.
Surgical management
In patients with intracerebral hemorrhage, neurosurgical
intervention may be undertaken to evacuate supratentorial
hematomas. Evidence to support this practice, however, is
very limited, with one large randomized trial suggesting no
significant benefit above medical management.
Decompression of cerebellar hematomas larger than
3cm in diameter can be life-saving and result in favorable outcomes in many patients.
606
SUBARACHNOID
HEMORRHAGE (SAH)
Subarachnoid hemorrhage is a common and devastating
condition, with mortality rates as high as 45% and significant morbidity among survivors.
The incidence increases with age, occurring most
commonly between 40 and 60 years of age (mean age
v50 years). SAH is about 1.6 times higher in women
than men.
Risk factors for SAH include hypertension, smoking,
female gender and heavy alcohol use.
Cocaine-related SAH occurs in younger patients.
Familial intracranial aneurysm (FIA) syndrome occurs
when two first- through third-degree relatives have
intracranial aneurysms.

aneurysmal SAH
30-day mortality rate after SAH ranges from 33% to
50%.
Severity of initial hemorrhage, age, sex, time to treatment, and medical comorbidities affect SAH outcome.
Aneurysm size, location in the posterior circulation, and
morphology also influence outcome.
Up to 14% of SAH patients may experience re-bleeding
within 2 hours of the initial hemorrhage.
Surgical versus endovascular

management of SAH
Endovascular coil insertion and surgical aneurysm clipping
both dramatically reduce early re-bleeding rates in SAH.
The choice of therapy will depend on local facilities and
expertise.
TRANSIENT ISCHEMIC
ATTACK (TIA)
CLINICAL PEARL
As for ischemic stroke, prompt determination of the
mechanism or underlying pathophysiology of an ischemic event is the key to appropriate and most effective secondary prevention. The earlier appropriate prevention can be commenced, the better the chance of
preventing the next event.
Denition
Transient ischemic attack is defined as a transient neurological event of presumed vascular etiology with symptoms and/
or signs that last for <24 hours. The majority of TIAs have
clinical features lasting <1 hour.
There has been a recent recommendation to define TIA
using MRI as a transient neurological event of presumed
vascular cause without associated changes of infarction on
diffusion-weighted MRI (DWI). This new imaging-based
definition is gaining favor and illustrates the fact that approximately 50% of TIAs that have a symptom duration exceeding 4 hours will be accompanied by evidence of infarction
on DWI.
Differential diagnosis of transient

neurological disturbances
There are a number of common causes of transient neurological disturbances (transient neurological attacks,
TNAs) that mimic the TIA syndromes. These are generally distinguishable by using detailed symptom analysis and
neuroimaging.
The most common TIA mimic is migraine with aura;
however, other less common mimic syndromes are partial seizures, hypoglycemia, transient global amnesia,
and functional or non-organic attacks including hyperventilation syndrome.
Pre-syncope and syncope are often referred to the neurologist for assessment of possible TIA; however, TIA
and stroke are extremely rare causes of transient loss of
consciousness alone.
Neuroimaging is important to rule out certain TIA
mimic syndromes such as small deep hemorrhages that
can cause transient symptoms, subdural hemorrhages,
cerebral neoplasms, and other structural pathologies that
could predispose to partial seizures.
Pathophysiology
TIA and ischemic stroke share the same vascular risk factors
and the same pathophysiology.
There is no reliable way to clinically determine whether
the abrupt onset of a neurological deficit will be reversible;
hence, if a patient is seen with clinical signs of significant
neurological impairment they should be regarded as being
in the process of having a stroke.
CLINICAL PEARL
Overall only approximately 1015% of all ischemic
cerebrovascular events will spontaneously resolve. In
general, therefore, all patients presenting with sudden
neurological symptoms and signs should be managed
with urgency.
done in ischemic stroke, by investigation to determine

the pathophysiology of ischemia.
The two very high recurrent stroke risk pathophysiologies to identify and manage within the initial 24 hours
of presentation are:
severe large vessel occlusive disease
atrial fibrillation (either persistent or transient).
The key investigations required, therefore, are imaging
of the extracranial and intracranial large vessels (ultrasound, CT angiogram or MRI angiogram), electrocardiography (EKG) and, if the EKG is negative, Holter
monitoring and/or echocardiography.

The risk of recurrent stroke after a TIA or a minor
stroke averages approximately 10% in the first month
following the index event.
There are, however, some patients with much higher
riskup to 20% in the initial week. This subgroup
at very high risk generally has underlying severe large
vessel disease or unrecognized/untreated atrial fibrillation (AF).
It is important to recognize that patients with high-risk
pathophysiologies, and all clinico-radiologically proven
TIA cases, should undergo screening for high-grade
large vessel disease and AF.
An additional high-risk scenario is crescendo TIA (2
TIAs in a week) where, again, the risk of early recurrent
stroke is high.

The specific therapies for stroke prevention following TIA
are identical to those described above for ischemic stroke.
As in ischemic stroke, the selection of therapies for the
prevention of recurrent events is based around determination of the underlying pathophysiology.
Recurrent stroke risk following TIA is front loaded,
meaning that the majority of the recurrent events occur
within the first days to weeks after the index event.
Early commencement of appropriate antithrombotic
therapy, blood pressure lowering and lipid lowering
therapies, along with carotid intervention for highgrade carotid stenosis, is of paramount importance.
DEMENTIA
Dementia is characterized by impairment of memory and at
least one additional cognitive domain where there is impairment (e.g. aphasia, apraxia, agnosia, executive function),
with decline from previous level of function severe enough
to interfere with daily function and independence.
Investigation
Diagnosis
A clinical and radiological (non-contrast CT as a minimum standard) diagnosis of TIA should be followed, as
Dementia is a clinical diagnosis and does lack precision

when the neurodegenerative process is in the early stages.
607
Presentation is often via a spouse or other informant

who brings a problem with memory and/or personality
and behavioral change to attention.
The normal cognitive decline associated with aging
consists primarily of mild changes in memory and the
rate of information processing, which are not progressive and do not affect daily function.
Patients with dementia often have difficulty with functions such as learning and retaining new information,
handling complex tasks, reasoning, spatial ability, orientation and navigation, speech and language function,
and social interaction and behavior.
The diagnosis of dementia must be distinguished from delirium and depression.
Delirium is usually acute in onset and is associated with
a clouding or fluctuation of consciousness, difficulty
with attention and concentration.
Patients with depression are more likely to complain
about memory loss than those with dementia.
Patients with dementia are frequently brought to physicians by their families, while depressed patients often
present by themselves.
Patients with depression may have signs of psychomotor
slowing and produce a poor effort on testing.
Mild cognitive impairment (MCI) is generally defined
by the presence of memory difficulty and objective memory impairment but preserved ability to function in daily
life. Patients with MCI appear to be at increased risk of
dementia.

Alzheimer disease (AD)
Alzheimer disease, the most common cause of dementia, is
a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults.
The main clinical manifestations of AD are selective
memory impairment and dementia.
While treatments are available that can modulate the
course of the disease and/or ameliorate some symptoms,
there is no cure, and the disease inevitably progresses in
all patients.
It is not rare for Alzheimer pathology to coexist with
other processes, including vascular lesions and vascular
dementia, cortical Lewy bodies and Parkinsons disease.
While the diagnosis is clinical, high-resolution MRI
scanning can quantify hippocampal volumes and may
aid diagnosis.
Genetic testing is not recommended in the routine
evaluation.
However, genotyping for apolipoprotein E J4 adds
marginally to the predictive value of clinical criteria for
AD and may stratify risk of conversion of amnesic MCI
to AD.
Genetic testing for presenilin-1 mutations is commercially available, but should be reserved for cases of onset
608
at <60 years of age in the setting of a positive family

history.
Patients with AD have reduced cerebral production of choline acetyltransferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function.
Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft,
and have been proved to mitigate symptoms and the rate
of symptom progression.
A treatment trial with a cholinesterase inhibitor is generally recommended for patients with mild to moderate
dementia (Mini-Mental State Examination score 1026).

Dementia with Lewy bodies is increasingly recognized clinically as the second commonest type of degenerative dementia after Alzheimer disease.
In addition to dementia, distinctive clinical features
include visual hallucinations, parkinsonism, cognitive
fluctuations, dysautonomia, sleep disorders, and neuroleptic sensitivity.
Cholinesterase inhibitors may represent a first-line
pharmacological treatment in DLB. Research suggests
that cholinesterase inhibitors are effective in symptomatic treatment of DLB, with reported benefit not only in
cognition but also for fluctuations, psychotic symptoms,
and parkinsonian symptoms.
Frontotemporal dementia (FTD)

Frontotemporal dementia typically presents as either a
progressive change in personality and social behavior or
as a progressive form of aphasia. In both cases there is
progression ultimately to a dementia.
The most common presentation of FTD is that of a progressive change of personality and behavior, with personality change, lack of insight, loss of social awareness,
emotional blunting and mental rigidity.
Cognitive functioning may be relatively intact early
in the course, with minimal memory loss and normal Mini-Mental State Examination (MMSE) scores;
however, over time, impairment of executive functions,
problem-solving, judgment, attention, organization and
planning develop.
Rarer forms of FTD are a predominant aphasia, either
progressive expressive and/or receptive, FTD associated
with motor neuron disease, and FTD associated with
corticobasal degenerationa syndrome of asymmetric
rigidity and apraxia.
Patients with progressive supranuclear palsy (PSP), a
clinical syndrome of supranuclear vertical-gaze palsy,
axial dystonia, bradykinesia, rigidity and falls, often also
develop a dementia syndrome with features that overlap
with FTD.
Pharmacological treatment in FTD is symptomatic and
aimed at alleviating neurobehavioral symptoms. However,
there is limited evidence of the efficacy of pharmacological
treatments modifying FTD.
Vascular (multi-infarct) dementia (VaD)

Vascular dementia is a heterogeneous syndrome in which
the underlying cause is cerebrovascular disease in some
form, and its ultimate manifestation is dementia.
There is considerable overlap between AD and VaD with
regard to comorbidity as well as shared risk factors and even
pathogenesis. The combination of pathologies may be more
common than either in isolation, and it is not generally easy
to identify the primary etiological entity.
Preventative agents and treatments for VaD are essentially those for prevention of small vessel and large vessel
cerebrovascular diseaseantiplatelet therapy, blood pressure lowering and lipid lowering therapies.
Parkinsons disease (PD) with dementia

While PD can coexist with other common causes of
dementia, such as Alzheimer disease and vascular dementia,
dementia is increasingly recognized as a common feature of
PD itself.
The clinical characteristics and course of dementia, its
pathological features, and the most appropriate treatment are areas of current investigation.
Clinical features can generally distinguish between
PD and other movement disorders associated with
dementia. However, whether PD dementia (PDD) and
dementia with Lewy bodies (DLB) are distinct disorders
or represent different presentations of the same disease is
an area of debate and investigation.
Diagnostic work-up of the dementia

patient
History relayed by the patient but most importantly also
that relayed by family members will provide much of
the diagnostic information.
Physical examination and initial objective cognitive
screening with the MMSE is then generally followed by
laboratory and imaging studies (Table 19-5, overleaf).
Investigations are largely performed to rule out reversible
or partially reversible pathologies such as hydrocephalus,
central nervous system (CNS) infection, occult structural pathology such as subdural hematomas and lowgrade tumors, and low-grade inflammatory processes
such as cerebral vasculitis. A diagnosis of depression
should be pursued with formal psychiatric assessment in
situations where there is any clinical suspicion.
There are many examination schemata for bedside testing of
memory and cognition. The MMSE (Figure 19-8, overleaf)
is commonly used, though it is now under copyright. Other
testing schemes such as the Montreal Cognitive Assessment
are available, and may be more sensitive. It is critical to be
aware of the limitations of any simple questionnaire, and
that they are performed within the limits of attention, language, the environment and education.
An MMSE score of less than 24 points is suggestive of
either dementia or delirium.
Using a cut-off of 24 points, the MMSE has a sensitivity
of 87% and a specificity of 82%; however, the test is
not sensitive for mild dementia, and scores may be influenced by age and education as well as language, motor
and visual impairments.
Studies suggest that high scores (23) and low scores
(<19) can be highly predictive in discriminating broad
mental competency from incompetency.
The MMSE has limitations for assessing progressive
cognitive decline in individual patients over time.
Changes of 2 points or less are of uncertain clinical
significance.

Normal pressure hydrocephalus (NPH)
Normal pressure hydrocephalus refers to a condition of
pathologically enlarged ventricular size with normal opening pressures on lumbar puncture.
CLINICAL PEARL
Normal pressure hydrocephalus is associated with a
classic triad of dementia, gait disturbance and urinary
incontinence.
Because NPH is potentially reversible by the placement

of a ventriculoperitoneal shunt, it is important to recognize
and accurately diagnose. However, there is little consensus
regarding the diagnosis of NPH and the selection of patients
for shunt placement.
MRI scanning can give some diagnostic guidance, with
reports that increased aqueduct of Sylvius flow is associated with the condition.
A generally used confirmatory test is the CSF tap
test where 3050 mL of CSF is removed with documentation of the patients gait and cognitive function
before and 3060 minutes after the procedure. Common parameters measured before and after CSF removal
include measures of gait speed, stride length, and tests
of verbal memory and attention. Documented improvement in one or more parameters following the tap test
has a high positive predictive value.
It is generally considered that gait impairment is most
responsive to shunting.
Cognitive impairment is more resistant to shunt therapy but can improve, especially if not severe at the time of
intervention.
Creutzfeldt-Jakob disease (CJD)

Creutzfeldt-Jakob disease is the most common human prion
disease, although it is still rare with an approximate incidence of 1 case of sporadic CJD per 1,000,000 population
per year.
Prion diseases share the common neuropathological features of neuronal loss, proliferation of glial cells, absence
of an inflammatory response, and the presence of small
vacuoles within the neuropil, producing a spongiform
appearance.
609
Table 19-5 Pathology work-up for dementia
TEST
INDICATION
INTERPRETATION
Blood tests, includes

FBC, biochemical
prole, TSH, vitamin B12
Routine
Useful for detection of systemic illness which may present with

cognitive slowing such as hypothyroidism
Also may reveal changes of chronic alcohol abuse and chronic
illness
Syphilis screening, HIV

serology
Anyone at risk
Assesses for the possibility of HIV dementia and syphilis-related

dementia
Copper studies
Young patient with

psychiatric presentation
Screen for Wilsons disease; also check LFTs and for Keyser
Fleischer rings
Brain imaging
Routine
Assesses for treatable forms of dementia, e.g. normal pressure

hydrocephalus, unrecognized vascular disease
May help stratify diagnosis
ADfrequently shows atrophy, with hippocampal atrophy
prominent
DLBfrequently normal
FTDmay show asymmetrical frontal (FTD) or temporal
(progressive non-uent aphasia, semantic dementia) atrophy
VaDdiffuse evidence of small- and/or large-vessel infarction
with volume loss*
CJDmay show cortical DWI restriction and changes in basal
ganglia
Lumbar puncture
Young or rapidly progressive

or
Clinical picture of NPH
May reveal subtle inammation (chronic meningitis, limbic

encephalitis), inltrative processes (meningeal metastases) and
allow protein 14,3,3 testing
May allow CSF tap test in patients with imaging and clinical
presentation of normal pressure hydrocephalus (take 2030mL)
Protein 14,3,3
Rapidly progressive
dementia with clinical
picture of CJD
A marker of rapid neuronal death, this is sensitive and specic

for CJD in an appropriately selected population. It should not be
used as a screening tool in general
Genetic testing
Strong family history or very

young onset
Testing of presenilin 1 can be considered in patients with veryyoung-onset AD

Familial FTD-MND may also be tested for an expanding number
of genes
PET/SPECT scanning
Complex cases only
Used only in complex cases, where the diagnosis is not clinically

apparent
Brain biopsy
Last resort
In rapidly progressive cases where the diagnosis remains unclear

despite comprehensive investigation (e.g. atypical presentation
of CJD with autoantibodies or progressive imaging changes
consistent with intravascular lymphoma)
* Some microvascular change is common in older patients presenting with dementia. For a diagnosis of vascular dementia, the imaging
ndings need to be congruent to the clinical history.
AD, Alzheimer disease; CJD, CreutzfeldtJakob disease; CSF, cerebrospinal uid; DLB, dementia with Lewy bodies; DWI, diffusionweighted imaging; FBC, full blood count; FTD, frontotemporal dementia; LFT, liver function test; MND, motor neuron disease; NPH,
normal pressure hydrocephalus; PET, positron emission tomography; SPECT, single-photon-emission computed tomography; TSH,
thyroid-stimulating hormone; VaD, vascular dementia.
Sporadic, familial, iatrogenic and variant forms of CJD are

the recognized forms.
The vast majority of CJD cases are sporadic (8595%),
while 515% are familial and iatrogenic cases account
for less than 1%.
610
Variant CJD has developed as a result of bovine-tohuman transmission of the prion disease of cattle bovine
spongiform encephalopathy (BSE). Variant CJD can be
distinguished from cases of typical sporadic disease by
patients being of considerably younger age at the onset
MMSE SAMPLE QUESTIONS

Orientation to time
What is the date?
Score ____ out of 5
Registration
Listen carefully. I am going to say three words. You say them back after I stop.
Ready? Here they are
APPLE (pause), PENNY (pause), TABLE (pause). Now repeat those words back
to me.
Score ____ out of 3
Naming
What is this? [Point to a pencil or pen.]
Score ____ out of 1
Reading
Please read this and do what it says. [Show examinee the words on the
stimulus form.]
Score ____ out of 1
CLOSE YOUR EYES
Figure 19-8 Sample questions from the Mini Mental State Examination
Questions reproduced by special permission of the Publisher, Psychological Assessment Resources, Inc., 16204 North Florida Avenue, Lutz,
Florida 33549, from the Mini Mental State Examination, by Marshal Folstein and Susan Folstein, Copyright 1975, 1998, 2001 by Mini Mental
LLC, Inc. Published 2001 by Psychological Assessment Resources, Inc. Further reproduction is prohibited without permission of PAR, Inc.
The MMSE can be purchased from PAR, Inc. by calling (813) 968-3003.
of symptoms, showing less rapid progression of illness,

and also by distinctive differences in neuropathological
features including the presence of prominent amyloid
plaques which stain intensely for prion protein.
Brain biopsy remains the gold standard diagnostic test;
however, MRI scanning can show relatively specific features with increased T2 and FLAIR signal intensity in the
putamen and head of the caudate and, less commonly, areas
of T2 and FLAIR signal hyperintensity being seen in the
globus pallidus, thalamus, cerebral and cerebellar cortex,
and white matter.
SEIZURES AND THE EPILEPSIES

Seizures can be defined as a transient occurrence with signs
and symptoms due to abnormal, excessive or synchronous
neuronal electrical activity within the brain.
They are a common symptom of a multitude of pathologies, some transient and some long-lasting, with ongoing
susceptibility to seizures (epilepsy). Due to issues in the
social domain of personal safety, in particular driving, there
is morbidity associated with seizures well outside the scope
of the seizure itself.
Seizure types
Seizures may be described as focal or partial (affecting part
of the brain), or generalized (affecting both hemispheres).
Focal seizures may spread from their initial site of activity to
involve both hemispheres, and the seizure is then referred
toas secondarily generalized.
When the brain is diffusely involved as in a generalized
seizure, consciousness is lost; but in focal seizures, consciousness may remain intact throughout the seizure,
termed simple partial, or may be lost after an aura or
focal motor onset, termed simple partial with secondary generalization.
When awareness is lost rapidly but there are clear focal
signs at onset, the seizure is usually referred to as complex partial.
When describing seizure phenomena, an emphasis is placed on the motor appearance of the seizure
(Table19-6, overleaf), especially when generalized. The
motor phenomena frequently help with the underlying
diagnosis of a patient with recurrent seizures.
In a patient with recurrent seizures, it is also important
to ask about other seizure types, as patients may have
611
Table 19-6 Appearance of seizures
TYPE
NOTES
Tonic
Sustained contraction of muscles with stiffening of the limb(s) or trunk
Clonic
Brief jerking movements, typically waxing then waning in rate
Tonicclonic
Tonic phase followed by clonic phase
Myoclonic
Brief shock-like jerks of the body or limbs. May cause dropping of objects in the patients hands
Atonic
Sudden loss of tone in the body, resulting in a fall to the ground. These seizures are the hallmark
of LennoxGastaut syndrome and are usually only present in severe epilepsy syndromes with
developmental delay. Injury frequently results if unprotected
Absence*
One of the few seizure types not dened by motor features, these episodes are generalized events
with loss of awareness but maintained tone
* It is important not to equate absence seizures with episodes of loss of awareness without tonicclonic activity. Many such episodes do
demonstrate focal motor signs such as head turning or eye deviation.
several types of seizures in some syndromes and may

not have recognized the significance of them (e.g. juvenile myoclonic epilepsy with generalized tonicclonic,
myoclonic and absence seizures).

In assessing a patient with a seizure, it is critical to first assess
whether indeed it is a seizure. The main differential for a
seizure is a syncopal episode, and with an adequate history
it is often possible to reliably distinguish these episodes. In
considering the differential, it is important to consider the
following aspects.
The situation
Events occurring in emotional situations or with prolonged standing in a stationary position are often syncopal events. Syncope may also occur with micturition or
in the shower with peripheral vasodilatation.
Events occurring during sleep while supine are much
more likely to be seizures than syncope.
The prodrome
Syncope frequently, though not always, has a prodrome
with lightheadedness, sweating, pallor, vision and aural
symptoms and collapse.
Seizures may have an aura, which is in fact a focal seizure within the brain, of which the patient is aware. It
is varied from patient to patient, but should be the same
(allowing scope for severity) within one patient for each
seizure focus.
It is important to note that seizures arising from the
temporal lobe may trigger a rising feeling, anxiety and
at times dj vu. This can be difficult to distinguish from
panic attacks, especially with anxiety and depression
frequently comorbid with epilepsy.
In patients with generalized epilepsy (e.g. juvenile
myoclonic epilepsy), there may be a longer prodrome,
612
inconsistent with an aura, in which patients are aware

that they are more likely to have a seizure.
The event
Frequently the least useful piece of history, twitching
and eyes rolling back in the head are often commented
upon but have no specific diagnostic value.
It should be noted that syncope frequently results in
brief seizure activity due to cerebral hypoxia, termed
convulsive syncope.
The presence or absence of tongue-biting and incontinence is neither sensitive nor specific and cannot be
relied upon.
A clear tonic then clonic phase may help suggest a generalized seizure.
Focal arm raising or hand posturing with specific head
turning and spread of jerking (Jacksonian march) is
helpful in identifying focal-onset seizures.
The post-ictal stage

A prolonged drowsy state, especially if focal neurology is
present, is suggestive of a seizure.
Briefer post-ictal phases may be syncope, seizure or
non-epileptic in origin.
CLINICAL PEARL
In the modern day of cell (mobile) phones with video
recorders, ask if anyone has a video of the event(s).
This may allow better assessment of the nature of the
event. Remember, the most useful piece of equipment
in the neurologists office is often a telephone!
Causes
Seizures are a symptom, and in an acute first seizure it is
imperative to consider the possible causes (Table 19-7).
Table 19-7 Causes of seizures
ETIOLOGY
Infection and
inammation
Neoplasia
EXAMPLES
Infective (meningo)encephalitis
Chronic CNS infection (e.g.
neurocysticercosis)
Autoimmune limbic encephalitis
(may present bizarrely)
Cerebral lupus
Gliomas and other primary CNS
neoplasms
Metastases
Lymphoma
Vascular
Stroke*
Subarachnoid hemorrhage*
Subdural hematoma
Eclampsia
Hypertensive encephalopathy
Metabolic
Hyponatremia
Hypoglycemia
Hypocalcemia
Uremia
Porphyria
Trauma
Head injury*
Neurosurgery*
Drugs and
withdrawal
Alcohol
Amphetamines, MDMA
Pethidine
Benzodiazepine or barbiturate
withdrawal
Many others
Neurodegeneration
Alzheimer disease
CreutzfeldtJakob disease
Epilepsy
Multiple causes
Psychiatric
Psychogenic non-epileptic
seizures
* May occur at the time of the insult, or may occur up to years

later.
CNS, central nervous system; MDMA, 3,4-methylenedioxy-Nmethylamphetamine (Ecstasy).

All patients with a first seizure warrant a thorough history, and screening for an obvious cause (e.g. a first seizure
in a young type I diabetic at night with a blood glucose of
1.5 g/L). Family history is important given the frequent
genetic basis of epileptic disorders.
Examination is frequently normal, but clinical findings
of ongoing Todds paresis, previous sequelae of strokes, or
clinical features of alcohol abuse are examples of physical

signs suggesting possible underlying etiologies.
Investigations are outlined in Table 19-8, overleaf.
CLINICAL PEARL
Generalized epilepsy can only be excluded by an electroencephalogram if performed during an attack.
The epilepsies
Often considered by the greater public to be a single disease, the epilepsies are disorders grouped together by the
predisposition to seizures, although there are many disparate causes, treatments and prognoses. They can be focal or
generalized, consist of one or more seizure types, and have a
specific age range of onset and, in some cases, of resolution.
Recognition of the correct seizure type(s) is critical to
appropriate treatment, and incorrect treatment may make
seizures worse. Indeed, anticonvulsants have a spectrum of
activity in a manner similar to antibiotics, and identification
of the correct seizure disorder is as important as recognition
of a bacterial pathogen causing infection.
In the past, epilepsies were defined as idiopathic where
genetics were likely to be the cause, or as symptomatic
when seizures were accompanied by other features. Cryptogenic was the term used when seizures were thought to
be symptomatic but a cause could not be identified (see
Box19-4).
With modern genetics, many syndromes with cognitive
impairment (e.g. Dravet syndrome) have been identified
as having distinct genetic causes. As such, there has been a
move toward classifying epilepsies as genetic, structural or
unknown. However, classification continues to be debated.
The importance of making a correct diagnosis for a
patient with epilepsy is manifold.
Box 19-4
Historical classication of epilepsy

Idiopathic focal
Benign epilepsy with
centrotemporal spikes
(rolandic epilepsy)
Early-onset benign
occipital epilepsy
(Panayiotopoulos
syndrome)
Idiopathic generalized
Childhood absence
epilepsy
Juvenile myoclonic
epilepsy
Juvenile absence
epilepsy
Cryptogenic/symptomatic
focal
Temporal lobe epilepsy
Cortical dysplasia
Post-traumatic epilepsy
Post-stroke epilepsy
Cryptogenic/symptomatic
generalized
(usually with cognitive
impairment)
West syndrome
LennoxGastaut
syndrome
Dravet syndrome
613
Table 19-8 Investigations for seizures
TEST
NOTES
Full blood count
Infection, chronic disease, alcohol abuse
Electrolytes, urea,
creatinine
Hyponatremia, uremia, hypocalcemia or severe hypomagnesemia
Blood glucose levels
Hypoglycemia
Alcohol abuse
Prolactin
Not for routine use. Can be elevated after syncope or with the use of psychotropic drugs, as
well as after a seizure. May occasionally help distinguish a psychogenic cause from generalized
seizure
Electrocardiograph
To exclude arrhythmogenic abnormalities that may lead to syncope, e.g. prolonged QT

syndrome, heart block
Brain imaging
Computed tomographyacutely, to exclude hemorrhage or mass

Magnetic resonance imagingto dene etiology, e.g. mesial temporal sclerosis, cortical
dysplasia, old hemorrhages, subtle inammation
CSF examination
If suspected acute or chronic infection, meningeal malignancy, or autoimmune encephalitis

(NMDA antibodies)
Electroencephalogram
(EEG)
Depending on the history and the seizure type, EEG has a variable sensitivity in detecting
epilepsy. Techniques such as hyperventilation and photic stimulation (ashing lights) may
further increase sensitivity. An EEG is almost always abnormal during a seizure (though some
focal seizures may be difficult to detect, and interictal abnormality may be present in many
patients. However, a normal interictal EEG cannot exclude epilepsy
When a clinical history is compelling for epilepsy, further provocation is usually undertaken in
the form of a sleep-deprived EEG, improving the likelihood of an intermittent abnormality being
found
CSF, cerebrospinal uid; NMDA, N-methyl-D-aspartate.
1 It allows selection of the most appropriate therapy

to maximize effectiveness and minimize dose and
side-effects.
2 It can provide prognosis as well as explanation for
seizures.
3 It can have genetic implications for parents and siblings
in the case of children with epilepsy.
4 Some epilepsies are surgically amenable if refractory.

Idiopathic generalized epilepsies
These epilepsies are notable for seizures that are electrographically generalized at onset on EEG. There is a significant contribution from genetic factors. Sodium valproate is
typically the first-line treatment.
Childhood absence epilepsy
Coming on in the childhood years (ages 49), children
have typical absence episodes in which they stop suddenly mid-activity for usually between 5 and 20 seconds,
from one or two to hundreds of times per day.
614
They are unresponsive during this period, and maintain

body tone.
They often return to their activity afterwards as if they
had never stopped.
It is readily controlled by sodium valproate or
ethosuximide.
Prognosis is usually good, with most children growing
out of it by adolescence.
EEG tends to be sensitive, with 3 Hz spike-wave
discharges the hallmark, often brought on by
hyperventilation.
Juvenile myoclonic epilepsy (JME)
Usually presenting in the 2nd decade of life, this epilepsy is
notable for:
1 myoclonusoften in the morning and when tired
2 generalized tonicclonic seizures (often with sleep
deprivation or alcohol)
3 absence episodes.
Not all patients will have all three seizure types.
EEG is once again reasonably sensitive, with a >3 Hz
polyspike-wave pattern.
Sodium valproate is usually first-line treatment,

although it may be problematic in young women of
childbearing age when pregnancy is likely.
Lamotrigine is second-line treatment, with levetiracetam and other broad-spectrum anticonvulsants used in
cases of ongoing seizures.
Most patients will have JME lifelong, and withdrawal of
medication even after 5 or more years of good control is
usually unsuccessful.
Symptomatic generalized epilepsies

These epilepsy syndromes are also notable for generalized
activity on EEG (but in different patterns), but have a much
worse prognosis. Most are associated with at least mild and
often more significant developmental delay.
West syndrome
Coming on usually before the age of 1 year, infants
with West syndrome suffer intermittent flexor spasms
(salaam spasms).
EEG reveals hypsarrhythmia, and treatment is frequently with corticosteroids or vigabatrin.
With development, most children develop Lennox
Gastaut syndrome.
LennoxGastaut syndrome (LGS)
The most common form of intractable epilepsy, children who develop this syndrome often have seizures
throughout their lives and into adulthood. Many have
significant developmental delay, making them reliant on
the care and support of others.
The hallmark of LGS is atonic seizures or drop attacks,
in which the patient loses all tone and drops to the
ground, often injuring themselves.
They may also have absence episodes, tonic seizures,
tonicclonic seizures, and may develop non-convulsive
status epilepticus, appearing not themselves and being
less interactive.
Medication with a clear role includes sodium valproate,
lamotrigine, topiramate, phenytoin, clonazepam, clobazam, and phenobarbitone. Many other anticonvulsants
may, paradoxically, worsen the situation, and should be
monitored carefully when used.
Dravet syndrome
(Generalized epilepsy with febrile seizures plus.)
Coming on at around 1 year of life, this syndrome is
fortunately rare.
It initially presents as febrile convulsions in an otherwise
normally developing child.
Over the next year, seizures become more common and
may be brought on by heat.
Seizures frequently appear focal, although generalized
and focal abnormalities may be present on EEG.
Patients with Dravet syndrome are often resistant to
medication, and treatment is best through specialized
units.
Common focal epilepsies

Temporal lobe epilepsy (TLE)
Temporal lobe epilepsy is the most common form of
epilepsy and may arise from any part of the temporal lobe, although it usually arises as a consequence of
scarring of the hippocampus, termed mesial temporal
sclerosis.
The pathology underlying this change is not well understood, although patients often have a history of febrile
convulsion.
Unlike the rest of the brain, seizures arising in the
mesial temporal lobe need not spread rapidly to cause
loss of consciousness. This results in frequent reports of
sensory aura at onset, which are in fact simple partial
seizures.
Frequent descriptions include a particular smell or taste,
a rising feeling in the chest, anxiety or fear, a feeling of
dj vu (having done something before) or jamais vu
(everything feeling unfamiliar), as well as music or a
stereotyped sound.
At times patients may have secondary generalized seizures, while others may have frequent aura in isolation.
Diagnosis
MRI is of particular utility in identifying mesial temporal sclerosis (Figure 19-9, overleaf).
EEG can confirm unilateral temporal dysfunction or
seizure.
Treatment
Treatment is usually with carbamazepine or lamotrigine, although a wide variety of anticonvulsants may be
used. Unfortunately, in some patients, seizures may
be resistant to medication and require high doses of
medication or multiple anticonvulsants.
In intractable seizures, epilepsy surgery may be considered in patients with TLE, by removing the anterior temporal lobe on the symptomatic side. However,
patient selection is critical due to the potential for resection of brain involved in language and memory and
that which is also important for mood. This assessment
should be performed through a specialist epilepsy unit.
Epilepsy associated with neuronal migration
disorder (e.g. cortical dysplasia)
In some patients, epilepsy arises as a consequence of
disordered migration of gray matter within the brain
during development. This can sometimes be attributed
to a fetal or neonatal trauma, although sometimes no
cause is identified.
Most neuronal migration disorders can be identified with dedicated, careful MRI sequences and even
more careful review of films. More extreme abnormalities such as megalencephaly (overgrowth of one
or both hemispheres), polymicrogyria (multiple small
disordered gyri) and, in the extreme, schizencephaly
615
Figure 19-9 (A) T1 coronal image through the hippocampi demonstrating reduced volume of the right
hippocampus relative to the left. (B) T2 image with increased signal within the right hippocampus, consistent
with sclerosis
(afissure in the brain connecting the surface with the

ventricle) should all be more readily identified.
Treatment is carbamazepine or lamotrigine as first-line
therapy, with multiple second-line options.
Surgery is not usually possible due to microscopic dysplasia, often extending outside the radiologically apparent region.
Status epilepticus may occur in patients with epilepsy

who have been poorly adherent, or when other precipitants have led to a deterioration in control. It may be
seen denovo in patients when symptomatic of intracranial
pathology or drug withdrawal, or in infective or inflammatory pathology.
Epilepsy as a symptom of acquired cortical injury

(e.g. stroke, tumor)
In the community, status epilepticus is usually managed by

paramedics with IV midazolam or other short-acting benzodiazepines. This allows termination of a seizure without
the risk of longer respiratory depression.
In brittle epileptic patients, rectal diazepam or buccal
midazolam may be used under direction of an epilepsy
plan.
In the hospital, a more measured approach is required.
Parenteral midazolam or diazepam is often useful initially, but in refractory status epilepticus the effect is
rapidly lost with resumption of seizures due to rapid
metabolism (midazolam) or redistribution (diazepam)
of these medications.
Clonazepam 0.250.5 mg is often given intravenously
to allow longer effect.
This is a common cause for seizures in the elderly.

Patients developing symptomatic epilepsy late in life will
typically require lifelong therapy.

All anticonvulsants have specific uses, as well as potential
side-effects. It is important when starting patients on anticonvulsants to do so with an understanding of:
1 the certainty of diagnosis
2 the type of epilepsy
3 side-effects
4 the implications for pregnancy.
Table 19-9 outlines important anticonvulsant medications
and indications for their use.
Status epilepticus
CLINICAL PEARL
Status epilepticus refers to a seizure that does not
remit for a period of 510 minutes or more, or multiple seizures without a return to normal consciousness
between them. It is a medical emergency.
616
Treatment
CLINICAL PEARL
Status epilepticus should not be managed in-hospital
with repeated boluses of diazepam intravenously. Diazepam is rapidly redistributed and the effect is rapidly
lost, minimizing effect and maximizing toxicity. The use
of a long-acting benzodiazepine such as clonazepam
0.250.5mg is recommended.
In known epileptic patients with likely non-adherence,

where possible it is best to give medication known to be
effective. For example, in a patient normally prescribed
Table 19-9 Anticonvulsant medications
DRUG
MECHANISM OF
ACTION
USES
SIDE-EFFECTS
Phenytoin
Sodium-channel blocking
agent
Status epilepticus (due to

availability for IV infusion)
Ataxia, drowsiness, nausea,

encephalopathy
Multiple drug interactions
Gum hypertrophy or cerebellar
degeneration possible with long-term use
Carbamazepine
Sodium-channel blocking
agent
Focal seizures
May worsen generalized seizures

Nausea, ataxia, elevated hepatic enzymes,
drowsiness, rash
Potential for StevensJohnson syndrome
in Han Chinese ethnicity, so must be
avoided
Agranulocytosis, which is usually
reversible
Sodium valproate
Multiple, including
sodium-channel
blockade, and increasing
cerebral GABA
Multiple actions
Broad-spectrum
anticonvulsant
First-line therapy in
generalized epilepsies
Weight gain, tremor, thrombocytopenia,

LFT dysfunction
Rarely but importantly, hyperammonemic
encephalopathy
Teratogenic, in particular neural tube
defects
Interacts with lamotrigine
Lamotrigine
Sodium-channel blocker
Broad-spectrum
anticonvulsant
Focal epilepsies
Useful in generalized
epilepsies
Second-line therapy in JME
CNS side-effects
StevensJohnson syndrome
Topiramate
Enhances central GABA

activity, and antagonizes
AMPA and kainate
glutamate receptors
Broad-spectrum
anticonvulsant
Migraine prophylaxis
Cognitive blunting and speech

disturbance
Acral paresthesiae
Kidney stones
Mood disturbance
Levetiracetam
Not fully known
Broad-spectrum
anticonvulsant
Renally excreted with
minimal interactions
Lethargy
Possible neuropsychiatric disturbance with
mood change and irritability
Clonazepam +
clobazam
Benzodiazepines
Broad-spectrum effect on
seizures
Predominantly used in
the short-term control
of epilepsy while titrating
other medication
Longer-term use should be limited to

intractable epilepsies due to tolerance,
difficulty with withdrawal, and the
potential for abuse
Phenobarbitone +
primidone
Barbiturates
Less commonly used now,

but some patients have
been on these drugs for
many years
Sedation
Narrow therapeutic index
Withdrawal seizures
Lacosamide
Slow inactivation of
sodium channels
Narrow spectrum, usually

as add-on therapy
Few interactions
Dizziness, diplopia and visual disturbance

Nausea and headache
AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNS, central nervous system; GABA, gamma-aminobutyric acid;
IV, intravenous; LFT, liver function test.
617
sodium valproate or levetiracetam, their dose can be

given IV.
When the background of the patient is not known, a
loading dose of phenytoin is recommended (15 mg/
kg). This should be given slowly through a large vein
to avoid venotoxicity and purple glove syndrome (see
Figure 19-10).
In cases refractory to this, patients are often loaded with
a further anticonvulsant, for example levetiracetam
1000mg.
When this is ineffective, infusions of midazolam or
thiopentone may be required with respiratory support
through intensive care.
Clinicians are frequently faced by patients with episodes
superficially similar to seizures.
It is important to mention that some of these events
may have an organic basis, and that paroxysmal movement disorders, parasomnias and syncope need to be
considered.
Psychogenic episodes may also present with attacks similar to seizures. They are currently referred to as psychogenic non-epileptic seizures (PNES).
Hysteria and pseudoseizures carry negative
connotations and are frequently pejorative in their
use, negating the distress and discomfort of the
patient.
Recognizing these attacks as such is critical, as they
do not respond to anticonvulsants (although in suggestible patients they may seem to do so initially)
and require psychological therapy.
More challenging is that PNES may complicate
the clinical picture in patients with documented
epilepsy.
Some features are very suggestive of PNES, although it is

important to remember that frontal lobe seizures or limbic
encephalitis may present bizarrely.
Forced eye closure during a seizure is a common feature
of PNES.
Typical epileptic seizures are usually rhythmic, coordinated and may follow a typical speed upslow down
pattern. PNES are often uncoordinated, arrhythmic, or
wax and wane multiple times in a single episode.
Other motor manifestations atypical for epilepsy include
pelvic thrusting, back arching (opisthotonus), side-toside movements of the body or head, alternating in the
plane of a movement (nodding then shaking the head),
or prolonged unresponsive atonia.
PNES typically occur in the presence of a witness, often
in a waiting room or a busy place.
Epileptic seizures should follow a similar activation pattern in that patientif video is available demonstrating
different motor activation with each event, it is strongly
suggestive of PNES.
Prolonged episodes >5 minutes are very common in
PNES, and some may last well in excess of 30 minutes.
Inpatients with prolonged PNES it is especially important to ascertain the diagnosis to avoid inappropriate
management as per refractory status epilepticus. Many
patients with PNES have ended up intubated in intensive
care, due to a failure of recognition of the true diagnosis.
Tongue biting and incontinence are less common in
PNES, but do occur. This feature cannot be relied upon
clinically.
Diagnosis
Diagnosis is frequently made with EEG recording during a
typical event.
Treatment
Management of patients with PNES is frequently
challenging.
It is best to present the finding of PNES to the patient as
a manifestation of stress, but one not under their direct
control. Validating that the episodes are distressing and
unpleasant is important.
Likening PNES to another disorder with a significant
relationship to stress, such as migraine, may promote
acceptance.
Ongoing supportive care during the transition to psychological therapy is recommended.
BALANCE, DIZZINESS AND

VERTIGO
Figure 19-10 Purple glove syndrome following a
phenytoin infusion
From Santoshi JA et al. Purple glove syndrome: a case report. Hand
surgeons and physicians be aware. J Plastic Reconstruct Aesthetic
Surg 2010; 63:e340ee342.
618
Balance is critical to a persons ability to interface with the

world and move through it. Its importance is most evident
when its deficiency affects a person.
It is important to remember that the sense of balance
is dependent on several discrete factors, and these must be
considered and tested separately. They are:
vestibular function (sensation of head position and

movement in space)
proprioception (joint position sense)
visual function (providing an alternative means of
judging position in space).
Dizziness is often a problem area for the clinician due to the
limited precision with which patients may describe it. The
term dizzy is often used to describe a number of pathophysiologically very different processes, and as such a great part
of the clinical skill of assessing dizziness requires teasing out
historical elements to better understand the patients own
complaint. It is also important to realize that nearly 50% of
the time, when asked to repeat a description for dizziness,
the nature of this will change. As such, in case of doubt it is
critical to properly assess a patient for a multifactorial cause.
Major differential diagnoses for dizziness include:
hemodynamic dizziness, including postural hypotension (lightheadedness)
vertigo (typically a sense of movement of self or world)
astasia (loss of balance without vertigo)
cognitive clouding and other nonspecific dizziness.
Hemodynamic dizziness or
lightheadedness
Syncope, and the dizziness beforehand, termed presyncope, are the final common pathways of hypoperfusion of the brain.
The duration of pre-syncope prior to fainting depends
on the degree and tempo of circulatory collapse, from
a prolonged period with prominent autonomic symptoms in vasovagal syncope to brief and sudden in cardiac
arrhythmia.
Those with a period of symptomatic pre-syncope may
be aware of lightheadedness, sweating or clamminess, a
tunneling of vision and alteration in hearing, and will
typically become pale. Symptoms typically occur when
upright, and recover with a supine position.
The etiology of hemodynamic dizziness is covered in Table
19-10.
Vertigo
Vertigo refers to a sense of movement, which may be rotational (spinning) or translational (linear movements).
It is a result of mismatch between visual and vestibular
sensory systems, and is often distressing and accompanied by nausea and vomiting.
It may be caused by pathology in any location within
the vestibular system peripherally or centrally, and can
be physiological (as seen in amusement rides with prolonged rotation).
The clinical accompaniment to vertigo is nystagmus,
defined by eye movements with a slow drift in a horizontal, vertical or rotational direction (due to the pathological process) with an opposite compensatory fast
phase. It is named after the direction of the fast phase, as
this is more evident to the observer.
Table 19-10 Etiology of hemodynamic dizziness
GENERAL
CLASS
CAUSE
Autonomic
Vasovagal syncope (neurocardiogenic

syncope)
Autonomic neuropathy or failure
Multisystem atrophy
Cardiac
Arrhythmia
Aortic stenosis
Hypovolemia
Dehydration
Hemorrhage
Addisonian state
Drugs
Antihypertensives
Antipsychotics
Cerebrovascular
Basilar insufficiency (rare!)
When symptoms are severe, nystagmus is usually easily

evident; but when symptoms are milder, more specialized techniques for assessing eye movements may be
necessary for the less skilled observer. It is worth noting
that nystagmus need not be accompanied by vertigo,
such as in congenital nystagmus, brief optokinetic nystagmus (seen in fellow passengers as a train pulls into
a station), or in gaze paretic nystagmus with lesions
within the oculomotor pathway.
The peripheral vestibular system

Each inner ear houses a vestibular labyrinth, with three semicircular canals orientated perpendicularly in a close approximation to paired eye muscles, and two otolith organs, the
utricle and the saccule, for horizontal translational accelerations and vertical (especially gravitational) accelerations
respectively (Figure 19-11, overleaf).
The vestibular organs are tonically active, and are balanced such that activation on one side is balanced by
proportional deactivation on the opposite side.
Vertigo often results when there is disturbance in this
balance between sides, with either increased activity
or silencing of an organ, or loss of connectivity of their
pathways more centrally.
Due to differences in etiology as well as clinical signs,
peripheral and central causes tend to be separated in discussion of causes of vertigo (Table 19-11, overleaf).
Vestibular neuritis and labyrinthitis

An acute peripheral lesion of the vestibular system is a common cause of acute severe vertigo. With regard to terminology, if auditory function is also involved the condition is
termed labyrinthitis, whereas sparing of auditory function
is termed vestibular neuritis.
The pathology of this process is poorly understood, with
an infectious or post-infectious etiology postulated as the
predominant cause in most cases. In older patients with vascular risk factors, it should be remembered that the internal
619
Figure 19-11 The anatomy of the vestibular and cochlear apparatus. Note the three orthogonally orientated
semicircular canals and the two otolith organs, the utricle and the saccule
From Minor LB. Physiological principles of vestibular function on earth and in space. OtolaryngologyHead Neck Surgery 1998;118
(3Suppl):S515.
Table 19-11 Important causes of vertigo
CAUSE
CHARACTERISTICS
Peripheral
Vestibular neuritis
Acute-onset vertigo, usually with

severe nausea and vomiting
Mnires disease
Episodic vertigo with hearing loss

and tinnitus
Benign paroxysmal
positional vertigo
(BPPV)
Paroxysms with movement, usually

seconds to a minute or two
Central
Stroke
Isolated vertigo extremely rare
Migraine
May occur disparate to headache
Demyelination
May have other neurological

ndings like RAPD (relative afferent
pupillary defect)
auditory artery is a branch of the anterior inferior cerebellar

artery (AICA), and an acute vestibular and auditory lesion
may be macrovascular in origin.
In the case of vestibular neuritis, vertigo results from
mismatch in vestibular inputs between sides. It presents
with acute-onset, usually severe (often to the point of
prostrating a patient) vertigo, and usually with severe
nausea and vomiting. In the acute phase it is usually
620
associated with persistent nystagmus, which should be

evident to the observer. It is always worse with movement, as this stresses an already challenged vestibular
system, but does not completely clear when still.
A hallmark of acute vestibular neuritis is loss of the
vestibulo-ocular reflex (VOR), which helps differentiate
it from a cerebellar lesion.
Benign paroxysmal positional vertigo (BPPV)

A diagnosis of BPPV implies a very particular pathology,
which is usually accompanied by a characteristic history.
It occurs due to loose crystalline matter within the semicircular canals (otoliths), impacting upon stereocilia and
causing vestibular mismatch with movements in a particular direction.
The commensurate history is one of paroxysms of vertigo, lasting seconds to a minute or two (rarely more),
occurring solely with movement and usually in a predictable manner.
The most common site is the posterior semicircular
canal, which results in vertigo on moving from lying
to sitting, when bending over and straightening again,
when looking up to hang clothing on the line, and particularly on rolling over in bed.
CLINICAL PEARL
Intermittent dizziness which occurs on rolling over in
bed or on lying down is very suggestive of benign paroxysmal positional vertigo.
The diagnosis can be confirmed by normal eye movements with the head still, and usually normal VOR on
head impulse testing but an abnormality on performing
a DixHallpike test (Figure 19-12).
In the absence of an abnormality on testing but with
a compatible clinical history with recent spontaneous
symptom resolution, a diagnosis can still be made with
relative confidence.
Patients may complain of dizziness between movements,
and while movement-phobic dizziness can occur in
BPPV, it is also important to remember that movements
stress an impaired vestibular system and that all vestibular
lesions are symptomatically worse with movement.
Should BPPV be evident on a DixHallpike maneuver,
a number of canalith repositioning maneuvers (CRMs)
can be performed, including the Epley and Semont
maneuvers. These involve a series of head positionings
designed to move the canaliths and can be essentially
curative, although canalithiasis can recur.
Mnires disease
The pathology of Mnires disease is much discussed
and incompletely understood, although it is believed
that both fluid and ion homeostasis play roles.
The pathological correlate is so-called endolymphatic
hydrops, although this process may be present in the
absence of Mnires disease.
The hallmark of this process is concurrent vestibular

and audiological symptoms, most often between the
ages of 20 and 40, but without any age limit.
The primary symptom complex is that of:
1 Episodic vertigousually 20 minutes to 24 hours.
2 Hearing loss:
a typically low-frequency, or low- and highfrequency, sparing the middle frequencies
b may fluctuate between attacks
c progressive with time.
3 Tinnitusoften low-pitch, machinery-like.
Additional symptoms may include nausea and a feeling of
aural fullness coinciding with attacks.
There is no definitive diagnostic test for Mnires disease, although with appropriate vestibular investigation,
especially during an attack, a diagnosis should be able to be
made with confidence.
Symptoms can be precipitated by both alcohol and
caffeine, and moderation in intake of both of these substances can be of benefit.
Salt restriction may also benefit symptoms.
Central pathologies
Migrainous vertigo (vestibular migraine)
Migraine is one of the most common causes of episodic dizziness in the community.
Symptoms are variable, with vertigo and dizziness
during and disparate to headaches, although for a definite diagnosis at least some attacks should be concurrent
with migrainous headache.
It typically lasts minutes to hours, but can be brief and
paroxysmal or more sustained.
It may cause a sense of spinning, translational movement, rocking, or some other form of dysequilibrium.
Diagnosis is typically made on clinical history with normal
clinical examination, and if assessed, normal vestibular function testing.
One of the most useful diagnostic aids is the response to
migraine prophylaxis.
CLINICAL PEARL
Figure 19-12 The DixHallpike test is performed

by lying a patient down from sitting, with the head
orientated 30 to the horizontal and turned 45
toward the side being tested. The patient should keep
their eyes open (often a problem in the severely dizzy
patient), and after a latency, nystagmus will be seen in
an earth-beating or geotropic direction. It will then
fatigue over seconds to a minute or so
From Hornibrook J. Benign paroxysmal positional vertigo (BPPV):
history, pathophysiology, office treatment and future directions.
IntJOtolaryngol 2011: 835671.
Migrainous vertigo is far more common than previously recognized, with approximately 10% of migraine
sufferers experiencing vestibular symptoms, and a
population prevalence of nearly 1%.
Stroke
Stroke is the most critical differential diagnosis in an
acutely vertiginous patient.
Isolated vertigo without any other neurological symptoms or signs is very rare in stroke. However, vertigo
may result from a variety of ischemic lesions, and other
neurological abnormalities may not be as obvious or distressing as the vertigo so must be properly assessed.
621
CLINICAL PEARL
Vertigo is very rare as an isolated sign in stroke, but other
signs can be missed easily if not properly assessed.
Vertigo may occur in the following strokes:

cerebellar infarction or hemorrhage
posterior inferior cerebellar artery (PICA) stroke
anterior inferior cerebellar artery (AICA) stroke.
Cerebellar stroke
This often presents with abrupt onset of ataxia with or
without vertigo.
Headache is not specific for ischemia or for hemorrhage,
although hemorrhage in particular may also cause severe
nausea and vomiting and often leads to drowsiness with
mass effect.
In this setting, nystagmus is usually worst when looking
to the side of the lesion, with drift toward the center and
fast-correction in the direction of gaze.
An absence of appendicular ataxia does not preclude
a diagnosis of cerebellar stroke, and gait may be solely
affected. This results in a difficult assessment in an
acutely vertiginous patient.
PICA infarction/lateral medullary syndrome
An easily recognized syndrome for a clinician looking
for it, this diagnosis is also too frequently missed due to
inadequate neurological examination.
This syndrome usually follows infarction in the territory
of the posterior inferior cerebellar artery, which is the
terminal branch of the vertebral artery before the two
sides join in the basilar artery.
Dissection of a vertebral artery often presents with this
syndrome (with or without further posterior infarction),
and must be considered.
CLINICAL PEARL
Clinical features of the lateral medullary syndrome:
Vertigonystagmus is usually horizontal in the direction of the lesion
Ipsilateral ataxia
Ipsilateral Horners syndrome
Contralateral spinothalamic sensory impairment
Ipsilateral vocal cord paresis t dysphagia
Muscle power and ne touch are clinically normal
in this syndrome, and limited clinical assessment will
be unrevealing. As a minimum, pain and temperature
should be assessed in acutely vertiginous patients
AICA infarction
The terminal anterior inferior cerebellar artery, a branch
of the basilar artery, perfuses the vestibulocochlear
end-organ, and so AICA infarction presents with
abrupt-onset deafness and peripheral vestibular symptoms analogous to vestibular neuritis.
622
If more extensive, other features include:

limb ataxia (cerebellar peduncular infarction)
facial paresis (lateral pontine infarction).
Demyelination
The presentation of demyelination-induced vertigo will be
variable, based on the location of the causative lesion.
Diagnosis in a patient with known multiple sclerosis is
not especially challenging, but as a clinically isolated syndrome a high level of suspicion is required, and MRI imaging is the most helpful investigation.

Acute therapy
Canalith repositioning maneuvers (CRMs)
As discussed above, these can be very effective in BPPV.
However, all patients with vertigo get worse with movement, and attempts at CRMs in a severely vertiginous
patient at rest can be distressing and unpleasant.
Antiemetics and vestibular sedatives
Phenothiazines, particularly prochlorperazine, are frequently
used acutely for antiemesis and have a vestibular-sedative
property. They can be helpful in the severely nauseated, prostrated patient, but should not be continued long-term.
Corticosteroids
There have been limited trials of acute corticosteroid therapy in vestibular neuritis, all with different regimens of drug
and delivery. There has been some evidence to suggest that
brief (5- to 7-day) courses of moderate-dose corticosteroids
have benefit in the resolution of symptoms, particularly
improving the speed of recovery.
Ongoing therapies
Vestibular rehabilitation
Often overlooked, this technique is one of the most helpful
approaches for long-term recovery for an acutely or chronically dizzy patient. It helps provide graded exposure to vestibular stimuli to facilitate central compensation for lesions
in the pathway.
Betahistine and diuretic therapy
These medications are thought to be able to reduce vestibular hydrops, and improve both symptoms and progression
of Mnires disease. They are not useful for other causes of
vertigo.
Migraine prophylaxis
In vestibular migraine, acute migraine therapies such as analgesics and triptan agents tend to be ineffective. However,
a range of prophylactic medications provide a reduction in
symptoms, as for migraine.

Oscillopsia
Oscillopsia is the result of bilateral vestibular pathology.
Due to absence of vestibular imbalance, vertigo does not

occur but the absence of reflexive control of eye movements with locomotion results in a feeling of the world
rapidly moving back and forth.
Such patients may also have severe balance impairment
when visual stimulation is removed, as in Rombergs test.
Similar generalized imbalance and multi-directional nystagmus can be seen with multiple drugs with CNS activities,
particularly anticonvulsant (most commonly phenytoin due
to its non-linear kinetics), and lithium intoxication.
Chronic dysequilibrium
In addition to hemodynamic and vestibular systems, patients
may describe dysequilibrium with a number of other pathologies. These are worth clinically assessing for before trying
to make a diagnosis.
Proprioceptive losspatients often describe clumsiness,
but may also describe sensory symptoms, especially
tight band-like feelings in the setting of dorsal column
involvement.
Extrapyramidal postural instabilitynot to be confused with postural hypotension, early loss of postural
righting reflexes is a feature of progressive supranuclear palsy (Richardson syndrome), and occurs later
in Parkinsons disease. This can be tested with the pull
test, whereby the examiner instructs the patient to
maintain their balance while being sharply but briefly
pulled backwards. While helping diagnostically, there is
no specific therapy other than risk reduction strategies
such as those employed through falls clinics.
The remainder of chronically dizzy patients are a struggle to
diagnose and to pigeonholesomething which often distresses them.
In studies of chronically dizzy patients, up to 80% of
patients had psychiatric comorbidity at the time of onset
of symptoms. This may lead to maladaptive central compensation. Patients may develop symptoms such as visual
vertigo, a feeling of severe imbalance in busy environments
such as shopping centers or traffic, or with flashing lights
and strobes. This may represent an inappropriate increase
in optokinetic stimulation, but also may have elements of
phobic behavior.
A combined vestibular rehabilitation and cognitive
behavioral strategy may be helpful, sometimes requiring
additional pharmacological intervention.
MOVEMENT DISORDERS
Patients with movement disorders typically present with
clinical symptoms and signs, and a diagnosis can often be
made through accurate description of these features. Indeed,
there remains no definitive diagnostic test for Parkinsons
disease to this day, and a compatible history and examination remains the mainstay of diagnosis for the most part.
However, with the development of imaging tools
together with genetic and immunological testing, the field
of movement disorders has become clearer on one level (the
pathophysiology of the disease process)but simultaneously
more confusing, with the understanding that a single disease

may present with either hyperkinetic or hypokinetic features, and sometimes both. Many disease processes can no
longer be linked to a single set of signs and symptoms, and a
high degree of suspicion needs to be maintained for treatable
conditions, such as Wilsons disease, which progress without
treatment and may result in death.
The other consideration in reviewing movement disorders is that the majority of these processes involve neural
circuitry within the basal ganglia, especially dopaminergic
pathways. This circuitry and transmitter is partially shared
with the mesolimbic and mesocortical pathways, which are
integrally related with psychiatric wellbeing. It is therefore
not surprising that a large proportion of patients with movement disorders may have psychiatric symptoms or comorbidities, a finding which challenges the physician seeing a
patient with abnormal movements in the absence of other
obvious pathology.
Tremor
With an appropriate approach, an accurate description of
the phenomenology of a patient with tremor helps greatly to
narrow the differential diagnosis. In assessing a patient with
tremor, it is important to look carefully at the patient as a
whole, even if they have noticed tremor only in a particular
region. If their hand is involved, it is important to take note
of additional head tremor, jaw tremor or even vocal tremor.
Any unusual posturing of the leg or abnormal rotation of
the head upon the neck should be noted. Often patients may
not be aware of these clinical signs, especially if a friend or
relative has prompted their visit.
In then assessing the tremor it is critical to assess it:
at rest (ideally in a couple of different resting positions)
held in a static posture (first with arms outstretched, then
with fingertips held beneath the nose and elbows up)
with movement toward a target.
Physiological tremor
Normal individuals have a high-frequency tremor of 1012
Hz which may be exacerbated by a variety of precipitants to
bring them to clinical attention. These can include:
drugscaffeine and stimulants, beta-agonists, theophylline or other stimulants of the adrenergic response
anxiety and stress
muscle fatigue and sleep deprivation.
Enhanced physiological tremor may be seen in drug or alcohol withdrawal, with thyrotoxicosis, or with fever. A tremor
resembling physiological tremor may be seen with drugs
such as sodium valproate or lithium.
Essential tremor (ET)

Essential tremor is estimated to have a prevalence of up to
5%. The name essential implies that the tremor is the solitary symptom of the diagnosis, and abnormal posturing or
features of other movement disorders all but preclude this
diagnosis. It is considered the most common cause of a postural tremor, with no tremor typically present at rest.
623
It is typically familial, often with a dominant history.

The tremor is often exacerbated by the same features
which increase physiological tremor listed above.
The term benign should be avoided, as it can be
a distressing and disabling problem for the affected
individual.
A typical history is one of tremor that worsens with efforts
to perform a fine motor task, particularly under stress or in
public (for example, drinking from a glass in public, trying
to get money out of a wallet at the cash register).
It may suppress with alcohol consumption.
The arms are typically involved (95%), and head (34%),
lower limbs (30%) and voice (12%) much less frequently
so, usually with the arms still predominant.
Treatment
Treatment is usually with a non-selective beta-blocker such
as propranolol, or if not able to be tolerated then a barbiturate such as phenobarbitone or primidone may be used,
although this is frequently limited by tolerability.
It is emerging that dystonic tremor may be frequently mistaken as both essential tremor or Parkinsons disease, with a
variable pattern of involvement, either resting or postural.
Unlike with ET, a patient with a dystonic tremor may
have abnormal posturing of the affected limb when outstretched, in addition to the tremor.
As with ET, the tremor will typically worsen with stress
or efforts to control it, but typically will not respond to
beta-blockers. It may, however, respond to anticholinergics
such as benzhexol/trihexyphenidyl or benzodiazepines.

Since Parkinsons 1817 description, a great deal more has
developed both in clinical assessment and treatment of PD.
However, the clinical hallmarks remain the same; they can
be summarized as in Figure 19-13.
The tremor in Parkinsons disease is a 46Hz resting
tremor, and may be noticed by observers before patients
themselves.
Tremor
Bradykinesia
Rigidity
Figure 19-13 Tremor, bradykinesia and rigiditythe

parkinsonian triad
624
It is usually seen in the hand at presentation, and may

be pill rolling although this is not always the case.
Idiopathic PD (iPD), i.e. drug-responsive Parkinsons disease without additional features of early
dementia, falls, gaze paresis or autonomic failure
(characteristics of Parkinsons plus disorders) or
without a clearly genetic basis, will almost always be
asymmetrical in presentation. Symmetry of tremor
should prompt further consideration.
Bradykinesia usually begins asymmetrically together
with the tremor, although the severity of these symptoms need not be linked. Patients may have tremorpredominant or bradykinetic-rigid presentations of iPD.
Its symptoms include not just slowing of movements but
also a decrease in amplitude of regular movements. This
may be evident through decreased arm swing, reduced
facial expression (hypomimia) or decreased volume in
the voice (hypophonia).
Rigidity is noted. It is the combination of rigidity and
tremor which leads to the cog-wheel movements classically described.
Gait disorder is a common feature of PD, with a
decreased stride length (shuffling), and difficulty initiating gait.
A person with PD may demonstrate festination
an appearance of hurrying, as their upper body
moves ahead of their center of gravity. Difficulty
turning is common, and turning by numbers may
be noted. Freezing may occur, where a patient is
unable to voluntarily initiate gait; cognitive tricks
may sometimes help in overcoming this.
Non-motor features
More recently, features of iPD have been described outside
of the typical motor symptoms.
Sleep disorder is very common, taking the form of rapid
eye movement (REM) sleep behavior disorder. While
dreaming, a person with PD may lash out or enact
dreams, while non-affected individuals are paralyzed in
REM sleep. This often precedes a diagnosis of iPD by
years.
Hyposmia has been described in PD, and is a research
tool in early diagnosis. It does require formal testing if
being relied on, as a persons reported sense of smell
often fails to correspond with what can be assessed with
bedside testing.
Psychiatric disturbances are recognized increasingly frequently in patients treated for PD. They can broadly be separated in dopa-dysregulation and impulse-control disorders (ICDs).
Dopa-dysregulation describes the phenomenon seen in
some patients where the dose of levodopa may be incrementally increased in the absence of clinical need. Given
fluctuation in the degree of symptoms, it may be hard
to recognize when a person is requesting more medication inappropriately, and collaborative history and a
high index of suspicion are essential.
ICDs include pathological gambling, shopping, eating,
hypersexuality, or repetitive performance of a task to
distraction (from drawing to internet chess), termed

punding (Figure 19-14). They most commonly occur
with dopamine agonist therapy, especially in high doses.
CLINICAL PEARL
When initiating a person on medication for Parkinsons
disease, especially dopamine agonists, it is absolutely
essential to disclose the risk of impulse-control disorders to them, as these may have socially and nancially devastating consequences.
Dementia has been recognized as a component of PD, but

should not be present at diagnosis or within 1 year of diagnosis, as this suggests dementia with Lewy bodies.
All patients with PD may demonstrate some form of
executive dysfunction on complex testing early in their
course, but the mean time to diagnosis of dementia in
PD is 10 years.
The pattern differs from Alzheimer disease, with lessprominent memory disturbance and more attentional
problems, apathy, language and visuospatial dysfunction.
Diagnosis
The diagnosis is a clinical one, but is supported by a clinically effective trial of treatment. However, as the condition
worsens with time, the predictability of medication response
becomes less, and often response to a dopa trial becomes
more difficult to interpret due to altered oral absorption and
a narrower therapeutic window. At such a time, the efficacy

of medication may be more evident when medication is
inadvertently omitted in a patient on long-term treatment.
There are tools available for supporting a diagnosis of
PD. DaT scanning is available in many countries to
assess pre-synaptic dopamine transport via means of a
nuclear ligand (Figure 19-15).
This typically shows a decrease in striatal dopamine,
with an asymmetry in keeping with the clinical state.
It does not, however, differentiate from other disorders of dopamine activity, from multisystem
atrophy to types of spinocerebellar ataxia.
A normal pattern should be seen in drug-induced
parkinsonism.
Due to the availability of this technology, the term
SWEDDs (symptoms without evidence of dopamine
deficiency) has been coined, with controversy about the
pathophysiological nature of patients in this group.
Treatment
Levodopa
Levodopa is absorbed from the proximal jejunum via
amino acid transporters, and is therefore competed
against by other dietary proteins.
It is rapidly degraded by monoamine oxidase (MAO),
and thus is always combined in formulation with a
peripheral MAO inhibitor.
After crossing the bloodbrain barrier it is metabolized
to dopamine, and can then be degraded by cerebral
MAO or catechol-O-methyl transferase (COMT).
Figure 19-15 (A) Normal DaT scan demonstrating

diffuse basal ganglia pre-synaptic activity of
dopamine transporter, with a comma shape.
(B) Abnormal result with asymmetrical activity
localized to the heads of the caudate nucleus,
indicating disordered dopamine transport consistent
with Parkinsons disease, multisystem atrophy or
progressive supranuclear palsy
Figure 19-14 An example of doodling punding
From OSullivan SS, Evans AH and Lees AJ. Punding in Parkinsons
disease. Pract Neurol 2007;7:3979.
From Kurian MA et al. Clinical and molecular characterisation

of hereditary dopamine transporter deciency syndrome: an
observational cohort and experimental study. Lancet Neurol
2011;10(1):5462.
625
CLINICAL PEARL
Levodopa competes with other dietary amino acids for
absorption, and should be taken at a time away from
protein-rich meals.
With a centrally dopaminergically deplete state, in early

stages of Parkinsons disease the benefit of a small dose
of levodopa may be marked, with a long, clinically good
response.
With further neurodegeneration of the substantia nigra,
doses may be required more frequently, and on average motor fluctuations and dyskinesias occur in 50% of
treated individuals by 5 years.
Patients may begin suffering from peak dose dyskinesias
with accompanying choreoathetoid or dystonic movements, which typically trouble them less than off times
when they are rigid. It is not infrequent for a clinically
dyskinetic patient to ask for an increase in treatment,
and this should prompt gathering of more collaborative
history and consideration of dopa-dysregulation.
Levodopa is available in multiple formulations, with
regular, fast-release and controlled-release forms.
Treatment side-effects include nausea, and fluctuations
in hemodynamic indices, frequently hypotension.
Hallucinations or other psychiatric disturbance early in the
treatment should prompt consideration of dementia with
Lewy bodies.
Dopamine agonists
Dopamine agonists are used in monotherapy or in combination with other medications, and have a longer half-life than
levodopa. As such, they may provide smoother and more
predictable pharmacokinetics, particularly in patients with
motor fluctuations. Unfortunately, their use is associated
with a higher risk of ICDs, and these must be monitored
for closely.
Entacapone
A COMT inhibitor, this drug increases the duration of
action of levodopa by reducing central metabolism. It is
especially helpful in patients requiring frequent dopa
administration.
Rasagiline/selegiline
These are centrally active MAO-B inhibitors.
There is limited evidence to suggest a neuroprotective
effect of rasagiline in terms of progression of PD with
time.
These drugs have a very modest effect in monotherapy,
and are advocated for early therapy of PD, delaying the
time to levodopa and reducing the incidence of motor
fluctuations.
Amantadine
Amantadine has weak dopaminergic action.
It was previously used in early PD to delay commencing levodopa, due to fear that an earlier start on
626
dopaminergic medication caused faster progression.

This assertion has subsequently been proven false, and
amantadine has since found its place in the treatment of
dyskinesias and peak-dose motor fluctuations.
Anticholinergics
This group of medications is reserved for younger
patients with tremor-predominant PD, and is used
uncommonly.
Side-effects include constipation, dry mouth and
confusion.
Apomorphine
Apomorphine is a highly emetogenic drug and can
only be given parenterally, usually via subcutaneous
injection.
It is used in advanced PD and may be given as a rescue
medication in a person with severe offs or freezing,
usually by a partner, or in some cases as an infusion.
It is dependent on injection technique, pumps and usually a partner willing to take on the responsibility of its
provision.
It is also very expensive on a yearly basis once costs are
considered, and should only be commenced by dedicated units with experience in its use.
Duodopa
A form of levodopa gel, this medication requires a percutaneous endoscopic gastrostomy tube with jejunal
extension (PEG-J tube) to allow continuous delivery
into the jejunum.
While this eliminates variability of absorption with progressive PD, and more direct titration of dose, it has
limitations in terms of cost, the willingness of a person
to have a PEG-J tube, the mechanics of delivery, and
availability.
Deep brain stimulation (DBS)
Prior surgical ablation of sites within the basal ganglia (for
example thalamotomies) has given way to stimulation by
stereotactically inserted pacemaker leads.
A variety of sites have been described (subthalamic
nucleus, globus pallidus interna, zona incerta and
pedunculopontine reticular formation), each with its
own particular benefits and risks.
Initially reserved for advanced PD, there is now increasing evidence for a positive costbenefit balance when
used in patients earlier in their course. There are a number of problems that can follow insertion, aside from the
surgical complications of infection and hemorrhage.
Patients may develop acute cognitive deterioration, hypophonia, facial paresthesiae, and mood
disorder.
DBS is not in general effective for patients with on
freezing, nor does it have benefit in loss of postural
reflexes and falls.
Patients with cognitive decline or frank dementia
should not be considered for DBS.
Deep brain stimulator lead

Electrodes
Subthalamic nucleus
Substantial nigra
Attempts to treat parkinsonism with dopaminergic medications are often met with exacerbations of hypotension.
Symptomatic treatment may be beneficial with:
fludrocortisone (a mineralocorticoid)
midodrine (an alpha-adrenergic agonist)
droxidopa (an adrenaline/noradrenaline precursor in
late-stage trials).
Connective wires
Pacemaker
Figure 19-16 A schematic for deep brain stimulation

A Parkinsons plus disorder, DLB is notable for early
dementia (at diagnosis or within a year of diagnosis of
PD) with marked fluctuations, and sensitivity to both
dopaminergic therapy (levodopa agonists) with hallucinations and sometimes confusion, and to dopamine
antagonists (haloperidol, risperidone) with severe worsening of mobility when given for hallucinations or
confusion.
Hallucinations are often visual and are frequently fully
formed, being of animals or people. They are almost
always silent, and insight may be present into the fact
they are indeed not real. A patient may be embarrassed about these, and it is important to query about
these symptoms in all patients with newly recognized
parkinsonism, as they are very specific for the diagnosis
ofDLB.
Treatment is probably best with cholinesterase
inhibitors.

A more rapidly progressive disorder than idiopathic PD,
MSA has no greatly effective therapies. It presents with:
parkinsonism, often symmetrical with minimal tremor
autonomic features, including:
erectile dysfunction (an early sign in men)
bowel and bladder dysfunction (constipation or
incontinence)
postural hypotension (often severe, and exacerbated
by dopaminergic medications)
hypophonia of speech
in some, disordered breathing and stridor
cerebellar degeneration (less common).

A syndrome of relentless midbrain degeneration, PSP is
marked by:
symmetrical parkinsonism, often with an extended,
upright posture (rather than the flexed, hunched PD
posture)
early falls with loss of postural reflexes
early dementia
degeneration of speech and swallow
eye movement abnormalities, including:
vertical-gaze palsy or slowing of saccades (more
than horizontal, which may also be affected)
loss of convergence.
Dopaminergic therapy is rarely beneficial, and the combination of dementia, impulsivity, and loss of postural reflexes
often results in personal injury. Therapy is usually secondary
prevention, with hip protectors for frequent falls, early speech
therapy and, if necessary, alternative feeding strategies.
Once termed corticobasal degeneration, only 50% of
patients with this clinical syndrome will have the pathological diagnosis on autopsy, and the name has therefore been
modified.
It presents with a starkly asymmetrical parkinsonism,
usually in the arm with minimal tremor. Features include:
marked asymmetry
bradykinesia and rigidity
loss of cortical sensation in the affected limb (astereognosis, agraphesthesia)
apraxia
in some, an alien limb phenomenon
aphasia.
With progression, a profoundly akinetic rigid limb usually
results. Treatment is supportive only.
Dystonia
Dystonia is the phenomenon of sustained or tremulous
abnormal posture of part of the body in response to inappropriate contraction of muscle groups, often opposing.
It may affect any voluntary skeletal muscle group,
including the face, limbs, vocal cords, or head and neck.
It may occur in a localized distribution (focal), may affect
two or more adjacent body regions in isolation (segmental), or may be more diffuse (generalized).
627
It may occur solely in response to particular activity

(writers cramp, musicians dystonia, golfers yips), and
may be able to be stopped with a seemingly incongruous movement (for example a single finger on the chin
in cervical dystonia), termed a geste antagonistique.
It may be associated with considerable pain if muscle
spasm is severe.
Together with a tendency for normal imaging and other
investigation, this makes dystonia a challenging clinical
diagnosis.
Dystonia may be primary (occurring spontaneously for no
reason, or in the case of a genetic process), or secondary (as a
symptom from another process). Causes of secondary dystonia include:
traumatic brain injury/neonatal cerebral hypoxia
drugsespecially neuroleptics and dopaminergic
antiemetics
neurodegenerative causes
Wilsons disease and other metabolic processes.
Treatment
Anticholinergics
Anticholinergics such as benztropine are used as an antidote to acute dystonia associated with neuroleptic or
antiemetic use.
They may also be useful in long-term dystonia, although
are limited by tolerability.
They may also be useful in a range of other neurolepticinduced movement disorders, with the exception of
tardive dyskinesias which are typically resistant.
Benzodiazepines
These may be useful as muscle relaxants and for sedation in
painful dystonia at night; however, increasing requirements
and dependency limit use.
large muscles are involved, toxicity limits dose and

botulinum toxin may not be useful.
Levodopa
In the rare genetic condition dopa-responsive dystonia
(DRD or Segawas disease), a profound response can be
seen to levodopa.
Given the potential for improvement in this subset of
patients, a levodopa trial is advocated, especially for
children presenting with dystonia.

Tics
Tics consist of repetitive, usually brief, irregular movements
of distinct muscle groups or vocalizations, which may be
preceded by a premonitory sensation of urge.
Tics may be simple (e.g. a jerk, gaze deviation or grunt)
or complex (mimicry of motor or speechechopraxia
and echolalia, coprolalia, or other mannerisms). They
may be incorporated into pseudomeaningful actions
(parakinesias).
Popular culture would have one believe that involuntary
shouting of expletives is a common phenomenon, but
coprolalia is a rare feature of tic disorders.
Tics are the hallmark of the genetic process of Tourette
syndrome, which demands both motor and vocal tics, but
may be seen in other neuropsychiatric processes such as
tuberous sclerosis or neuroacanthocytosis (Figure 19-17).
Tourette syndrome begins in childhood, and is usually
accompanied by features of obsessivecompulsive disorder (OCD). It is worsened by stimulant and levodopa
administration, and may be suppressed with neuroleptic
medications, or monoamine depletors such as tetrabenazine. It is typically combined with an antidepressant for OCD and attentional deficits.
Baclofen
A GABA (gamma-aminobutyric acid) sub-unit agonist,
baclofen is less sedating than benzodiazepines, and is
often helpful in decreasing muscle spasm.
In severe cases it may be given intrathecally via a pump
under the supervision of a specialized unit.
Tizanidine
A centrally active alpha2-agonist, tizanidine has better
tolerability than baclofen or benzodiazepines, and may
be used in their place or in combination with them.
Liver function abnormality, or rarely hepatocellular
necrosis, limits its use in some countries.
Botulinum toxin
In limited dystonia, injection of botulinum toxin into
involved muscle groups may decrease the level of spasm
and provide substantial relief. This can be repeated with
recurrent need, often on a 3-monthly basis.
Unfortunately, in more widespread dystonia or when
628
Chorea
Chorea is a phenomenon characterized by involuntary, random, dance-like movements that may involve any part of
the body, as well as the inability to sustain motor postures
(motor impersistence). Chorea is uncommon, and varied
in its cause (Box 19-5).
Treatment
Treatment (after managing the underlying cause or removing any potentially causative drugs) is with agents such as
tetrabenazine, or with neuroleptics.
Myoclonus
While grouped with movement disorders, myoclonus
and its negative counterpart asterixis may be a feature
of a large number of neurological and systemic processes
(Box 19-6).
It is characterized by brief, shock-like movements or
loss of muscle tone.
Box 19-6
Causes of myoclonus
Physiological
Hypnic jerks
Metabolic causes
Hepatic encephalopathy
Uremic encephalopathy
Electrolyte abnormalities
Drugs
Opioids
Lithium
Antidepressants
Alcohol withdrawal
Figure 19-17 A blood lm demonstrating

plentiful acanthocytes (arrow) from a patient with
neuroacanthocytosis
From Bertram KL and Williams DR. Diagnosis of dystonic syndromes:
a new eight-question approach. Nature Rev Neurol 2012;8:27583.
Box 19-5
Causes of chorea
Genetic causes
Huntington disease
Huntington-disease-like syndromes
Immunological causes
Rheumatic fever (Sydenhams chorea)
NMDA encephalitis
Infection
Syphilis
Metabolic disease
Wilsons disease
Porphyria
Manganese toxicity
Pharmacological causes
Levodopa
Amphetamines
Cocaine
Phenothiazines
NMDA, N-methyl-D-aspartate.
Epilepsy syndromes
Juvenile myoclonic epilepsy
Myoclonic epilepsy syndromes
Immunological
Post-infective
Paraneoplastic
Neurodegeneration
CreutzfeldtJakob disease
Genetic neurodegeneration
Ischemic
Post-hypoxia
Treatment
Sodium valproate and clonazepam are agents that may be
helpful in suppressing myoclonus in the appropriate settings.
However, myoclonus should be regarded as a symptom and
not a diagnosis.
NMDA encephalitis
Originally described in the setting of ovarian teratoma,
this autoimmune process may also occur in the absence of
a malignancy. It results from the formation of antibodies
against the NMDA (N-methyl-D-aspartate) receptor.
A typical presentation is one of initial neuropsychiatric
disturbance with memory loss, psychotic features and
sleep disturbance, which then proceeds to impaired
level of consciousness and seizures, sometimes requiring
intubation and respiratory support.
A common feature is the development of a stereotyped
movement disorder, often faciobrachial, not accompanied by electrographic seizure.
Treatment is by immunosuppression, usually by IVIg
(intravenous immunoglobulin) or plasma exchange in
the initial phase, and often requiring ongoing steroid or
cyclophosphamide therapy.
629
MULTIPLE SCLEROSIS AND

CNS INFLAMMATION
Central nervous system inflammatory processes are some of
the most unusual and capricious pathologies in the field of
neuroscience. Their presentation is wide and varied depending on the site of inflammation, from optic involvement
through to sphincter dysfunction, which can be contrasted
with peripheral nerve demyelination. They may be monophasic, or may relapse and remit over days, weeks or years,
or they may be progressive. There is a geographical gradient
for prevalence, and racial factors may play a role in the typical nature of a presentation.
Primary progressive (PPMS)

The most feared form of MS, this type is associated with
an inexorable deterioration in function over time without any of the typical relapses.
Epidemiologically, it often affects older individuals, and
there is a more equal gender ratio.
Therapeutic options remain supportive only at this time.
Progressive-relapsing (PRMS)
While often separated due to little recovery between
attacks, this type tends to be treated as per RRMS, due
to distinct relapse episodes with or without resolution of
acute symptoms between attacks.
This subtype is notable for ongoing additional clinical
progression between acute relapses.
CLINICAL PEARL
The hallmark of multiple sclerosis is central nervous
system demyelinating lesions disseminated in space
and time.
Multiple sclerosis is a disorder of patchy inflammation

through the brain and/or spinal cord.
Pathologically, inflammation results in localized demyelination, giving rise to what was originally described
macroscopically as sclerosisa hardening of these
regions, which came to be known as plaques.
Perivascular T-lymphocyte and macrophage infiltration
is seen acutely with relative sparing of axons; although
more chronically, scarring with glial changes and axonal
loss occurs.
Inflammation is typically seen in areas of rich vascular
supply, including the corpus callosuman area unlikely
to be involved in vascular processes.
Classication
Multiple sclerosis can be divided into four main groups,
with attendant therapeutic implications.
Relapsing-remitting (RRMS)
The most common form of MS, some 65% of patients
fall into this group.
An individual has multiple discrete attacks (termed
relapses), with improvement between episodes being
variable.
It may appear clinically complete or leave impairment.
Residual neurological symptoms may compound over
time, with resultant disability.
Secondary progressive (SPMS)
After following a relapsing-remitting pattern for years,
a patient may cease having defined relapses, although
deficits may slowly worsen.
The pathology of this process is much debated, but may
relate to secondary neurodegeneration following initial
insults.
630
Presentation
The presentation of MS is highly variable, with atypical
symptoms and signs common. However, there are some
typical presentations and clinical symptoms, which raise the
pre-test likelihood of MS.
Optic neuritis
Optic neuritis is a common initial presentation for MS.
It presents with acute to subacute unilateral ocular pain
on eye movement, which improves, giving way to visual
impairmentoften in the form of a central scotoma,
with impaired acuity and early loss of color discrimination. A relative afferent pupillary defect (RAPD) is seen
clinically.
CLINICAL PEARL
Color vision is impaired early in optic neuritis, and normal color sensitivity suggests a different diagnosis in
the presence of impaired acuity.
Bilateral or rapidly sequential optic neuritis is very

uncommon in MS, and should raise the possibility of
neuromyelitis optica, Lebers hereditary optic neuropathy (a mitochondrial disorder, affecting young men
more than women, with painless loss of vision) or
neurosarcoidosis. However, asymmetric bilateral symptoms may be seen if the optic chiasm is involved.
Internuclear ophthalmoplegia (INO)
Occurring due to lesions within the medial longitudinal
fasciculus, INO results from decoupling of the abducens
nucleus (the lateral gaze center) and the contralateral oculomotor nucleus.
On lateral gaze, the abducting eye rapidly moves to target, while the adducting eye moves either incompletely
or more slowly (depending on severity).
The abducting eye has nystagmus evident until fixation
is achieved (Figure 19-18).
This is not seen purely in MS. In myasthenia gravis an

identical pattern is seen, and this is used diagnostically
with the ice-pack or ice-on-eyes test (see clinical
pearl in the section on myasthenia), as neuromuscular
transmission improves with cooling.
This phenomenon also explains why an increased
body temperature with infection (such as a urinary
tract infection) may make symptoms and signs more
prominent, causing what is widely referred to as a
pseudo-exacerbation.
+Nystagmus
Complete right INO
Partial right INO
Figure 19-18 Internuclear ophthalmoplegia (INO).

The top image shows normal gaze to the right. With
gaze to the left, the right eye lags behind the left
(middle image) and may fail to adduct completely
(bottom image). However, in milder INO it may only
be a lag in the adducting eye which is evident
This may also be seen in other lesions of the brainstem, such
as vascular disease and infiltrative processes, but abruptonset INO in a young patient is very suggestive of MS.
Sensory symptoms
These are common in MS, and almost ubiquitously
present in a patient with significant disability.
The nature and distribution of these may be varied and
are multimodal, involving proprioceptive and/or spinothalamic (pain and temperature) tracts.
At times a heightened sensitivity or dysesthesia is
reported, and pain may be reported.
Trigeminal neuralgia is sometimes described, and
other wise radicular-sounding symptoms may occur in
the limbs or trunk.
It is frequently seen that sensory involvement seems
patchy and does not conform to known dermatomal
maps.
Other symptoms
Motor symptoms, vertigo and nystagmus, ataxia, and
sphincter dysfunction are all seen with regularity in multiple
sclerosis. While these are less suggestive of MS in the acute
phase in a de novo patient, a high degree of suspicion needs
to be maintained.
Other symptoms which become more prevalent with
chronicity include:
fatiguealmost ubiquitous in MS, this can be managed
with energy conservation techniques, a rehabilitation
approach and at times, medication
mood disturbancedepression is a common bedfellow
of MS, and when unmanaged can lead to further treatable morbidity for an already difficult condition
cognitive dysfunctionfrequently not considered, this
may further complicate MS and its management, especially with disease progression.
Diagnosis of multiple sclerosis

The diagnosis of MS is a clinical one, requiring dissemination of CNS-demyelinating lesions in both space and time.
Dissemination in space is demonstrated by:
one or more MRI T2 lesions in at least two of four
typical CNS sitesperiventricular (Figure 19-19),
juxtacortical, infratentorial and spinal
Lhermittes phenomenon
A clinical symptom seen with lesions of the high cervical
spine (including non-demyelinating causes), Lhermittes
phenomenon is a brief shock-like sensation radiating from
the neck, down into the back or limbs on flexing the neck.
Uhthoffs phenomenon
This describes the phenomenon by which neurological
symptoms worsen with an increased body temperature.
It can be seen with exercise, a hot shower or with fevers.
Patients with MS often remark that their symptoms are
worse in summer for this reason.
Figure 19-19 Sagittal T2-FLAIR showing typical

Dawsons ngers, which are an MRI appearance
resulting from periventricular plaques. This nding is
reasonably specic for multiple sclerosis
631
or
additional symptoms not attributable to one of
these sites (for example optic neuritis with multiple
periventricular lesions).
Dissemination in time is demonstrated by:
two separate and distinct clinical attacks
or
concurrent presence of gadolinium contrastenhancing and non-enhancing MRI lesions
or
development of new lesions, especially if contrastenhancing, on follow-up MRI (with or without
clinical symptoms).
It is also important to note that for a diagnosis of MS, there
should be no other more likely diagnosis available.
Clinically isolated syndrome (CIS)
This is a term for a presentation with a single episode of
demyelination, with or without other lesions. Approximately 80% of such patients will go on to have a diagnosis of
MS given time, although this figure varies depending on the
syndrome and the duration of follow-up.
In addition, with MRI more widely available, the concept of radiologically isolated syndrome (RIS) has also been
describedradiological evidence of demyelination in the
absence of clinical symptoms. There is clear evidence of a
substantial conversion to clinical MS, but current management for this syndrome is controversial.
Further investigations
Cerebrospinal uid examination
Once a routine part of MS diagnostics, CSF examination is now often bypassed in clear cases, although with
investigational markers of prognosis and disease activity
it may return to use in all patients.
The pathological hallmark in MS is the presence of
unmatched oligoclonal globulin bands (OCBs) in CSF,
when compared with plasma.
OCBs are more sensitive for MS in temperate geographical areas than in equatorial areas.
There is evidence that those with positive OCBs early
in disease face a more rapid progression in disability.
OCBs, when present in the situation of CIS, are also
indicative of increased risk for progression to definite MS.
Electrophysiology
Evoked studies may also be used to assess the integrity of
visual and proprioceptivesensory pathways, with delays
seen in previous demyelination.
Visual evoked responses (VERs) may be tested with
flash or a checkerboard pattern. They are sensitive for
optic neuritis, even after vision returns to normal. However, adequate vision for fixation is necessary, and in the
absence of patient cooperation, absent results cannot be
interpreted.
Somatosensory evoked potentials (SSEPs) are also
performed at times, and have their place when spinal
632
symptoms are present, although they may be positive in

around three-quarters of patients with MS even when
symptoms are not present. They are most often used in
atypical or contradictory cases.
Management of multiple sclerosis

Management of a patient with MS falls into three separate
components:
1 Management of acute episodes of neurological
symptoms.
2 Management of the underlying disease, with view to
disease modification.
3 Symptomatic management of symptoms and disability, from mobility to mood to cognitive disturbance,
fatigue and urological function.
The options for long-term management of MS have
exploded in recent years. There is a strong case for optimal
control of MS early in a patients course, with a view to preventing long-term disability. Long-term drug management
is best provided through a specialist unit, with consideration of safety, efficacy, likelihood of pregnancy and side-effect profile being paramount. (Long term management of
relapsing-remitting MS is outlined in Table 19-12.)
Management of acute exacerbations
CLINICAL PEARL
Prior to initiating treatment for an acute exacerbation of multiple sclerosis, it is important to exclude
pseudo-exacerbation due to such complications as
urinary tract infection or constipation. This will avoid
the risk of unnecessary corticosteroid therapy.
Corticosteroids
Used both intravenously and orally, as a general rule
corticosteroids have a role in MS only in the setting of
an acute attack.
The most common form of management is with a 3- to
5-day course of intravenous corticosteroid, commonly
methylprednisolone, at a dose of 5001000mg/day.
This is associated with an increased likelihood of
improvement or stability of symptoms when compared
with placebo at 5 weeks.
Some clinicians follow with an oral corticosteroid taper,
though this has no evidence base.
It should be noted that gadolinium enhancement on
MRI improves with corticosteroids regardless of clinical
state, and using this as a surrogate for clinical status is
not advised.
CLINICAL PEARL
Oral corticosteroids should be avoided in optic neuritis, as they may be less effective than when used intravenously.
Table 19-12 Long-term drug management of relapsing-remitting multiple sclerosis
DRUG
MECHANISM OF ACTION
SIDE-EFFECTS
Beta-interferons
Immune modulation
Flu-like illness
Depression
Abnormal LFTs
Neutralizing antibodies can reduce efficacy
Glatiramer acetate
Random mixture of peptides made from four

amino acids, with antigenic similarity to myelin
basic protein, against which it is thought to
immunologically compete
Local injection-site complicationspain and

redness
Syndrome of ushing, sweating, shortness of
breath and palpitations
Natalizumab
Alpha-4 integrin inhibitor (monoclonal antibody)

Prevents lymphocyte migration across the
bloodbrain barrier
PML in a small number of patients

Herpesvirus reactivations
Fingolimod
Sphingosine analog interfering with lymphocyte

migration
Lowers lymphocyte count by 2030% by
sequestering them in lymph nodes
Bradycardia at onsetrequiring supervised

administration on the rst dose in a hospital
setting
Increased risk of both herpesvirus infections and
possibly malignancy, including skin cancer
PML
Teriunomide
The active metabolite of leunomide,

teriunomide interferes with pyrimidine
synthesis. This pathway is required by activated
lymphocytes to expand
Liver dysfunction, sometimes severe

Cytopenias
Opportunistic infection
StevensJohnson syndrome
Teratogenic
Dimethyl fumarate
Unknown
Flushing
Gastrointestinal symptoms such as nausea,
abdominal pain and diarrhea
Abnormal LFTs
Cytopenias
Cladribine
Lymphocyte-specic chemotherapeutic agent
Teratogenic
Myelosuppression
Alopecia
LFTs, liver function tests; PML, progressive multifocal leukoencephalopathy.
Symptomatic treatments
Spasticity
Baclofen, a GABAB agonist, improves spasticity through
activation of inhibitory spinal and other central neurons.
Use is limited by sedation, frequently occurring above
75mg/day, in addition to the frequent reduction in tone
resulting in significant pyramidal weakness.
Tizanidine is an alternative when sedation is problematic.
Baclofen can be given intrathecally in appropriately
selected patients.
Lethargy
Multiple factors affect energy levels, and the importance
of adequately assessing mood and treating depression if
present cannot be understated. Amantadine has been used

for fatigue in MS, and has relatively few side-effects at a dose
of 100mg daily or twice a day.
Urinary symptoms
Urinary urgency is a common symptom in patients with
MS, and anticholinergic medication may be of use in
such a patient.
Oxybutinin, solifenacin or newer generations of antimuscarinic drugs are available, and may be tried after
ensuring that voiding is complete.
In patients with incomplete voiding, anticholinergic use
may precipitate urinary retention, and post-void bladder
scanning is recommended prior to commencing one of
these drugs.
633
When significant residuals are present, it is usually necessary to commence intermittent self-catheterization.
CLINICAL PEARL
Check post-void residual bladder volumes before starting anticholinergics for urinary urgency, as they may
worsen retention.
Pain
Pain is common in MS, and therapy should be directed
toward the cause of this.
Pain resulting from spasticity may improve with
baclofen or botulinum toxin in extreme cases.
Neuropathic pain may be improved with adjuvant analgesics, and neuralgia may benefit from the addition of
carbamazepine.
Neuromyelitis optica (NMO;

Devics disease)
Long thought of as a variant of MS, evidence has mounted
over recent years that this is a pathophysiologically distinct
disorder, with a more significant humoral etiology.
NMO is a disorder characterized by severe optic neuritis and transverse myelitis with longitudinally extensive
lesions (three or more vertebral segments).
It has a female preponderance greater than MS, and is
not associated with the presence of CSF oligoclonal
bands.
The clinical disorder of NMO is typically relapsing,
often with discrete, devastating attacks of demyelination
with variable recovery.
It is associated with the presence of antibodies to
aquaporin-4, which are pathogenic.
Diagnosis is made on the basis of imaging (Figure
19-20), and aquaporin-4 antibodies.
Figure 19-20 Longitudinally extensive transverse

myelitis (LETM), typical of neuromyelitis optica

ADEM is a disorder predominantly affecting children.
It follows infection by days to a month or so, although
in approximately one-third of cases an antecedent event
cannot be identified (more in adults).
Fever, headache, malaise and meningism may accompany initial symptoms, which typically worsen to nadir
over 47 days with multifocal demyelination of cerebral,
brainstem and spinal-cord white matter.
Symptoms include unilateral or bilateral pyramidal signs, acute hemiparesis, ataxia, optic neuritis and
encephalopathy.
In adults, peripheral nerve demyelination may also
occur.
Diagnosis
Treatment
Early treatment is critical, as disability often accrues
rapidly.
Initial treatment is usually with pulse methylprednisolone, 1g/day for 35 days.
Given the humoral nature of NMO antibodies, plasma
exchange is advocated early in those patients not
responding to cocorticosteroids.

(ADEM) and transverse myelitis (TM)
Demyelination is not limited to chronic, relapsing disorders
such as MS and NMO. It may also be seen as a monophasic illness, typically post-infectious in etiology. Multiple
viral and bacterial infections, including HIV, may precede
a presentation with multifocal neurological symptoms and
encephalopathy (ADEM) or spinal-cord syndrome (TM).
634
Laboratory investigation may demonstrate CSF pleocytosis or transient oligoclonal bands, although it may
also be normal.
MRI typically shows multifocal white matter lesions
without any significant temporal dispersion (Figure
19-21).
Treatment
Treatment is with pulse steroid therapy with or without
a taper, and in unresponsive cases plasma exchange can
be considered.
Prognosis is usually good, although when ADEM follows measles infection recovery may be less optimal.
Transverse myelitis
TM may also follow infection, although it may also be
idiopathic in cause.
In some cases it may be a symptom of a more systemic

process such as sarcoidosis or systemic lupus erythematosus (SLE).
A majority of the time it is a monophasic illness,
although in 5% of cases it may be the first episode of
MS.
Neurological involvement includes motor, sensory and
autonomic symptoms, although pain frequently precedes all of these other features.
CLINICAL PEARL
At the clinical nadir of transverse myelitis, approximately half of patients will be paraplegic.
Recovery follows a rule of thirds for complete recovery,

partial recovery and significant ongoing disability.
CLINICAL PEARL
Only 5% of patients with transverse myelitis go on to
develop multiple sclerosis.
Diagnosis
As with ADEM, CSF pleocytosis may be seen at times,
while oligoclonal bands may also be transiently seen.
Imaging of the spine typically reveals increased T2 and
FLAIR signal in the region of demyelination.
Treatment
Pulse corticosteroid is once again the modality of choice for
acute management.
NEUROLOGICAL
MANIFESTATIONS OF
SARCOIDOSIS AND BEHETS
DISEASE
Sarcoidosis
Neurosarcoid may present peripherally or centrally, and
may present in the absence of involvement of pulmonary, cutaneous or other typical sites for sarcoidosis.
The most common presentation relates to leptomeningeal infiltration by non-caseating granulomas,
leading to multiple cranial nerve palsies (typically facial
or optic nerves), or endocrine dysfunction due to pituitary involvement (Figure 19-22, overleaf).
It may also present with parenchymal, spinal or peripheral nerve involvement.
Behets disease
Behets disease may cause CNS effects, with a brainstem and posterior fossa inflammatory process causing
ataxia and/or hemiparesis (Figure 19-23, overleaf).
It may also lead to thrombosis of cerebral venous drainage with resultant intracranial hypertension.
NEUROMUSCULAR DISEASE
The peripheral nervous system makes up the entire system
outside of the brain and spinal cord, and may be affected by
a huge range of pathologies, some of which have also central
or systemic features.
Figure 19-21 T2 magnetic resonance imaging of the brain of a child with acute disseminated encephalomyelitis.
(A) Tumefactive change in the right temporo-occipital brain, with (B) additional T2 signal hyperintensity in the
brainstem and cerebellar peduncle. (C) Patchy gadolinium enhancement on post-contrast T1
From Bester M, Petracca M and Inglese M. Neuroimaging of multiple sclerosis, acute disseminated encephalomyelitis, and other
demyelinating diseases. Semin Roentgenol 2014;49(1):7685.
635
A
Figure 19-22 Sarcoidosis. (A) Gadolinium-enhanced coronal T1 image showing right tentorial durally based
mass (arrow). (B) Gadolinium-enhanced coronal T1-weighted image showing nodular leptomeningeal
enhancement in the basilar cisterns and posterior fossa
From Shah R, Roberson GH and Cur JK. Correlation of MR imaging ndings and clinical manifestations in neurosarcoidosis. Am J Neuroradiol
2009;30:95361 (www.ajnr.org).
It may also be paraneoplastic, and in particular dermatomyositis is associated with an elevated risk of cancer (relative risk 27), although this is in a minority of
cases.
Polymyositis and dermatomyositis are often grouped
together, separated by the presence of skin rash in the
latter. However, while there may appear to be overlap,
they are quite different entities pathologically and therefore physiologically.
They present with proximal myopathy and elevated
creatine kinase (CK).
Diagnosis is made electrophysiologically, with compatible autoantibodies (anti Jo-1 in particular), and biopsy.
MRI can sometimes show patchy inflammation within
muscle.
Figure 19-23 FLAIR signal change in the midbrain in a
patient with Behets disease, extending into the pons
and left thalamus on other slices
From Aksel Siva and Sabahattin Saip. The spectrum of nervous
system involvement in Behets syndrome and its differential
diagnosis. J Neurol 2009;256:51329. DOI 10.1007/s00415-0090145-6
Myopathy
Disease of muscle presents, not surprisingly, with muscle
weakness and, in some disorders, pain. Processes affecting
muscle integrity are myriad, and in this area more than any
other in the peripheral neuraxis the whole patient must be
considered, and indeed myopathy is frequently seen by physicians outside of neurology.
An overview of myopathy is provided in Table 19-13.
Inammatory myopathy
Inflammatory myopathy may be seen in isolation, or in
the presence of other autoimmune disease.
636
Treatment
Treatment is with immunosuppressive therapy, usually
with corticosteroids, despite any evidence-based trials.
A dose of 1 mg/kg/day of prednisolone is commonly used. Tapering should be done after a month
or so of therapy, based on clinical response.
Azathioprine and methotrexate are also used as steroidsparing agents.
Worse weakness, a longer duration of illness, and bulbar
features are worse prognostic signs at diagnosis.
Inclusion-body myositis
Often initially diagnosed as polymyositis, this condition
usually presents more insidiously with more notable distal weakness, including wrists and finger flexors.
Muscle biopsy may display diagnostic features including cytoplasmic inclusions and vacuolar degeneration
(Figure 19-24, overleaf).
Corticosteroids and a variety of immunosuppressive
agents have been tried with minimal clinical success,
Table 19-13 An overview of myopathy
PROCESS
CLINICAL FEATURES
CK
NCS/EMG
BIOPSY FINDINGS
Inammatory
Polymyositis (PM)
Proximal myopathy, pain in 25%

(not prominent)
++
Myopathic
(patchy)
Patchy involvement,
with inammation within
fascicle
Dermatomyositis
As per PM with skin changes
++
Myopathic
Perivascular
inammation
Inclusion-body myositis*
(considered by some to be
degenerative)
Proximal, but may have distal

involvement (wrists, nger
exors)
Normal or +
Myopathic
Cytoplasmic inclusion
bodies
Mixed connective tissue

disease
Should have features of

SLE/Sjgrens syndrome/
scleroderma in addition to PM
++
Myopathic
Non-specic necrosis
and regeneration
Infective
Often acutely painful
May be +++
Statins
Myalgias and/or myopathy

Can be frank rhabdomyolysis
Normal to
+++
May be
myopathic
Corticosteroids
Usually insidious with proximal

myopathy
Usually
normal
Should be
normal
Type II ber loss
Alcohol
Acute with rhabdomyolysis;

chronic with type II atrophy
Patients often have neuropathy,
cerebral features
+ to +++
Normal in
chronic
May be
myopathic
Variable depending on
clinical picture
Antiretrovirals
Proximal weakness and

myalgia/tenderness
+ to ++
Myopathic
Ragged red bers
Colchicine
Proximal weakness (lower limbs

> upper limbs) in long-term use
(or overdose)
++
Myopathic
with
myotonia
May be confused with

polymyositis
Cushings syndrome
Weight gain, striae
Normal
Usually
normal
Type II ber loss
Hypothyroidism
Weight gain, myxedema
Normal
or mildly
myopathic
Non-specic (TSH much

more helpful!)
Thyrotoxicosis
Weight loss, tremor

Eye signs in Graves disease
Normal or +
Normal
or mildly
myopathic
Variablemay have ber

loss/brosis/necrosis
Renal failure
Painless; may have associated

neuropathy
May be
normal
May be subtle
Mitochondrial disorders
Often progressive; extraocular

muscles especially commonly
involved
Disorders of glucose and

lipid metabolism
Variable depending on disease;

may have exercise-induced
rhabdomyolysis
Muscular dystrophies
(disorders of muscle
structure)
Variable; usually progressive

weakness with aging
Depends on etiology
Drugs
Endocrine
Metabolic and genetic
Myopathic
changes
Ragged red bers on

biopsy
Diseasespecic
Diseasespecic
Disease-specic
Diseasespecic
Diseasespecic
Disease-specic
CK, creatine kinase; SLE, systemic lupus erythematosus; TSH, thyroid-stimulating hormone.
637
rarely in diabetes mellitus, although they are typically

accompanied by features of neuropathy.
Genetic disorders
Making up a small percentage of patients with symptomatic
muscle weakness, the number of described muscular disorders continues to expand with improvements in investigative genetic techniques. In many of these disorders cardiac
muscle may also be involved, and the involvement of this
should always be assessed.
Duchenne muscular dystrophy
Figure 19-24 A granule-lled cytoplasmic inclusion

seen on Gmri trichrome staining of a muscle
biopsy from a patient with inclusion body myositis
From Agamanolis DP. Neuropathology: an illustrated interactive
course for medical students and residents. Northeast Ohio Medical
University (NEOMED).
Duchenne muscular dystrophy is an X-linked condition,

marked by pseudohypertrophy of musculature and progressive weakness during childhood, with a patient (almost
always male) typically wheelchair-bound by 12 years of age.
It is caused by a mutation (typically frameshift) in a
myofibrillar protein called dystrophin, and less severe
mutations are seen in a less rapidly progressive form
referred to as Beckers muscular dystrophy.
Cardiac muscle is involved, and dilated cardiomyopathy
often develops in the teenage years.
Other muscular dystrophies

which has led some to regard this condition as more of a
neurodegenerative process.
Drug-induced myopathy
A variety of drugs can cause acute myopathy with rhabdomyolysis, or chronic myopathy in long-term use.
Some drugs exert an effect through direct muscle toxicity (alcohol, colchicine), while others affect muscle
cellular metabolism leading to secondary toxicity
(statins, antiretrovirals).
Corticosteroids and thyroxine (in supraphysiological
doses) cause myopathy through secondary humoral
processes.
A thorough drug history should be taken on any
patient presenting with myopathy or myositis, including non-prescribed intake, as recreational drugs such as
cocaine and amphetamines may cause muscle toxicity.
Biopsy is not usually required, but rather treatment is
withdrawn and the patient observed for improvement.
In the case of corticosteroid use for inflammatory or
other disorders, often CK levels and electromyography
(EMG), together with MRI if necessary, suffice to avoid
biopsy.
Endocrine and metabolic processes
Disordered muscle function may be seen in a Cushingoid state, as well as with both hypothyroidism and
thyrotoxicosis.
Typically, abnormality of electrophysiological or laboratory testing is not found in this case, unless disease
is severe. Clinical history and examination is likely to
reveal other abnormalities.
Myopathy may also be seen in renal failure and very
638
Multiple other genetic causes of muscular dystrophy have

now been described (Box 19-7); and with these, variability in the presentation. The core feature is that of proximal
muscular weakness, which may progress with time.
Mitochondrial disorders
This includes a large number of distinct disorders, all resulting from defects in the mitochondrial respiratory chain
pathway.
Defects can be in mitochondrial DNA (inherited maternally with variable heteroplasmy), or in autosomal genes
coding for mitochondrial proteins.
Tissues affected include those with a high energy
requirement, and therefore muscles and nerves feature
highly (Box 19-8).
The hallmark of mitochondrial disorders where muscle is affected is the presence of ragged red fibers on
biopsy, an appearance due to an aggregation of abnormal mitochondria.
Other diagnostic tests that may assist include:
resting lactate levels
CSF lactate levels
Box 19-7
Genetic muscular dystrophies

Limb girdle (multiple types)
Facio-scapulo-humeral
Oropharyngeal
Distal
Myotonic
Box 19-8
Features of mitochondrial disorders

Progressive external ophthalmoplegia
Myopathy
Deafness
Diabetes mellitus
Stroke-like episodes
Seizures
Visual failure
Lactic acidosis
Gastrointestinal symptoms
MRI imaging t magnetic resonance spectroscopy

(lactate peaks)
genetic testing of blood, hair or muscle tissue.
Specialized mitochondrial respiratory chain testing may be
performed, but is of very limited availability.
Other disorders of energy production

in muscle
A number of disorders have now been described in which
muscle may be injured, especially when exerted. This typically occurs in people with episodes of rhabdomyolysis after
exertion, and is sometimes life-threatening.
The two most common disorders are McArdles diseasea glycogen storage disorder; and CPT (carnitine
palmitoyltransferase 1) deficiencya disorder of fattyacid metabolism.
Both can be ascertained by muscle biopsy with appropriate staining by a specialist center.
Figure 19-25 Myasthenia gravis patient with bilateral

ptosis
From Liu GT, Volpe NJ and Galetta SL. Neuro-ophthalmology:
diagnosis and management, 2nd ed. Elsevier, 2010.
When more severe, extraocular muscles may have

little or no movement, and this can confound the
usually fluctuating and fatiguing picture of MG.
More than 80% of patients will have ocular symptoms, and myasthenia may be limited to eye movements alone.
A smaller proportion of patients present with myasthenic involvement of other muscles, notably a dropped
neck, bulbar weakness, limb weakness or even respiratory muscle weakness. These features should always
warrant a search for fatiguability elsewhere.
Sensory symptoms should not occur, though are sometimes reported as a heavy sensation.
Pathophysiology
NEUROMUSCULAR DISORDERS
This group of disorders broadly covers disease states in which
symptoms occur due to abnormalities in the transmission of
action potentials across the neuromuscular junction, resulting in disordered muscular contraction.
It encompasses myasthenia gravis, LambertEaton myasthenic syndrome (LEMS) and rare congenital myasthenic
syndromes.
Myasthenia gravis (MG)

Myasthenia gravis is an autoimmune process that results
from production of autoantibodies to proteins involved in
the signaling pathways in the postsynaptic neuromuscular
junction.
The predominant feature of MG is fatiguable weakness.
With often single nerve to single muscle fiber innervation and constant activity, extraocular musculature is
most commonly the first site of symptoms, and patients
frequently present with fluctuating diplopia or ptosis
(Figure 19-25).
Pathophysiologically, the antibody most commonly implicated is an antibody to inotropic nicotinic receptors to acetylcholine (ACh), hence known as an acetylcholine receptor
antibody (AChR Ab), which is present in more than 80%
of myasthenic patients but only 50% of myasthenic patients
with disease limited to extraocular muscles. An additional
antibody to muscle-specific kinase (MuSK), a part of the
receptor complex, is seen in more than 50% of the remaining patients.
The antibody leads to inadequate signaling resulting from
a single vesicle release pre-synaptically, with reduced receptors
or impaired signaling pathways. This results in an increase in
the number of vesicles released in response to a single action
potential. This may compensate adequately at rest; but with
activity, the pre-synaptic store of vesicles may be exhausted
and this leads to the development of clinical weakness.
Clinical assessment
MG is a neurological mimic, and a high degree of
suspicion must be maintained in assessing patients
with weakness, diplopia or bulbar symptoms, as a
639
routine neurological examination of tone, power and

reflexes may not be able to detect the critical feature of
fatiguability.
Fatiguability is tested in ocular musculature by asking a
patient to maintain gaze in a position which historically
makes the diplopia worse, usually in the midline vertical.
In this position it is critical to observe both pupils
for drift of the eye as well as both eyelids for fatiguing ptosis.
A patient can be asked to count loudly to 20, or if shoulder abduction is strong on testing bilaterally, one arm
can be exercised and then shoulders can be tested again.
CLINICAL PEARL
A simple and safe bedside test with good sensitivity and
excellent specicity in ocular myasthenia is an ice-pack
test (also referred to as an ice on eyes test). In this
test, an eye with ptosis or external ophthalmoplegia is
covered with a cold pack (wrapped to protect the eye),
and after cooling the musculature is re-tested. A clinical improvement should be seen, with deterioration
again as cooling wears off. A positive test has excellent
specicity. The alternative test, the edrophonium (Tensilon) test, is being used less commonly due to safety
concerns and is no more specic.
Diagnostic testing
A temporary improvement in clinical signs is seen in a

positive test, but when mild or subjective the test is of
uncertain value.
Serological tests
Reliable ACh receptor antibody and MuSK testing is
available, and these combined have a >90% sensitivity
to the diagnosis of MG.
In a patient with suspected myasthenic crisis, delays in
obtaining results of serological tests may necessitate the
use of alternative tests.
Nerve conduction studies
Routine nerve conduction studies and EMG in MG are
normal, but pattern of fatigue can be assessed through
repetitive stimulation studies, and neuromuscular junction
exhaustion is assessed through a technique called single-fiber EMG, both of which have very high sensitivities and
specificities (in an appropriate clinical setting) when assessed
by an experienced neurophysiologist.
CT scan of the chest
This should be performed in any patient with MG to
assess for the presence of a thymoma, which is present in
around 15% of patients with another 75% having thymic
hyperplasia.
Treatment
Edrophonium (Tensilon) test

Edrophonium is a short-acting acetylcholine esterase
inhibitor which facilitates an increase in the amount of
acetylcholine at the neuromuscular junction, and therefore improves myasthenic symptoms temporarily.
It must be given intravenously as a fast push, and has
potential cholinergic side-effects including bradycardia,
hypotension, sweating and salivation. Bradycardia may
be precipitous, and to block this unwanted stimulation
of parasympathetic muscarinic receptors, atropine is
sometimes given in addition.
The therapy of MG has several components, with treatment

aimed at:
symptomspyridostigmine, physostigmine
disease controlcorticosteroids, azathioprine, IVIg,
plasma exchange, rituximab, thymectomy (Figure
19-26).
Longer-lasting acetylcholine esterase inhibitors such as pyridostigmine are frequently prescribed to assist symptomatic
fatigue of neuromuscular transmission.
They do not treat the underlying autoimmune biology.
Immunotherapy
Myasthenia
Acute
Corticosteroid
Symptomatic
Pyridostigmine
Steroid sparing
agent
(Azathioprine,
MMF)
Thymectomy
IVIG/plasma
exchange
Rituximab if
refractory
Figure 19-26 Treatment of myasthenia gravis. IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil
640
Side-effects include bradycardia and gastrointestinal

cramping or diarrhea, which frequently limits dose.
Corticosteroids are first-line agents in the management of
the immunological drive of MG, although they can exacerbate weakness if started at too high a dose.
As such, doses of 1020mg/day of prednisolone tend to
be a starting dose, with an increase over days or weeks to
1mg/kg/day. With improvement in symptoms, the dose
can then be reduced over time.
If a faster response is required, either IVIg or plasma
exchange may be helpful.
Azathioprine or sometimes mycophenolate can be used
in patients with severe or longstanding myasthenia with
a view to reducing long-term steroid dose and exposure.
There is little evidence for benefit in the first year of
therapy, and it is only with prolonged use that patients
may be able to reduce their steroid dose.
Thymectomy is indicated in any patient with a thymoma,
and is also advocated for patients with chronic disease. Acute
thymectomy is dangerous in an uncontrolled patient.
Rituximab is a B-cell-depleting monoclonal antibody
which has found a place in patients with chronic intractable
myasthenia.

There are hundreds of causes of peripheral nerve injury, but
most present with a fairly restricted group of symptoms:
abnormal sensation (numbness, pain or loss of joint position sense) and/or weakness. Because of this, the pattern of
involvement is essential to the clinician seeing a person with
a peripheral nerve problem, much of which is dependent on
the anatomy of the nerve.
Anatomy
Nerve fibers are the axonal processes of the somata of each
nerve cell. Disconnection of a distal axon from the soma
results in death of the nerve fiber distal to the disconnection,
although the nerve proximal to it remains alive.
The somata of nerves are located in different locations for
motor neurons (in the anterior horn of the spinal cord), and
Nerve roots
Dorsal root ganglion (site of
(sensory nerve body) radiculopathy)
in the dorsal root ganglion (outside of the spinal cord) for sensory nerves (Figure 19-27).
Nerves may be myelinated (large fibers), facilitating fast
speeds of neurotransmission, or unmyelinated (small fibers).
Different-sized nerve fibers tend to have different functions,
which are summarized in Table 19-14, overleaf.
Some pathologies affect one or another type of nerve
more than others, with symptoms compatible with the type
of fiber affected.
For example, alcohol abuse (without other vitamin deficiencies) commonly leads to a small-fiber peripheral
neuropathy with burning and loss of pain sensation,
together with autonomic features.
In contrast, a lead neuropathy affects large motor fibers,
and tends to spare sensory nerves.
The impact on the nerve also depends on where the insult to
the nerve is located anatomically, and disorders of peripheral
nerves are named for this (Table 19-15, overleaf).
Motor neuron disease (MND)/

amyotrophic lateral sclerosis
Often grouped with peripheral nerve disorders for ease,
it is now understood that MND is a disorder affecting
both peripheral motor neurons, with progressive death
of cell somata, and central neurons, especially in the
frontotemporal regions.
This causes a picture of frontotemporal cognitive impairment in some patients with frank dementia in others.
Central features may precede the peripheral findings,
and in other patients peripheral features are prominent
or present in isolation.
It is this mixed pattern of central and peripheral denervation which gives MND its characteristic clinical features,
of patchy mixed upper motor neuron involvement (hyperreflexia, increased tone, jaw jerk) and lower motor neuron
involvement (flaccid tone, muscle fasciculations, atrophy).
As it is a process involving only motor nerves, sensation
should not be affected (although with loss of strength and
muscle bulk, occasional compression peripheral neuropathies may also occur).
Sensory inputs
Peripheral
nerve
Neuromuscular junction
Motor neuron
Muscle
Figure 19-27 The peripheral neuraxis. Disease processes can occur anywhere between the muscle and the
spinal cord, and can sometimes be mixed
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Table 19-14 Type and function of peripheral nerves
GROUP
A (large myelinated)
MODALITY
Motor
Sensory
SUBGROUP
FUNCTION
Motor neurons
Gand L
Muscle spindle bers
Muscle spindle and proprioception
Fine touch
Some pain, temperature, electric, crude touch
B (small myelinated)
Autonomic
Presynaptic autonomic nerves
Sensory
Pain and temperature, burning and itch
Autonomic
Post-ganglionic nerves
Table 19-15 Diseases of peripheral nerves
LOCATION OF
INSULT
NOMENCLATURE
EXAMPLES
Anterior horn of cord

(motor somata)
Motor neuronopathy (anterior horn cell

disease)
Motor neuron disease*

Spinomuscular atrophy
Poliomyelitis
Nerve roots
Radiculopathy
Meningeal inltration
Foraminal stenosis
Dorsal root ganglion
Sensory neuronopathy
Paraneoplastic
Sjgrens syndrome associated
Inammatory
Plexus
Plexitis/plexopathy
Brachial neuritis (inammatory)

Traumatic (e.g. Klumpkes palsy, which affects C8
and T1 nerve roots)
Diabetic amyotrophy
Single peripheral nerve
Mononeuropathy
Median neuropathy (carpal tunnel)

Radial neuropathy (Saturday night palsy)
Multiple individual
peripheral nerves
Mononeuritis multiplex
Vasculitis
Multifocal compressive mononeuropathies
Patchy involvement
Neuropathy
Demyelinating processes (GuillainBarr, chronic

inammatory demyelinating polyneuropathy)
Diffuse involvement
Length-dependent peripheral neuropathy

(i.e. longer nerves affected rst)
Diabetes mellitus
Alcohol
CharcotMarieTooth syndrome (some types)
* Disease also affects upper motor neurons, giving characteristic features.
Diagnosis
There is no single investigation capable of diagnosing MND,
although neurophysiological studies with a compatible history can come close. A thorough investigation is often performed looking for potential differential diagnoses, given the
morbidity associated with this condition.
642
Neurophysiology
This can demonstrate evidence of lower motor neuron
involvement, with fasciculations as well as other features
of denervation a prominent feature. The pattern is typically asymmetric.
Abnormality is also seen on single-fiber EMG performed in specialized centers.

More recently, transcranial magnetic stimulation of
the cortex has been used to study motor excitability to
assess for central involvement in motor pathways, but
this is not widely available.
Imaging
MRI of the spinal cord and brain are often done where bulbar or upper motor neuron features predominate, to exclude
focal pathology causing bulbar or myelopathic features.
Occasionally frontotemporal atrophy may be seen.
Serology
Investigation is often performed for patchy inflammatory demyelinating processes such as multifocal motor
neuropathy, which also presents with asymmetrical
lower motor neuron symptoms and is usually strongly
responsive to immunomodulation with IVIg or plasma
exchange.
This differential does not cause upper motor neuron
signs, and rarely involves cranial nerves (although cranial nerve XII involvement has been reported).
Treatment
There is very limited pharmacotherapy with any efficacy
in MND, although riluzole has been shown to improve
survival by approximately 6 months.
With disordered respiratory musculature, overnight
hypoventilation and desaturation are common. In
patients with adequate bulbar function to tolerate it,
non-invasive ventilatory support may be beneficial for
quality of life, and potentially survival.
Similarly, invasive feeding strategies should be discussed
while a patient is fit enough to undergo insertion of gastrostomy tubes, with a view to keeping weight up and
preventing additional loss of muscle bulk and fitness.
Demyelinating neuropathy and

GuillainBarr syndrome (GBS)
With a range of disorders in this group, the clinical
history can range from very acute and symmetrical to
exceedingly slow and asymmetrical.
The pathology is one of destruction or functional blockade of myelin on large nerve fibers, through an antibody-mediated process.
The targets of these antibodies are typically ganglioside molecules; these have structural similarities to a
number of bacterial and viral proteins, with antibodies
often forming through the process known as molecular
mimicrythat is, antibodies formed to pathogens (e.g.
Campylobacter jejuni) which then cross-react with self
molecules.
Acute inflammatory demyelinating polyneuropathies come
under the diagnostic umbrella of GuillainBarr syndrome. They commonly follow an acute gastrointestinal
or respiratory tract infection, and typical clinical features

include:
1 Ascending bilateral motor weakness (although features
start in the hands or face in about 10%).
2 Peripheral sensory impairment:
a paresthesiae are common, although often mild
b pain is actually very common, present more than
50% of the time, and may be variable in site and
extent.
3 Facial and respiratory weakness develop in approximately half and one-third respectively.
4 Dysautonomia is also common, and often not properly
considered (constipation, urinary retention, postural
hypotension, tachycardia).
It is also worth noting that there are a large number of
subtypes of GBS in which sensory or motor features may
be present in isolation, or there may be a craniofacial predominance in MillerFisher syndrome and Bickerstaffs
encephalitis.
GBS typically progresses over 2 weeks, and patients
should reach the nadir of neurological deterioration within
a month; a slower deterioration suggests an alternative diagnosis such as chronic inflammatory demyelinating polyneuropathy (CIDP).
Diagnosis
Laboratory assessment
Routine blood examination is typically unremarkable,
although on serological studies of ganglioside antibodies a variety of antibodies may be seen. However,
the absence of these does not preclude a diagnosis of
GBS.
A lumbar puncture is often performed to assess for evidence of albumino-cytological dissociationthe presence of elevated CSF protein without a pleocytosis. This
is present in 8090% of patients at 1 week.
GBS is an uncommon seroconversion illness in HIV
infection; however, testing for HIV should be considered in an at-risk individual.
Neurophysiological studies
When performed very early, these may be normal.
With progression, sensory responses may be absent and
slowing of motor conduction as well as conduction may
be evident.
Changes are typically patchy; the nerve should not
appear uniformly affected in a typical case of GBS.
Therapy
After reaching nadir, recovery usually occurs over weeks
and months, although this may be incomplete.
Given that the initial decline may be precipitous, acute
therapy is critical.
The dominant modality of therapy is with IVIg or
plasma exchange. Recovery may be much faster than
643
one may expect in nerve injury, suggestive that part of

the symptomatology may relate to functional blockade of molecules with a role in neurotransmission in
myelinated fibers, in addition to loss of myelin.
Corticosteroids are ineffective in GBS.
Axonal forms of GBS also exist, though these are fortunately rare. Recovery in these variants is exceedingly
slow, and often partial. Urgent intervention is therefore
indicated in any patient with a clinical phenotype of
GBS.
Supportive care is critical in GBS, especially in patients
with facial and bulbar weakness. Close supervision in a
facility capable of intubation is indicated in all patients
with GBS yet to respond to immunological treatment.
Diffuse peripheral polyneuropathy is a common clinical
finding, and typically presents with subacute to chronic
sensory disturbance (burning or numbness), starting
distally in the feet and slowly progressing proximally.
Motor weakness may occur as the condition becomes
more marked.
Autonomic nerves are also variably involved, and
the degree of involvement may help with differential
diagnosis.
Unfortunately for the assessing clinician there are hundreds
of causes of peripheral neuropathy, which makes an allinclusive assessment challenging (Table 19-16).
Table 19-16 Some of the more common causes of peripheral neuropathy
DISEASE
AUTONOMIC
FIBER
SIZE
COMMON CLINICAL
PRESENTATION
SENSORY
MOTOR
Diabetes
+++
++
S>L
Burning starting in feet; glove and

stocking
Alcohol
+++
++
S>L
Burning in feet
Often cerebellar, ocular or cognitive
features
Critical illness
++
++
++
Mixed
Weakness, difficulty weaning from

ventilator
Vitamin B12
+++
L>S
Sensory ataxia; often dorsal column

signs
Uremia
+++
S>L
Glove and stocking
Malignancy
+++
++
Variable
Variable; may have other neurological

features; may have cachexia and
muscle weakness
Liver failure
+++
Often S > L
Glove and stocking
Paraprotein
Anti-MAG
++
++
Both
Slowly progressive glove and stocking
MGUS
++
++
S>L
Glove and stocking
POEMS
++
++
Both
Progressive sensorimotor involvement

with other features of myeloma
Amyloidosis
++
+++
S >> L
Painful neuropathy with autonomic

dysfunction
Chemotherapy
(platinum,
taxanes, etc.)
+++
L>S
Glove and stocking patternmay

be rapidly progressive with repeat
exposure
HIV
+++
Both
Progressive glove and stocking
Hereditary
(multiple
disorders)
Variable
Variable
Variable
Variable
Typically do not have dysesthesia or

pain (may be present late)
HIV, human immunodeciency virus; L, large; MAG, myelin-associated glycoproteins; MGUS, monoclonal gammopathy of uncertain
signicance; POEMS = polyneuropathy, organomegaly, endocrinopathy, M-spike, skin changes; S, small. L > S indicates that large bers are
affected more than small bers.
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History is critical, providing information about the

tempo of progression, age of onset, pattern of involvement
(small fiber/large fiber/motor fiber/autonomic involvement),
comorbidities, and other neurological symptoms.
CLINICAL PEARL
If ankle jerks are present clinically, a substantial largeber neuropathy is very unlikely.
patient attention and motivation and may be difficult to

interpret.
In some centers autonomic function testing is also possible, which is occasionally indicated.
Laboratory investigation
It is near-impossible to perform a screen for all causes of
neuropathy; routine investigation should include the investigations shown in Table 19-17.
Treatment
Investigation
Neurophysiology may be used to assess for the presence
and clinical extent of a neuropathy. However, it only
tests large-fiber function, and in a patient with smallfiber symptoms (burning pain) and a normal examination, a normal nerve conduction study does not rule out
small-fiber involvement.
In some centers psychophysical testing of small
fiber-function is possible, but these are dependent on
Treatment is aimed at an underlying cause if one can be

found, with a view to prevention of progression.
A low dose of tricyclic antidepressant such as amitriptyline, or gabapentin, may be beneficial for uncomfortable
dysesthetic neuropathic symptoms such as burning or
sensitivity to pressure.
Secondary prevention should also be remembered, with
regular podiatry review and foot care, well-fitting shoes,
and appropriate pressure care.
Table 19-17 Laboratory investigation for neuropathy
INVESTIGATION
RATIONALE
Full blood count
Variety of changes present in vitamin deciencies, alcohol abuse and

malignancies
Urea, electrolytes, creatinine
To assess renal function
Assesses for evidence of liver failure; albumin as marker of systemic

health; review globulin levels
Fasting blood sugar glucose tolerance test
Note that symptoms of small-ber neuropathy may develop with

impaired glucose tolerance
Serum and urine protein electrophoresis with

immunoxation
Assess for the presence of a paraprotein, including some which are

pathogenic in low concentrations
Vitamin B12
Assess for deciency
Erythrocyte sedimentation rate
Nonspecicraised in malignancy, paraprotein, (auto)inammation
Antinuclear antibodies/anti-neutrophil
cytoplasmic autoantibody (ANA/ANCA)
Especially if subacute or mononeuritis multiplexfeatures of vasculitis
Consider HIV/syphilis
If either is possible the patient should be tested
645
1 A 75-year-old man is referred for assessment for possible Parkinsons disease. His family have noticed that he is
shuffling in his gait more than previously. Which of the following would make you most concerned about a diagnosis
of dementia with Lewy bodies?
A Minimal tremor
B Postural hypotension
C REM (rapid eye movement) sleep behavior disorder
D Early memory loss with frequent falls
E The hallucination of his mother, who visits for tea every day
2 An 18-year-old man is referred to you after two generalized tonicclonic seizures in 3 months. He reports having
had twitches or jerks at times when tired, and in the mornings on and off for a few years. His electroencephalogram
demonstrates intermittent generalized polyspike and wave discharges. Which medication is usually considered rst-line?
A Carbamazepine
B Phenytoin
C Sodium valproate
D Topiramate
E Clonazepam
3 A 48-year-old woman presents to emergency with acute severe rotatory vertigo present for several hours. She is very
nauseated. On examination she has horizontal nystagmus beating toward the right in all positions, worse on gaze
to the right, and is deaf in the left ear. There is no tinnitus. She has a positive head impulse test to the left. Clinical
examination is unremarkable other than a skew deviation on assessment of eye movements. The most likely
diagnosis is:
A Mnires disease
B Benign positional vertigo
C Vestibular neuritis
D AICA (anterior inferior cerebellar artery) stroke
E Lateral medullary syndrome
4 A 24-year-old man with developmental delay and a history of LennoxGastaut syndrome is brought in to the
emergency department in status epilepticus from his group home. His medications include sodium valproate 1500mg
twice daily, topiramate 200mg twice daily and primidone 250mg three times daily. He has not been unwell and has
been taking his medications normally. Despite 4 doses of intravenous diazepam in the ED he continues to seize. The
probable reason for this is:
A He takes primidone, which has induced his liver enzymes, clearing diazepam quickly.
B These are behavioral episodes and are unlikely to respond to antiepileptic therapy.
C He has not been loaded with phenytoin.
D Diazepam redistributes rapidly within the various uid compartments within the body, allowing a return of seizure
activity.
E He probably has an intracranial pathology causing new onset of seizures and he requires a computed tomography
scan and lumbar puncture.
5 A 73-year-old man with a 5-year history of Parkinsons disease is brought to see you by his wife, as he has been
sleeping very poorly. She says that he spends much of the night sitting up playing computer chess, and that he is too
tired during the day to be as social as previously. He was diagnosed with tremor-predominant Parkinsons disease,
although he had signicant REM (rapid eye movement) sleep behavior disorder for the previous 34 years. His current
medication regimen includes pramipexole extended-release (ER) 3.75mg/day, levodopa/carbidopa 100/25 mg four
times a day and entacapone 200mg three times daily. He feels that control is pretty good, although he wouldnt
mind a little more medication for a period around 2 p.m. when he feels slower. Clinically he looks a little dyskinetic,
although his wife says this occurs a minority of the time. What is the most appropriate management step?
A Reduce pramiprexole ER to 3mg/day
B Increase the pramiprexole ER to 4.5mg/day
C Add amantadine 100mg daily
D Check iron studies and arrange a sleep study
E Prescribe some nocturnal zolpidem to help him sleep
6 A 24-year-old woman presents with pain behind the right eye with movement, which resolves as she notices
altered vision in that eye. She notices that everything looks gray and her acuity is 6/36. She is given intravenous (IV)
methylprednisolone 1g for 3 days and her symptoms settle. Magnetic resonance imaging (MRI) of the brain at that
time is unremarkable. Two months later she has symptoms in her right leg with some difficulty walking, and a bandlike sensation around the umbilicus. An MRI shows a small plaque in her thoracic spine. She receives oral prednisolone
100mg daily for 5 days as she is still mobile and wishes to avoid hospital. She is commenced on beta-interferon as an
outpatient, while further assessment is pending. A month later she presents with acute onset paraplegia, coming on
over 2 days, and urinary retention. What is the best management strategy?
646
A
B
C
D
E
IV steroids, continue beta-interferon, re-image the brain and spine, and perform a lumbar puncture
IV steroids, cease beta-interferon, re-image the brain and spine, and perform a lumbar puncture
Insert a catheter and treat for a urinary tract infection, hold off on steroids for now
IV steroids, continue beta-interferon, check for neutralizing antibodies, re-image the spine
IV steroids, stop beta-interferon and start ngolimod, re-image the brain and spine
7 A 48-year-old man presents with a 1-week history of weakness in the legs and back pain. He has recently been
on holiday to Thailand and did have gastroenteritis while there, 2 weeks before. Clinically he is able to walk only
with assistance and has grade 2/5 power distally in the legs and 34/5 power more proximally. Reexes are absent
throughout. While he has no sensory symptoms, he reports altered cold and vibration sensation distally. He has
a history of non-Hodgkin lymphoma for which he received R-CHOP chemotherapy 5 years previously, and is in
remission. Which is not a possible diagnosis?
A GuillianBarr syndrome due to campylobacter exposure
B Myasthenia gravis
C GuillianBarr syndrome secondary to HIV seroconversion illness
D Central nervous system lymphoma recurrence in the cauda equina
E Chemotherapy-induced neuropathy
8 A 55-year-old woman is referred for assessment of progressive proximal muscle weakness causing problems standing
from a chair and getting up stairs over 4 months. She has hypothyroidism on thyroxine 100microg daily, and was on
simvastatin for dyslipidemia until 2 months ago when her family physician stopped it due to her symptoms. She has gout,
for which she takes allopurinol 300mg daily. She denies signicant muscle pain, although her muscles may become sore
with prolonged use. There is no rash. Her creatine kinase is 4000 U/L. Which of the following is most likely?
A Statin myopathy
B Metabolic myopathy due to thyroid disturbance
C Inclusion-body myositis
D Statin-induced autoimmune myositis
E Allopurinol-induced myopathy
9 A 46-year-old women presents with a 4-day history of headache, fever and increasing confusion. She is brought to
the emergency department and is noted to be drowsy, disorientated in time and place, and to have difficulty following
two-stage commands according to the documented observations on arrival. A non-contrast computed tomography
scan of the brain is performed soon after arrival and is reported as normal. You are called to see her as she is found to
have become suddenly unresponsive to voice, not opening her eyes, with symmetrical localization to painful stimuli
only. Her Glasgow Coma Scale score is measured at 6. The most appropriate advice for the immediate management is:
A Airway support in the ED and lumbar puncture/cerebrospinal uid examination
B Airway support in the ED and commencement of intravenous anticonvulsant medication
C Urgent magnetic resonance imaging of the brain
D Urgent electroencephalography
E Intensive-care consultation
10 A 55-year-old woman with a past history of depression and migraine with aura presents with a 6-month history of
increasing chronic daily generalized throbbing headache, associated with intermittent visual blurring and nausea. She
has tried her usual anti-migraine therapy (aspirin 900mg stat + metoclopramide 10mg stat orally) on a number of
occasions without benet. On specic questioning she has sleep disturbance and irritability and is concerned about
something sinister underlying the headaches. Neurological examination (including good visualization of the optic
discs) is normal apart from muscle tenderness in the scalp and over the occiput. Her blood pressure is 145/85 mmHg.
The most appropriate initial management recommendation is:
A Urgent brain magnetic resonance imaging (MRI) and a 3-day trial of regular indomethacin
B Addition of a tryptan for exacerbations of her headache and physical therapies for neck and scalp discomfort
C Commencement of amitriptyline 25mg nocte and non-urgent brain computed tomography
D Commencement of a selective serotonin reuptake inhibitor and non-urgent brain MRI
E Trials of bilateral greater occipital nerve local anesthetic/corticosteroid injection
11 A 24-year-old woman with a strong family history of migraine with aura presents with intermittent hemicranial
throbbing headache associated with the development of tender swelling over the temple on the side of the headache.
The swelling will last up to 1 hour and settles spontaneously. She admits to being very concerned about the possibility
of a brain tumor. Neurological examination between events is normal. The most likely initial clinical diagnosis is:
A Anxiety and a non-organic neurological disturbance
B Somatoform disorder
C Migraine with aura
D Migranous hygroma
E Temporo-mandibular joint dysfunction
12 A 64-year-old male is found collapsed in the toilet by his wife at 0330 hours. The wife recalls that he woke her up as
he got out of bed to go to the toilet and that she heard him collapse a few moments later. When she attended, he was
unable to speak and appeared weak down his right side. He arrives in the emergency department at 0415 hours, and
shows clinical features of a major left hemisphere stroke but vital signs are stable. The most important initial aspect of
your clinical assessment is:
647
A
B
C
D
E
Performing a standardized stroke assessment stroke tool to assign a stroke severity score
Determining the patients pre-morbid functional status
Performing a Glasgow Coma Scale
Performing a checklist for thrombolysis eligibility
Interviewing the wife to clarify the time of onset
13 A 77-year-old male presents with transient sudden loss of speech and right hand weakness. Symptoms are fully
recovered over 45 minutes, and by the time he arrives in hospital and is seen in the emergency department, he
is neurologically back to normal. He is a reformed smoker with a past history of coronary artery bypass grafting
5 years previously for triple-vessel disease. His medication includes aspirin 100 mg daily and atorvastatin 40 mg
daily. His electrocardiograph (EKG) on arrival captures a brief period of atrial brillation. The most appropriate initial
management plan for this patient is:
A Add clopidogrel to aspirin after an urgent non-contrast computed tomography (CT) scan is performed, and
organize an outpatient Holter monitor and follow-up.
B Arrange magnetic resonance imaging (MRI) scan of the brain and MRI angiography of the extracranial and
intracranial vessels for the next day, but make no change in therapy until the results of the scan are known.
C Admit to hospital for EKG telemetry and further investigation of the mechanism of the transient ischemic attack.
D Urgent non-contrast CT scan, and if no hemorrhage commence anticoagulation with low-molecular-weight
heparin and arrange outpatient carotid duplex scan.
E Urgent non-contrast CT scan plus CT angiogram of the extracranial and intracranial vessels. If no evidence of
intracranial hemorrhage, commence one of the novel oral anticoagulants.
14 A 37-year-old male is found collapsed after being last seen well 6 hours previously. Clinical examination reveals a
right hemisphere stroke syndrome. Non-contrast computed tomography (CT) scanning of the brain shows extensive
early ischemic change throughout the right hemisphere. CT angiography shows a distal right internal carotid artery
occlusion. The most appropriate initial management of this patient is:
A Supportive care in an acute stroke unit
B Stroke-unit care and a repeat CT or magnetic resonance imaging in 12 hours time if the patient remains clinically stable
C CT perfusion imaging and consideration for endovascular therapy
D Admission to intensive care for induced hypothermia for neuroprotection
E Intravenous thrombolysis with alteplase 0.9mg/kg
ANSWERS
1 E.
The hallucinations of people, often familiar and typically silent, are a hallmark feature of dementia with Lewy bodies (DLB).
Patients, however, are often embarrassed about these and do not describe them unless they are specically asked about
it. It is helpful to know this before treatment, as trials of dopaminergic therapy often worsen hallucinations. Minimal tremor
may be present in DLB, but it may also be seen in idiopathic Parkinsons disease (iPD) and other disorders with parkinsonism.
Postural hypotension is the hallmark of multisystem atrophy (MSA) when present early, usually with other signs of autonomic
failure (erectile dysfunction, bowel and bladder symptoms). REM sleep behavior disorder is often seen in iPD prior to the
diagnosis. Early memory loss and frequent falls strongly raise the possibility of progressive supranuclear palsy.
2 C.
The man has presented with a history typical of juvenile myoclonic epilepsy (JME). This diagnosis is signicant, as it usually
requires lifelong therapy. It is part of the group termed idiopathic generalized epilepsies (IGEs) and sodium valproate is
regarded as rst-line therapy. More importantly, carbamazepine may worsen control.
3 D.
The patient has presented with an acute vestibular syndrome, and the rst consideration in the emergency room is to
differentiate a peripheral and a central pathology. Clinical assessment has been proven to be more sensitive than acute
magnetic resonance imaging for this differentiation. It relies upon three elements:
a head impulse testing (abnormal in peripheral disease)
b nystagmus descriptionunidirectional horizontal torsional element in peripheral disease; may change direction in
central pathology
c assessment for skew deviation (present in central disease).
In this case, the patient presents with some signs consistent with a peripheral process (head impulse test, pattern of
nystagmus), but also a skew deviation, which cannot be ignored. This is often seen in AICA infarcts, as the labyrinthine
artery (a terminal branch) may be involved, causing infarction of the vestibular organ and cochlear on that side, with other
central signs (skew).
4 D.
LennoxGastaut syndrome (LGS) is a common cause of medically refractory epilepsy in the community. Even with best
medical management, breakthrough seizures are common, sometimes resulting in status epilepticus. This clinical scenario
is remarkably common for the neurologist, and demonstrates the importance of using a benzodiazepine with appropriate
pharmacokinetics to terminate status epilepticus in a patient such as this. Intravenous clonazepam or a continuous
648
midazolam infusion would be more appropriate strategies. While answer A is correct, it is not the cause for the diazepam
failing to work. Behavioral episodes are common in patients with LGS, but should be easily contrasted to status epilepticus.
Phenytoin may be necessary, but should not be given without appropriate consideration in patients with a long history of
medically refractory epilepsy. Finally, breakthrough seizures are common in patients such as this and, while worthwhile
considering, a new pathology causing status epilepticus is uncommon.
5 A.
The patients disturbance is typical of punding, in which patients develop a compulsive fascination with and performance
of a particular task. It is an impulse-control disorder (ICD) and is most commonly seen with dopamine agonists, often at
higher dose. Punding warrants reduction in the dose of dopamine agonist, despite patient requests to increase the dose.
The disorder does not sound consistent with restless legs syndrome, nor should it warrant regular therapy with a nocturnal
sedative. Amantadine is helpful for dyskinesias, but will not treat the presenting complaint.
6 B.
While the patient has a history and presentation which satises the criteria for multiple sclerosis (MS), neuromyelitis optic
(NMO) requires consideration due to an optico-spinal presentation and increasing severity of attacks over a short duration
of time. More importantly, in NMO the treatment required is different and beta-interferon is thought to worsen attacks in
NMO. NMO differs from MS in that the number of attacks a patient has is proportional to the disability, so further diagnostic
assessment is required. NMO-antibodies should be assessed in cerebrospinal uid (CSF) and/or serum; CSF oligoclonal
bands would be positive in MS but negative in NMO. Repeat imaging of the spine is important, with long segment lesions
in the spine another strong indicator of NMO. Cerebral lesions are seen in about 50% of cases of NMO, although usually in
a pattern atypical for MS.
While draining the bladder and assessing for urinary tract infection is critical, answer C is incorrect as a pseudoexacerbation
due to infection should not be proportionally much worse than an initial presentation. Neutralizing antibodies may form
to beta-interferon, causing treatment failure, but this time window would be extremely unusual and unlikely to explain the
presentation. Fingolimod should not be commenced without a little more consideration, as NMO would require different
treatment.
7 B.
This presentation is not consistent with myasthenia gravis, which usually presents with ocular, bulbar or cervical symptoms
and does not have sensory symptoms on clinical examination. The history does suggest an episode of GuillainBarr
syndrome, and in a patient with risk factors for seroconversion illness for HIV (the patient may have also had contact with
sex-workers in Thailand), HIV must be considered. Options D and E may not explain his signs individually, but in a patient
with previous neurotoxic chemotherapy, long-term areexia due to neuropathy may be present, while his acute symptoms
could represent acute cauda equina disease.
8 D.
A newly recognized pathology, anti-HMG-CoA antibody testing may help conrm this diagnosis. Long-term
immunosuppression is required, and withdrawal of this may cause disease relapses many years down the track. A typical
(toxic) statin myopathy would be expected to settle within 2 months from cessation of treatment. Metabolic myopathy
should not cause creatine kinase (CK) up to 4000 U/L. Inclusion-body myositis would not typically be associated with
such a high CK, nor acute onset. It commonly affects older individuals. Allopurinol does not cause myopathy, though
colchicine, another agent used for gout, can cause a severe myopathy.
9 B.
Meningo-encephalitis is the most likely underlying diagnosis, and urgent airway support plus management for possible
non-convulsive seizures is the best initial option.
10 C.
This is a classic clinical scenario of mixed headache syndrome associated with depression of moodtricyclics are the
treatment of choice.
11 D.
This is a rare diagnosis but important to recognize.
12 E.
Dening the time of onset of the acute stroke is the most important initial issue and this will require direct communication
with the witness.
13 E.
There is a possibility here of both a cardioembolic and a large-artery embolic mechanism, so there is a need to examine
the large vessels but also cover for the atrial brillation. NOACs (new oral anticoagulants) are now the best option in terms
of efficiency and effectiveness.
14 B.
This patient may be suitable for decompressive hemicraniectomy, and repeat imaging can assist in determining the degree
of brain swelling and the timing of this intervention.
649
CHAPTER 20
PSYCHIATRY FOR THE INTERNIST

Brian Kelly
CHAPTER OUTLINE
EATING DISORDERS
DEPRESSION
SUICIDE AND DELIBERATE SELF-HARM
ANXIETY DISORDERS
PSYCHOTROPIC AGENTS
POST-TRAUMATIC STRESS DISORDER

(PTSD)
SOMATIZATION
Depression, anxiety and substance-use disorders are the
most common psychiatric conditions in the community.
Rates of these disorders are significantly elevated among
patients with physical illness, e.g. stroke, diabetes mellitus, cancer, chronic renal or respiratory disease, epilepsy,
or disorders associated with chronic pain. The relationship
between psychiatric disorder and physical illness operates
in a number of directions. Psychiatric disorder such as
depression may increase the risk of developing a serious
physical illness, and physical illness may be a trigger to the
development of a depressive or anxiety disorder. These
psychiatric conditions also commonly coexist, hence
patients with one disorder (e.g. depression) will often have
CLINICAL PEARL
Even though a patients symptoms of depression or
anxiety may seem like an understandable response
to life stress, especially when coping with signicant
physical illness, their distress and psychological symptoms may be indicative of a signicant psychiatric disorder such as major depression or an anxiety disorder,
requiring further assessment and specic treatment.
Lithium carbonate
Anticonvulsants
Antidepressants
symptoms of another condition such as anxiety or, in some

cases, problematic substance use (e.g. alcohol misuse).
It is important to recognize and treat these disorders
early. They contribute to significant suffering and increases
in levels of disability. Having a coexisting psychiatric illness
increases the functional impairment associated with physical
illness, and can have an adverse effect on the outcomes of the
physical illness.
DEPRESSION
The core features of depression reflect persistent disturbance
in mood that interferes with a persons functioning in areas
such as relationships, work and family or social roles. They
include:
low mood
loss of interest
loss of capacity for pleasure/enjoyment.
These are typically accompanied by indecision, irritability,
feelings of guilt and hopelessness, and/or suicidal ideation.
Low self-worth is a key feature that often discriminates
651
major depression from other states associated with low

mood (e.g. bereavement).
Depression usually causes a range of physical symptoms alongside these psychological features. These physical
symptoms are often the key presenting complaints for many
patients. The most common presenting symptoms are:
fatigue and malaise
poor sleep (particularly early morning wakening)
weight changes
loss of sexual drive or problems with sexual function
complaints of physical pain (e.g. muscle aches or pains,
or headaches).
It is always important to remember to ask about depressive
symptoms, as depression is a common but frequently missed
treatable condition. Many patients are initially hesitant to
discuss their emotional concerns, and can be more comfortable discussing physical symptoms. This requires the clinician to confidently and sensitively ask about the patients
feelings and emotions.
Patients may not use the term depression themselves
to describe their problem. Asking them to explain what
they have been experiencing in their own words is useful.
Simple questions such as How have you been feeling
in general lately? or How would you describe your
mood? can be useful ways to begin the discussion.
It should also be noted that the physical symptoms of
depression are less sensitive in detecting depressive disorder, especially in people with established physical illness.
In making a diagnosis of major depression, a focus on the core
mood symptoms outlined above is necessary, alongside
attention to the key clinical signs of these mood disorders
(e.g. patient being withdrawn, avoiding eye contact, appearing sad, tearful or disinterested, or restless and agitated).
As is the case with other psychiatric syndromes, depression may occur as a direct physiological effect of an underlying
physical illness. The potential organic causes of depression
are extensive, but include:
malignancy (e.g. lung, pancreatic and other gastrointestinal malignancies, and central nervous system tumors)
infection (especially chronic infection e.g. with human
immunodeficiency virus, EpsteinBarr virus)
substance misuse, including intoxication and withdrawal (e.g. alcohol, amphetamines)
prescribed drugs (e.g. antihypertensives, corticosteroids)
hematological conditions (e.g. anemia)
neurological conditions (such as Parkinsons disease,
multiple sclerosis, dementia especially subcortical
dementias)
endocrine disorders (e.g. Cushings disease, Addisons
disease, hypothyroidism).
CLINICAL PEARL
Depression, especially in the elderly, may mimic a
dementia-like clinical deterioration (so-called depressive pseudodementia), which improves with treatment
of the underlying depressive disorder.
652
ANXIETY DISORDERS
Anxiety disorders in general are characterized by marked
apprehension, dread and fear, with associated autonomic
arousal that may present as persistent generalized anxiety
(generalized anxiety disorder) or manifest in frequent panic
attacks (panic disorder; repeated discrete episodes of severe
anxiety), sometimes accompanied by problematic avoidance
of panic-triggering situations (e.g. avoidance of leaving the
home in agoraphobia, or being among unfamiliar people as in
social phobia).
While anxiety is a normal reaction in frightening situations, anxiety disorders differ in the persistence of the anxiety over time, and the impact on a persons functioning
(e.g. interfering with work, social or family life). Like
depression, these conditions often present with somatic
or physical symptoms. In the case of anxiety disorders the
physical symptoms often reflect autonomic arousal. These can
include complaints of epigastric discomfort and other gastrointestinal (GI) complaints; dizziness, dyspnea, paresthesiae and tachycardia or hyperventilation in a panic attack; or
muscle tension and aches.
People suffering panic disorder will often experience a
fear of having an acute severe physical condition (such as a
heart attack) or even of dying in an episode, compounded
by the symptoms of dyspnea, dizziness or even chest tightness that can occur in an acute panic attack, and hence tend
to present to emergency departments requiring evaluation.
It is important to remember to assess anxiety symptoms at
the same time as evaluating the physical complaints. Simple
reassurance can be helpful but is insufficient alone. Treatment will require specific psychological and pharmacological treatment of the panic disorder once a full assessment
has been undertaken. This includes cognitivebehavioral
anxiety management strategies.
CLINICAL PEARL
The differential diagnosis of panic disorder or severe
anxiety symptoms includes the following medical conditions you should remember:
serotonin toxicity
pheochromocytoma
hyperthyroidism
hypoglycemia
sedative or alcohol withdrawal
cardiac arrhythmia.
Excessive caffeine consumption can also be a contributing factor for some patients.
POST-TRAUMATIC STRESS
DISORDER (PTSD)
Post-traumatic stress disorder refers to persistent distress
following major events. The sorts of situations that typically trigger post-traumatic stress symptoms are those outside the range of usual experience and often entail threat
to life, or confrontation with the death or injury of others
(e.g. accidents, injuries, assaults, or even the diagnosis of a
Chapter 20 Psychiatry for the internist
life-threatening physical illness), or exposure to major disaster events (e.g. cyclones, bushfires) where there is loss of life
and/or property.
The symptoms of PTSD are typically intrusive (e.g.
unwanted distressing images or memories, as if reliving
aspects of the event) or feelings of being emotionally numb,
disconnected, or avoiding reminders of the event or similar
situations or places. PTSD is often associated with symptoms of both anxiety and depression and, especially when
chronic, may be complicated by substance misuse, often as a
response to unrelieved distress.
SOMATIZATION
Somatization refers to the expression of a persons emotional
distress in the form of physical or so-called somatic symptoms (hence the term somatization to describe this pattern
of presentation of psychological distress, and the term somatoform disorders for a set of conditions in which medically
unexplained physical symptoms are the chief complaints).
Abnormal illness behavior is another term sometimes used
to describe maladaptive ways of perceiving and responding
to ones health status.
Somatization may be brief and transient in situations of
high stress and resolve as the underlying psychological
distress is addressed.
In other situations it may manifest as severe and persistent medically unexplained symptoms in one or more
body systems (e.g. persistent unexplained neurological
symptoms such as pain, sensory disturbance or loss of
function).
There may be a pattern of persistent and excessive attention to bodily complaints with a heightened fear of disease, conviction of the presence of disease, failure to be
reassured to the contrary, and repeated presentations for
help (also referred to as hypochondriasis).
In conversion disorder there is usually a loss of function
(e.g. movement of a limb, or loss of sensation mimicking
a neurological condition), often triggered by psychological stress and usually with a prior history of similar
symptoms.
Somatization can also be secondary to other psychiatric
conditions (such as depressive disorders), and can occur
in patients with schizophrenia (e.g. with bizarre somatic
delusions and/or somatic hallucinations).
CLINICAL PEARL
Remember that somatoform disorder is not a diagnosis based solely on the exclusion of physical illnesses.
It also requires positive supporting evidence of concurrent psychological or social triggers, and usually a prior
history of presentation with medically unexplained
symptoms. It tends to have its onset in the adolescent
and young adult years, and there should be great caution making the diagnosis for the rst time in an elderly
person.
Longitudinal studies have indicated a high rate of undiagnosed medical conditions in patients diagnosed with
this group of disorders. Adequate investigation of potential organic causes is important, but should be undertaken
alongside early assessment of a potential psychological contribution to the patients symptoms and behavior. Somatoform disorders can also occur in people with existing
physical illness, and contribute to otherwise unexplained
exacerbations of their symptoms. An example is the patient
with established epilepsy who presents with pseudoseizures
at a time of family conflict.
In some cases the physical symptoms may directly reflect
the somatic symptoms of anxiety or depression. For
example, a person with persistent anxiety may focus on
persistent GI disturbance (epigastric discomfort, diarrhea) or cardiorespiratory symptoms of a panic attack.
A patient with depression may present with persistent
fatigue and malaise, or persistent weight loss.
A comprehensive history and examination addressing
both psychological and physical symptoms and signs,
and judicious investigation of potential organic causes
of symptoms, is usually necessary. Early recognition of
such somatic presentations of distress is beneficial.
By virtue of their persistence and repeated presentation to
physicians despite reassurance and investigation, these conditions are very susceptible to sometimes frustrated or judgmental responses from clinicians, over-investigation or
over-treatment, and iatrogenic illness. Patients may find it
difficult to consider the psychological component of their
problems, and be sensitive to feeling that they are not being
believed or taken seriously by their physician. Hence it is
not uncommon for conflict to emerge between patients and
physicians or between clinicians involved in the patients care.
It is important to remember that these conditions represent significant and potentially treatable clinical disorders. Treatment requires a clear understanding of the
problem and its causes (by all involved), early psychiatric
consultation, a nonjudgmental attitude to patients, and
efforts to draw the patients attention to the psychological factors that may be contributing to their distress.
Explaining the interaction and link between emotional
states and physical health can sometimes do this.
A key clinical point to note is that it is important to
assess and treat any depressive and anxiety disorders that
can give rise to somatization (secondary somatization).
In rare instances, patients with psychosis may develop delusions concerning physical symptoms (e.g. that they have
cancer and are dying, such as in depression with psychosis);
psychiatric inpatient treatment is usually required in these
cases.
EATING DISORDERS
Eating disorders include anorexia and bulimia nervosa,
binge-eating disorder and clinical presentations with subsyndromal or mixed features of both conditions.
Anorexia and bulimia nervosa occur much more commonly in women than in men. They tend to present to
653
physicians with symptoms relating to abnormal dietary

patterns, including the consequences of efforts to reduce
weight (e.g. self-induced vomiting, laxative or diuretic
abuse) or, in the case of anorexia, the metabolic and
endocrine consequences of dietary restriction.
Binge-eating disorder is more likely to present in the
context of weight disorder.

Anorexia nervosa is characterized by:
significant weight loss (<85% of normal weight for age
and height)
altered body image with relentless pursuit of thinness
refusal to maintain normal bodyweight
extreme fear of gaining weight, with marked caloric
restriction
weight-controlling behaviors such as excessive exercise,
laxative abuse or purging.
Anorexia nervosa carries a high mortality rate, chiefly due
to the chronic metabolic effects of starvation. The condition
also carries a markedly elevated risk of suicide.
In bulimia nervosa, weight may be within normal or
overweight range and is characterized by:
regular episodes of uncontrolled eating of large amounts
of food
weight-control mechanisms (including self-induced
vomiting, diuretic and/or laxative abuse)
often-excessive guilt and remorse about binge-eating.
In both instances there is a preoccupation with weight and
shape, food and diet.
Complications
The chief physical complications of an eating disorder
include:
metabolic disturbances (e.g. hypokalemia), due to
repeated vomiting or laxative and/or diuretic abuse (this
may also occur in bulimia nervosa)
endocrine complicationshyopogonadism with amenorrhea and loss of secondary sexual characteristics, osteoporosis with an increased risk of fractures
fatigue and weakness
bradycardia and hypothermia
hair loss and lanugo body hair
dependent edema
dehydration
cognitive changes and potentially reversible cerebral
atrophic changes
eroded dental enamel as a consequence of repeated
vomiting (also occurs in bulimia nervosa).
Diagnosis and management

The differential diagnosis for anorexia nervosa should
include any condition that could lead to severe weight
loss and the metabolic changes outlined above. This
654
includes primary endocrine and metabolic disorders

(e.g. Addisons disease, hypopituitarism), chronic infection leading to weight loss, or primary central nervous
system (CNS) disorders.
Differential diagnosis of bulimia includes disorders such
as gastric outlet obstruction, and neurological disorders
(such as CNS tumors), especially conditions associated with hyperphagia; including rare disorders such as
KluverBucy syndrome.
Common presenting symptoms of an eating disorder
include amenorrhea or unexplained weight loss and fatigue,
or unexplained metabolic disturbance (e.g. hypokalemia).
Overall, effective treatment generally entails close links
between psychiatric and medical management.
Behavioural management of disordered eating patterns,
and individual psychotherapy (often with family intervention and education), are the mainstay of psychiatric
management. Antidepressant medication has been beneficial in the treatment of bulimia.
Medical management of starvation and re-feeding needs
to address potentially life-threatening metabolic disturbance (e.g. hypophosphatemia), necessitating electrolyte and vitamin supplementation.
Patients with eating disorders often have concurrent
major depressive disorder, and symptoms of disordered
eating (e.g. binge-eating and purging) can be exacerbated by a depressive disorder. Treatment of the depression will then improve the abnormal eating behavior.
SUICIDE AND DELIBERATE

SELF-HARM
Suicide and attempted suicide (i.e. deliberate harm with
the intention of suicide) are usually associated with an
underlying psychiatric disorder.
Deliberate self-harm (DSH, also called parasuicidal
behavior) is a term used to refer to self-injury which
may be motivated by frustration or distress but not necessarily an intention to die (e.g. cutting).
It can often be difficult to differentiate these in the acute
presentation.
The behaviors in DSH can be very dangerous and
life-threatening, and in general it is best to assume that
the behavior is with suicidal intent until assessment
indicates otherwise.
It can be difficult to interpret suicidal intent from the
behaviors alone (what seems like a trivial overdose may
have been undertaken with serious intent to die by the
patient who has limited knowledge of drug effects).
In general, though, actions that are more violent and
potentially irreversible (such as shooting, hanging,
jumping from buildings) or those where careful planning is evident (e.g. carbon monoxide poisoning) indicate a stronger intention to die.
It is also important to ask about children who may be in the
care of the patient, and consider any child protection issues.
Assessment of suicide risk involves careful review of

the following:
Presence of suicidal thoughtsEver thought you did
not want to go on with your life? or Ever considered
taking your own life?
Degree of suicidal intentWhat have you considered
doing? or What did you think would happen as a result
of ?
Presence of suicidal plansDid you ever find yourself
taking steps to end your life or thinking through what
you would do to end your life?
Assessment of hopelessness. Hopelessness is an important indicator of future suicide risk, so it is important to
ask about future life plans and expectations (e.g. hope
that current problems can be improved, or hope for resolution of current difficulties, or specific positive future
plans).
The presence of alcohol or substance abuse. This can
significantly increase the risk of suicide.
Connection to others can be protective (e.g. children
or others dependent on the person). Conversely, social
isolation increases the risk of suicide.
Severity of depression or other psychiatric symptoms. In
some cases, severely depressed people may believe that
their suicide will relieve others of the burden of the persons problems (they would be better off); hence, asking about how others might be affected by the persons
self-harm or suicidal behavior is important.
A prior history of suicide attempt or deliberate selfharm, or a family history of suicide/attempted suicide,
are associated with elevated risk of suicide.
Factors that are associated with an increased risk of suicide
include:
the presence of current psychiatric disorder (commonly
depression, anxiety and substance-use disorder, especially alcohol abuse)
psychotic illness (e.g. schizophrenia or current depression with psychosis)
the presence of a chronic physical illness
social isolation or lack of social support
recent loss or interpersonal conflict (including separation or threatened separation)
recent stress, such as financial strain.
CLINICAL PEARL
Remember: the best clinical approach to suicide prevention is to ask patients about suicidal thoughts or
behaviors, respond with appropriate clinical steps to
ensure safety, and assess for and instigate appropriate
management of the psychiatric disorders that usually
accompany these conditions.
It is important to ask about alcohol use. Alcohol intoxication

is often associated with suicidal behaviors. Alcohol use
canlower mood, and intoxication impairs judgment and can
increase the likelihood of a person acting on suicidal feelings. It is important to address problematic alcohol use in
the management plan.
In general, people who are suicidal require urgent psychiatric assessment and treatment, usually in an inpatient facility
to ensure safety and supervision until improvement occurs.
PSYCHOTROPIC AGENTS
The following section details specific medical considerations
in the use of commonly prescribed psychotropic agents.
Lithium carbonate
Lithium carbonate is used in the treatment of bipolar disorder and, in some instances, for recurrent depressive disorder.
There are a number of key issues in the care of the patient
receiving lithium.
Lithium is closely monitored using serum levels, with a
recommended therapeutic range of 0.60.8 mmol/L for
maintenance treatment and 0.81.2 mmol/L for acute
treatment (e.g. of a manic episode).
Symptoms of lithium toxicity include polyuria, polydipsia, tremor, dysarthria, poor concentration and, as
levels increase, sometimes delirium. Lithium toxicity
is potentially fatal, and may require saline diuresis and
dialysis to reduce serum levels.
Lithium is excreted via the kidney. Any reduction in
renal function (e.g. coexisting renal disease, advancing age) can increase the risk of lithium toxicity. This
includes dehydration or fluid restriction. Drugs such
as non-steroidal anti-inflammatory drugs (NSAIDs),
angiotensin-converting enzyme inhibitors (ACEIs),
angiotensin II receptor antagonists (ATRAs) or thiazide
diuretics can also cause lithium toxicity through reducing renal excretion.
Long-term complications of lithium therapy include
hypothyroidism, nephrogenic diabetes insipidus and
progressive decline in glomerular filtration rate.
Lithium therapy requires monitoring of lithium levels,
thyroid function and renal function. After achieving a
stable serum level of lithium, lithium levels should be
checked every 36 months, along with serum creatinine
and electrolytes. Thyroid function (including thyroidstimulating hormone, TSH) should be checked regularly also (every 612 months).
Lithium is contraindicated in the 1st trimester of pregnancy due to its association with cardiac abnormalities
such as Ebsteins anomaly. Any woman who has been
exposed to lithium during pregnancy should have a
high-resolution fetal echocardiogram around 1820
weeks of gestation.
Anticonvulsants
Anticonvulsant medication such as sodium valproate, carbamazepine and lamotrigine have an established role as mood
stabilizers in people suffering recurrent major depression or
bipolar disorder, including acute mania.
655
Common side-effects include weight gain, GI symptoms, sedation, tremor and mild elevation in hepatic
enzymes.
Recommended monitoring varies between agents, but
includes regular assessment of weight, full blood count,
liver function, glucose and lipid profiles, and serum
drug levels to establish therapeutic dosage (noting that
this differs in range from levels recommended for epilepsy management).
These agents carry a risk of teratogenicity, particularly
neural tube defects.
This class of drugs is generally used in the treatment of acute
and chronic psychotic disorders (e.g. schizophrenia, bipolar
affective disorders). Their therapeutic effect is chiefly mediated by dopamine receptor (D2) blockade in the CNS. They
are often sub-classified as:
typical antipsychotics (e.g. chlorpromazine, haloperidol), which have stronger affinity for the D2 receptor,
including those receptors in the basal ganglia, hence
conferring greater potential for extrapyramidal side
effects
atypical or 2nd-generation antipsychotics, with less
affinity for the extrapyramidal D2 receptor (e.g. clozapine, olanzapine, risperidone).
Most antipsychotic drugs are absorbed rapidly from the gut
and are highly lipid-soluble, and there is high interpatient
variability in the pharmacokinetics of and responses to these
drugs.
Neurological side-effects of these agents include the
following.
Sedation
Extrapyramidal disorders:
Acute dystonias (including potentially fatal laryngeal dystonia)these require urgent treatment with
rapid-acting antiparkinsonian agents (e.g. intramuscular benztropine).
Drug-induced parkinsonismif cessation of antipsychotic is not possible, the condition is treated
with concurrent use of antiparkinsonian drugs.
Longer-term, potentially irreversible tardive dyskinesia (TD). Treatment includes reduction in the
dose of antipsychotic agents if possible, or the use
of an alternative antipsychotic agent if necessary
(such as clozapine) with less potential to induce
TD. Gamma-aminobutyric acid (GABA) agonists
(e.g. baclofen, sodium valproate) have been trialed
in treatment of TD, and tetrabenazine has been
approved for use in TD.
Akathisiacharacterized by persistent motor restlessness, this can occur at low dose and is highly distressing. Akathisia needs to be differentiated from agitation
due to psychosis or mood disturbance, as the latter
may necessitate increased dose whereas akathisia is
treated with cessation of the antipsychotic agent if
possible. Beta-blockers and benzodiazepines have
been used to treat akathisia.
656
Neuroleptic malignant syndromethis can occur at

any time during treatment with antipsychotic agents,
reflecting dopamine receptor antagonism. This potentially fatal condition is characterized by hyperthermia,
diaphoresis, hypertonia and bradyreflexia, delirium and
autonomic dysfunction (tachycardia, tachypnea and
hypertension). The syndrome is most consistently associated with an elevated creatine kinase and leukocytosis. Risk factors include intercurrent dehydration and
recent dose increase. The key differential diagnoses are
(see Table 20-1):
malignant hyperthermia
serotonin toxicity
systemic infection and other causes of elevated body
temperature.
Metabolic and endocrinological effects include the
following:
Weight gain, hyperglycemia and dyslipidemia can occur.
Patients receiving antipsychotic medication are at
increased risk of developing metabolic syndrome. Monitoring of weight and the development of insulin resistance and dyslipidemia are important aspects of clinical
management.
Hyperprolactinemia can occur due to dopamine blockade, and lead to galactorrhea and amenorrhea.
Sexual side-effects include reduced libido, impaired
sexual arousal, erectile dysfunction and anorgasmia
(due to dopamine, acetylcholine and alpha-receptor
blockade).
Clozapine
Clozapine is an atypical antipsychotic agent with a specific
role in severe chronic schizophrenia unresponsive to other
treatments. Unlike other antipsychotic agents, clozapine
treatment is monitored using serum levels.
Important aspects of clozapine treatment include the
need to monitor white cell count for the development of
potentially fatal neutropenia and agranulocytosis, cardiac
ultrasound for potential clozapine-induced cardiomyopathy, and monitoring for the development of the metabolic syndrome. Common side-effects are sedation and
sialorrhea.
Antidepressants
(e.g. fluoxetine, sertraline, citalopram)
The adverse effects of this class of antidepressants reflect
central and peripheral manifestations of serotonin overactivity, e.g. diaphoresis, tremor, hyperthermia, myoclonus, ataxia, hyper-reflexia, diarrhea, agitation and delirium.
Sexual dysfunction is a common side-effect.
Serotonin toxicity is a serious complication of these
drugs, and is characterized by the acute development of
symptoms. This is commonly triggered by either deliberate SSRI overdosage or concomitant use of other drugs
with serotonergic activity (e.g. other antidepressant
agents such as tricyclic antidepressants or monoamine
oxidase inhibitors [MAOIs] with serotonergic activity,

analgesic agents such as tramadol, or fluconazole).
SSRIs have also been associated with the development
of inappropriate ADH (antidiuretic hormone) secretion, leading to clinically significant hyponatremia.
With prompt recognition and treatment, the prognosis
is generally good.
Treatment involves withdrawal of the SSRIs and other contributing or related drugs. In severe cases (with hyperthermia, delirium and autonomic instability), hospitalization
is necessary, with supportive care including hydration and
antipyretic agents. Benzodiazepines may be useful for tremor
and agitation, and cyproheptadine is usually recommended.
Serotoninnoradrenaline reuptake inhibitors

(SNRIs)
(e.g. venlafaxine, desvenlafaxine, mirtazapine, duloxetine)
In addition to the potential to cause symptoms of serotonin overactivity and serotonin toxicity (see above), other
side-effects of drugs in this class include sedation and weight
gain (mirtazapine). Venlafaxine is associated with hypertension at higher doses and with cardiac effects (e.g. QRS
widening).
See Table 20-1 for the differential diagnosis of serotonin

toxicity and other key conditions.
Tricyclic antidepressants (TCAs)

(e.g. amitriptyline, imipramine, doxepin, nortriptyline)
TCAs have significant side-effects including the
following.
Anticholinergic effectsthe basis of most significant
side-effects: urinary retention, constipation, precipitation
of narrow-angle glaucoma, and propensity to delirium.
Cardiac toxicity is characterized by increasing sinus tachycardia; increased duration of refractory period; delays in
atrioventricular (AV) conduction, including AV block,
with prolongation of QRS duration and QT intervals,
and T-wave changes; and potential for supraventricular
tachycardia and ventricular arrhythmias. These effects are
potentially life-threatening in overdose.
Postural hypotension may occur due to alpha-adrenergic
blockade.
Other common adverse effects include sedation, mild
intention tremor, and sexual dysfunction (e.g. erectile
dysfunction and anorgasmia).
Table 20-1 Differentiating serotonin toxicity from neuroleptic malignant and other syndromes
CONDITION
DRUG
PUPIL
SIZE
MUSCLE
TONE
TENDON
REFLEXES
ONSET
Serotonin toxicity
SSRIs
Mydriasis
pp
<12 h
Neuroleptic malignant
syndrome (NMS)
Dopamine
agonists
Normal
Lead-pipe
rigidity
Sluggish
13 days
Malignant hyperthermia
Anesthetic agents
Normal
Rigid
30 min24 h
Anticholinergic syndrome
TCAs or other
ACh-blocking
agents
Mydriasis
Normal
Normal
13 days
ACh, acetylcholine; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
657
1
An 18-year-old female university student has recently been admitted to hospital for investigation of unexplained
hypokalemia. She is an accomplished triathlete. She has been amenorrheic for 6 months and her body mass index is
13 kg/m2. Which of the following is the most likely to indicate the presence of an eating disorder in this patient?
A Excessive fear of gaining weight
B Excessive exercise
C Weight loss >15% of normal weight
D Unexplained vomiting
A 55-year-old man has been receiving sertraline 250mg/day for treatment of a major depressive disorder. He was
recently prescribed tramadol for acute musculoskeletal pain. He presents feeling generally unwell, with diarrhea,
excessive sweating, tremor and mild fever. He has difficulty concentrating and has an unsteady gait. Which of the
following would be the most consistent with the likely diagnosis?
A Tachycardia
B QTc prolongation
C Agitation
D Hyper-reexia
E Leg cramps
A 58-year-old man with a longstanding history of bipolar affective disorder presents distressed, complaining of feeling
generally unwell with unusual neurological symptoms including recent onset of intention tremor and unsteady gait.
He also complains of recent loose bowel motions. He has had no previous symptoms of this nature. On examination,
he is afebrile and has a marked intention tremor but normal muscle tone. His medications include lithium carbonate
750mg/day and olanzapine 5mg/day and he has recently commenced lisinopril 10mg/day, for hypertension. The
most likely diagnosis is:
A Lithium toxicity
B Somatoform disorder
C Neuroleptic malignant syndrome
D Drug-induced parkinsonism
E Hypochondriasis
ANSWERS
1
A.
The patients body mass index is indicative of her being underweight. Excessive fear of gaining weight despite weight loss
indicates disturbance of body image that is essential for the diagnosis of anorexia nervosa. Excessive exercise, weight
loss and vomiting may also occur in this condition, and help in making a diagnosis (but also require the fear of gaining
weight), but alone they are less indicative.
D.
This man has serotonin toxicity clinically. Tramadol, an opioid analgesic, is a serotonin-releasing drug. Hyper-reexia,
in the context of selective serotonin reuptake inhibitor (SSRI) use, is the most indicative of serotonin toxicity from this list
of options. Tachycardia and agitation may occur but are not specic to this syndrome. Prolongation of QTc interval occurs
with other psychotropic agents (e.g. antipsychotic agents or tricyclic antidepressants), but is not a typical feature
of this syndrome.
A.
The symptoms are typical of early lithium toxicity. The addition of lisinopril is likely to have increased his serum lithium
levels (by reducing the renal excretion of lithium) and to have precipitated toxicity at doses that were previously well
tolerated. While a somatoform disorder can present with neurological symptoms, this is most unlikely in a man of this
age in the absence of prior unexplained symptoms or any apparent precipitating events. Furthermore, such a premature
diagnosis of somatoform disorder would place this patient at serious risk of life-threatening undetected lithium toxicity.
Neuroleptic malignant syndrome is important to consider in any patient taking a dopamine antagonist (in this instance
olanzapine), but would usually be associated with elevated temperature and muscle rigidity. Drug-induced parkinsonism
would cause a typical resting tremor and increased muscle tone.
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CHAPTER 21
CLINICAL INFECTIOUS DISEASES

Iain Gosbell
CHAPTER OUTLINE
CLINICAL APPROACH TO INFECTIOUS
DISEASES
Overview
History
Examination
DIAGNOSTICS IN INFECTIOUS DISEASES

SELECTED COMMON CLINICALLY

IMPORTANT ORGANISMS
Selected bacteria
Selected viruses
Selected fungi
Selected parasites
ANTI-INFECTIVE TREATMENT
Choice of empirical and denitive antibiotics
What therapy other than antibiotics is required?
Ongoing assessment and further results
What is the duration and endpoint of treatment?
ANTI-INFECTIVE AGENTS
Antibiotics
Antiviral agents
Antifungals
SPECIFIC SYNDROMES
Acute fever
Drug fever
INFECTIONS IN SPECIAL HOSTS AND

POPULATIONS
Infections in immunosuppressed patients
SYSTEMIC VIRAL INFECTIONS
HIVsee Chapter 17
Hepatitis virusessee also Chapter 13
Herpesviruses
Zoonoses
INFECTION PREVENTION AND CONTROL
Education
MRO surveillance
Infection control measures
Decolonization
659
CLINICAL APPROACH TO
INFECTIOUS DISEASES
Overview
Despite vast improvements in public health, sanitation and
vaccination, and huge technological advances in medicine,
infectious diseases remain a major cause of morbidity and
mortality.
Many infectious diseases exhibit a characteristic pattern
of symptoms and signs, aiding diagnosis:
clinically obvious signs and symptoms, e.g. chickenpox
obvious system involvement without the pathogen
being clear, e.g. pneumonia
obvious infection present, but not localized, e.g. fever.
The extent of initial investigation, and provision of empirical treatment, depends on a number of factors:
the severity of the manifestations
the time course of progression of the illness
the vulnerability of the underlying host; an immunosuppressed host may display more subtle clinical signs of
infection
public health or infection control significance.
CLINICAL PEARL
The time course of most infectious diseases, and their
response to treatment, is well known. Deviation from
the expected time course should prompt a reappraisal
of the initial diagnosis and the treatment, and potentially the collection of further specimens. Monitoring
of acute phase reactants such as C-reactive protein or
pro-calcitonin may help inform the clinician regarding
response to treatment.
History
Key features in the history include the following.
Onset and time coursefor example, sudden onset of
fever and chills suggests bacterial infection.
Systemic symptomsfever, chills, sweats, malaise,
weight loss, fatigue, lethargy, anorexia.
Localizing symptoms may help pinpoint the site of
infection.
Medication history is pivotal, including previous antibiotics and other drugs.
Past medical historyimmunosuppression, vaccination.
Exposure history, including:
sexual
family
occupational
travel.
Recent surgery or injury.
Examination
Physical examination in infectious diseases aims to establish
the following.
Is the patient febrile? Is there tachycardia or relative
bradycardia? Is there tachypnea?
Is septicemia or shock present?
Is the illness systemic, or organ-based?
Are there any features highly suggestive of particular
infections?
The vital signs answer the first two questions; the rest of the
physical examination the other two.
Ophthalmic examination may reveal conjunctivitis with
some systemic infections. There may be hemorrhages
in infective endocarditis, and scleral jaundice may be
detectable in hepatic infections.
Central nervous system (CNS) examination involves
assessment of mental status. If headache is prominent,
evidence of meningitis (photophobia, neck stiffness, difficulty with straight leg raising) should be sought.
Cardiovascular examination includes inspecting for
peripheral stigmata of infective endocarditis and murmurs. Heart failure, pericardial rub and tamponade
should be sought.
Respiratory examination is important to identify lower
respiratory infections.
Abdominal examination specifically seeks evidence
of splenomegaly, hepatomegaly, tenderness, and peritonism.
Genitourinary examination is required if symptoms
relating to this system are present, or if there is any evidence in the history and examination of sexually transmitted diseases.
If the patient reports musculoskeletal symptoms, it is
important to ascertain whether there is muscle tenderness or induration, which could indicate pyomyositis or
underlying osteomyelitis. Similarly, evidence of arthritis should be sought.
ENT (ear, nose, throat) examination is particularly
important in children. The pharynx should be inspected,
cervical lymphadenopathy sought, sinus tenderness
examined for, and auroscopic examination performed.
All medical devices, especially intravenous and other
catheters, should be examined for evidence of local
inflammation.
It is important to examine areas of the body which are covered by bedclothes or medical apparatus such as casts. It is
not infrequent to discover suppurating wounds and bedsores
in this way, especially in an obtunded patient.
Important physical signs

Body temperature
Fever is characteristic of most infections but can be absent,
particularly in the old and the immunosuppressed.
660
Chapter 21 Clinical infectious diseases
Patients with hypothermia often are septic.

Sometimes the pattern of temperature over time can
suggest particular diagnoses.
If malaria remains untreated for some time, synchronization of parasite release from red cells can
cause fevers every 2 or 3 days; this is rarely seen in
practice.
Brucellosis characteristically causes an undulant
fever that waxes and wanes over a several-day cycle.
Hectic fevers with high peaks accompanied by chills
and rigors are characteristic of abscesses.
If the cause of the fever is unclear, examination for
goiter and evidence of thyrotoxicosis and features of
Graves disease is required.
Mostly, however, temperature patterns do not correlate with specific diagnoses.
Rash
The presence of rash can be diagnostic, e.g. chickenpox,
herpes zoster, meningococcal disease and measles, so the
time course, distribution and morphology need to be carefully noted.
Lymphadenopathy
Viral infections such as human immunodeficiency virus,
EpsteinBarr virus or cytomegalovirus can manifest with
widespread lymphadenopathy, and splenomegaly. Conversely, localized lymphadenopathy is seen with local suppurative conditions such as cellulitis.
DIAGNOSTICS IN INFECTIOUS
DISEASES
One of the pivotal choices in infectious diseases is knowing who to investigate, and then which investigations to
choose.
Infections that are minor and self-limiting or easily
treated, such as mild cellulitis, cystitis, gastroenteritis or
mild upper respiratory infections, do not require diagnostic tests.
However, if the result of the investigation makes a material difference to management, or the patient is seriously
ill, or the initial diagnosis of a minor condition appears
to be incorrect, or might affect anti-infective choice or
direct public health interventions, then such tests should
be ordered.
Diagnostic microbiology is still labor-intensive in terms of
setting up assays, interpretation and reporting of results. It
is very helpful if the laboratory has a clinical vignette, especially in special scenarios such as illness in a returned traveler
or immunosuppression.
Microscopy and culture

Microscopic techniques that are commonly used include
Gram stains, but also wet films (e.g. urine and cerebrospinal fluid examinations) and other microscopic techniques
such as immunofluorescence. Direct microscopy results are
quick but less reliable; culture is much more sensitive at the
expense of specificity, particularly for sites that are normally
not sterile.
Antigen detection
Antigen tests are useful for a small and diverse number of
pathogens, such as respiratory viruses, Clostridium difficile,
Giardia intestinalis, Cryptococcus spp. and hepatitis B.
Nucleic acid detection

Nucleic acid detection (the polymerase chain reaction
[PCR] and similar methods) is particularly useful for those
organisms that are hard to cultivate.
Nucleic acid detection is useful in diagnosing respiratory
viruses (such as influenza, human metapneumovirus,
respiratory syncytial virus [RSV]), sexually transmitted
agents (e.g. Neisseria gonorrhoeae, Chlamydia spp.), agents
causing meningitis (e.g. Neisseria meningitidis, Staphylococcus pneumoniae, enteroviruses, varicella zoster virus
[VZV]), and in the evaluation of immunosuppressed
patients (especially with herpes viruses).
For pathogens such as cytomegalovirus (CMV), human
immunodeficiency virus (HIV), hepatitis B virus (HBV)
and hepatitis C virus (HCV), quantitation (viral load)
can be performed, which can be informative to the state
of disease and the response to therapy.
Serology
Serological tests which measure the humoral response
to infectious agents are especially useful for difficult-tocultivate pathogens. Generally the immunoglobulin M
(IgM) response occurs in acute infection, followed by the
IgG response.
The preferred format and sensitivity and specificity of
serology tests vary pathogen by pathogen. Results in serological testing should generally be interpreted in the light of
other information.
Many considerations come into the interpretation of microbiology results. If a bacteriology specimen came from a site
that normally harbors commensal flora, growth of bacteria
might not reflect the organisms actually causing the infection. In general, specimens taken from normally sterile sites
such as blood, joint fluid, and cerebrospinal fluid are more
reliable.
661
SELECTED COMMON
CLINICALLY IMPORTANT
ORGANISMS
Selected bacteria
A working classification of commonly encountered pathogenic bacteria is shown in Table 21-1.
CLINICAL PEARL
Beware the following four bacteria that can cause rapid
overwhelming sepsis and death in normal hosts:
1
2
3
4
Neisseria meningitidis
Streptococcus pyogenes.
At any given time 20% of people are colonized with Staphylococcus aureus, yet it can also cause disease ranging from
minor skin and soft tissue infections to overwhelming sepsis
and death. It also causes many healthcare-associated infections such as intravenous catheter sepsis and surgical site
infections.
S. aureus has the propensity to acquire resistance genes
via horizontal gene transfer. Methicillin-resistant
S.aureus (MRSA) strains caused outbreaks in hospitals
in the 1970s and became established in hospitals in

many countries (notably, not northern Europe), with
strains being characteristically multi-drug-resistant and
only susceptible to a limited number of drugs.
Community MRSA strains emerged in Chicago intravenous (IV) drug users in the 1980s and in multiple
countries simultaneously in the 1990s. These strains
were genetically distinct, frequently caused skin and
soft tissue infections, particularly large boils, were more
frequent in indigenous peoples and those from lower
socioeconomic groups, and were usually susceptible to
most, if not all, non-beta-lactams.
With respect to invasive disease due to S. aureus, it is
important to define the extent of disease. In S. aureus
bacteremia, echocardiography should be performed to
seek endocarditis, and the patient questioned at intervals about bone and joint pain, and if this is present then
septic arthritis or osteomyelitis should be investigated
for. If a focus of infection is identified, then control of
the sepsis by drainage of pus and/or surgery will result
in a much prompter response. If no focus or metastatic
complication of bacteremia is identified, a minimum of
2 weeks of IV antibiotics is required; complicated bacteremia requires longer. Invasive disease can be due to
methicillin-resistant strains (Figure 21-1).
Streptococcus pneumoniae is a commensal of the human upper
and lower respiratory tract, but on occasion can cause invasive disease ranging from otitis media to pneumonia, bacteremia, septicemia and meningitis.
Table 21-1 Common pathogenic bacteria encountered in medicine
GRAM STAIN
RESULT
Gram-positive
cocci
GENUS/GENERA
SPECIES
Staphylococcus
Streptococcus
Beta-hemolytic streptococci, (including S. pyogenes, S. dysgalactiae)
Alpha- and non-hemolytic streptococci
Enterococcus
Enterococcus faecalis
Enterococcus faecium
Enterobacteriaceae
(coliforms)
Escherichia coli, Klebsiella spp., Proteus spp.

ESCAPPM or SPACE organisms
Respiratory tract GNRs
Haemophilus inuenzae, Moraxella catarrhalis
Pseudomonads
Pseudomonas aeruginosa
Gram-negative
cocci
Neisseria spp.
Neisseria meningitidis, Neisseria gonorrhoeae
Anaerobes
Multiple
Bacteroides fragilis, other Gram-negative and Gram-positive anaerobic

species
Gram-negative
bacilli
ESCAPPM, Enterobacter, Serratia, Citrobacter, Acinetobacter, Proteus (vulgaris), Providentia and Morganella spp.; GNRs, Gram-negative
rods; SPACE, Serratia, Proteus, Acinetobacter, Citrobacter and Enterobacter spp.
662
ribosomal protein translation, at least in vitro, decrease

exotoxin production and are recommended in severe
invasive disease.
S. pyogenes is normal flora in the throat, so its isolation is
not specific for pharyngitis. Isolation from wound culture is more suggestive. Blood cultures are usually negative, but are absolutely specific for invasive disease.
Patients with invasive or immune disease sometimes have
anti-streptolysin O and/or anti-DNase B antibodies.
Figure 21-1 Empyema due to community-acquired

methicillin-resistant Staphylococcus aureus
Pneumococcal infections are more common at the
extremes of life. Persons with asplenia and defective
humoral immunity are unable to clear opsonized bacteria, and are at substantial risk of overwhelming pneumococcal sepsis.
Vaccines utilizing capsular polysaccharides produce an
evanescent immune response; conjugation of the polysaccharide to a protein increases the intensity and duration of the humoral response. Technically, only a few
serotypes can be included in these conjugated vaccines.
Diagnosis of pneumococcal disease at times can be
difficult.
Isolation of bacteria in blood or CSF is diagnostic
but many cases have negative cultures, particularly
if antibiotics are being given prior to cultures.
The organism is part of normal respiratory flora, so
isolation of S. pneumoniae here is not diagnostic of
invasive disease.
PCR is quite sensitive in detecting pneumococci in
CSF, although is less sensitive in blood. Recent urinary antigen tests are more sensitive and specific for
invasive disease.
Streptococcus pyogenes
Streptococcus pyogenes is a commensal of the human nasopharynx and can cause a wide range of disease by direct invasion, such as pharyngitis, cellulitis and bacteremia, or by
immunological phenomena such as rheumatic fever, poststreptococcal glomerulonephritis and erythema nodosum.
The organism has never been reported to be resistant to
penicillin but is acquiring resistances to other drugs such
as macrolides and tetracyclines. This is significant clinically, as drugs such as clindamycin that interfere with
Neisseria meningitidis is a common commensal of the upper

respiratory tract that can cause invasive disease including
bacteremia and meningitis, and on occasion unusual manifestations such as peritonitis and septic arthritis. Septicemic
cases often have the typical petechial rash which can evolve
into purpura fulminans.
Infection is more common in young children and in situations with close crowding, such as in barracks, daycare centers, and aggregations of people. In Western
countries, serogroups B and C were typical until conjugated serogroup C vaccine was introduced.
People with terminal complement deficiencies are much
more likely to develop invasive meningococcal disease,
but paradoxically the mortality is markedly less.
Diagnostic tests include rapid tests such as Gram stain
of CSF or material from skin lesions; and PCR on CSF
and blood, which is the most sensitive test. Traditional
tests include culturing organism from blood and CSF.
Serology is useful in PCR and culture-negative patients.
N. meningitidis remains sensitive to penicillin, and mortality is less the earlier antibiotics are given. Supportive
care, including inotropes and organ support, is often
needed. Activated protein C should be administered if
purpura fulminans is imminent.
Alpha- and non-hemolytic streptococci

These are commensal flora in the upper respiratory tract
and GI tract. Their main clinical significance is as causes of
endocarditis (see Chapter 8).
Enterococcus species
The two main species causing human infections are
Enterococcus faecalis and E. faecium.
All enterococci are resistant to cephalosporins; penicillins are bacteriostatic, but are rendered bactericidal
with the addition of aminoglycosides such as gentamicin, which is necessary in endocarditis. Enterococci are
resistant to most non-beta-lactams, with the exception
of linezolid.
Vancomycin-resistant enterococci (VRE) have emerged
in recent years and are proving very difficult to control.
Most patients with VRE are only colonized, but these
patients are an important reservoir. Bacteremia with
VRE has about 40% mortality.
Control of VRE transmission has proven to be very difficult and involves a multifaceted approach to address
663
environmental reservoirs, impose strict infectioncontrol maneuvers, and robust antibiotic stewardship
policies.
Escherichia coli, Klebsiella species and Proteus

species
These species are normal flora of the GI tract and are
seen in community-onset infections relating to the GI
and urinary tracts.
Various types of E. coli can cause toxin-related disease, including gastroenteritis and hemolytic uremic
syndrome.
In general these species are more susceptible to antibiotics than other groups of Gram-negative organisms,
but significant resistance is increasing: 50% of E. coli in
Western countries is now resistant to amoxicillin/ampicillin, and increasingly resistances to quinolones and
other drugs including 3rd-generation cephalosporins
are being seen.
ESCAPPM or SPACE organisms

ESCAPPM = Enterobacter, Serratia, Citrobacter, Acinetobacter, Proteus (vulgaris), Providentia and Morganella spp.
SPACE = Serratia, Proteus, Acinetobacter, Citrobacter and
Enterobacter spp.
Infections caused by these organisms are typical of
Enterobacteriaceae, i.e. GI-tract-related infections, urinary tract infections, IV line infections, bacteremia and
septicemia, but are more frequently seen in patients
with hospital contact and are more resistant to antibiotics. They frequently (especially with Enterobacter species)
have constitutively repressed cephalosporinases selected
out by 3rd-generation cephalosporins.
Selected viruses
Human immunodeficiency virus, hepatitis B virus and hepatitis C virus are covered in other chapters of this book (HIV
in Chapter 17, and hepatitis in Chapter 13).
Herpes simplex virus 1 (HSV-1) and 2 (HSV-2)

Herpes simplex viruses are acquired by mucosal contact
from other people.
Characteristically there is a primary infection, which
can be severe, then a period when the virus lies dormant
in dorsal root ganglia from which it can reactivate to
cause recurrent infections.
HSV-1 usually causes oro-labial manifestations and
HSV-2 usually causes genital lesions.
There is often a warning tingling and numbness just
prior to the onset of the lesions, which are often very
painful. The characteristic lesions are small vesicles
on a red base. Occasionally, particularly with primary
episodes and with severe disease, dissemination and/or
neurological manifestations may occur.
Transmission from mother to baby can occur if a
woman has an active herpetic lesion in the genitals
during parturition. Neonatal HSV-2 is a severe, generalized infection with septicemia, hepatitis, thrombocytopenia, other organ dysfunctions, and widespread
mucocutaneous herpetic lesions. Pregnant women with
a history of genital herpes require careful genital examination (Figure21-2), and Cesarean section should be
performed if there are any lesions.
Treatment
Drugs such as acyclovir (aciclovir) are highly active
against HSV-1 and -2.
Pseudomonas aeruginosa is an environmental saprophyte which can colonize patients with leg ulcers,
abnormal lower respiratory tracts (chronic obstructive
pulmonary disease [COPD], bronchiectasis, and cystic fibrosis), and biliary abnormalities: obstructions,
stents, and following ERCP (endoscopic retrograde
cholangiopancreatography).
P. aeruginosa is intrinsically resistant to most antibiotics
but is covered by anti-pseudomonal penicillins (e.g. piperacillin), anti-pseudomonal cephalosporins (e.g. ceftazidime, cefepime), and aminoglycosides or quinolones, and
readily develops resistance to these agents.
Bacteroides fragilis and other anaerobic

Gram-negative and Gram-positive species
Anaerobic organisms are usually considered as a group
because the infections they cause are usually polymicrobial
infections related to mucosal surfaces, secondary to a mucosal breach, and often involve other organisms such as Enterobacteriaceae, streptococci and enterococci.
664
Figure 21-2 Primary genital herpes simplex virus

type2 infection of the vulva
From Mandell GL, Bennett JE and Dolin R. Mandell, Douglas, and
Bennetts Principles and practice of infectious diseases, 7th ed.
For minor infections in the normal host, antiviral treatment is most effective if given in the first 48 hours after
vesicle appearance.
Severe infections require IV acyclovir. Primary infection
and recurrences are more severe and slower to respond
to treatment if there is T-cell immune deficiency; in this
setting, secondary prevention is required.
Vaccines against HSV-1 and -2 are in development and are
likely to be clinically available soon.
CLINICAL PEARL
Herpes simplex encephalitis needs to be considered in
any patient presenting with encephalitis. Diagnosis is
with polymerase chain reaction of cerebrospinal uid;
serology is not helpful here. Characteristically, magnetic resonance imaging shows temporal lobe involvement. Treatment with intravenous acyclovir (aciclovir)
is safe and extremely effective.
Varicella zoster virus (VZV)

Varicella zoster virus causes chickenpox (primary infection)
and shingles (reactivation).
Chickenpox is highly contagious. It is manifested by a
systemic infection with a rash consisting of vesicles on
a red base, involving most of the body. Some patients
develop pneumonitis, particularly if the patient is adolescent or adult. Other complications include encephalitis and hepatitis. Chickenpox is more severe in the
immunosuppressed.
On resolution, the virus lies dormant in dorsal root ganglia and characteristically this can cause shingles, usually
after the 6th decade where herpetic lesions erupt in a
dermatomal distribution. This occurs most frequently
on the trunk, but sometimes in other areas like the divisions of the trigeminal nerve.
Shingles occurring in those younger than 50 years, or
more than once, should raise the suspicion of underlying immunosuppression.
Diagnosis of chickenpox and shingles is usually selfevident; appearances can be atypical in the immunosuppressed and testing is more useful here.
The best test is PCR on fluid and cells from the base
of vesicles.
Immunofluorescence is also quite sensitive.
Culture is usually negative and is not recommended.
Serology has a limited use in the diagnosis of chickenpox, but testing for IgG to VZV is useful to determine whether the patient is immune, e.g. a contact
of a case.
Therapy for primary and recurrent VZV is with antiviral
drugs such as acyclovir (aciclovir). These drugs are most
efficacious if started within 4872 hours of the onset of
lesions. They are still effective beyond that, particularly
in the immunosuppressed or in severe disease.
If there is a VZV exposure event, those who are
IgG-negative are regarded as susceptible.
Exposed nonimmune healthcare workers are

excluded from work from days 1421 in case they
develop chickenpox.
Varicella zoster immune globulin (VZIG) is given
to immunosuppressed, nonimmune contacts.
The incubation period can be prolonged if VZIG or
antivirals are given.
An efficacious vaccine is now available and is incorporated into immunization schedules. The vaccine
protects against shingles in those aged above 50 years.
EpsteinBarr virus (EBV)

EpsteinBarr virus is usually acquired during adolescence or young adult life by mucosal contact with other
people.
It characteristically manifests with pharyngitis and
widespread lymphadenopathy, and sometimes other
manifestations such as splenomegaly and hepatitis.
Taking amoxicillin provokes a maculopapular rash in
>95% of cases.
The blood film usually shows atypical lymphocytes, and
the diagnosis is made by demonstrating heterophile antibodies (monospot test), or more specifically by demonstrating anti-VCA (viral capsid antigen) IgM antibodies.
Other manifestations of EBV infection include malignancies (lymphoproliferative diseases, Burkitts lymphoma, nasopharyngeal carcinoma, primary CNS
lymphoma, especially seen in immunosuppression),
chronic EBV disease, EBV-associated hemophagocytic
lymphohistiocytosis and X-linked lymphoproliferative
syndrome. These diseases require the requisite histology
plus demonstration of EBV, usually by PCR.
There are no antivirals with sufficient activity to be
therapeutically useful.
There is no vaccine.
Cytomegalovirus (CMV)
Cytomegalovirus is a human herpesvirus (HHV-5)
which commonly causes an infectious mononucleosislike illness in young adults. Fever, sore throat, lymphadenopathy and hepatitis are the common symptoms,
although infection may be asymptomatic.
Like all herpesviruses, CMV is never eradicated following
infection, which results in a particular risk of reactivation
disease in the immunosuppressed host. Patients with cellular immune deficiency, such as in acquired immune
deficiency syndrome (AIDS) or post organ transplant, are
at risk of CMV infection of the lungs, retina and gastrointestinal tract. This is a life-threatening situation.
CMV is also a major cause of congenital infection (see
Chapter 25).
Acute CMV infection can be confirmed by the presence
of specific IgM, or by detection of viral DNA. In the
reactivation illness in the setting of immunosuppression,
serum viral DNA levels may be useful, but tissue biopsy
with typical histological appearance of intranuclear
inclusions, or positive viral culture, is diagnostic.
665
Treatment is not required in the immunocompetent host

as the disease is self-limiting. In the immunosuppressed,
treatment is necessary with ganciclovir, valganciclovir,
cidofovir or foscarnet.
Adenovirus
Adenoviruses are small ribonucleic acid (RNA) viruses that

are implicated in common human infections such as upper
respiratory infections. Diagnosis of adenoviruses can be by
immunofluorescence on respiratory specimens, or demonstration of a serological response. PCR is not widely available.
Human parvovirus B19

Parvovirus B19 most frequently causes a benign exanthem of childhood, erythema infectiosum (fifth disease,
slapped face syndrome).
Infection can result in red-cell aplasiain the fetus this
causes profound anemia leading to hydrops fetalis, and
in those with hematological dyscrasias or immunosuppression infection can be prolonged, leading to pure red
cell aplasia.
Diagnosis is by detecting an IgM response or by PCR.
Enteroviruses
The most common manifestation is a systemic infection
with fever, and sometimes end-organ disease such as
myocarditis and aseptic meningitis.
Aseptic meningitis is manifested by headache, photophobia, neck stiffness and fevers. Bacterial meningitis is the important differential diagnosis. CSF
examination reveals raised protein and normal glucose with a mononuclear pleocytosis, but occasionally on the first day or two of illness there can be
neutrophil pleocytosis.
Enteroviruses are an uncommon cause of gastroenteritis.
The diagnosis is made by exclusion of bacterial pathogens and demonstration of enterovirus RNA in CSF by
PCR. Serology is insensitive and non-specific.
Severe systemic infection with myocarditis and hepatitis
can occur in infections acquired during birth. Pleconaril
has been trialed in neonatal disease.
Immunodeficiency states see more severe cutaneous manifestations, esophagitis and bloodstream
infections.
Upper GI tract surgery can be complicated by deep
infections with Candida spp.
Candidemia is seen in patients with total parenteral
nutrition and patients with extensive mucositis (usually
due to chemotherapy).
Candidemia can be complicated by seeding of the
retina (leading to endophthalmitis).
Hepatosplenic candidiasis manifests with multiple liver
and spleen lesions in neutropenic patients.
C. albicans is usually sensitive to a wide range of topical
and systemic antifungals; however, with widespread use
of azoles some resistance is seen, and Candida spp. not
susceptible to fluconazole are increasingly seen. Here
it is important to take specimens for fungal culture to
confirm species and sensitivities.
Cryptococcus species
Three species of Cryptococcus are clinically significant: C.grubii (serogroup A), C. neoformans (serogroup D), and C. gattii
(serogroup B or C).
C. grubii and C. neoformans are found in bird guano, and
C. gattii is associated with river red and forest red gum
trees.
Acquisition of Cryptococcus is by inhalation of airborne
forms, causing pulmonary infection, followed by hematogenous dissemination to other sites, usually the leptomeninges and/or brain parenchyma.
Cryptococcomas (Figure 21-3) and obstructive hydrocephalus are more common with C. gattii.
Diagnosis involves demonstrating cryptococcal antigen
in blood or CSF, or culturing the organism.
Amphotericin B (usually a lipid formulation) is the
Selected fungi
Yeasts
Candida species
Candida spp. are commensals of the human GI and genitourinary tracts, and can cause clinical infections in those
exposed to broad-spectrum antibiotics and those with either
neutropenia or T-cell immune deficiency.
C. albicans is the most common species, but other species of Candida are increasingly seen due to the increasing use of antifungals to which these other species are
often resistant.
Clinical infections include diaper rash, vaginitis, oral
candidiasis, and infection of skinfolds, particularly in the
obese.
666
Figure 21-3 Cryptococcoma of the right lung
mainstay of treatment; results are better if flucytosine

is co-administered. Flucytosine levels are measured,
as clearance is variable and accumulation is typical if
amphotericin causes renal failure. Patients require prolonged amphotericin B and flucytosine, followed by oral
fluconazole.
Elevated CSF pressure is an important complication
of cryptococcal meningitis, associated with severe
sequelae. This is managed with serial lumbar punctures;
CSF shunting is often required.
Molds
Aspergillus species
Aspergillus spp. are ubiquitous environmental fungi, the
spores of which are continuously inhaled.
Colonization with Aspergillus spp. is frequently seen in
patients with underlying processes such as bronchiectasis or lung cavities. Colonization per se does not require
specific treatment.
Allergic bronchopulmonary aspergillosis manifests with
cough and wheeze, peripheral eosinophilia and an elevated IgE level. A. precipitans in high titer is diagnostic.
The treatment is to modify the immune response with
inhaled, and sometimes systemic, corticosteroids.
Aspergillomas are fungal balls in cavities, usually seen
on CT scan (Figure 21-4). Treatment of this is difficult:
excision is best, but often such patients will not tolerate
extirpation.
Invasive disease is more likely if there is immunosuppression,
particularly profound neutropenia, for more than a week.
Diagnosis is difficult: accurate diagnosis requires
demonstrating fungi invading lung tissue on biopsy,
which is usually not performed.
High-resolution CT scanning can demonstrate suspicious lesions, especially progressive cavities with a crescent sign.
Isolation of Aspergillus from respiratory tract specimens
in the setting of neutropenia, especially with a suspicious CT scan, is suggestive.
Aspergillus is rarely isolated from blood.
Serial blood galactomannan levels or PCR can be useful
in diagnosing invasive aspergillosis.
Voriconazole is more efficacious than amphotericin B in
treatment; however, it is pivotal that the patients have a loading dose, to avoid delaying therapeutic steady-state levels.
Alternative drugs include amphotericin B, echinocandins,
and posaconazole.
Agents of mucormycosis
Mucormycosis is caused by Rhizopus spp., Rhizomucor
spp., Cunninghamella spp., Saksenaea spp., Absidia spp., and
Mucorspp.
Invasive rhinocerebral mucormycosis occurs in diabetics, typically presenting with diabetic ketoacidosis, and
rapidly progressive invasive disease including severe
facial pain, periorbital edema, invasive infection emanating from sinuses destroying bone, and progressive
cranial nerve palsies.
Aggressive debridement and systemic antifungals are
essential, but despite this death is frequent.
More recently, pulmonary mucormycosis is an emerging infection in those who are profoundly neutropenic
and in organ-transplant recipients.
Diagnosis usually requires a tissue sample, and is often
postmortem.
The agents of mucormycosis are intrinsically (i.e. naturally) resistant to azoles and have been emerging since
the use of widespread prophylaxis with broad-spectrum
antifungals in severely immunosuppressed people. Successful therapy involves reversal of immunosuppression,
and high-dose liposomal amphotericin B.
Dimorphic fungi
Dimorphic fungi (Histoplasma capsulatum, Blastomyces
dermatitidis and Coccidioides imitis) are primarily seen in
arid regions of the southwestern United States, except
H. capsulatum which is seen in patients with contact with
caves containing bat guano. Another species, Penicillium
marneffii, is seen in Southeast Asia.
When cultured in the laboratory these agents are
hazardous to laboratory personnel, who need to be
forewarned.
Figure 21-4 Computed tomography scan showing

aspergilloma in a patient with underlying chronic
obstructive pulmonary disease
Histoplasma capsulatum
Acute primary infection is usually manifested by fever
and malaise, headache, and respiratory symptoms.
There are usually few clinical signs; chest X-rays may
show a patchy multilobar pneumonia, and lymph nodes
may be enlarged.
Acute histoplasmosis usually resolves, but can progress
to chronic pulmonary infection, disseminate to any part
667
of the body, or reactivate in immunosuppression, especially in patients with AIDS.

Diagnosis is by isolation of fungus, demonstration of
antigen, demonstration of typical findings on histology
enhanced by special stains, the histoplasmin skin test,
and serological response.
Self-limited infections require no treatment. Azoles
should be used in mild disease, and liposomal amphotericin B in severe infections.
Blastomyces dermatitidis
Inhalation results in pulmonary infection, which may
disseminate to skin, bones and the genitourinary system
or other sites.
Diagnosis is suggested by finding granulomas and compatible yeasts in microscopy of involved tissues, confirmed by culture. Serology is unhelpful, and PCR is
not available.
Azoles are used in mild to moderately severe cases, and
amphotericin B for severe disease.
Coccidioides imitis
Seroprevalence is high in the southwestern United
States.
Infection is usually pulmonary, but can disseminate.
Neurological disease presents with headaches, confusion and seizures, and focal neurological signs.
Diagnosis is based on isolation of this fungus from
involved tissues and/or CSF, demonstrating a serological
response, or a delayed hypersensitivity skin reaction.
Treatment was previously with amphotericin B, but
azoles can be used.
Selected parasites
Strongyloides stercoralis is commonly found in underdeveloped
regions, particularly in tropical areas.
Infection is long-term. T-cell immunosuppression can
result in rhabditiform larvae invading the gut and carrying Enterobacteriaceae into the blood, causing an overwhelming bloodstream infection.
It is important to screen patients from endemic areas
who require immunosuppression for Strongyloides,
with serology and stool examination (microscopy and
Harada-Mori filter-paper culture test), and treat those
who are positive.
Treatment is with either ivermectin or albendazole.
Malaria
Malaria is a systemic infection caused by one or more of five
species of Plasmodium: P. falciparum, P. vivax, P. malariae,
P.ovale and P. knowlesi, which are transmitted by mosquitoes in tropical areas.
P. falciparum can cause rapidly progressive parasitemia in
those who are nonimmune, such as young children or
travelers to endemic areas.
668
P. knowlesi is a recently described species; recent studies

show it is common in Southeast Asia and causes appreciable morbidity and some mortality.
The other Plasmodium spp. also cause significant morbidity and some mortality.
All species are acquiring resistance to drugs active in
prophylaxis and treatment.
Diagnosis of malaria has traditionally been via thick and
thin films of blood. The sensitivity is dependent on the
microscopist.
Immunochromogenic tests are available for P. falciparum
and P. vivax; this test does not require a microscope.
PCR is the most sensitive test, but is not usually
available.
With respect to the treatment of malaria, it is imperative to admit to hospital any febrile traveler as they may
have a rapidly progressive infection such as P. falciparum
malaria.
Malaria treatment is updated continually based on patterns of drug resistance, and it is important to consult
physicians familiar with malaria, and current recommendations such as those from Therapeutic Guidelines,
the World Health Organization (WHO) or the Centers
for Disease Control (CDC).
Counseling is pivotal for those traveling to malarious
areas.
Mosquito bite prevention is important, as high levels
of drug resistance are common. Use of insecticideimpregnated mosquito nets and mosquito repellent
that contains N,N-diethyl-3-methylbenzamide
(DEET) is strongly recommended. Individuals
should refrain from going out at night, as malarious
mosquitoes bite between dusk and dawn.
For chemoprophylaxis, up-to-date information is
available via internet services from the WHO, CDC
and other groups. Specific recommendations depend
on the itinerary and planned activities, which will
determine the likelihood of being bitten by malarious mosquitoes and the local drug resistance.
ANTI-INFECTIVE TREATMENT
CLINICAL PEARL
Principles of anti-infective treatment:
1 Establish whether or not infection is present.
2 Predict or identify the likely organisms.
3 Decide whether antibiotics are required.
4 Prescribe empirical and then denitive anti-infectives.
5 Consider host factors.
6 Decide whether other therapy is required.
7 Evaluate progress and further information to modify treatment.
8 Dene treatment duration and endpoints.
Antibiotics are unique among pharmacological agents in

that the effect on living organisms, including pathogenic
micro-organisms, is not confined to the patient being

treated. Humans and animals share their microflora quite
widely. Antibiotic resistance is driven by widespread use of
antibiotics in people and animals.
In general, for trivial infections it is probably not necessary to do diagnostic testing, but if testing may alter
therapy, particularly where the possibility of drugresistant bacteria exists or if confirmation of a viral
infection means that antibiotics could be terminated, it
is worth performing these tests. In addition, in patients
who are moderately to severely unwell, tests are critical
to first establish the diagnosis, and then to establish what
organism is present and whether it might be resistant to
empirical antibiotics.
As always, history and examination are the most pivotal
aspects of medical assessment.
Constellations of symptoms might suggest the possibility of an infection, and what is involved or whether it
might be a systemic infection.
Vital signs indicate whether fever and/or shock are
present.
Physical examination might reveal signs suggesting a
particular organ system.

Once the presence of infection is established, common
causative organisms are quite predictable, as shown in
Table 21-2. The list of pathogens is broader in immunosuppressed hosts, as discussed in a later section.
Table 21-2 Some causes of common infections in normal hosts
INFECTION
COMMON PATHOGENS
Undifferentiated
systemic sepsis
Organisms that can cause rapidly fatal infections need to be covered: Streptococcus
pneumoniae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus pyogenes
Immunosuppression increases the list of likely pathogens
Need to consider whether meningitis might be also present
Children <4 months of age: group B streptococci, Escherichia coli, other Gram-negative bacilli
Upper respiratory tract

infection (URTI)
Rhinovirus, coronavirus, metapneumovirus, respiratory syncytial virus

Inuenza virus
Pharyngitis
URTI viruses
EpsteinBarr virus
Community-acquired
pneumonia
Rhinovirus, metapneumovirus, respiratory syncytial virus

Inuenza virus
Haemophilus inuenzae, Moraxella catarrhalis
Urinary tract infection

(UTI)
Escherichia coli
Staphylococcus saprophyticus
Proteus spp., other Gram-negative bacilli
Skin and soft-tissue

infections
Streptococcus pyogenes, other beta-hemolytic streptococci

Intra-abdominal
infections
Usually mixed infections with fecal ora, i.e., Enterobacteriaceae (coliforms), anaerobes, various
streptococci and enterococci
Bone and joint

infections
Classically Staphylococcus aureus

Sometimes Streptococcus pyogenes
Various pathogens, the likelihood of each depending on whether a native or a prosthetic valve,
and presence of risk factors such as intravenous drug use and intravenous catheters
Meningitis
Enterovirus
Other viruses
Listeria monocytogenes
Gram-negative bacilli
669

Invasive bacterial infections, especially if severe, must
prompt prescription of antibiotics. However, most
infections are viral and/or trivial and do not require antibiotics; prescribing here adds to antibiotic resistance and
exposes patients to the risk of side-effects.
Antibiotics have not been shown to confer benefit in
acute otitis media.
In influenza, neuraminidase inhibitors only show benefit if initiated within the first day or two with illness in
mild disease; it is still unknown whether they have a role
in severe disease.
Minor boils can be treated with a drain and refrain
strategy.
Choice of empirical and denitive

antibiotics
CLINICAL PEARL
Considerations in choosing empirical antibiotics:
Likely bacteria
Likely site of infection
Host factors such as age and immunosuppression
Pharmacokinetics (e.g. oral bioavailability, elimination half-life)
Numerous guidelines exist for choosing empirical and

definitive antibiotics, which take into consideration local
antibiotic resistances and available antibiotics. Many hospitals and health services have their own policies and guidelines for antibiotic prescription and use.
Table 21-3 Host factors affecting anti-infective agent

selection
FACTOR
Previous adverse
drug reaction
May recur on rechallenge with

same or similar drug
Age
Gastric pH
Ultra-absorption of drugs affected

by gastric acidity
Renal dysfunction
Profound effects on drugs

eliminated by renal excretion
Hepatic dysfunction
Profound effects on drugs

eliminated primarily by hepatic
excretion
Binding to bone/
teeth
Binding causes staining of

non-erupted teeth, which is
permanent
Genetic or metabolic
abnormalities
Slow acetylators
G6PD (glucose-6-phosphate
dehydrogenase) deciency
Induction of hepatic
cytochromes
Increased metabolism of other

drugs affected by these enzymes
Inhibition of hepatic
cytochromes
Decreased metabolism of other

drugs affected by this enzyme
system
Pregnancy
Increased clearance and volume

of distribution
Effects on fetus
Multiple different effects

guidelines exist for specic
antibiotics in pregnancy
and lactation (e.g from the
Therapeutic Guidelines Group)
Increased clearance
and Vd (volume of
distribution)
Burns
Adolescents and young adults
Septicemia
Concentration in
breast milk
Breastfeeding infants will

probably receive a low dose of
the drug
Site of infection hard

to penetrate
Central nervous system/eye

Abscesses
Vegetations, bones, devitalized
tissues
Biolm infections
Intracellular pathogens

Table 21-3 shows a number of host factors that need consideration in the selection of anti-infective drugs.
What therapy other than antibiotics is

required?
Proven ancillary treatments are shown in Table 21-4.
Immune modulators have been extensively trialed in sepsis,
and have mostly been found to not improve outcome.
Ongoing assessment and further

results
If the initial therapy appears not to be working, consider the
possibilities listed in Table 21-5.
EFFECT
What is the duration and endpoint of

treatment?
Most of the common infections have a standard duration of treatment. For conditions such as endocarditis,
these durations have been established by clinical trials.
Giving shorter courses has a high failure rate, and longer
courses do not appreciably increase the success rate.
670
For serious infections that do not have endpoints defined

by clinical trials, the progress can be followed by the history (the symptoms have resolved), clinical examination
(signs of inflammation have subsided), and investigations such as acute phase reactants and imaging.
Table 21-4 Proven ancillary measures used in

treatment of specic infections
INFECTION
MEASURE
Abscess
Drainage (radiological or surgical)
Endocarditis
Valve replacement
Pneumococcal
meningitis
Administration of corticosteroids
prior to antibiotics
Tetanus
Anti-tetanus immunoglobulin
If indices such as white cell count, neutrophils, platelet

count, C-reactive protein, and pro-calcitonin are raised
in the acute infection, normalization in the context of
clinical resolution probably indicates resolution.
Organ imaging such as CT and MRI scanning can
detect formation of new abscesses and collections, and
other destructive complications of the infection. However, MRI and radionucleotide scans detect inflammation long after micro-organisms have been killed, and if
used as a primary endpoint can prolong therapy.
ANTI-INFECTIVE AGENTS
Antibiotics
Table 21-5 Reasons for apparent failure of
anti-infective treatment
REASON
FOR
FAILURE
SPECIFIC PROBLEM
Diagnosis
wrong
Incorrect infection diagnosed

Illness is not due to infection
Inadequate
treatment
Pathogen is not susceptible to antiinfective agent

Undrained pus
Wrong dose, dosing interval or route of
administration
Infection at privileged site
Non-adherence
Host factors
Patient is immunosuppressed
Chronic disease such as diabetes,
alcoholism, chronic organ disease
Inadequate
blood levels
Malabsorption (e.g. shock,

gastrointestinal tract derangement)
Increased hepatic clearance
Interaction with other drugs
Infected
foreign body
Intravenous lines, surgical and

radiological implants
Complication
of infection
Undrained pus
Spread of infection
Superinfection at original site, including
by multidrug-resistant organisms (MROs)
New problem
New infections such as urinary tract

infection or pneumonia
Thromboembolic disease
Treatment
complication
Infected intravenous line

Non-infective thrombophlebitis from
intravenous line
Drug fever
Surgical site infection
Beta-lactams
Beta-lactams bind to penicillin-binding proteins in the
bacterial cell wall and inhibit cell-wall synthesis and
repair.
These drugs are usually bactericidal.
A summary of the classification and activity of common
beta-lactams against commonly encountered bacteria is
shown in Table 21-6 (overleaf).
Penicillins are divided into groups, as shown in Table
21-6. The main problems with penicillins include hypersensitivity, diarrhea, GI tract intolerance, hemolytic
anemia, and hepatitis (particularly with flucloxacillin).
Cephalosporins are better tolerated and cause fewer
allergic reactions than penicillins, but they select out
bacteria that are intrinsically resistant to them such as
enterococci, MRSA, multiresistant Gram-negative
bacilli, and Clostridium difficile.
They are arbitrarily divided into four generations,
with the early generations having good Grampositive activity but lesser Gram-negative activity,
and with Gram-negative activity increasing down
the generations.
Most recently, some cephalosporins with antiMRSA activity have been developed, e.g. ceftaroline.
Aztreonam, a monobactam, has good Gram-negative
activity including against Pseudomonas aeruginosa, but
has poor activity against Gram-positive organisms and
anaerobes. It has a niche role in being able to be given
to patients with major penicillin allergies, including
anaphylaxis.
Carbapenems include imipenem, meropenem, ertapenem and doripenem. These are the most broadspectrum antibiotics covering Staphylococcus aureus,
Enterococcus spp., Enterobacteriaceae including most that
have broad-spectrum beta-lactamases, P. aeruginosa
(not ertapenem), and anaerobes. The major gaps in the
coverage of carbapenems are: MRSA, VRE, Gramnegatives with metallo-beta-lactamases, C. difficile,
Stenotrophomonas maltophilia, and nonbacterial pathogens
such as yeasts. Side-effects from carbapenems include
hypersensitivity, diarrhea including C. difficile colitis,
hemolytic anemia, hepatitis, and cholestasis.
671
higher than with beta-lactams. Alternative drugs such

as vancomycin are inferior to beta-lactams for serious
infections with organisms such as methicillin-sensitive
S. aureus.
Beta-lactam allergy
1020% of patients are labeled as being allergic to penicillin, but only about one-tenth of these are truly allergic.
The cost of the alternative drug therapy is considerably
Table 21-6 Activity of beta-lactams against selected bacteria commonly encountered in clinical practice
Staphylococcus
aureusa
ANTIBIOTIC
Streptococcus
spp.
Enterococcus
spp.b
Coliformsc
ESCAPPM/
SPACE
Pseudomonas
aeruginosad
Anaerobese
Penicillins
Penicillin
5%
+++
+++
Ampicillin,
amoxycillin
5%
+++
+++
Flucloxacillin,
nafcillin
+++
Ticarcillin,
piperacillin
5%
+++
+++
++
Amoxycillin/
clavulanate
+++
+++
+++
++
+++
Piperacillin/
tazobactam
+++
+++
+++
++
+++
Cefazolin,
cephalexin
+++
+++
Cefotetan
++
++
Cefoxitin
++
Ceftriaxone,
cefotaxime
++
++
+++
Ceftazidime
+++
+++
Cefepime,
cefpirome
++
+++
+++
+++
+++
+++
+++
+++
Meropenem
+++
+++
+++
+++
+++
+++
Ertapenem
+++
+++
+++
+++
+++
Cephalosporins
Monobactams
Aztreonam
Carbapenems
Methicillin-resistant S. aureus (MRSA) strains are resistant to all beta-lactams (except new anti-MRSA cephalosporins such as ceftaroline).
Vancomycin-resistant enterococci (VRE) are virtually always resistant to penicillins and carbapenems.
c
Coliforms are common Enterobacteriaceae, i.e. Escherichia coli, Klebsiella pneumonia, K. oxytoca and Proteus mirabilis.
b
Pseudomonas aeruginosa is intrinsically resistant to most antibiotics; it can also acquire resistance to anti-pseudomonal antibiotics.
Anaerobes are considered as a group, as most infections are polymicrobial and speciation is not performed by diagnostic laboratories
except in special circumstances.
+++, >90% effective; ++, 5090% effective; +, 1050% effective; , <10% of strains are susceptible; ESCAPPM, Enterobacter spp., Serratia
spp., Citrobacter spp., Acinetobacter spp., Proteus vulgaris, Providentia spp. and Morganella spp.; SPACE, Serratia spp., Proteus vulgaris,
Acinetobacter spp., Citrobacter spp. and Enterobacter spp.; V, variable, depending on strain.
672
Establishing the presence or absence of true penicillin

allergy is desirable (see Chapter 17).
CLINICAL PEARL
Most patients labeled with penicillin allergy are not
allergic to penicillin. Always check the nature of the
allergy and consider referral to an immunologist for
further evaluation.
Non-beta-lactams
A summary of the activity of common non-beta-lactams
against commonly encountered bacteria is shown in
Table21-7 (overleaf).
Aminoglycosides
Aminoglycosides include streptomycin, gentamicin, netilmicin, tobramycin and amikacin.
Aminoglycosides cover aerobic Gram-negative organisms (Enterobacteriaceae and P. aeruginosa), but not
Gram-positive organisms or anaerobes.
Gentamicin is the most commonly used aminoglycoside, and tobramycin and amikacin are reserved for
infections with gentamicin-resistant bacteria. Amikacin also has a special role in atypical Mycobacterium and
Nocardia infections.
Synergy between aminoglycosides and cell-wall-active
agents such as glycopeptides and penicillins is seen
in most enterococci, hence the use in enterococcal
endocarditis.
Aminoglycosides are rapidly bactericidal and are
important drugs in treating Gram-negative bacteremia,
but they have considerable renal and 8th nerve toxicity.
Risk factors for toxicity include age, excessive dosing,
or prolonged regimens, but toxicity can be seen after
just one or two doses.
Deafness and loss of vestibular function is often permanent and very disabling. As a consequence of this, it is
recommended to use aminoglycosides empirically for
short courses only.
Prolonged treatment is not justified except in the synergistic role for enterococcal endocarditis, and for treatment of some unusual infections such as extremely
resistant Gram-negative bacilli, atypical mycobacteria
and nocardioforms.
CLINICAL PEARL
If aminoglycosides are given for more than 2 days, it is
essential to perform therapeutic drug monitoring. With
once-daily dosing, trough levels are hard to interpret
and various other methods are advised, with the most
accurate being methods that calculate area under the
curve.
Glycopeptides
These include vancomycin and teicoplanin.
They inhibit cell wall synthesis of Gram-positive
organisms.
Both drugs are eliminated by renal excretion.
They cover most Gram-positive organisms, but are less
efficacious than beta-lactams for sensitive organisms and
should be reserved for MRSA and coagulase-negative
streptococci.
Adverse drug reactions include renal and 8th nerve
toxicity, which is probably more common in current
regimens where doses are higher to increase efficacy.
Neutropenia and drug rashes are seen.
Therapeutic drug monitoring of trough levels is indicated to assess therapeutic efficacy.
CLINICAL PEARL
Too-rapid infusion of glycopeptides can cause a nonimmunoglobulin-E-mediated histamine release from
mast cellsthe red person syndrome.
Lipopeptides
Lipopeptides include daptomycin, which acts by binding
to the cell wall of Gram-positive bacteria in a calciumdependent way, resulting in potassium efflux from the
cell, loss of membrane potential and cell death.
The spectrum of activity is very similar to that of
vancomycin.
Toxicity includes myalgias.
Daptomycin is inactivated by pulmonary surfactant
and should not be used in pneumonia; however, it is
efficacious in hematogenous lung abscesses caused by
S.aureus.
It is equally efficacious as vancomycin for the treatment
of MRSA endocarditis.
Macrolides/lincosamides
Macrolides and lincosamides, while chemically different, are
grouped together because of their biological similarities.
They bind to the 50S ribosomal subunits and inhibit
protein translation.
They cover Staphylococcus aureus, most strains of Streptococcus pyogenes, and have variable activity against
Streptococcus pneumoniae.
They also cover some anaerobes, Legionella species,
Mycoplasma pneumoniae and have variable activity against
Chlamydia species, but do not cover Haemophilus influenzae, Moraxella catarrhalis and Gram-negative bacilli.
Erythromycin can cause problems with GI intolerance
and can also cause hepatitis, deafness with high-dose IV
regimens, and is quite irritating to veins.
Lincomycin and clindamycin cover most strains of
S. aureus and S. pyogenes, and have quite good activity
673
Table 21-7 Activity of non-beta-lactams against bacteria commonly encountered in clinical practice
Staphylococcus
aureusa
ANTIBIOTIC
Aminoglycosides
Streptococcus
spp.
MRSAb
i,g,h
i
Enterococcus
spp.c
Coliformsd
ESCAPPM/
SPACE
Pseudomonas
aeruginosae
Anaerobesf
+++
+++
++
+++
+++
Gram+
Vancomycin,
teicoplanin
+++
+++
Daptomycin
+++
+++
+++
+++
Gram+
Erythromycin
++
Clindamycin
+++
++
Azithromycin
++
++
++
Nalidixic acid
+++
+++
Ooxacin
+++
++
++
++
Ciprooxacin
+++
+++
+++
+++
Moxioxacin
+++
+++
+++
+++
++
++
Linezolid
+++
+++
+++
+++
Co-trimoxazole
+++
Tetracycline
+++
++
Tigecyclinej
+++
+++
+++
+++
+++
+++
++
Rifampicin
+++
+++
Fusidic acid
+++
+++
Chloramphenicol
+++
+++
++
++
++
Colistin
++
k
+++
+++
+++
+++
+++
Mupirocin
+++
+++
Metronidazole
+++
Fosfomycin
l
Methicillin-sensitive Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) strains have variable susceptibilities to non-beta-lactams and these are strain-dependent,
vary between geographical locations and on whether the acquisition is community- or healthcare-related. Typically, nosocomial strains are
multidrug-resistant but retain susceptibility to glycopeptides, lipopeptides, linezolid, quinupristin/dalfopristin, tigecycline, rifampicin, fusidic
acid, chloramphenicol and mupirocin; community strains are typically susceptible to most or all non-beta-lactams with the most common
resistance being to macrolides/lincosamides.
c
Vancomycin-resistant enterococci (VRE) are resistant to most drugs but usually retain susceptibility to linezolid, quinupristin/dalfopristin,
daptomycin, and tigecycline.
d
Coliforms are common Enterobacteriaceae, i.e. Escherichia coli, Klebsiella pneumonia, K. oxytoca and Proteus mirabilis.
e
Pseudomonas aeruginosa is intrinsically resistant to most antibiotics; it can also acquire resistance to anti-pseudomonal antibiotics.
f
Anaerobes are considered as a group, as most infections are polymicrobial and speciation is not performed by diagnostic laboratories except
in special circumstances.
g
Some strains of S. aureus test susceptible in vitro, but aminoglycosides are ineffective as monotherapy and there is no impact on mortality or
length of stay in combination with cell-wall-active agents.
h
Some rare strains of MRSA have reduced susceptibility to vancomycin.
i
Azithromycin is active against Salmonella enterica Typhi, including multidrug-resistant strains and Shigella spp.
j
Tigecycline has low blood levels and therefore is ineffective for bloodstream infections.
k
Proteus spp. are highly resistant.
b
Topical only.
+++, >90%effective; ++, 5090% effective; +, 1050% effective; , <10% of strains are susceptible; ESCAPPM, Enterobacter spp., Serratia spp.,
Citrobacter spp., Acinetobacter spp., Proteus vulgaris, Providentia spp. and Morganella spp.; Gram+, Gram-positive anaerobes only; SPACE,
Serratia spp., Proteus vulgaris, Acinetobacter spp., Citrobacter spp. and Enterobacter spp.; V, variable, depending on strain.
674
against anaerobes but do not cover Gram-negatives.

The most common side-effect is a maculopapular rash.
They can cause GI upset, and clindamycin was the first
drug to be reported to cause pseudomembranous colitis
due to Clostridium difficile.
Azithromycin has good coverage against atypical respiratory pathogens and Chlamydia species, and is usually
well tolerated but can cause GI upset. Azithromycin has
activity against some Enterobacteriaceae, and has a new
role in the treatment of multiresistant Salmonella enterica
Typhi.
Roxithromycin is an orally available macrolide, with
coverage against atypical pneumonia agents such as
M. pneumoniae, and Chlamydia spp., and is also active
against Haemophilus and Moraxella spp. and has variable
activity against S. aureus, S. pyogenes and S. pneumoniae.
It is usually well tolerated.
Clarithromycin is active against atypical respiratory
pathogens, has variable activity against S. pneumoniae, is
active against M. pneumoniae and Chlamydia spp., and is
the most active macrolide against atypical mycobacteria.
Clarithromycin is usually well tolerated, but can cause
GI intolerance and hypersensitivity reactions.
Quinolones
Quinolones include nalidixic acid, early-generation fluoroquinolones including norfloxacin, ciprofloxacin and ofloxacin, and newer-generation fluoroquinolones including
levofloxacin and moxifloxacin.
These drugs have a dual ring structure and differ in
their side-chain moieties, which affect the antibacterial spectrum and pharmacokinetic properties. They
act by inhibiting type II isomerases, DNA gyrase and
topoisomerase IV, causing degradation of DNA and cell
death.
Most quinolones have good oral bioavailability, such
that IV use is not indicated except in malabsorption
states.
Norfloxacin has low blood levels and is only used for
urinary tract infection and enteric fever.
Ciprofloxacin and norfloxacin had excellent coverage
against Enterobacteriaceae and P. aeruginosa when introduced, but resistance is now common in many parts
of the world. Later-generation compounds have better Gram-positive coverage, and also are active against
anaerobes, M. pneumoniae, Chlamydia spp. and Mycobacteria spp., including the tubercule bacillus.
The most common adverse drug effect is GI tract
intolerance.
Rupture of the Achilles tendon has been reported, due
to interference with cross-linking of type IV collagen.
Quinolones can also cause neurological manifestations
including confusion and seizures, particularly in the
elderly, and more unusually can cause hepatitis and
acute renal failure.
QTc prolongation can occur with later-generation
quinolones.
Oxazolidinones
Linezolid is the first oxazolidinone, which acts by a
novel mechanism to inhibit protein synthesis by binding to the 50S ribosome at its interface with the 30S
sub-unit, preventing formation of the 70S initiation
complex.
It has consistent activity against Gram-positive
bacteria.
It has no activity against most Gram-negative
organisms except Neisseria spp.
There is in vitro activity against some atypical mycobacteria and nocardioforms.
Despite being bacteriostatic, it is efficacious in serious
S. aureus infections; including endocarditis, where it has
been used in treatment of strains with reduced vancomycin susceptibility.
It might be superior to vancomycin for MRSA
pneumonia.
It is also useful for VRE infections.
Resistance is rare, but is increasingly seen.
Anemia and thrombocytopenia are commonly seen in
patients treated for >2 weeks, and occasionally irreversible peripheral and optic neuropathy is seen.
Folate antagonists
Sulfonamides and trimethoprim inhibit sequential steps
of folic acid synthesis. They are absorbed orally with
high bioavailability, and penetrate into most tissues
including bone, and the CNS.
Due to resistance, coverage of commonly encountered
staphylococci, streptococci and coliforms is uneven;
it does not cover Haemophilus spp., Moraxella spp. or
P.aeruginosa.
Co-trimoxazole (trimethoprim/sulfamethoxazole) has
a special role in Pneumocystis jirovecii and Nocardia spp.
infections.
The sulfonamide moiety is responsible for most of the
serious side-effects, including skin rashes, Stevens
Johnson syndrome, erythema multiforme, hepatitis,
interstitial nephritis, and drug fever.
50% of patients with AIDS treated with high-dose
co-trimoxazole develop a rash; roughly half can be
desensitized.
Tetracyclines and tigecycline
Tetracyclines bind to the 30S ribosomal sub-unit,
inhibiting protein synthesis.
These drugs are well absorbed orally and penetrate into
all tissues except the CNS.
Many different tetracyclines have been available, and
mainly differ in their half-life.
They are broad-spectrum antibiotics, but widespread
resistance has emerged by several mechanisms including active efflux, ribosomal mutations, and changes in
permeability.
675
Coverage of S. aureus, Streptococcus spp., Enterobacteriaceae

and anaerobes is patchy, but these drugs are particularly
useful for Chlamydia spp., Mycoplasma spp., Rickettsia
spp. and prophylaxis of malaria.
They also have non-antimicrobial uses in dermatology
and for pleurodesis.
CLINICAL PEARL
Adverse drug reactions to tetracyclines include staining
of non-erupted teeth, and thus these drugs are contraindicated in pregnancy, lactation and in children less
than 8 years of age.
Tetracyclines can cause photosensitization and GI upset.

Doxycycline must be taken in the upright position with
plenty of fluids to avoid lodgement in the esophagus,
causing a severe burn.
Minocycline can also cause benign intracranial hypertension, and vertigo.
Tigecycline is only available intravenously and is
extremely broad-spectrum, covering most Gram-positive
and Gram-negative pathogens (except P. aeruginosa) and
anaerobes, and also has activity against MRSA, VRE,
multiresistant Enterobacteriaceae, and atypical mycobacteria.
Rifamycins
Rifamycins include rifampicin and rifabutin. These
agents inhibit DNA-dependent RNA polymerase.
They are well absorbed orally, and can be given intravenously. They have a short half-life, but a long postantibiotic effect and are given once daily.
These drugs penetrate most tissues including bone,
but do not penetrate into the CNS. Coverage is
broad, including S. aureus, Mycobacteria spp., selected
Gram-negative organisms (e.g. N. meningitidis and
H.influenzae, where they have a public health but not
a treatment role), and anaerobes. They have no activity
against streptococci.
Rifampicin penetrates well into the nasopharynx, and
thus is useful in eradicating staphylococcal carriage
states (in combination treatment), and as monotherapy
in prophylaxis against N. meningitidis and H. influenzae
type B.
High-level resistance by single base-pair mutation
occurs rapidly if monotherapy is given, so combination
treatment is given, e.g. in the treatment of tuberculosis
or MRSA infections.
Rifamycins are potent inducers of hepatic cytochrome
enzymes, and thus diminish the activity of drugs such
as warfarin, hormonal contraceptives, and anticonvulsants. These agents stain the urine and tears. Other
side-effects include hepatitis, drug fever, rashes, and
interstitial nephritis.
Fusidic acid
Fusidic acid is a steroid antibiotic which interferes with
cell wall synthesis and elongation factor G.
676
It is well absorbed orally. It can be given intravenously,

but can cause significant hepatitis given in this way.
It penetrates into most tissues, including bone and the
CNS.
Fusidic acid covers S. aureus, including most MRSA
strains, but it does not cover streptococci or Gramnegative organisms, and anaerobes.
Adverse drug reactions include GI tract intolerance,
hepatitis, and rashes.
CLINICAL PEARL
The combination of fusidic acid and HMG-CoA reductase inhibitors is associated with rhabdomyolysis,
including fatal cases. If fusidic acid must be used, e.g.
for treatment of multiresistant MRSA infections, it is
recommended to stop the HMG-CoA reductase inhibitor for the period the patient takes fusidic acid.
Chloramphenicol
Chloramphenicol binds to the 50S ribosomal sub-units,
inhibiting protein synthesis.
This drug is bacteriostatic.
It is very well absorbed and universally distributed in the
body, including into the CNS.
It has very broad spectrum of coverage of most aerobic and anaerobic organisms, and had roles in invasive infections with S. enterica Typhi, H. influenzae and
N.meningitidis until superseded by other drugs.
Chloramphenicol induces reversible myelosuppression
commonly, but has a 1:10,000 risk of aplastic anemia,
and accordingly is rarely used in Western countries.
Topical preparations remain widely used and do not
incur this risk.
Colistin
Colistin is a detergent which disrupts bacterial cell walls, and
is particularly active against aerobic Gram-negative bacilli,
except Proteus spp.
Due to significant renal toxicity it was relegated to
topical use until the emergence of extremely drugresistant Gram-negative pathogens such as Acinetobacter
baumannii and P. aeruginosa, where there were few
other options.
A major problem with this drug is that blood levels are
usually just above the minimum inhibitory concentration (MIC) of infecting organisms.
The drug is efficacious in bloodstream infections, but
not in other infections such as ventilator-associated
pneumonia, where lung tissue levels are less than the
MIC.
Colistin has also been shown to be efficacious and nontoxic when administered intrathecally in the treatment
of multi-antibiotic resistant A. baumannii meningitis.
Fosfomycin
Fosfomycin inhibits an enzyme which catalyzes the first step
in bacterial cell wall synthesis.
It is a bactericidal agent with a broad spectrum of activity, including MRSA and multi-drug-resistant Enterobacteriaceae and P. aeruginosa.
The drug is readily absorbed following oral administration and achieves moderate blood levels with a half-life
of 612 hours.
It is excreted unchanged in urine and feces and penetrates into most sites except the CSF.
It has been used in the treatment of urinary tract infection, and has also been used in small groups of patients
with other infections such as osteomyelitis or severe
staphylococcal infections, and has been trialed in surgical prophylaxis.
Nitroimidazoles
Metronidazole and tinidazole are commercially available
nitroimidazoles.
These are well absorbed after most routes of administration, and have excellent tissue penetration, including the
CNS and bone. Activity is high against most anaerobes
except Peptostreptococcus spp., and they also cover protozoans such as Giardia intestinalis and Gardnerella vaginalis.
Adverse drug reactions include metallic taste, and a
disulfiram-like interaction with ethanol, which is to be
avoided during therapy with this agent.
Antibiotic resistance
Resistance to antibacterial agents can be coded for by genes
on the bacterial chromosome and/or plasmids. There are
four basic mechanisms of resistance, as shown in Table 21-8.
Table 21-8 Mechanisms of antibiotic resistance, with typical examples
MECHANISM
SPECIFIC ENTITY
ANTIBIOTIC
TYPICAL SPECIES
Inactivating enzymes
Beta-lactamases
Penicillinase
Penicillin
TEM/SHV beta-lactamase
Amoxicillin
Escherichia coli
Extended-spectrum betalactamase (ESBL)
Ceftriaxone
Klebsiella pneumonia
Metallo-beta-lactamase (MBL)
Meropenem
Enterobacteriaceae
Gentamicin
Klebsiella pneumonia
Chloramphenicol acetyl
transferase (CAT)
Chloramphenicol
Salmonella enterica
Modied PBP2a
Methicillin
Methicillin-resistant
Ciprooxacin
Aminoglycoside-modifying
enzymes
Acetyl transferases
Altered target sites
Penicillin-binding proteins
(PBPs)
DNA gyrase
Ribosomes
MLSB
Erythromycin
RNA polymerase
rpoB
Rifampicin
Dihydrofolate reductase
Various
Sulfonamides
Escherichia coli
Various
Meropenem
tetM
Tetracyclines
Enterobacteriaceae
Decreased permeability
Altered porins
Active efflux
DNA, deoxyribonucleic acid; MLSB, macrolide, lincosamide and streptogramin B; RNA; ribonucleic acid; rpoB, gene encoding RNA
polymerase; SHV, sulfhydryl variable specicity; tetM, tetracycline resistance gene.
677
Antiviral agents
CLINICAL PEARL
Antiviral agents are virustatic rather than virucidal, and
thus efficacy relies on the host immune system. Thus in
the immunosuppressed, especially with herpes viruses,
ongoing antiviral suppression is often required.
Drug susceptibility testing is problematic with antiviral

agents, because readily available in vitro systems to test this
do not exist in clinical laboratories. However, with the
maturation of molecular technology, testing for known
resistance determinants in specific viruses can be done.
Additionally, in infections such as HIV, hepatitis B and
hepatitis C, viral load can be quantitated by PCR, which
can be used to ascertain disease activity and gauge the
efficacy of therapy.
Drugs used in the treatment of HIV/AIDS are discussed
in Chapter 17; other antivirals are discussed below.
Interferons
Interferons are part of the antiviral immune response.
Synthetic alpha-interferon has activity against hepatitisB, hepatitis C, HIV and human papillomaviruses.
Interferons are not absorbed orally, and are administered
generally by subcutaneous injection, or intralesionally
for warts.
Treatment usually causes significant symptomatology,
including influenza-like illness, depression, and reactivation
of dormant autoimmune processes.
Uncoating inhibitors
Amantadine/rimantadine
These drugs block M2 protein channels in influenza virus
envelopes. They are only active against influenza A strains
and resistance emerges rapidly, and they have substantial
CNS toxicity. Consequently, they have been replaced by
neuraminidase inhibitors.
Nucleoside analogues
Acyclovir (aciclovir), famciclovir, valaciclovir
Valaciclovir is a pro-drug of acyclovir (aciclovir).
Famciclovir is the pro-drug of penciclovir.
Acyclovir and penciclovir are phosphorylated by virally
encoded thymidine kinase to monophosphate forms,
which are phosphorylated to triphosphates by cellular
kinases, which are then incorporated into DNA as a
false base and terminate replication.
These drugs are highly active against HSV-1 and
HSV-2, and to a lesser degree against VZV. They do
not inhibit CMV or EBV at levels achievable in humans.
These drugs are well tolerated, with the main toxicity
being renal impairment due to crystallization in the renal
678
tubules, particularly with high-dose IV administration.

This is less likely in adequately hydrated patients.
Oral treatment is sufficient for minor HSV and VZV
infections, but in severe disease, especially in immunosuppressed individuals, IV acyclovir is used.
Resistance to these agents is seen in HSV in severe
immunosuppression, such as untreated HIV infection.
There is cross-resistance to all members in this category
and also to ganciclovir, but not foscarnet, which is used
in this situation.
Ganciclovir and valganciclovir
Valganciclovir is the pro-drug of ganciclovir.
Ganciclovir is not absorbed orally, but valganciclovir is.
Ganciclovir is phosphorylated within infected cells by
the CMV UL97 protein, and after further phosphorylation by cellular kinases inhibits CMV DNA polymerase,
and thus viral replication.
Ganciclovir is quite potent against HSV and VZV, but
acyclovir and analogues are clinically effective and far
less toxic, and thus ganciclovir is not used here.
For CMV disease in the immunocompetent patient,
ganciclovir is usually considered too toxic to use, but
disease in the immunocompromised can be very severe
and treatment normally consists of induction therapy
with IV ganciclovir and then maintenance therapy.
Ganciclovir also has activity against EBV and the human
herpesviruses HHV-6, HHV-8 and HHV-7, but this is
not clinically useful.
Ganciclovir causes bone marrow suppression. It is
renally excreted, and dosage reduction is required in
renal impairment.
Nucleotide analogues
Cidofovir
Cidofovir is a nucleotide analog active against HSV-1,
HSV-2, CMV and VZV.
It is nephrotoxic, and thus less frequently used than
ganciclovir or foscarnet.
It has a long half-life, allowing weekly dosing.
It has a niche use in progressive vaccinia virus infections.
Direct DNA polymerase inhibitors

Foscarnet
Foscarnet is a pyrophosphate analog directly inhibiting
herpesvirus DNA polymerase.
It is particularly useful in acyclovir-resistant strains of
herpes simplex and ganciclovir-resistant CMV.
Foscarnet is eliminated by renal excretion, and dose
reduction is required in renal impairment.
The main adverse drug reaction is renal failure, and
sometimes hypercalcemia and pancreatitis can occur.
Assembly/maturation/release agents
Oseltamivir and zanamivir
These agents are active against influenza A and B, and
work by inhibiting neuraminidase, which impairs virion
assembly and release from infected cells.
Despite widespread use in the H1N1/09 influenza pandemic, resistance was remarkably rare.
Strains that are resistant to oseltamivir remain sensitive
to zanamivir.
Oseltamivir is available only as an oral formulation,
which was problematic during the influenza pandemic
where an IV neuraminidase inhibitor would have been
useful.
Other antivirals
Ribavirin
Ribavirin is a purine analog requiring intracellular
phosphorylation for antiviral activity, the exact mechanism of which is unclear.
In vitro activity against many DNA and RNA viruses
is seen, but this is not replicated clinically for most of
these.
Respiratory syncytial virus (RSV) infections respond to
nebulized ribavirin; however, ribavirin is quite toxic,
teratogenic, and possibly carcinogenic to healthcare
workers. Administration requires the use of a tent apparatus to isolate the patient from the healthcare workers
for occupational health. It is therefore usually given
intravenously for this indication, a route that does not
have demonstrated efficacy.
Ribavirin was used in the early stages of the severe acute
respiratory syndrome (SARS) epidemic in 2002/2003
but was found to lack efficacy.
Ribavirin exhibits activity against hepatitis C virus
when administered with other drugs such as interferon.
It is used in severe measles and viral hemorrhagic fevers,
and had been used in influenza prior to the availability
of neuraminidase inhibitors.
Antifungals
Antifungal drugs were slow in development because of the
similarities of complicated fungal cell metabolism to that
of mammalian cells. Early agents were far too toxic to be
clinically useful. Antifungal therapy was revolutionized
by the development of azoles, which are considerably less
toxic as well as efficacious, and most recent agents have very
broad-spectrum activity. The classification and activity
spectra of modern antifungals against selected fungal pathogens are shown in Table 21-9 (overleaf).
Azoles
Azoles inhibit C14 alpha-demethylase, which interferes
with the synthesis of an important cell wall constituent,
ergosterol.
A wide repertoire of systemic azoles is now available,

including ketoconazole, fluconazole, itraconazole,
voriconazole and posaconazole.
Miconazole is too slow-acting and toxic for use today.
Ketoconazole
Ketoconazole is an early azole with significant hepatotoxicity and GI intolerance. It also inhibits P450 cytochrome
enzymes, resulting in drug interactions.
Itraconazole
Itraconazole is active against yeasts and molds, including
Aspergillus spp.
Patients with AIDS and bone-marrow transplants have
decreased absorption.
Blood levels are quite variable, and in serious infections
therapeutic drug monitoring is recommended.
There is low penetration into the CNS, but good penetration into most other tissues.
The drug inhibits P450 cytochrome enzymes.
Fluconazole
Fluconazole is a triazole drug with good activity against
yeasts, particularly Candida spp. (except some intrinsically
resistant species: C. krusei, C. parapsilosis and most C. glabrata) and Cryptococcus spp.
Intravenous and oral formulations are available.
Oral bioavailability is excellent, so this route is preferred
except in malabsorption states.
Penetration into all tissues is excellent, including vitreous humor, subarachnoid space and brain parenchyma.
The drug is eliminated by the kidney.
The drug is well tolerated usually, with much less hepatotoxicity than with other azoles.
Like other azoles, it inhibits cytochrome P450 enzymes,
resulting in drug interactions.
Voriconazole
Voriconazole is a more recently available triazole with significant activity against molds, especially A. fumigatus, and
emerging mold species such as Scedosporium spp.
There is good oral absorption, and there is also an IV
preparation.
It is necessary to give a loading dose to get patients to
therapeutic levels, which is particularly important in
systemic infections.
Voriconazole is used prophylactically in acute myeloid
leukemia (AML) and transplantation patients experiencing severe immunosuppression.
While suppressing infections with Candida spp. and
Aspergillus spp., emerging infections with species resistant to voriconazole, such as agents of mucormycosis,
are now being seen.
Pharmacokinetics are highly variable between individuals, necessitating therapeutic drug monitoring.
679
YEASTS
DIMORPHIC
FUNGI
Candida spp.
MOLDS
Histoplasma
capsulatum
Aspergillus
fumigatus
++
++
+++
++
++
++
+++
++
+++
+++a
+++
+++
++
++
+++
++
+++
+++
++
++
+++
+++
+++
+++
+++b
+++
++
+++
+++
+++
+++
+++
not used
++
not used
not used
not used
+++a
not used
not used
not
used
not used
+++b
not used
not used
not used
not used
C.
albicans
C.
glabrata
C.
krusei
C.
parapsilosis
Ketoconazole
Itraconazole
++
Fluconazole
+++
Voriconazole
+++
Posaconazole
Cryptococcus spp.
Scedosporium
prolicans
Agents of
mucormycosis
Fusarium
solani
Azoles
Polyenes
Amphotericin
B
Echinocandins
Caspofungin
Allylamines
Terbinane
Miscellaneous
5-Flucytosinec
a
The combination of voriconazole and terbinane shares in vitro synergy; case reports demonstrate clinical efficacy of this combination.
The combination of ucytosine with amphotericin B results in better outcomes in non-immunocompromised patients with cryptococcal meningitis.
c
5-Flucytosine monotherapy results in the rapid emergence of resistance in most fungi.
b
680
Table 21-9 Activity of antifungal agents against selected yeasts and molds seen in systemic fungal infections
Toxicity includes visual disturbances and hallucinations

due to effects on the retina, but only last a day or two;
this is more likely in patients with high blood levels.
Voriconazole can derange liver function tests, and is
an inhibitor of cytochrome P450 enzymes, causing
important interactions with many of the drugs used in
transplantation.
Posaconazole
Posaconazole has a similar spectrum of activity and sideeffects to voriconazole. It is only available as an oral preparation, and absorption is better if given with fatty foods.
Therapeutic drug monitoring for azoles
Pharmacokinetics of azoles are highly variable, particularly
for itraconazole, voriconazole and posaconazole, and thus for
serious infections in which these agents are used, therapeutic
drug monitoring is recommended.
Table 21-10 Management of acute fever
STEP
Identify patients
requiring urgent
intervention
Vital signs consistent with shock

Confusion, seizures, dehydration
Meningitis
Sepsis in asplenic patients
Febrile neutropenia
Identify people with

localized or easily
diagnosed infection
Many infections have a typical

clinical syndrome, for example
pneumonia, gastroenteritis
Identify patients
potentially harboring
serious infection
Rapid progression
Rigors
Muscle pain
Decreased level of
consciousness
Vomiting, especially with
abdominal pain or headache
Unexplained rash
Jaundice
Elderly patients
Injection-drug users
Diabetes mellitus
Travel history
Possibility of zoonosis
Contact with meningococcal
disease
Investigations
Septic work-up:
Full blood count
Chest X-ray
Urine analysis and urine
microscopy and culture
Blood cultures
Imaging
Admission
Patients with possibility of serious

infection or presence of risk
factors, as outlined above
Patient re-presenting with febrile
illness
Temporal course suggesting
progression
Ampholenes
Amphotericin B intercalates between phospholipids, disrupting the lipid structure of the cell membrane of fungi,
causing cell death.
Amphotericin B deoxycholate is the original formulation. It is considerably toxic, causing predictable shortterm and long-term renal impairment, and fever and
rigors with infusion.
More recent lipid preparations are less toxic but considerably more expensive.
Amphotericin B is broadly active against most molds
and yeasts, except for Scedosporium spp. and Fusarium spp.
Echinocandins
Echinocandins (caspofungin, anidulafungin and micafungin) inhibit glucan formation in the fungal cell wall, terminating cell replication.
Although not absorbed orally, good levels are obtained
following IV administration, and these drugs penetrate
well into most issues.
They are eliminated by hepatic excretion, but do not
interact with the cytochrome P450 system.
Side-effects have been relatively few; they do not appear
to interact with many medications, unlike the azoles,
and thus are particularly useful in transplantation.
Echinocandins have excellent activity against most Candida and Aspergillus spp., but are not active against fungi
lacking glucan such as Cryptococcus spp.
SPECIFIC SYNDROMES
Acute fever
The steps in Table 21-10 are suggested in managing those
with acute onset of fever.
COMMENT

Pyrexia or fever of unknown origin is defined as a patient
with an unexplained fever despite an extensive set of investigations, generally over at least 1 week for a hospitalized
patient, and 2 or 3 weeks for one investigated as an outpatient. Such investigation would include the usual septic
work-up (shown in Table 21-10), plus organ imaging and
investigation for autoimmune disease.
Common causes of PUO are shown in Table 21-11,
overleaf.
681
Table 21-11 Common causes of fever of unknown origin in HIV-negative patients
TYPE OF DISEASE
(% OF PUO CASES)
Infection (~30%)
Neoplasm (~15%)
Autoimmune disease (~25%)
SUBTYPE OF DISEASE
EXAMPLES
Bacterial/mycobacterial
Tuberculosis
Culture-negative endocarditis
Deep abscess
Osteomyelitis
Pericarditis
Enteric fever
Brucellosis
Psittacosis
Viral
Cytomegalovirus
EpsteinBarr virus
Human immunodeciency virus (not
previously diagnosed)
Other
Q-fever
Malaria
Amebiasis
Toxoplasmosis
Hematological
Lymphoma
Leukemia
Solid tumors
Kidney
Lung
Atrial myxoma
Stomach
Disseminated carcinoma

Granulomatous disease
Sarcoidosis
Crohns disease
Granulomatous hepatitis
Vasculitic disease
Polyarteritis nodosa
Polymyalgia rheumatica/giant cell arteritis

Miscellaneous (~20%)
Drug fever
Thromboembolic disease
Endocrine disease
Hyperthyroidism
Addisons disease
Factitious fever
HIV, human immunodeciency virus; PUO, pyrexia of unknown origin.
The approach to a patient with PUO is essentially that of

any infectious disease, involving a very thorough history
and examination. Diagnostic work-up generally starts with
noninvasive tests, then works through imaging, and then
more invasive tests involving tissue biopsies. The rapidity
with which one would escalate through this range of tests
682
depends on how unwell the patient is, and whether there

are symptoms, signs or blood tests that are consistent with
serious organic illness.
The initial round of investigation should ensure that
pivotal sections of the history and examination and septic
work-up are not being missed.
The history of each symptom needs to be established

with respect to time course, duration and severity.
Collaborative history is often useful, and a history of
occupational and animal exposures, overseas travel, sexual history and drug use should be sought.
Physical examination is to be thorough, and as well
as the usual cardiovascular, respiratory and abdominal
examination, examination of the integument, lymph
glands, eyes including fundi, temporal arteries, and thyroid gland for evidence of hyperthyroidism is necessary.
Rectal, pelvic and breast examinations should be considered, and evidence of thrombosis sought.
Investigations should include:
Full blood count and blood film examination.
34 sets of blood cultures.
Acute phase reactants, including ESR, C-reactive
protein and possibly pro-calcitonin.
Urine analysis, urine microscopy, and culture.
Chest X-ray.
Liver function tests.
Electrolytes, creatinine, and urea.
Immunological tests, including anti-nuclear antibodies
(ANA), rheumatoid factor, ANCA (anti-neutrophil
cytoplasmic autoantibody), anti-double-stranded
DNA (ds-DNA) antibodies, and antiphospholipid
antibodies.
Serological testing should include an HIV antibody test
and testing for EBV and CMV, and, depending on likelihood, entities such as Q-fever, brucellosis, leptospirosis, syphilis, psittacosis, toxoplasmosis and hepatitis A, B
and C.
Tuberculosis should be specifically sought with a full
range of tests.
Organ imaging is pivotal in evaluating PUO. Many
occult diagnoses of yesteryear such as liver abscesses are
readily diagnosed by CT.
Nucleotide imaging is sometimes useful. Gallium scanning can help elucidate which organ system may be
responsible in more obscure cases. Occasionally, a bone
scan can detect inflammatory conditions of the bones
such as osteomyelitis, and entities such as SAPPHO
syndrome (synovitis, acne, palmo-plantar pustulosis,
hyperostosis, osteitis).
Echocardiography is essential to rule out endocarditis.
If the diagnosis is not forthcoming, further rounds of investigation and their invasiveness will depend on how ill the
patient is, and whether there is evidence of serious organic
disease. If this is so, more invasive tests such as tissue biopsies
should be considered.
Tissues such as skin, lymph nodes, muscle and bone
marrow are generally safely sampled.
Other more invasive biopsies should be reserved for
those in which the diagnosis is elusive and imaging or
blood tests suggest a particular organ is involved such as
the liver.
Occasionally, diagnostic laparotomy has been used in the

past to diagnose PUO. This has been supplanted by laparoscopy, which is much safer for the patient, allows direct
visualization of most intra-abdominal organs and allows for
sampling under controlled conditions.

A wide range of skin and soft tissue infections are seen in
clinical practice, as shown in Table 21-12 (overleaf).
Furuncles and carbuncles

A furuncle is extension of folliculitis into the dermis.
A carbuncle is the confluence of several furuncles, usually
seen in areas of hairy skin.
They are classically caused by S. aureus, and are the hallmark of community MRSA.
Treatment involves incision and drainage, and hygiene
measures.
It has been shown that for lesions less than 5 cm in diameter, incision and drainage alone is just as good as incision and drainage followed by antibiotics. Additionally,
the widespread use of antibiotics increases resistance in
MRSA.
However, if the lesion is greater than 5 cm and/or systemic sepsis is present, systemic antibiotics should be
used.
It is important to take swabs, because many of these
lesions are now due to MRSA strains, and the susceptibility to non-beta-lactams is becoming less predictable.
It is important to detect a history of recurrent boils in
the patient or family members. If this is present, then
a staphylococcal eradication regimen should be applied
once all acutely pyogenic lesions are controlled.
CLINICAL PEARL
10-point plan to eradicate Staphylococcus aureus
carriage:
1 Control all the patients pyogenic lesions rst.
2 Treat all family members simultaneously.
3 Take showers, not baths, and use an antistaphylococcal soap or body cleanser.
4 Do not share towels, clothing, or other linen that
comes into contact with the skin.
5 Change underwear daily and night attire regularly.
6 Use tissues rather than a handkerchief; do not pick
the nose.
7 Avoid sports that cause sweating and friction with
clothes.
8 Wash clothes and bed linen in hot water and dry in
the sun.
9 Apply nasal mupirocin appointment for 10 days.
10 Reduce weight if overweight, and follow a balanced
diet.
683
Table 21-12 Skin and soft tissue infections, and common pathogens
INFECTION
USUAL PATHOGENS
LESS-COMMON PATHOGENS
Impetigo
Folliculitis
Boils and carbuncles
Erysipelas (skin infection

conned to the upper dermis;
Figure 21-5)
Streptococcus pyogenes,
group G streptococci
Group B streptococci
Cellulitis
Group G streptococci
Group C streptococci
Group B streptococci
(especially diabetics)
Pseudomonas aeruginosa; other resistant Gramnegative bacilli (immunosuppressed patients)

Pasteurella multocida (cat or dog bites)
Aeromonas spp. (fresh/brackish water; patients with
cirrhosis)
Vibrio spp. (salt/estuarine water; patients with cirrhosis)
Erysipelothrix rhusopathiae (injury from saltwater sh
or crustaceans)
Mycobacterium marinum (indolent infection after
water exposure)
Pseudomonas aeruginosa (spa pools)

Malassezia furfur
Cellulitis
Cellulitis is a pyogenic infection of the skin and soft tissue,
and is usually caused by beta-hemolytic streptococci, sometimes in conjunction with S. aureus.
Mostly it involves the lower limbs (Figure 21-6), and
risk factors for this infection include obesity, tinea,
ulcers, chronic venous disease, and diabetes mellitus.
Gram-negative organisms can be introduced by certain
exposures such as to water.
Figure 21-5 Facial erysipelas

Failure of the above regimen usually means inadequate
adherence, or a new staphylococcal carrier has been introduced to the group.
If there has been adequate adherence and no identified
re-introduction of S. aureus, then it is reasonable to consider repeating the regimen but also using systemic antibiotics, usually containing rifampicin in combination
with another drug.
Note that rifampicin has important drug interactions
such as interfering with the oral contraceptive pill,
which is usually an issue in these family groups.
It is necessary to use a second agent in conjunction with rifampicin to prevent the emergence of
resistance.
684
Figure 21-6 Cellulitis of the anterior aspect of the

right leg
Patients with hepatic cirrhosis are predisposed to infections with Vibrio and Aeromonas spp., which can be rapidly progressive.
In the case of mild cellulitis, blood cultures are generally
negative, but in cases of sepsis then blood cultures can be
very informative.
Any purulent or ulcerated lesion should be swabbed.
Sometimes the pathogen can be obtained by aspirating
the leading edge.
In S. pyogenes cellulitis the anti-streptolysis O titer
(ASOT) and/or DNase B may be positive, but is not
helpful if negative.
With respect to empirical therapy, anti-staphylococcal
penicillins or 1st-generation cephalosporins cover both
beta-hemolytic streptococci and S. aureus.
If there are boils or abscesses, the possibility of MRSA
should be covered.
If there are risk factors for Gram-negative organisms,
cover should be broadened.
It is vitally important to recognize abscess collections, and
necrotizing fasciitis. This latter diagnosis is suggested by
rapid progression with severe pain, and a much discolored
limb in a septicemic patient. This should prompt referral to
a surgeon for urgent debridement, sending samples to the
laboratory for microbiological examination. Hyperbaric
oxygen should be considered. S. pyogenes and polymicrobial
coliform/anaerobe infections need to be covered, generally
with a carbapenem plus a macrolide to inhibit ribosomal
translation of exotoxins should the etiology be S. pyogenes.
Once the pathogen is identified, antibiotics can be modified.
Drug fever
Drug fevers are important to recognize to avoid unnecessarily long courses of antibiotics and series of investigations.
It is important to have a full history of the drugs that have
been taken in the past few weeks, including those that
have been discontinued.
Table 21-13 lists drugs known to cause drug fever, classified by pathological mechanism.
CLINICAL PEARL
Factors suggesting the possibility of drug fever:
Patient taking medication known to cause fever
Initiation of possible offending agent within the last
week or two before fever
Absence of a clinical source of infection
Patient looks relatively well
Relative bradycardia
Rash
Eosinophilia
Particular organ dysfunction which may be part of
the drug reaction, including derangement of liver
function tests and elevated creatinine
Fever resolves within days of terminating the offending drug
Re-challenge that causes fever is highly suggestive
(but could result in a more serious reaction and is
generally best avoided).
Table 21-13 Drugs known to cause drug fever
TYPE OF
REACTION
IMPLICATED DRUGS
Hypersensitivity
Phenytoin, carbamazepine
Penicillins, cephalosporins
Sulfonamides
Nitrofurantoin, minocycline
Abacavir
Allopurinol
Alpha-methyldopa
Thermoregulator
interference
Major tranquilizers, tricyclic

antidepressants
Methylenedioxymethamphetamine
(Ecstasy), amphetamines, cocaine
Direct pyrogens
Amphotericin B
Pharmacological drug action
Tumor lysis syndrome following
chemotherapy and/or radiotherapy
JarishHerxheimer reaction
following treatment of spirochete
and mycobacterial infections
Idiosyncratic
Malignant hyperthermia:
succinylcholine, halothane
Neuroleptic malignant syndrome:
major tranquilizers
Serotonin toxicity: selective
serotonin reuptake inhibitors, lithium,
L-tryptophan
INFECTIONS IN SPECIAL HOSTS

AND POPULATIONS
Infections in immunosuppressed
patients
Immunocompromised patients are increasingly seen as more
patients are subjected to more aggressive immunosuppressant therapies.
In infections in the immunosuppressed:
Localizing information may be minimal or absent, and
presentations can be atypical.
Symptoms and signs may appear or increase on restitution of the immune deficit
Physical examination must be thorough, is needed regularly, and includes sites such as the perianal region and
CNS.
The range of pathogens is considerably broader.
There can be more than one infection.
Empirical treatment needs to be broad-spectrum, but
can be tailored to specific pathogens.
685
A wide range of diagnostic tests, including invasive

ones, needs to be applied.
Neutropenia
Neutropenia induced by cytotoxic chemotherapy, especially
for acute myeloid leukemia (AML) and in bone marrow
transplantation, is commonly seen. As the neutrophil count
drops below 1.0 w 109 cells/L, opportunistic infection becomes
much more common, and below 0.1 w 109 cells/L rapidly overwhelming bacterial infections may occur. With severe and
prolonged neutropenia, invasive fungal infections are seen.
With the onset of fever in a neutropenic patient, it is
important to do a full clinical examination including
perianal areas and eyes, IV lines, plus chest, cardiovascular and abdominal examinations.
Multiple sets of blood cultures, urine examination,
and chest X-ray should be done, and broad-spectrum
anti-pseudomonal beta-lactams instituted immediately.
Common sites of infection are the lungs and IV devices,
and so high-resolution CT scanning of the chest is very
important.
About 20% of patients will have positive blood cultures.
The diagnosis of invasive fungal infections is problematic, as
the gold standard tissue for diagnosis is usually not available.
Bronchoscopy may yield potential pathogens.
Biomarkers such as galactomannan levels are unreliable
in isolation, although serial galactomannan assays or
PCR assays of blood have some utility.
Box 21-1 shows pathogens that should be considered in
febrile neutropenic patients with pulmonary infiltrates.
Humoral immunodeciency
Box 21-1
Causes of pulmonary inltrates and

lesions in neutropenia
Bacteria
Enterobacteriaceae
Legionella pneumophila
Viruses
Inuenza
Human metapneumovirus
Respiratory syncytial virus
Rhinovirus
Parainuenza virus
Fungi
Aspergillus spp.
Agents of mucormycosis
Scedosporium spp.
Reactivation
Mycobacterium tuberculosis
Dimorphic fungi
Non-infectious causes
Pulmonary edema
Neoplasm
Pulmonary hemorrhage
Pneumonitis (drug-induced)
Pneumonitis (radiation-induced)
Patients with multiple myeloma, chronic lymphocytic leukemia, nephrotic syndrome and protein-losing enteropathy
have defective humoral immunity, and are at greater risk of
infection with encapsulated bacteria (such as S. pneumoniae
and N. meningitidis). Although the response is impaired, it
is recommended to vaccinate such patients against these
organisms, and consider infusions of gammaglobulin.
Cellular immunodeciency
General points
Patients with HIV/AIDS, or those on various immunosuppressant drugs administered as part of transplantation regimens or in the treatment of autoimmune and hematological
disorders or primary cellular immune defects, have defective
cellular immunity and are predisposed to infections with
intracellular pathogens, both primary infections and reactivation with the agents shown in Table 21-14.
The term sexually transmitted infections denotes

infections in which the primary mode of transmission is
sexual.
Some infections not classified as STIs can be transmitted sexually (e.g. hepatitis B virus, CMV, C. albicans).
These infections often involve a period of latency and
a high proportion of asymptomatic cases, which facilitates transmission. They also feature a lack of protective
immunity at the mucosal level, allowing for repeated
infections.
Contact tracing is very important in the control of STIs.
There can be important cultural considerations here,
such as with culturally and linguistically diverse people,
indigenous people, or sexual minority groups. It is often
useful to engage the assistance of social workers and STI
nurses in counseling and contact tracing.
Splenectomized patients
Patients who are asplenic are unable to clear opsonized bacteria and are particularly prone to overwhelming infections
with S. pneumoniae, but also with N. meningitidis and (historically) H.influenzae. It is recommended to vaccinate such
patients against these pathogens, give prolonged prophylactic beta-lactams, and counsel them to present immediately
for antibiotics should fever and rigors occur.
686
Table 21-14 Opportunistic pathogens seen in cellular immunodeciency
TYPE OF
ORGANISM
Viruses
Bacteria
Fungi
Parasites
SPECIES
TYPICAL INFECTIONS
Cytomegalovirus
Viremia
End-organ disease
Herpes simplex virus
More severe local diseases

May disseminate
Varicella zoster virus
Severe primary infection

Severe reactivation often with secondary dissemination
EpsteinBarr virus
Various malignancies
JC virus
Progressive multifocal leukoencephalopathy (PML)
Reactivation
Can be atypical
Non-tuberculous mycobacteria
Pulmonary
Disseminated
Salmonella enterica
Disseminated
Listeria monocytogenes
Meningitis
Hepatitis
Disseminated
Nocardia spp.
Pulmonary
Brain abscess
Disseminated
Cryptococcus spp.
Meningitis
Disseminated
Pneumocystis jirovecii
Pneumocystis pneumonia
Dimorphic fungi
Reactivation (sometimes years after exposure)
Autoinfection
Can have secondary Gram-negative bacteremia
Toxoplasma gondii
Cerebral abscesses
Drug resistance is known to be a serious issue with

treating gonorrhea, and may well be a serious issue in
treating other STIs.
Many isolates of N. gonorrhoeae from certain geographical areas are resistant to what were first-line drugs,
and have to be treated with parenteral drugs; and panresistant strains are likely to be seen soon.
CLINICAL PEARLS
Patients with sexually transmitted infections (STIs)
may have multiple sexually transmitted infections, including asymptomatic ones. All STI patients
should be tested for HIV, syphilis, gonorrhea, Chlamydia trachomatis, and hepatitis B as a minimum,
plus other STIs that are locally prevalent.
Prompt empirical treatment and contact tracing are
essential in disease control.
History
History taking and examination, as in all areas of medicine,
are pivotal in the evaluation of a patient for STIs.
In particular, elucidation of symptomatology pertaining to the genitals can be delicate, and achieving rapport with the patient and gaining their confidence are
important in getting full details of sexual partners and
sexual acts undertaken.
Confidentiality is very important in this area, and in STI
clinics clients are often identified by a number rather
than by name and date of birth, to facilitate attendance
and specific questioning about sexual history, sexual
acts including vaginal, anal and oral sex, use of sex toys,
accessory drugs and substances.
A past history of STIs is important, as is a travel history
that includes places visited and sexual activities during
the trip. The geographical area where the patient was
687
exposed influences diagnostic considerations; acquisition in less-developed countries increases the chance of
HIV and syphilis, for example.
Medications and allergies are important, especially if
the patient might have a drug-resistant pathogen or the
symptomatology might be an adverse consequence of
adrug.
Examination
The examination needs to involve a full examination of the
anogenital region as well as the rest of the body. It is important to have a private area with a comfortable examination
couch and good lighting, and a full range of equipment
(i.e.swabs and speculae) on hand.
The presence of HIV can be suggested by wasting, oral
candidiasis and/or seborrheic dermatitis.
Rashes can occur in HIV seroconversion, acute CMV
and EBV (especially if antibiotics have been taken), and
also secondary syphilis.
Lymphadenopathy and/or hepatosplenomegaly can
occur in systemic viral infections including HIV, EBV
and CMV.
With respect to genital examination, the presence of
vesicles on a red base suggests herpes simplex virus
(HSV) infection.
A painless red lesion could be a syphilitic chancre.
Painful red lesions could suggest lymphogranuloma

venereum.
Urethral or cervical discharge suggests gonococcal or
chlamydial infection.
Warts can be found on the genitals or anal region.
A full set of diagnostic specimens should be taken during the
physical examination.
Diagnostic specimens include urethral or cervical swabs
for Gram stain, culture and PCR for N. gonorrhoeae and
C. trachomatis, swab of ulcers for dark-field examination for T. pallidum, and high vaginal swab for wet film
(Trichomonas spp.) and culture (C. albicans).
Investigations
Table 21-15 shows diagnostic tests for specific STIs.
Managementgeneral
The general principles of STI management include
counseling, advice about safe sex and prevention of STIs,
contact tracing, and provision of empirical treatment.
Empirical treatments are aimed at likely pathogens and
usually select agents that have a higher adherence.
Partner notification is important, as is notification to
the relevant public health authorities, and follow-up for
test-of-cure specimens and definitive results.
Table 21-15 Diagnostic tests for sexually transmitted infections
PATHOGEN
HSV-2 or HSV-1
Neisseria gonorrhea
Chlamydia
trachomatis
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SPECIMEN
Viral swab
DIAGNOSTIC TESTS
COMMENTS
PCR
PCR is the best test and is now widely available
IF
Quick, high sensitivity and specicity
Culture
Slower, superseded
Blood
IgG, IgM, WB
Usual in seroprevalence surveys but not helpful

in routine diagnosis of HSV
Vaginal or
urethral swab;
rst pass urine
PCR
Fast and sensitive; no antibiotic data
Vaginal or
urethral swab
Culture
Bacterium is fragile and can die before reaches

laboratory; could inoculate plates at bedside
Culture allows for susceptibility testing
Special swabs facilitate survival of organism
during transport to laboratory
Vaginal or
urethral swab
IF
Quick and sensitive; superseded by PCR
Vaginal or
urethral swab;
rst-pass urine
PCR
Sensitive, specic and widely available
Vaginal or
urethral swab
IF
Sensitive but superseded by PCR
Vaginal or
urethral swab
Culture
Requires transport media and special culture

methods; superseded by PCR
PATHOGEN
Treponema pallidum
Human
immunodeciency
virus (HIV)
SPECIMEN
DIAGNOSTIC TESTS
COMMENTS
Swab
Dark-eld examination
Some utility in diagnosing genital chancre

Not useful in pharynx or anus as spirochetes are
part of normal ora
Blood
EIA (ELISA)
Usual screening test; if positive, traditional tests

(RPR, TPPA, etc) performed to conrm
Like all syphilis serological tests, can be falsely
negative in early primary disease so retest if
primary disease possible
RPR (VDRL)
Reaginic test, titer some reection of disease

activity, falls with successful treatment
RPR supersedes VDRL which requires
microscopy
TPPA/TPHA
Specic test, quite sensitive, stays positive for life
FTA-ABS
Used as conrmation of new diagnosis
WB
Used as conrmation of new diagnosis
EIA
Can test for HIV-1, HIV-2, also p24 Ag in some

formats
p24 Ag EIA
Useful in seroconversion if EIA negative
WB
Used as conrmation of EIA; can be positive,

negative or indeterminate
If indeterminate, pattern can suggest likelihood
of HIV especially if new bands evolve on
subsequent testing
VL
Useful in determining blood level and also

response to antiretroviral treatment
Blood
Gardnerella vaginalis
Vaginal swab
Wet lm
Coccobacilli replace lactobacilli and adhere to

squamous epithelial cells (clue cells)
Trichomonas vaginalis
Vaginal swab
Wet lm
Typical morphology and motility on wet lm
Haemophilus ducreyi
Swab of lesion
Gram stain
Typical small Gram-negative coccobacilli
Culture
Culture of organism
Donovan bodies (unculturable)
Calymmatobacterium
granulomatis
Swab/biopsy/
impression
smear of lesion
Wrights or Giemsa stain
Chlamydia
trachomatis (LGV
strains)
Blood
Serology
Human papillomavirus
Papanicolaou
smear
Cytology stain
Tissue
PCR
Atypical or malignant cells
EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay (old term for EIA); FTA-ABS, uorescent Treponema antibody
absorption test; IF, immunouorescence test; IgG, immunoglobulin G; IgM, immunoglobulin M;; LGV, lymphogranuloma venereum; p24
Ag, p24 antigen; PCR, polymerase chain reaction; RPR, rapid plasma reagin test; TPHA, Treponema pallidum hemagglutination test; TPPA,
Treponema pallidum particle agglutination test; VDRL, Venereal Diseases Reference Laboratories test; VL, viral load; WB, western blot.
689
Specic entities
Urethritis
Patients with urethritis are treated empirically for gonococcal and chlamydial infection.
Antibiotic resistance is highly variable between countries, being common in underdeveloped countries and
still unusual in isolated communities.
Sex worker movement between countries can
import STIs, including drug-resistant strains of
Neisseria gonorrhoeae.
Many strains of N. gonorrhoeae seen today are resistant to
all oral agents, including quinolones, necessitating the
use of 3rd-generation cephalosporins.
Chlamydia trachomatis lacks a cell wall and so is not
affected by beta-lactams, but is susceptible to tetracyclines and macrolides.
If N. gonorrhoeae or C. trachomatis is not demonstrated,
the patient is considered to have non-specific urethritis.
Agents such as Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis, Neisseria meningitidis and
Haemophilus spp., and viruses such as HSV and human
papillomavirus (HPV), can be implicated.
N. gonorrhoeae infects any columnar epithelium, and
so infections of the rectum, pharynx and conjunctiva
can occur. Anti-gonococcal drugs such as penicillin or
spectinomycin do not clear pharyngeal carriage, and so
quinolones or 3rd-generation cephalosporins need to be
used here.
Proctitis
Patients with proctitis present with tenesmus, anal discharge, and blood and mucous in the stools.
Etiologies include N. gonorrhoeae, HSV, C. trachomatis,
Shigella spp. and Campylobacter spp.
Diagnosis is confirmed at proctoscopy, at which time
swabs can be taken for Gram-stain for gonococci within
neutrophils, culture and/or PCR, and viral swabs taken
for HSV PCR.
Stools should be submitted for Shigella spp. and Campylobacter spp. culture.
Lower abdominal pain and fever, and tenderness on

rocking the cervix during pelvic examination, are
characteristic.
Specimens for N. gonorrhoeae and C. trachomatis should
be taken (urine and/or cervical swabs), and antibiotics
covering STI organisms and ascending normal flora
initiated (such as cefoxitin + doxycycline, ceftriaxone +
metronidazole + doxycycline).
Vaginal infections
Three common vaginal infections are candidiasis, bacterial
vaginosis, and Trichomonas spp.
Candidiasis is usually due to C. albicans but can be due
to other Candida species, particularly in immunocompromised people. Diagnosis is by seeing typical inflamed
areas with curd-like deposits and positive fungal culture.
Candidal organisms can also be seen on Gram stain and
wet films. Treatment is with topical antifungal creams,
but more recently fluconazole orally 150 mg as a single
dose has proved to be highly effective.
Bacterial vaginosis is an alteration of normal vaginal flora, where the normal lactobacilli are replaced
by organisms such as Gardnerella vaginalis, Mycoplasma
hominis, Mobiluncus species and anaerobes. Diagnosis
is by observing a clear or frothy discharge with a fishlike odor, and a wet film that shows replacement of
the normal bacilli with coccobacilli organisms, often
found adherent to the surface of squamous epithelial
cells (clue cells). Bacterial vaginosis is associated with
premature labor, and ascending infections in pregnant
women. Treatment is with oral metronidazole 500 mg
twice daily for 7 days, although a significant number of
cases will resolve without treatment.
Trichomonas vaginalis is a protozoan that is transmitted
sexually, and the diagnosis is readily made by observation of motile protozoans on a wet film. The patient and
partners are treated with metronidazole, tinidazole or
clindamycin.
Genital ulceration
STIs causing genital ulceration include HSV, syphilis (see
later section), chancroid, donovanosis, and lymphogranuloma venereum.
Cervicitis
Cervicitis presents with discharge, and during speculum examination pus can be seen coming out of a friable
uterine os.
Etiology is usually N. gonorrhoeae or C. trachomatis.
Investigation and treatment is as per urethritis.
HSV typically is revealed as small vesicles on a red base,

which may burst to form ulcers which can coalesce.
Primary infections range from asymptomatic to severe,
with bilateral lesions, and also systemic features such as
fever and enlarged inguinal lymph nodes. On occasion
there is urinary retention, and sometimes neurological
complications such as aseptic meningitis.
Recurrences are usually less severe and vary considerably in frequency.
Diagnosis is made by observation of classic lesions with
virological confirmation. PCR is highly sensitive and
specific and is the test of choice, superseding immunofluorescence and culture.
Pelvic inammatory disease

The etiology of pelvic inflammatory disease is often sexually transmitted organisms such as N. gonorrhoeae and
C. trachomatis in young women, and ascending infections with rectovaginal flora in older women.
Actinomycosis can complicate those with intrauterine
contraceptive devices.
690
Serology is not usually useful in the diagnosis of herpes

genitalis.
Treatment is with a thymidylate kinase inhibitor (famciclovir, valaciclovir or acyclovir/aciclovir).
Suppressive treatment can be considered for frequent
recurrences.
Disease tends to be more severe, prolonged, and sometimes progressive in the immunosuppressed, and in this
group drug resistance can also occur.
Recently, a vaccine against carcinogenic HPV types 6,

11, 16 and 18 has been licensed and is already decreasing
the incidence of cancer of the cervix.
This disease can be detected by screening with Papanicolaou smears, and following up on smears showing
suspicious cells.
HPV can be detected in tissue biopsies by various
techniques, with the most sensitive being nucleic acid
detection.
Chancroid
Molluscum contagiosum
Chancroid is caused by Haemophilus ducreyi and is seen in

northern Australia, Asia and Africa.
It presents with multiple tender ulcers and inguinal
lymphadenopathy.
The diagnosis is made by swabbing the lesions and
observing typical organisms on Gram stain, and sometimes positive culture. There is no serological test.
Therapy is with a 3rd-generation cephalosporin, quinolone or azithromycin.
Molluscum contagiosum is caused by a poxvirus that

causes centrally umbilicated raised lesions on the skin.
In a normal host these regress spontaneously, but can
progress in the immunosuppressed.
Treatment if required is with cryotherapy, diathermy,
curettage, or de-roofing lesions and applying glacial acetic acid or trichloracetic acid.
Donovanosis
Donovanosis is caused by Calymmatobacterium granulomatis, an unculturable organism, which causes beefy red
exuberant lesions on the glans penis or in the perianal
area.
Diagnosis is made by seeing classic lesions and observing
Donovan bodies on Wrights or Giemsa stain of swabs
or tissue.
Donovanosis requires a prolonged course of antibiotics
to be adequately treated. Erythromycin or tetracycline
should be taken for 3 weeks.
Lymphogranuloma venereum (LGV)
Lymphogranuloma venereum is caused by LGV strains of
Chlamydia trachomatis.
This disease manifests with transient ulceration followed by increasing inguinal lymphadenopathy.
Diagnosis is made by demonstrating a raised antibody
titer to this organism and sometimes culture or immunofluorescence of fluid from a bubo.
Treatment is with tetracyclines or macrolides.
Syphilis
Syphilis is caused by Treponema pallidum and has been famous
in the past as a great mimic of various diseases.
In more recent times its incidence and prevalence has
been increasing, particularly in men who have sex with
men, and it is also highly prevalent in the developing
world and in some indigenous communities.
Primary infection may be manifested by Hunterian
chancre, which is a painless red papule found on the
genitals or sometimes perianally. This lesion resolves.
A few weeks later, patients may manifest secondary
syphilis, which is usually characterized by vasculitis,
typically including a maculopapular rash that involves
the palms and soles (Figure 21-7), and often a febrile
illness with lymphadenopathy and hepatosplenomegaly.
This will eventually resolve, and the disease becomes
quiescent or latent. Latent disease of less than 2 years
Human papillomavirus (HPV)

70 types of HPV are described.
Types 6 and 11 cause asymptomatic infections or genital warts that are not associated with
malignancy.
Types 16, 18, 31, 33, and 35 cause asymptomatic
anogenital infections, which can lead to the development of squamous cell carcinomas of the cervix
but also of the anus.
Treatment of genital warts can be challenging; it involves
ablation with cryotherapy, diathermy, application of
podophyllin residues, and sometimes intralesional interferon injection.
Figure 21-7 Maculopapular rash on the palms from

secondary syphilis
From Ortega KL, Rezende NPM and Magalhes MHCG. Diagnosing
secondary syphilis in a patient with HIV. Br J Oral Maxillofacial
Surg 2009;47(2):16970. The British Association of Oral and
Maxillofacial Surgeons.
691
duration is considered early latent disease, and beyond

this it is late latent disease.
Years after initial infection, vasculitis can be manifested
by neurological manifestations such as cognitive impairment, tabes dorsalis, and Argyll Robertson pupils.
Co-infection with HIV can result in atypical manifestations of syphilis and false-negative diagnostic tests, and
increases the chance of relapse after treatment.
Diagnosis
Occasionally, if a chancre is seen then diagnosis can be made
by dark-field examination of fluid from this lesion. For most
cases, the diagnosis is made serologically.
Usually enzyme immunoassay (EIA) is used as a screening test. This is quite sensitive and specific, but like all
syphilis tests can be falsely negative in early syphilis.
If the index of suspicion is high, tests should be
repeated several weeks later.
If the EIA is positive, this is confirmed with traditional syphilis tests which include reaginic and
treponemal tests.
Reaginic tests use cardiolipin antigen, which crossreacts against antibodies produced in syphilis but also in
other diseases, especially autoimmune disease.
Reaginic tests include the traditional Venereal Diseases Reference Laboratory (VDRL) test, which is
very labor-intensive, utilizing light microscopy, and
thus has been replaced by the rapid plasma reagin
(RPR) test.
Reaginic tests achieve high titers in active disease,
especially secondary or tertiary, and the success of
treatment can be measured by the extent of fall in
titer.
Treponemal tests utilize spirochete antigen. These
include Treponema pallidum hemagglutination (TPHA)
and Treponema pallidum particle agglutination (TPPA)
tests. These tests are more specific for syphilis infection,
and remain positive for life following infection.
To gain greater specificity with the diagnosis, sera yielding positive reaginic and/or treponemal tests are usually
confirmed with a further fluorescent Trepenoma antibody absorption (FTA-ABS) test, or sometimes with
other tests such as a western blot.
It is important to note that in early primary syphilis, and
sometimes in late disease in patients with AIDS, that
false-negative results can occur with all of these tests.
Treatment
Penicillin is the only drug of proven efficacy to treat
syphilis.
Different intensities in durations of treatment are recommended for the different stages of syphilis.
3rd-generation cephalosporins have been recommended
in some regimens, particular for HIV-positive individuals as this facilitates outpatient parenteral treatment, but
evidence of efficacy in trials is lacking.
Alternatives for penicillin-allergic patients such as doxycycline are unproven. It is generally recommended that
692
patients said to be allergic to penicillin should be evaluated, and if found to truly be allergic to consider desensitization, particularly if the patient has late latent or
tertiary syphilis and/or is immunosuppressed, especially
due to HIV infection.
All patients treated for syphilis require follow-up RPR
at 3, 6, 12 and 24 months. The lack of a fourfold decrease
in RPR titer at 6 months usually requires repeat treatment. Patients can be reinfected with Treponema pallidum.
SYSTEMIC VIRAL INFECTIONS

HIV
See Chapter 17 for HIV/AIDS. All patients with an STI
should have HIV testing.
Hepatitis viruses
Hepatitis A infection can be seen in men who have sex
with men, sometimes causing outbreaks, and is particularly seen in people who have fecaloral contact.
Hepatitis B can be transmitted sexually, and should be
screened for when evaluating patients with STIs.
Vaccines against hepatitis A and hepatitis B are available,
and should be given to those at risk.
Hepatitis C is rarely transmitted sexually.
See Chapter 13 for additional information on the diagnosis
and treatment of hepatitis.
Herpesviruses
EBV and CMV exposures are more common in those
with multiple sexual contacts. These infections can be
manifested as primary infection. Diagnosis is usually
readily made serologically.
All herpesviruses have latent states, and can reactivate in
immunodeficiency states such as in AIDS.
Diagnosis and treatment are covered earlier in the chapter.
Zoonoses
General
Zoonoses are caused by a complex group of pathogens,
numbering in the hundreds.
The definition is usually considered to be an infection
that derives from vertebrate animals.
Most emerging infectious diseases begin as zoonoses.
Infectious diseases such as AIDS, tuberculosis and measles began as zoonoses, and common infections such as
influenza are still predominantly zoonotic.
Transmission can be via many routes, such as eating
uncooked or cooked tissues of an animal, contact with
the excreta of an animal, inhaling aerosolized material
from an animal, the bite of an animal, or by transmission from animal to human by the bite of an invertebrate such as an insect.
History
The history of exposure is important in evaluation of all
infectious diseases.
The possibility of zoonotic infection is usually elucidated from the history.
An extensive history of all travel, both recent and in the
past and including immigration, is important.
Occupational exposures, and hobbies and interests
including pets kept at home and interest in hunting,
bushwalking and other such activities, needs to be
explored.
CLINICAL PEARL
The following suggest the possibility of a zoonosis:
Travel history
Occupation as veterinarian, farmer or abattoir
(slaughterhouse) worker
Unusual food ingestion
Hobbies such as hunting, trapping, bushwalking,
adventure holidays
Characteristic skin lesions
Eating, being bitten by, or being exposed to particular animals
Sometimes the possibility of zoonotic infection is not

considered until clinical features, imaging or diagnostic
test results are suggestive, and specific questioning then
reveals possible or definite animal exposure.
Additionally, there is extensive trade, both legal and
illegal, in animals and animal products, which in conjunction with increased air travel results in greater range
and frequency of exotic zoonoses being encountered.
Rabies post-exposure prophylaxis should be given if an

animal from a country with rabies is involved.
Specic examples of zoonoses

Selected zoonotic infections are considered in Table 21-16,
overleaf.
Lyme disease (Borrelia burgdorferi)

Lyme disease is a tick-borne illness endemic in the United
States (north central and northeast) and Europe.
In stage I (early, delayed), a red lesion (erythema
migrans; Figure 21-8), often with a bulls-eye appearance, develops. Serology is of no value in this stage and
treatment is usually doxycyoline.
If untreated, early disseminated disease (stage II) may
manifest with fever, myalgia, lymphadenopathy, myocarditis (first-degree heart block) and aseptic meningitis
(cranial neuropathy, retinopathy).
Months to years later, migratory monoarthritis or rarely
encephalopathy may occur (stage III).
Serology (enzyme immunosassay [EIA], then confirmatory western blot) is only useful in stages II or III. Testing
should be reserved for those who live in an endemic area or
have traveled to one, with clinically suggestive symptoms
or signs.
Other tick-borne illnesses
Other tick-borne illnesses in the US include babesiosis
(causing fever and hemolysis), southern tick-associated rash
illness (a stage I Lyme-like disease) and ehrlichiosis (fever,
myalgia, headache, lymphopenia, abnormal transaminases).
CLINICAL PEARLS
Animal bites can transmit ora from an animals
mouth (Pasteurella multocida, Capnocytophaga
spp., anaerobes, Clostridium tetani) or inoculate a
patients endogenous ora (S. aureus).
Patients at risk of sepsis from animal bites include
those with asplenia, diabetes, cancer, cirrhosis and
lymphedema.
Tissue destruction and late presentation increase
the risk of infection.
Management
Irrigation and/or debridement and/or surgical
exploration.
Tetanus prophylaxis.
Antibiotics are aimed at flora of animal mouths and
human, e.g. the use of penicillin/beta-lactamase inhibitor combinations, or a 3rd-generation cephalosporin +
metronidazole.
Figure 21-8 Erythema migrans in Lyme disease

From Bhate C and Schwartz RA. Lyme disease. Part I: advances and
perspectives. J Am Acad Dermatol 2011;64(4):61936. American
Academy of Dermatology, Inc.
693
TYPICAL
PATIENT
ANIMAL
PRESENTATION
ORGANISMS
INVESTIGATION
TREATMENT
Cat
Cat owner
Infected cat bite or

scratch
Pasteurella multocida
Capnocytophaga spp.
Anaerobes
Clostridium tetani
Wound swab
Tetanus prophylaxis
Penicillin, 3rd-generation
cephalosporins, quinolone
Cat
Cat owner
Cat scratch fever
Bartonella henselae
Serology; blood culture
Self-limited usually
If prolonged, end-organ
disease: azithromycin
If immunosuppressed:
get advice
Dog
Dog owner
Infected dog bite
As per cat bite
Wound swab
As per cat bite
Dogs,
raccoons,
cats, monkeys
Bite in a country that

has rabid animals
Rabies
Rabies
Nil
Post-exposure vaccination
Cats, dogs,
pigs, horses
Human in close
contact
Staphylococcal infection
MRSA
MRSA can be humanosis
then transferred to humans.
Horses and pigs have own
MRSA strains
Wound swabs,
occasionally blood cultures
Anti-MRSA antibiotics
Monkey
Bite
Simian herpes
Simian herpesvirus
Nil
Acyclovir (aciclovir)
Birds, esp.
psittacine
Bird breeders, vet

workers, tree workers,
mowing lawn
Psittacosis
Chlamydia psittaci
Serology
Doxycycline; macrolides
Reptiles
Reptile owners
Salmonellosis
Salmonella spp.
Blood, stool cultures
Quinolones, 3GC,
azithromycin
Monkeys
Airborne exposure
Tuberculosis (TB)
Sputa: Mantoux test; IGRA
Anti-TB treatment
Livestock
Abattoir (slaughterhouse) worker
Systemic febrile illness:

Q-fever, brucellosis,
leptospirosis
Coxiella burnetii
Brucella spp.
Leptospira interrogans
Serology; culture for

Brucella spp.
Doxycycline
Various
Highly contagious
and exposure may
not be recognized
Systemic illness,
occasionally endocarditis
Coxiella burnetii
Serology; PCR
Resolved: no treatment
Acute: doxycycline
Endocarditis: rifampicin +
doxycycline, surgery
694
Table 21-16 Selected zoonoses from specic animals
Sheep, cattle,
kangaroos
Rare lamb, beef or

kangaroo meat eater
Toxoplasmosis
Congenital
toxoplasmosis
Reactivation in immunocompromised
Toxoplasma gondii
Serology
Immunocompromised: CT
brain, tissue biopsy
Primary disease: none

Pregnancy: specialist
evaluation and treatment
Immunocompromised:
sulfadiazine + pyrimethamine
Pigs
Pig hunter
Brucellosis
Brucella suis
Serology; blood cultures
Doxycycline + gentamicin
Ungulates
(cattle, goats,
sheep)
Drinkers of
unpasteurized milk/
milk products
Brucellosis
Brucella abortus, Brucella

melitensis, Brucella ovis
Blood cultures; serology
Doxycycline + gentamicin
Fish
Fish handlers
Erysipeloid
Erysipelothrix rhusopathiae
Characteristic lesions,
biopsy for culture
Penicillin
Fish
Aquarium-keepers
Mycobacterium marinum
Biopsy for culture and

histopathology
Antituberculous
chemotherapy
Bats
Bat keeper
Contact or bite of bat:

rabies-like illness
Australian bat lyssavirus
Exposure to bats
Post-exposure prophylaxis
with rabies vaccine
Sheep
Farmer, shearer
Vesicle on hand
Orf virus
Nil; EM on biopsy
Nil; antibiotics if secondary

infection
Sheep
Past farm contact
Hydatid disease
Echinococcus granulosus
CT: cystic lesions in liver,

lung, other tissues
Serology
Extirpation + albendazole
praziquantel
Various
Farmers, bushwalkers
Fever, conjunctivitis,
hepatitis, renal
impairment, aseptic
meningitis
Leptospira interrogans
Serology
Mild and settled: no

treatment
Not mild: doxycycline,
penicillin or 3rd-generation
cephalosporin
CT, computed tomography; EM, electron microscopy; IGRA, interferon-gamma release assay; MRSA, methicillin-resistant Staphylococcus aureus; PCR, polymerase chain reaction.
695
CLINICAL PEARL
Returned travelers with animal exposures may harbor
exotic zoonoses, some of which have signicant morbidity and mortality. Urgent infectious diseases consultation is strongly recommended; internet resources
are useful to identify zoonoses (and other infections)
associated with the geographical areas visited. The list
of these includes hundreds of pathogens. Selected
examples are:
Rocky Mountain spotted fever (USA)rash, fever,
headache, arthralgia, tick exposure (Figure 21-9)
Lyme disease (North America, Europe)
Rabies (predominantly Asia and Africa)
Plague (Middle East)
INFECTION PREVENTION
AND CONTROL
Infection prevention and control is gaining center stage in
modern hospitals due to the continually increasing problem
of multidrug-resistant organisms (MROs). The patients
themselves, the hospital environment, apparatus used on
patients, and healthcare workers can be reservoirs of these
organisms, and share organisms.
The major MROs of importance are given in Table
21-17.
Successful infection prevention and control programs
involve all seven pillars of infection control:
1 Administrative support
2 Education
3 Judicious use of antibiotics
4 MRO surveillance
5 Infection control precautions
6 Environmental measures
7 Decolonization.
All successful infection control programs have substantial administrative support. These programs are very
expensive and require specific budgetary allocation.
There also need to be management directives, and an
organized program with buy-in from all members of
staff.
Figure 21-9 Rocky Mountain spotted fever
Photo courtesy of the CDC Public Health Image Library. CDC.
Education
Continuous education is required of all levels of hospital
worker, from senior management down through senior
Table 21-17 Multi-resistant organisms seen in modern hospitals
ACRONYM
ORGANISM
ANTIBIOTIC RESISTANCE
TYPICAL INFECTIONS
MRSA
Methicillin-resistant Staphylococcus
aureus
All beta-lactams;
usually multidrug-resistant
Community MRSA usually
non-multidrug-resistant
Bloodstream infection
Surgical site infection
Intravenous catheter
infection
VRE
Vancomycin-resistant enterococci
Vancomycin; intrinsically
resistant to most antibiotics
ESBL
Extended-spectrum beta-lactamases
(seen in Enterobacteriaceae)
Most penicillins and

cephalosporins
Usually resistant to other drugs
also

Hospital-acquired
pneumonia
MBL
Metallo-beta-lactamase (of
pseudomonads, Acinetobacter
spp., Enterobacteriaceae)
All beta-lactams including

carbapenems
Usually harbor resistance to
most other drugs

Hospital-acquired
pneumonia
Cdiff
This species is intrinsically

resistant to most antibiotics
Pseudomembranous colitis
696
medical, nursing and allied health clinicians, to frontline

workers, and probably also the patients and the public.

Antibiotic stewardship programs are now integral to
hospital prescribing practice in Western countries,
as selection of MROs is enhanced by high uses of
broad-spectrum antibiotics.
Antibiotic stewardship programs must be supported by
management and by senior clinicians.
Computer programs are now available to facilitate antibiotic stewardship programs.
The physical environment is an important reservoir of
MROs, especially VRE, C. difficile and multiresistant
Gram-negative bacilli.
Eliminating this requires a rigorous program of environmental cleaning, involving adequate resources, training
of cleaners, auditing of performance, and using the right
disinfectants.
Aerosolized hydrogen peroxide/silver nanoparticles
have been found to eliminate MROs from hospital
environments.
Decolonization
MRO surveillance
With each MRO the numbers of asymptomatic carriers
outnumbers those with overt infection, but both groups
constitute the patient reservoir.
Screening aims to detect the asymptomatic carriers in
order to isolate them, and prevent transmission.
Infection control precautions

These involve isolating patients with communicable
pathogens (not just the MROs), wearing gowns and
gloves, and the presence of effective hand hygiene.
Hand hygiene requires a comprehensive program of
education and auditing, and has been shown to decrease
MRO transmission and hard endpoints such as MRSA
bacteremias.
Decolonization of many patients with MRSA is feasible

if they do not have mitigating factors such as chronic
ulcers or contaminated indwelling catheters.
It involves skin decontamination with medicated soaps
and/or body washes, and nasal mupirocin ointment for
7 days.
If this fails, seek other carriers in the family group and
treat them.
Should this fail, re-treating with the addition of systemic
antibiotics including rifampicin (noting the toxicity and
drug interactions), plus another agent to prevent resistance, can be considered.
It is not known how to eradicate VRE or multiresistant
Gram-negative bacilli from the GI tract reservoir.
Successful treatment of C. difficile involves eradicating
the carrier state.
CLINICAL PEARL
The Five Moments of Hand Hygiene, as espoused by
the World Health Organization, is pivotal in preventing
transmission of pathogens between patients. These
ve moments are:
1 Before patient contact
2 Before a procedure
3 After a procedure or body uid exposure risk
4 After patient contact
5 After contact with patient surroundings
697
1 The recommended treatment of methicillin-resistant Staphylococcus aureus (MRSA) boils is:
A Nafcillin
B Ceftobiprole
C Linezolid
D Incision and drainage
E Mupirocin
2 Which of the following does not cover anaerobes?
A Penicillin
B Tetracycline
C Nafcillin
D Chloramphenicol
E Clindamycin
3 Which opportunistic pathogen is not covered by caspofungin?
A Aspergillus fumigatus
B Candida albicans
C Cryptococcus gattii
D Candida glabrata
4 Which antibiotic can be given to a 5-year-old child with infected atopic dermatitis due to swab-proven community
methicillin-resistant Staphylococcus aureus (MRSA)?
A Moxioxacin
B Ciprooxacin
C Tetracycline
D Cotrimoxazole
E Tigecycline
5 Relative bradycardia can be seen in infections with which organism?
A Inuenza virus
B Salmonella enterica Typhi
C Lyssavirus
D Methicillin-resistant Staphylococcus aureus (MRSA)
E Aspergillus fumigatus
6 A 23-year-old man returns from a holiday in Bangladesh. He presents with fever and rigors and, apart from looking
unwell, has a normal physical examination. Blood cultures show Gram-negative bacilli. Which is the most likely
pathogen from this list?
A Community methicillin-resistant Staphylococcus aureus (MRSA)
B Plasmodium falciparum
C Campylobacter jejuni
D Bacillus anthracis
E Salmonella enterica Typhi
7 A 30-year-old man returns from a holiday in Africa and reports a painful red sore on his penis. What is the most likely
diagnosis?
A Syphilitic chancre
B Genital herpes
C Tuberculosis
D Lymphogranuloma venereum
E Chancroid
8 Which of the following is never zoonotic?
A Methicillin-resistant Staphylococcus aureus (MRSA)
B Pubic lice
C Salmonella enterica
D Severe acute respiratory syndrome (SARS)
E H1N1/09 inuenza A
9 A tree surgeon presents with a chronic headache and low-grade temperature. He has extensive exposure to birds and
also gum trees. Lumbar puncture shows elevated pressure of 35cmH2O, raised protein, low glucose, mononuclear
pleocytosis and positive cryptococcal antigen. HIV antibody test is negative. Magnetic resonance imaging shows
cryptococcomas and no hydrocephalus. Which species is more likely?
698
A
B
C
D
E
Cryptococcus grubii
Cryptococcus neoformans
Cryptococcus gattii
Cryptococcus albidus
Cryptococcus uniguttulas
10 Considering the scenario in question 9, what is the recommended treatment?

A Amphotericin B + uconazole
B Amphotericin B + ucytosine
C Amphotericin B + ucytosine + gamma-interferon
D Amphotericin B + ucytosine + ventriculoperitoneal shunt
E Amphotericin B + ucytosine + serial lumbar punctures
ANSWERS
1 D.
The treatment of any supercial collection of pus is ideally with incision and drainage. This is more effective than antibiotic
treatment. This is particularly the case with MRSA, given the limited range and toxicity of available antibiotics.
2 C.
Nafcillin is a beta-lactam antibiotic with no activity against anaerobic bacteria. Penicillin has variable activity against
anaerobes; and clindamycin, chloramphenicol, and tetracycline all have moderate activity.
3 C.
Caspofungin has strong activity against Candida species, moderate activity against Aspergillus, and no activity against
Cryptococcus.
4 D.
The activity of moxioxacin, ciprooxacin and tetracycline against community MRSA is all variable, but these strains are
nearly always susceptible to cotrimoxazole. Tigecycline has strong activity against MRSA, but is only able to be given
intravenously. Cotrimoxazole is therefore the appropriate choice.
5 B.
Relative bradycardia in a febrile patient is a classic symptom of Salmonella enterica Typhi infection. One would expect a
tachycardia in the setting of infection with all of the other organisms.
6 E.
MRSA and Bacillus anthracis are Gram-positive organisms. Campylobacter jejuni does not usually grow in commonly used
blood culture systems. Plasmodium falciparum is a parasite. Salmonella enterica Typhi is the only Gram-negative bacteria
likely to be grown from a blood culture in this situation.
7 E.
Chancroid is caused by Haemophilus ducreyi and is prevalent in Africa. It causes painful genital ulceration and inguinal
lymphadenopathy. Syphilitic chancres and genital ulcers when caused by lymphogranuloma venereum are usually
painless. Herpes simplex usually causes painful vesicles. Tuberculosis of the penis is exceedingly rare and usually painless.
8 B.
SARS results from infection with a coronavirus that has been isolated in a number of species of animals in China, including
the civet and the cat. H1N1/09 inuenza A is endemic in swine, and caused the 2009 inuenza epidemic. MRSA can be
transferred from a number of domestic animals, including dogs, to humans. Salmonella can be transferred to humans
from reptiles. In contrast, pubic lice are obligate parasites of humans, and can be transferred directly from human to
human.
9 C.
This is a classic description of a Cryptococcus gattii infection in a patient who works with gum trees and presents with
cryptococcomas. C. gatii is contracted from certain varieties of gum tree, and is more likely to cause crytococcomas,
especially in the brain, than other cryptococcal infections. C. neoformans and C. grubii are contracted from birds, so could
be less likely culprits in this situation. C. albidus and C. uniguttulas only very rarely cause human infection.
10 E.
The recommended treatment for cryptococcal central nervous system infection is a combination of amphotericin B
and ucytosine. The ucytosine improves the efficacy of the amphotericin B. Azole antifungals are less effective in this
situation. Serial lumbar punctures will reduce the elevated cerebrospinal uid pressure that frequently accompanies this
condition, and may prevent the need for ventriculoperitoneal shunting.
699
CHAPTER 22
IMMUNIZATION
Rob Pickles
CHAPTER OUTLINE
GENERAL PRINCIPLES
IMMUNIZING AGENTS
FACTORS AFFECTING IMMUNOGENICITY

Chemical and physical properties of antigens
(vaccines)
Contraindications
Egg allergy
BOOSTER DOSES
IMMUNIZATION IN SPECIFIC POPULATIONS
Preconception
Breastfeeding
Oncology patients
Hemopoetic stem-cell transplant (HSCT)
recipients
HIV/AIDS
Asplenia
Travel vaccines
POST-EXPOSURE PROPHYLAXIS (PEP)

Specic intramuscular immune globulin
preparations (hyperimmune globulins)
Specic immune globulins for intravenous use
ROUTINE IMMUNIZATION OF ADULTS
Pregnancy
Globally, vaccination prevents at least 3 million deaths annually. Vaccination is responsible for the only successful global
eradication of an infectious disease (namely smallpox). The
introduction of Haemophilus influenzae type B immunization (Hib) in the early 1990s resulted in a greater than 90%
reduction in cases of invasive H. influenzae type B disease.
No vaccine is 100% effective, nor 100% safein target
populations, however, the benefits greatly exceed the risks.
Benefits extend to both the individual and to the community as a wholewith a sufficiently large proportion of the
community vaccinated, unimmunized individuals are protected by a process of herd immunity.
GENERAL PRINCIPLES
Active immunization involves induction of immunity
by the administration of live attenuated or inactivated
organisms or their components, stimulating antibody or
cell-mediated immunity against the disease.
Passive immunization involves provision of temporary
immunity via administration of exogenously produced
antibody (including transplacental transfer from mother
to fetus).
701
IMMUNIZING AGENTS
Immunizing agents may be vaccines, toxoids or
immunoglobulins.
Vaccinea preparation of attenuated live or killed
micro-organisms, consisting of either full organisms or
components (e.g. surface antigen of hepatitis B) administered to induce immunity.
Toxoida modified bacterial toxin rendered nontoxic
but capable of inducing formation of antitoxin.
Immunoglobulina sterile solution of antibody derived
from human blood, indicated for passive immunization
against hepatitis A and measles.
Intravenous immune globulin (IVIG) is used as

replacement therapy in IgG-deficient states, as well
as certain immunological conditions (e.g. immune
thrombocytopenic purpura [ITP], GuillainBarr
syndrome).
Specific immunoglobulin comprises special preparations selected from donor pools with high levels of
antibody content against a specific diseasehepatitis B immune globulin (HBIG), varicella immune
globulin (VZIG), rabies immune globulin (RIG)
and tetanus immune globulin (TIG).
Table 22-1 outlines the uses of vaccines in a range of diseases.
Table 22-1 Diseases prevented by vaccines available for use in Australia, the US and Europe, according to
microbial and antigenic type
INACTIVATED VACCINES
LIVE
VACCINES
WHOLE
MICROBE
SUB-UNIT
OTHER
TYPICAL PRIMARY
POPULATIONS
Bacterial diseases
Anthrax
Cholera
Cell ltrate
Live (oral)
Occupational
Whole
Endemic areas, travelers
Diphtheria
Toxoid
Throughout life
Haemophilus
inuenzae type b
Proteinconjugated
polysaccharide
Infants, children
Proteinconjugated
polysaccharide,
polyvalent
Varies by country; children,

adolescents, travelers
Meningococcal,
some or all of
serogroups A, C, Y,
and W135
Polysaccharide,
polyvalent
Pertussis
Multiple
acellular
components
Pneumococcal
Polysaccharide,
polyvalent
Tetanus
Typhoid
Live (oral)
Tuberculosis
(Bacillus Calmette
Gurin [BCG])
Live
Vi capsular
polysaccharide
Throughout life
Proteinconjugated
polysaccharide,
polyvalent
Infants, children, elderly; those

with chronic disease
Toxoid
Throughout life
Varies by country; children,
select other groups
Viral diseases
Hepatitis A
Hepatitis B
702
Whole
Varies by country; infants,

children, adolescents,
occupational, travelers, men
who have sex with men
Surface antigen
Varies by country; infants,

children, adolescents,
occupational, travelers, sex
workers, men who have sex
with men
Chapter 22 Immunization
INACTIVATED VACCINES
LIVE
VACCINES
WHOLE
MICROBE
Inuenza A and B
SUB-UNIT
OTHER
Split virus
Japanese
encephalitis
TYPICAL PRIMARY
POPULATIONS
Elderly, plus other groups,
such as children, adolescents,
occupational
Whole
Measles
Whole
Infants, children
Mumps
Whole
Infants, children
Papillomavirus,
types 6, 11, 16, 18
Poliovirus
Virus-like
particles
Whole
Rabies
Adolescents, adults
Whole
Infants, children
Whole
Occupational, postexposure
Rotavirus (monoor pentavalent)
Whole
Infants
Rubella
Whole
Infants, children
Tick-borne
encephalitis
Whole
Vaccinia (to
prevent smallpox)
Whole
Occupational
Varicella
Whole
Infants, children
Yellow fever
Whole
Zoster
Whole
Elderly
*Multiple entries within a row indicate availability of more than one type of vaccine for that disease.
Adapted from Cohen J, Powderly WG and Opal SM. Infectious diseases, 3rd ed. St Louis: Mosby, 2010.
CLINICAL PEARLS
Immunization may be active (with induction of protective immune response), or passive (short-term
passive antibody administration).
Active vaccination may be achieved with toxoids
(modied toxins), inactive products (killed organisms
or sub-units), or live attenuated organisms.
FACTORS AFFECTING
IMMUNOGENICITY
Chemical and physical properties of
antigens (vaccines)
Live attenuated viruses (e.g. measles, mumps, rubella)
multiply in the body until checked by the immune
response, and induce long-lasting immunity.
Killed vaccines generally induce shorter-lived immunity, usually requiring subsequent booster doses
to maintain immunity (diphtheria, tetanus, rabies,
typhoid). Exceptions include hepatitis B and inactivated
polio vaccination, where immunity lasts 10 years or
more.
Most vaccines are protein antigens that induce
T-cell-dependent immunity with booster effects on
repeat immunization. These vaccines produce good
immune responses in all age groups.
Purified bacterial polysaccharide capsule vaccines
induce B-cell-dependent immunity, which is not longlasting, requires frequent repeat vaccination and induces
a poor immune response in children under 2 years of
age (meningococcal, pneumococcal, and typhoid polysaccharide vaccines).
Conjugation of a carrier protein to a polysaccharide
vaccine induces a T-cell immune response, producing
long-lasting immunity (Hib, pneumococcal conjugate
vaccine).
703

Age, nutrition, immune status, pregnancy, stress, and infections all affect the immune response (see below).
Intramuscular and subcutaneous administration results
in mostly an IgG response.
Oral or intranasal vaccination induces mostly a local IgA
response with some systemic IgG response.
Intradermal dosing allows reduction in dose, with
potential cost savings.
Immune response to some inactivated vaccines or toxoids may be enhanced by the addition of adjuvants such
as aluminium salts (diphtheria and tetanus toxoids, hepatitis B, acellular pertussis vaccines).
The mechanism of enhancement is unknown, but
involves the innate immune system.
Contraindications
Anaphylaxis to a prior dose of the same vaccine
Intercurrent febrile illness (temperature >38.5C) should
prompt deferral of immunization
Live vaccines:
severe immune deficiency
immunosuppressant drugs
immune globulin receipt within 311 months
BOOSTER DOSES
General recommendations regarding the need for booster
doses of specific vaccines are given in Table 22-2.
IMMUNIZATION IN SPECIFIC
POPULATIONS
See Figure 22-1 at the end of the chapter for a summary of
immunization recommendations.
Pregnancy
Influenza vaccine is the only vaccine specifically recommended during pregnancy, due to the risk of severe
infection.
All other vaccines, particularly live attenuated vaccines,
are generally contraindicated in the pregnant woman
fever is considered potentially teratogenic, whether
vaccine- or illness-induced.
Live attenuated vaccines are considered potentially teratogenic, although no definite risk has been
demonstrated.
Preconception
The preconception health check should review the need
for measles, mumps, rubella, varicella, diphtheria, tetanus and pertussis vaccinations.
Women should avoid becoming pregnant within 28
days of receipt of live vaccines.
Breastfeeding
Rubella vaccine virus is detectable in breast milk following

vaccination, and has resulted in mild infection in the infant.
No evidence of harm has been detected in breastfed infants
where the mother has been vaccinated.
Family history of an adverse event

Convulsions
Previous illness similar to the target illness
Prematurity
Stable neurological conditions
Intercurrent antibiotic treatment (except oral typhoid
vaccine)
Egg allergy
Egg allergy is not a contraindication for measlesmumps-rubella (MMR) vaccine.
Caution should be exercised with influenza vaccinea
split-dose protocol should be considered.
Yellow fever vaccine is contraindicated if a patient has
anaphylaxis due to eggs.
CLINICAL PEARL
Polysaccharide capsule vaccines induce B-cellmediated immunity, which is of short duration (23
years) and is ineffective in children under 2 years of
age.
704
Issues in the immunocompromised host include the risk of a
reduced immune response to immunization, and the potential for disseminated infection with live vaccine organisms.
Factors to consider are:
the degree of immunosuppression
the risk posed by the target infection.
A corticosteroid dose >60 mg/day for >1 week requires
delaying administration of live attenuated vaccines for
3months after cessation of therapy.
Vaccines absolutely contraindicated are:
Bacillus CalmetteGurin (BCG)
smallpox
oral cholera
oral typhoid.
Yellow fever vaccine requires caution in certain situationsthe risk of disease versus the risk of vaccination
Table 22-2 Booster doses for specic vaccines
VACCINE
COMMENTS REGARDING BOOSTERS
Diphtheria
DTPa at 4 years
dTpa at 1217 years
dTpa at 10 and 20 years after primary immunization, then at age 50
Haemophilus inuenzae
type B
Booster at 12 months
Single dose in splenectomy if not previously vaccinated
Hepatitis A
Single booster 12 months after primary dose
Hepatitis B
Not generally recommended
Human papillomavirus
Unknown
Japanese encephalitis
Unknown
Meningococcus
Single booster polysaccharide vaccine 35 years after initial dose

Boosters not required for conjugate vaccine
Pertussis
Single booster at age 50 generally recommended, repeated at age 65; consider if

undertaking high-risk travel and no booster within 5 years
Pneumococcus
23vPPV: single booster after 5 years; indigenous and other high-risk populations
revaccinate 5 years after 2nd dose or at 65 years (whichever is later)
7vPCV: single booster at 2 years in high-risk and indigenous children
Poliomyelitis
Age 4 years; adults only if at especially high risk (travel)
Q fever
Revaccination contraindicated
Rabies
Every 2 years or if titer <0.5 IU/mL
Tetanus
DTPa age 4 years

dTpa age 1217 years, then age 50 (Australia); dTpa every 10 years (US)
Typhoid
Oral vaccine: booster at 5 years

Vi capsule vaccine booster every 2-3 years if ongoing exposure
DTPa, diphtheriatetanuspertussis (acellular); dTpa, diphtheriatetanuspertussis (acellular; adult formulation); PCV, pneumococcal
conjugate vaccine; PPV, pnenumococcal polysaccharide vaccine.
(risk of developing viscerotropic disease) needs to be

considered.
Oncology patients
If well and in remission and infection-free for >6
months, the following vaccines may be given:
DTPa (acellular diphtheriatetanuspertussis; adult
form is dTpa)
hepatitis B
MMR
inactivated poliomyelitis vaccine (iPV)
Hib (if patient <5 years of age)
varicella after completion of therapy.
If there are hematological malignancies associated with
invasive pneumococcal disease, such as myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma or chronic
lymphocytic leukemia (CLL), vaccination should occur
at diagnosis, before chemo/radiotherapy, or on completion of therapy.
Influenza vaccination is indicated in all cancer patients
over 36 months of age.

Where possible, potential recipients should be immunized pre-transplant.
Live vaccines are contraindicated post-transplantation.
Inactivated vaccines can be given 612 months posttransplantation, although immune responses may be
blunted.
Hemopoetic stem-cell transplant

(HSCT) recipients
Protective immunity to vaccine-preventable infections
is partly or completely lost after allogeneic or autologous
HSCT.
Most vaccines are delayed for at least 12 months
post-transplantation, due to poor immune responses
during this time. Immunity testing is recommended
before and after hepatitis B, measles, rubella and varicella to determine the need for future doses.
705
HIV/AIDS
BCG is absolutely contraindicated in patients with
human immunodeficiency virus (HIV) or acquired
immune deficiency syndrome (AIDS).
See Figure 22-1 (at the end of the chapter) for other
recommendations.
Provided that CD4+ cells are >250/mm3, many live
attenuated vaccines can be administered safely.
CLINICAL PEARL
Live attenuated vaccines are generally contraindicated
in immunosuppressed individuals.
Asplenia
Patients with anatomical or functional asplenia (seen
in some patients with systemic lupus erythematosus or
celiac disease) should receive pneumococcal, meningococcal and Hib vaccination.
Receipt of a conjugate vaccine should be followed by

polysaccharide vaccine 6 months later.
Certain occupations are associated with an increased risk of
some vaccine-preventable diseases.
Infected workers (especially healthcare and child-care
workers) are at risk of transmitting infections such
as influenza, rubella, measles, mumps, pertussis, and
others to susceptible contacts, with potentially serious
outcomes.
The current recommended vaccines for people at risk
of occupationally acquired vaccine-preventable diseases
are shown in Table 22-3.
Travel vaccines
There is a need to consider routine immunization status
as well as specific travel-related vaccine requirements in
those embarking upon travel.
Table 22-3 Vaccines for occupational exposure
OCCUPATION
DISEASE/VACCINE
Healthcare workers
Hepatitis B
Inuenza, pertussis (dTpa), MMR if not immune, varicella
(if seronegative)
Working with children
Pertussis (dTpa)
MMR, varicella (if not immune)
Hepatitis A (child-care and preschool)
Carers
Hepatitis A and B (intellectual disability)

Inuenza (aged care)
Emergency service personnel (including in correctional

facilities)
Hepatitis B
Inuenza
Laboratory personnel (routinely working with infectious

tissues)
Q fever (veterinary specimens)

Rabies
Anthrax, vaccinia poxviruses, poliomyelitis, typhoid, yellow
fever, meningococcal disease, Japanese encephalitis
Veterinarians (and students, nurses)
Q fever
Rabies (lyssavirus)
Poultry workers
Inuenza
Bat handlers, wildlife officers
Rabies (lyssavirus)
Abattoir (slaughterhouse) workers, livestock transporters,

sheep shearers/farmers, goat farmers, saleyard workers
Q fever
Embalmers
Hepatitis B, BCG
Sex-industry workers
Hepatitis A and B
Tattooists, body piercers
Hepatitis B
Plumbers
Hepatitis A
BCG, Bacillus CalmetteGurin; dTpa, diphtheriatetanuspertussis (acellular, adult formulation); MMR, measles-mumps-rubella.
706
Travelers visiting friends and relatives (VFRs) are generally at high risk of acquiring travel-related infections.
Vaccines may be required (in order to cross international
borders), or recommended (according to the risk of infection in the area of travel).
Country-specific recommendations are available at
http://www.cdc.gov/travel and http://www.who.int/
ith/en.
POST-EXPOSURE PROPHYLAXIS
(PEP)
Hepatitis A
Hepatitis A vaccination is preferred over immune globulin for PEP and for protection of travelers.
Patients aged <12 months or >40 years, the immunocompromised, and those with chronic liver disease,
should be given immune globulin.
Immune globulin is effective if given within 14 days of
exposure.
Measles
Immune globulin is effective if given within 6 days of exposure to at-risk individuals.
It should be given along with rabies vaccine in previously unvaccinated exposed individuals.
RIG is unnecessary in those who received rabies vaccine
more than 8 days earlier.
Tetanus immune globulin (TIG)

Tetanus immune globulin is indicated for those with
tetanus-prone wounds with no history of prior tetanus
vaccination.
Combined tetanus and diphtheria vaccination should
be administered simultaneously at a different site, and a
primary course of vaccination should be completed.
Varicella zoster immune globulin (VZIG)

The decision to administer VZIG depends on:
the likelihood that the exposed person is not
immune
the probability of exposure resulting in infection
and the likelihood that complications of varicella
will develop.
VZIG should be given to neonates whose mothers
develop varicella 5 days before to 48 hours after birth.
VZIG should be administered within 96 hours of
exposure.
VZIG may not prevent infection but usually attenuates
it, with resultant subclinical or mild infection.
Subsequent varicella vaccination should be given
5months after VZIG, unless contraindicated or clinical
varicella develops.
Specic intramuscular immune

globulin preparations (hyperimmune
globulins)
Specic immune globulins for

intravenous use
Hepatitis B immune globulin (HBIG)
Cytomegalovirus (CMV IVIG)
Hepatitis B immune globulin is recommended following

exposure to known hepatitis B (HBV)-infected sexual
partners or to HBV surface antigen (HBsAg)-positive
blood by the percutaneous (72 hours) or mucous membrane (14 days) route.
Children born to HBsAg-positive mothers should be
given HBIG at birth as well as a dose of hepatitis B
vaccine.
This is given for prophylaxis of CMV disease in CMVseronegative organ-transplant recipients.
Botulism IVIG
Botulism IVIG is indicated for infant botulism.
Rabies immune globulin (RIG)
ROUTINE IMMUNIZATION OF
ADULTS
Rabies immune globulin is prepared from previously

immunized humans.
A recommended schedule for adult immunizations is given

in Figure 22-1 (overleaf).
707
Recommended Adult Immunization ScheduleUnited States - 2014

Note: These recommendations must be read with the footnotes that follow
containing number of doses, intervals between doses, and other important information.
Figure 1. Recommended adult immunization schedule, by vaccine and age group1
VACCINE d
AGE GROUP f
19-21 years
22-26 years
27-49 years
Influenza 2,*
Tetanus, diphtheria, pertussis (Td/Tdap) 3,*
Varicella
50-59 years
60-64 years
65 years
1 dose annually
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
4,*
2 doses
Human papillomavirus (HPV) Female 5,*
3 doses
Human papillomavirus (HPV) Male 5,*
3 doses
Zoster 6
1 dose
Measles, mumps, rubella (MMR)
7,*
1 or 2 doses
Pneumococcal 13-valent conjugate (PCV13) 8,*
1 dose
Pneumococcal polysaccharide (PPSV23) 9,10
1 or 2 doses
Meningococcal 11,*
1 dose
1 or more doses
Hepatitis A 12,*
2 doses
Hepatitis B 13,*
3 doses
Haemophilus influenzae type b (Hib) 14,*
1 or 3 doses
*Covered by the Vaccine Injury Compensation Program

For all persons in this category who
meet the age requirements and who
lack documentation of vaccination or
have no evidence of previous infection;
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of prior episode of zoster
Recommended if some other risk
factor is present (e.g., on the basis of
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VACCINE d
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and persistent
chronic
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INDICATION f Pregnancy virus [HIV])
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disease Diabetes personnel
Influenza 2,*
1 dose IIV annually
Tetanus, diphtheria, pertussis (Td/Tdap) 3,*

Varicella 4,*
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
Human papillomavirus (HPV) Male
3 doses through age 26 yrs
Contraindicated
Measles, mumps, rubella (MMR)
7,*
8,*
1 or 2 doses
Meningococcal 11,*
1 or more doses
2 doses
Hepatitis A 12,*
3 doses
13,*
Haemophilus influenzae type b (Hib)

Injury Compensation Program
1 or 2 doses
1 dose
Pneumococcal polysaccharide (PPSV23) 9,10
*Covered by the Vaccine
1 dose
Contraindicated
Pneumococcal 13-valent conjugate (PCV13)
Hepatitis B
2 doses
5,*
1 dose IIV or LAIV

annually
1 dose IIV annually
Contraindicated
Human papillomavirus (HPV) Female 5,*
Zoster
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pregnancy
1 dose IIV or
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From Centers for Disease Control and Prevention, www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf
708
Footnotes
Recommended Immunization Schedule for Adults Aged 19 Years or Older: United States, 2014
1. Additional information
Additional guidance for the use of the vaccines described in this supplement
is available at www.cdc.gov/vaccines/hcp/acip-recs/index.html.
Information on vaccination recommendations when vaccination status is
unknown and other general immunization information can be found in
the General Recommendations on Immunization at
$$$ Y$Y$Y$ YE??>5 .
Information on travel vaccine requirements and recommendations (e.g.,
for hepatitis A and B, meningococcal, and other vaccines) is available at
http://wwwnc.cdc.gov/travel/destinations/list.
Additional information and resources regarding vaccination of pregnant women
can be found at http://www.cdc.gov/vaccines/adults/rec-vac/pregnant.html.
2. Influenza vaccination
Annual vaccination against influenza is recommended for all persons
aged 6 months or older.
Persons aged 6 months or older, including pregnant women and persons
with hives-only allergy to eggs, can receive the inactivated influenza
vaccine (IIV). An age-appropriate IIV formulation should be used.
Adults aged 18 to 49 years can receive the recombinant influenza vaccine
(RIV) (FluBlok). RIV does not contain any egg protein.
Healthy, nonpregnant persons aged 2 to 49 years without high-risk medical
conditions can receive either intranasally administered live, attenuated
influenza vaccine (LAIV) (FluMist), or IIV. Health care personnel who care
for severely immunocompromised persons (i.e., those who require care in
a protected environment) should receive IIV or RIV rather than LAIV.
The intramuscularly or intradermally administered IIV are options for
adults aged 18 to 64 years.
Adults aged 65 years or older can receive the standard-dose IIV or the
high-dose IIV (Fluzone High-Dose).
3. Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination
Administer 1 dose of Tdap vaccine to pregnant women during each
pregnancy (preferred during 27 to 36 weeks gestation) regardless of
interval since prior Td or Tdap vaccination.
Persons aged 11 years or older who have not received Tdap vaccine
or for whom vaccine status is unknown should receive a dose of Tdap
followed by tetanus and diphtheria toxoids (Td) booster doses every 10
years thereafter. Tdap can be administered regardless of interval since
the most recent tetanus or diphtheria-toxoid containing vaccine.
Adults with an unknown or incomplete history of completing a 3-dose
primary vaccination series with Td-containing vaccines should begin or
complete a primary vaccination series including a Tdap dose.
For unvaccinated adults, administer the first 2 doses at least 4 weeks apart
and the third dose 6 to 12 months after the second.
For incompletely vaccinated (i.e., less than 3 doses) adults, administer
remaining doses.
Refer to the ACIP statement for recommendations for administering Td/
Tdap as prophylaxis in wound management (see footnote 1).
4. Varicella vaccination
All adults without evidence of immunity to varicella (as defined below)
should receive 2 doses of single-antigen varicella vaccine or a second
dose if they have received only 1 dose.
Vaccination should be emphasized for those who have close contact
with persons at high risk for severe disease (e.g., health care personnel
and family contacts of persons with immunocompromising conditions)
or are at high risk for exposure or transmission (e.g., teachers; child
care employees; residents and staff members of institutional settings,
including correctional institutions; college students; military personnel;
adolescents and adults living in households with children; nonpregnant
women of childbearing age; and international travelers).
Pregnant women should be assessed for evidence of varicella immunity.
Women who do not have evidence of immunity should receive the first
dose of varicella vaccine upon completion or termination of pregnancy
and before discharge from the health care facility. The second dose should
be administered 4 to 8 weeks after the first dose.
Evidence of immunity to varicella in adults includes any of the following:
documentation of 2 doses of varicella vaccine at least 4 weeks apart;
U.S.-born before 1980, except health care personnel and pregnant women;
history of varicella based on diagnosis or verification of varicella disease
by a health care provider;
history of herpes zoster based on diagnosis or verification of herpes
zoster disease by a health care provider; or
laboratory evidence of immunity or laboratory confirmation of disease.
5. Human papillomavirus (HPV) vaccination
Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2)
and quadrivalent HPV vaccine (HPV4), and one HPV vaccine for use in
males (HPV4).
For females, either HPV4 or HPV2 is recommended in a 3-dose series for
routine vaccination at age 11 or 12 years and for those aged 13 through
26 years, if not previously vaccinated.
For males, HPV4 is recommended in a 3-dose series for routine vaccination
at age 11 or 12 years and for those aged 13 through 21 years, if not
previously vaccinated. Males aged 22 through 26 years may be vaccinated.
5. Human papillomavirus (HPV) vaccination (contd)

HPV4 is recommended for men who have sex with men through age 26
years for those who did not get any or all doses when they were younger.
Vaccination is recommended for immunocompromised persons
(including those with HIV infection) through age 26 years for those who
did not get any or all doses when they were younger.
A complete series for either HPV4 or HPV2 consists of 3 doses. The second
dose should be administered 4 to 8 weeks (minimum interval of 4 weeks)
after the first dose; the third dose should be administered 24 weeks after
the first dose and 16 weeks after the second dose (minimum interval of
at least 12 weeks).
HPV vaccines are not recommended for use in pregnant women. However,
pregnancy testing is not needed before vaccination. If a woman is found
to be pregnant after initiating the vaccination series, no intervention
is needed; the remainder of the 3-dose series should be delayed until
completion of pregnancy.
6. Zoster vaccination
A single dose of zoster vaccine is recommended for adults aged 60 years
or older regardless of whether they report a prior episode of herpes zoster.
Although the vaccine is licensed by the U.S. Food and Drug Administration
for use among and can be administered to persons aged 50 years or older,
ACIP recommends that vaccination begin at age 60 years.
Persons aged 60 years or older with chronic medical conditions may be
vaccinated unless their condition constitutes a contraindication, such as
pregnancy or severe immunodeficiency.
7. Measles, mumps, rubella (MMR) vaccination
Adults born before 1957 are generally considered immune to measles and
mumps. All adults born in 1957 or later should have documentation of 1 or
more doses of MMR vaccine unless they have a medical contraindication
to the vaccine or laboratory evidence of immunity to each of the three
diseases. Documentation of provider-diagnosed disease is not considered
acceptable evidence of immunity for measles, mumps, or rubella.
Measles component:
A routine second dose of MMR vaccine, administered a minimum of 28
days after the first dose, is recommended for adults who:
are students in postsecondary educational institutions;
work in a health care facility; or
plan to travel internationally.
Persons who received inactivated (killed) measles vaccine or measles
vaccine of unknown type during 19631967 should be revaccinated with
2 doses of MMR vaccine.
Mumps component:
A routine second dose of MMR vaccine, administered a minimum of 28
days after the first dose, is recommended for adults who:
are students in a postsecondary educational institution;
work in a health care facility; or
plan to travel internationally.
Persons vaccinated before 1979 with either killed mumps vaccine
or mumps vaccine of unknown type who are at high risk for mumps
infection (e.g., persons who are working in a health care facility) should
be considered for revaccination with 2 doses of MMR vaccine.
Rubella component:
For women of childbearing age, regardless of birth year, rubella immunity
should be determined. If there is no evidence of immunity, women who
are not pregnant should be vaccinated. Pregnant women who do not have
evidence of immunity should receive MMR vaccine upon completion or
termination of pregnancy and before discharge from the health care facility.
Health care personnel born before 1957:
For unvaccinated health care personnel born before 1957 who lack
laboratory evidence of measles, mumps, and/or rubella immunity or
laboratory confirmation of disease, health care facilities should consider
vaccinating personnel with 2 doses of MMR vaccine at the appropriate
interval for measles and mumps or 1 dose of MMR vaccine for rubella.
8. Pneumococcal conjugate (PCV13) vaccination
Adults aged 19 years or older with immunocompromising conditions
(including chronic renal failure and nephrotic syndrome), functional or
anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants who
have not previously received PCV13 or PPSV23 should receive a single
dose of PCV13 followed by a dose of PPSV23 at least 8 weeks later.
Adults aged 19 years or older with the aforementioned conditions who
have previously received 1 or more doses of PPSV23 should receive a dose
of PCV13 one or more years after the last PPSV23 dose was received. For
adults who require additional doses of PPSV23, the first such dose should
be given no sooner than 8 weeks after PCV13 and at least 5 years after
the most recent dose of PPSV23.
When indicated, PCV13 should be administered to patients who are
uncertain of their vaccination status history and have no record of previous vaccination.
Although PCV13 is licensed by the U.S. Food and Drug Administration
for use among and can be administered to persons aged 50 years or
older, ACIP recommends PCV13 for adults aged 19 years or older with
the specific medical conditions noted above.
Figure 22-1 Recommended immunization schedule for adults, United States, 2014 continued
709
9. Pneumococcal polysaccharide (PPSV23) vaccination

When PCV13 is also indicated, PCV13 should be given first (see footnote 8).
Vaccinate all persons with the following indications:
all adults aged 65 years or older;
adults younger than 65 years with chronic lung disease (including
chronic obstructive pulmonary disease, emphysema, and asthma),
chronic cardiovascular diseases, diabetes mellitus, chronic renal failure, nephrotic syndrome, chronic liver disease (including cirrhosis),
alcoholism, cochlear implants, cerebrospinal fluid leaks, immunocompromising conditions, and functional or anatomic asplenia (e.g., sickle
cell disease and other hemoglobinopathies, congenital or acquired
asplenia, splenic dysfunction, or splenectomy [if elective splenectomy
is planned, vaccinate at least 2 weeks before surgery]);
residents of nursing homes or long-term care facilities; and
adults who smoke cigarettes.
Persons with immunocompromising conditions and other selected
conditions are recommended to receive PCV13 and PPSV23 vaccines. See
footnote 8 for information on timing of PCV13 and PPSV23 vaccinations.
Persons with asymptomatic or symptomatic HIV infection should be
vaccinated as soon as possible after their diagnosis.
When cancer chemotherapy or other immunosuppressive therapy is
being considered, the interval between vaccination and initiation of
immunosuppressive therapy should be at least 2 weeks. Vaccination
during chemotherapy or radiation therapy should be avoided.
Routine use of PPSV23 vaccine is not recommended for American Indians/
Alaska Natives or other persons younger than 65 years unless they have
underlying medical conditions that are PPSV23 indications. However, public health authorities may consider recommending PPSV23 for American
Indians/Alaska Natives who are living in areas where the risk for invasive
pneumococcal disease is increased.
When indicated, PPSV23 vaccine should be administered to patients who
are uncertain of their vaccination status and have no record of vaccination.
10. Revaccination with PPSV23
One-time revaccination 5 years after the first dose of PPSV23 is recommended for persons aged 19 through 64 years with chronic renal failure
or nephrotic syndrome, functional or anatomic asplenia (e.g., sickle cell
disease or splenectomy), or immunocompromising conditions.
Persons who received 1 or 2 doses of PPSV23 before age 65 years for any
indication should receive another dose of the vaccine at age 65 years or
later if at least 5 years have passed since their previous dose.
No further doses of PPSV23 are needed for persons vaccinated with
PPSV23 at or after age 65 years.
11. Meningococcal vaccination
Administer 2 doses of quadrivalent meningococcal conjugate vaccine
(MenACWY [Menactra, Menveo]) at least 2 months apart to adults of all
ages with functional asplenia or persistent complement component
deficiencies. HIV infection is not an indication for routine vaccination with
MenACWY. If an HIV-infected person of any age is vaccinated, 2 doses of
MenACWY should be administered at least 2 months apart.
Administer a single dose of meningococcal vaccine to microbiologists
routinely exposed to isolates of Neisseria meningitidis, military recruits,
persons at risk during an outbreak attributable to a vaccine serogroup,
and persons who travel to or live in countries in which meningococcal
disease is hyperendemic or epidemic.
First-year college students up through age 21 years who are living in
residence halls should be vaccinated if they have not received a dose on
or after their 16th birthday.
MenACWY is preferred for adults with any of the preceding indications
who are aged 55 years or younger as well as for adults aged 56 years or
older who a) were vaccinated previously with MenACWY and are recommended for revaccination, or b) for whom multiple doses are anticipated.
Meningococcal polysaccharide vaccine (MPSV4 [Menomune]) is preferred
for adults aged 56 years or older who have not received MenACWY previously and who require a single dose only (e.g., travelers).
Revaccination with MenACWY every 5 years is recommended for adults
previously vaccinated with MenACWY or MPSV4 who remain at increased
risk for infection (e.g., adults with anatomic or functional asplenia, persistent complement component deficiencies, or microbiologists).
12. Hepatitis A vaccination
Vaccinate any person seeking protection from hepatitis A virus (HAV)
infection and persons with any of the following indications:
men who have sex with men and persons who use injection or noninjection illicit drugs;
persons working with HAV-infected primates or with HAV in a research
laboratory setting;
persons with chronic liver disease and persons who receive clotting
factor concentrates;
persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A; and
12. Hepatitis A vaccination (contd)

unvaccinated persons who anticipate close personal contact (e.g.,
household or regular babysitting) with an international adoptee
during the first 60 days after arrival in the United States from a country with high or intermediate endemicity. (See footnote 1 for more
information on travel recommendations.) The first dose of the 2-dose
hepatitis A vaccine series should be administered as soon as adoption
is planned, ideally 2 or more weeks before the arrival of the adoptee.
Single-antigen vaccine formulations should be administered in a 2-dose
schedule at either 0 and 6 to 12 months (Havrix), or 0 and 6 to 18 months
(Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is
used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose
schedule may be used, administered on days 0, 7, and 21 to 30 followed
by a booster dose at month 12.
13. Hepatitis B vaccination
Vaccinate persons with any of the following indications and any person
seeking protection from hepatitis B virus (HBV) infection:
sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than 1 sex partner during
the previous 6 months); persons seeking evaluation or treatment for
a sexually transmitted disease (STD); current or recent injection drug
users; and men who have sex with men;
health care personnel and public safety workers who are potentially
exposed to blood or other infectious body fluids;
persons with diabetes who are younger than age 60 years as soon as
feasible after diagnosis; persons with diabetes who are age 60 years or
older at the discretion of the treating clinician based on the likelihood
of acquiring HBV infection, including the risk posed by an increased
need for assisted blood glucose monitoring in long-term care facilities, the likelihood of experiencing chronic sequelae if infected with
HBV, and the likelihood of immune response to vaccination;
persons with end-stage renal disease, including patients receiving
hemodialysis, persons with HIV infection, and persons with chronic
liver disease;
household contacts and sex partners of hepatitis B surface antigenpositive persons, clients and staff members of institutions for
persons with developmental disabilities, and international travelers
to countries with high or intermediate prevalence of chronic HBV
infection; and
all adults in the following settings: STD treatment facilities, HIV testing and treatment facilities, facilities providing drug abuse treatment
and prevention services, health care settings targeting services to
injection drug users or men who have sex with men, correctional
facilities, end-stage renal disease programs and facilities for chronic
hemodialysis patients, and institutions and nonresidential day care
facilities for persons with developmental disabilities.
Administer missing doses to complete a 3-dose series of hepatitis B
vaccine to those persons not vaccinated or not completely vaccinated.
The second dose should be administered 1 month after the first dose; the
third dose should be given at least 2 months after the second dose (and
at least 4 months after the first dose). If the combined hepatitis A and
hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1, and 6 months;
alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and
21 to 30 followed by a booster dose at month 12 may be used.
Adult patients receiving hemodialysis or with other immunocompromising
conditions should receive 1 dose of 40 mcg/mL (Recombivax HB)
administered on a 3-dose schedule at 0, 1, and 6 months or 2 doses of 20
mcg/mL (Engerix-B) administered simultaneously on a 4-dose schedule
at 0, 1, 2, and 6 months.
14. Haemophilus influenzae type b (Hib) vaccination
One dose of Hib vaccine should be administered to persons who have
functional or anatomic asplenia or sickle cell disease or are undergoing
elective splenectomy if they have not previously received Hib vaccine.
Hib vaccination 14 or more days before splenectomy is suggested.
Recipients of a hematopoietic stem cell transplant should be vaccinated
with a 3-dose regimen 6 to 12 months after a successful transplant,
regardless of vaccination history; at least 4 weeks should separate doses.
Hib vaccine is not recommended for adults with HIV infection since their
risk for Hib infection is low.
15. Immunocompromising conditions
Inactivated vaccines generally are acceptable (e.g., pneumococcal,
meningococcal, and inactivated influenza vaccine) and live vaccines
generally are avoided in persons with immune deficiencies or
immunocompromising conditions. Information on specific conditions
is available at http://www.cdc.gov/vaccines/hcp/acip-recs/index.html.
Figure 22-1 Recommended immunization schedule for adults, United States, 2014 continued
710
1 The following are all live attenuated vaccines except:
A Yellow fever vaccine
B Japanese encephalitis vaccine
C MMR (measles-mumps-rubella)
D Varicella vaccine
E Oral typhoid vaccine
2 The following statements regarding pneumococcal polysaccharide vaccine (23vPPV) are correct except:
A It is indicated in asplenic individuals.
B HIV-infected individuals should be offered 23vPPV.
C It stimulates T-cell-mediated immunity.
D It is poorly immunogenic in children aged less than 2 years.
3 A 50-year-old man is being assessed for renal transplantation. His hepatitis B serology shows:
i HBsAg negative
ii HBsAb negative
iii HBcAb positive.
These results are consistent with all the following statements except:
A The patient has immunity to hepatitis B from prior vaccination.
B The patient has had prior hepatitis B infection.
C This could be a false positive result.
D The patient has chronic hepatitis B infection.
E The patient has occult hepatitis B infection.
4 A 28-year-old woman with stable human immunodeciency virus (HIV) infection is planning to travel to South America
for 3 months. Her CD4+ cells are 450/mm3 (32%) and she is stable on her current antiretroviral regimen. Which one of
the following vaccines poses no risk of disseminated infection to her?
A Oral typhoid vaccine
B BCG (Bacillus CalmetteGurin)
C Varicella zoster vaccine
D Yellow fever vaccine
E Typhoid Vi vaccine
5 A 25-year-old pregnant woman known to be a carrier of hepatitis B virus wishes to discuss strategies to prevent
transmission of HBV to her child. Which of the following statements is incorrect in the setting of a pregnant woman
infected with hepatitis B?
A Approximately 5% of children will acquire infection transplacentally.
B Administration of hepatitis B vaccine at birth will prevent 90% of cases of vertical transmission.
C A strategy of hepatitis B vaccine plus immune globulin will prevent at least 95% of cases of vertical transmission.
D Antiviral therapy with entecavir given in the nal trimester has not been shown to prevent neonatal infection.
E Elective Caesarean section has not been shown to prevent transmission from occurring at delivery.
6 The following statements about diphtheria vaccination are true except:
A The vaccine is a live attenuated preparation, and is contraindicated in immunocompromised patients.
B Protective levels of antitoxin are induced in more than 90% of recipients who complete the vaccination schedule.
C The vaccine is a puried preparation of inactivated diphtheria toxin and is known as a toxoid.
D Vaccination does not prevent acquisition or carriage of the causative organism.
E The adult formulation has a lower concentration of the agent, as local reactions are thought to relate to age and
dose.
7 Which of the following vaccines is contraindicated in those with a documented egg allergy?
A Typhoid Vi
B Cholera
C Yellow fever
D Varicella zoster
E MMR( measles-mumps-rubella)
8 Which of the following is absolutely contraindicated in people with HIV/AIDS, regardless of CD4+ count?
A BCG (Bacillus CalmetteGurin)
B Cholera
C Smallpox
D Typhoid
E Varicella zoster
711
9 Which of the following is contraindicated in a renal transplant patient?

A Oral typhoid vaccine
B DTP (diphtheriatetanuspertussis) vaccine
C Hepatitis A vaccine
D Japanese encephalitis vaccine
E Rabies vaccine
10 All of the following are specically recommended for healthcare workers except:
A DTP (diphtheriatetanuspertussis) vaccine
B Hepatitis A vaccine
C Hepatitis B vaccine
D Inuenza vaccine
E MMR (measles-mumps-rubella) vaccine
ANSWERS
1 B.
Japanese encephalitis vaccine is an inactivated vaccine. Yellow fever, MMR and oral typhoid vaccines are all live attenuated
vaccines. Varicella vaccine and varicella zoster vaccine (VZV) are both live attenuated vaccinesVZV is approximately
14 times as potent as varicella vaccine, and must only be given to people with prior immunity to varicella.
2 C.
Polysaccharide capsule vaccines stimulate B-cell-mediated immunity. Pneumococcal polysaccharide vaccine is indicated
in asplenic individuals (over 50 years of age) or with certain chronic diseases, as well as HIV-infected individuals, all of
whom are at greater risk of invasive pneumococcal disease. Polysaccharide capsule vaccines stimulate B-cell immunity,
and as such are poorly immunogenic in children under 2 years of age and require booster doses to maintain immunity.
3 A.
Hepatitis B immunity due solely to vaccination is characterized by the presence of anti-surface-antigen antibodies (HBsAb)
alone. Thus, a previously immunized patient who has HBcAb in addition to HBsAb is immune on the basis of natural
infection rather than immunization. Isolated anti-core-antigen antibodies (HBcAb) may be due either to prior hepatitis
B infection with loss of HBsAb over time, low-level chronic infection, or occult infection. Determination of HBV DNA
levels are needed to exclude chronic or occult infection. Administration of a single dose of hepatitis B vaccine will lead to
detection of HBsAb in the setting of prior infection, although in practice this is rarely seen. In some cases the presence of
HBcAb alone represents a false-positive nding.
4 E.
Typhoid Vi vaccine is a capsular polysaccharide vaccine and is quite safe to be given to an immunocompromised host.
All the other vaccines are live attenuated vaccines which pose variable risks of disseminated infection in this setting. BCG
in particular is absolutely contraindicated in all adults with HIV infection regardless of their CD4+ cell counts.
5 B.
Administration of hepatitis B vaccine alone to a neonate whose mother is a carrier of HBV (especially if she is HBeAgpositive) will prevent about 70% of vertical transmissions. Addition of hepatitis B immune globulin to vaccination will
result in 95% protection, with the remaining 5% of cases being transplacentally infected. To date, neither antiviral therapy
given during the nal trimester of pregnancy nor Caesarean section have been shown to add further to the strategy of
administration of vaccine plus hyperimmune globulin to the neonate at birth.
6 A.
Diphtheria vaccine is a toxoid preparation available only in combination with tetanus and other antigens. It results in
protective levels of antitoxin in >90% of vaccines. Vaccination does not prevent acquisition or carriage of the causative
agent, Corynebacterium diphtheriae, but reliably prevents clinical disease. Administration of pediatric formulations to adults
results in a higher incidence of local reactions due to the higher dose of toxoid found in pediatric preparations.
7 C.
Yellow fever vaccine is derived from embryonated chicken eggs, and patients with egg-associated anaphylaxis should not
receive yellow fever vaccine nor inuenza vaccine. The other vaccines listed are not egg-derived and can be safely given
to those with egg allergy.
8 A.
BCG vaccination in people with HIV infection may result in fatal disseminated BCG infection regardless of CD4+ cell counts,
and as such is absolutely contraindicated. Smallpox, oral typhoid and varicella zoster vaccines may, after consultation and
careful consideration of the balance of risk versus benet, be given to patients with normal CD4+ cell counts. Varicella zoster
vaccine may also be given to patients with documented immunity, although is not generally recommended.
712
9 A.
Oral typhoid vaccine is a live attenuated vaccine, and is therefore contraindicated in immunosuppressed individuals such
as solid-organ transplant recipients. All the other agents are inactivated agents or, in the cases of diphtheria and tetanus,
toxoids and can safely be given to immunosuppressed individuals.
10 B.
All healthcare workers should receive MMR, annual inuenza, DTP (adult formulation) and hepatitis B vaccines. Healthcare
workers in the pediatric setting, or those working with the developmentally delayed, should also consider hepatitis A
vaccine.
713
CHAPTER 23
DERMATOLOGY FOR THE PHYSICIAN

Brad Frankum
CHAPTER OUTLINE
ACNE
AUTOIMMUNE DISEASES OF THE SKIN
Psoriasis
Bullous lesions
Livedo reticularis
SKIN PROBLEMS ASSOCIATED WITH

UNDERLYING SYSTEMIC DISEASE
The skin and mucous membranes frequently reveal clues to
underlying medical illnesses, and both a history of rash or
skin lesions and an examination of the skin should be a routine part of the assessment of the medical patient.
The skin is easily accessible to biopsy. A low threshold
should exist for a biopsy of abnormal skin in a patient with
a systemic illness in whom there is diagnostic uncertainty.
A number of skin-related symptoms or signs may either
be evidence of a primary dermatological disorder, or secondary to other systemic disease.
Pruritus
Pigmentation
Photosensitivity
Red person syndrome (erythroderma or
exfoliative dermatitis)
Facial ushing
GENETIC OR CONGENITAL SKIN DISEASES

The phakomatoses
SKIN DISEASE ASSOCIATED WITH

MALIGNANCY
Treatment comprises:
Rosacea: topical antibiotics (erythromycin, metronidazole) or long-term oral antibiotics (doxycycline, minocycline); avoidance of caffeine, alcohol, UV radiation,
spicy foods.
Acne vulgaris:
mildtopical benzoyl peroxide or retinoid
moderateadd oral antibiotic (doxycycline, minocycline) or (in females) oral contraceptive pill (OCP)
severe (cystic)oral isotretinoin.
ACNE
AUTOIMMUNE DISEASES OF
THE SKIN
It is important to distinguish acne vulgaris from rosacea

(Box23-1, overleaf).
The skin is an immunologically active tissue, with persistent

exposure to an environment that contains both toxic and
715
Box 23-1
Differentiation of acne vulgaris and

rosacea
Acne vulgaris
Commences at
puberty
Comedones,
pustules, cysts
Affects face and
trunk
Can be a sign of
androgen excess
in females; sideeffect of steroid
use, including
corticosteroids
Rosacea (Figure 23-1)

Generally occurs in middle
age
Caucasian skin predominantly
Female preponderance
Papules, telangiectasia,
pustules (no comedones)
Centrofacial, often with
rhinophyma, and blepharitis
No systemic disease
associations
Facial ushing, especially with
alcohol use
Figure 23-1 Severe rosacea with (A) scattered

papules on the face and involvement of the nose, and
(B) severe inammation with redness and signicant
edema
From Ferri FF. Ferris Clinical advisor 2014. Philadelphia: Elsevier, 2014.
potentially allergenic substances. The skin is also the site of a

number of primary and systemic autoimmune diseases.
Psoriasis
Clinical features
Psoriasis is common, affecting up to 3% of the
population.
The rash has a predilection for the elbows, buttocks,
knees and scalp.
The usual rash is plaque-like with a silvery scale and an
erythematous base (Figure 23-2).
Nail abnormalities are very common, especially onycholysis and pitting. Subungual hyperkeratosis and a
pathognomonic yellow-brown discoloration known as
oil spots can also be seen.
Erythrodermic psoriasis, generalized pustular psoriasis,
and psoriasis associated with arthropathy can be classified as severe forms of the disease.
Guttate psoriasis is an acute form of disease with small
psoriatic lesions, often following streptococcal sore
throat.
716
Figure 23-2 Psoriasis subtypes: (A) small plaque

psoriasis, (B) localized thick plaque psoriasis, (C) large
plaque psoriasis, (D) inammatory localized psoriasis,
(E) erythrodermic psoriasis, and (F) psoriasis and
psoriatic arthritis
From Menter A et al. Guidelines of care for the management of
psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and
guidelines of care for the treatment of psoriasis with biologics. J Am
Acad Dermatol 2008;58(5):82650.
Oral corticosteroids, interferons, beta-blockers, lithium,

and antimalarial drugs can exacerbate psoriasis.
Cardiovascular disease, obesity, and the metabolic syndrome are more common in psoriatic patients than the
general population.
Treatment
Topical corticosteroids.
Topical tar preparations.
Topical synthetic vitamin D analog (calcipotriol).
Ultraviolet-B (UVB) therapy.
Topical calcineurin inhibitors for facial or flexural
disease.
Acitretin is a 2nd-generation retinoid that is used
in the treatment of psoriasis and psoriatic arthropathy. Adverse effects include teratogenicity, hepatitis,
hypertriglyceridemia, cheilitis, xerosis, alopecia and
bony hyperostosis.
Methotrexate or cyclosporine (ciclosporin) may be
used for treatment of severe skin disease and psoriatic
arthropathy.
Chapter 23 Dermatology for the physician
Biological agents are increasingly being used with success in severe diseaseTNF (tumor necrosis factor)
inhibitors (infliximab, etanercept) or interleukin (IL)12/23 blockers (ustikinumab).
Rest, compression bandaging, and non-steroidal antiinflammatory drugs (NSAIDs) may help.
Recalcitrant cases may require oral corticosteroids or
systemic immunosuppression.
Bullous lesions
Erythema nodosum is in fact a form of panniculitis.

It presents with tender, red, palpable lesions predominantly on the pretibial area (Figure 23-3).
Causes
Sarcoidosis
Streptococcal infections (beta-hemolytic)
Drugs, e.g. sulfonamides, penicillin, sulfonylureas,
estrogen
Tuberculosis
Other infections (less common), e.g. lepromatous
leprosy, histoplasmosis, blastomycosis, coccidioidomycosis, toxoplasmosis, Yersinia, Chlamydia, lymphogranuloma venereum
Systemic autoimmune diseasesystemic lupus erythematosus (SLE), antiphospholipid syndrome, scleroderma
Behets syndrome
Pregnancy
Idiopathic
Pemphigus vulgaris
Clinical features
Pemphigus vulgaris usually presents in the 5th to 7th
decade.
Mucosal involvement is always presentoral, pharyngeal, conjunctival, and genital ulcers or blisters.
Flaccid blisters (Figure 23-4) are seen on the scalp, face,
axillae and upper trunk (especially at sites of trauma or
pressure), and are painful.
Nikolskys sign is positive (affected superficial skin can
be moved over the deeper layer).
Pathology
Skin biopsy reveals acantholysis (rounded keratinocytes
resulting from detachment of intercellular adhesion),
and intraepithelial vesicles.
Immunofluorescence shows immunoglobulin G (IgG;
intercellular substance antibody) and C3 deposits in the
interepithelial spaces.
Serum titer of IgG anti-desmoglein-3 antibody is useful
to monitor disease activity.
Treatment
The lesions often resolve spontaneously over weeks to
months.
Treatment is largely directed at the underlying cause.
B
Figure 23-4 Pemphigus vulgaris: (A) painful tongue
lesions; (B) typical skin bullae and ulcerations
Figure 23-3 Erythema nodosum
From Edgin WA, Pratt TC and Grimwood RE. Pemphigus vulgaris

and paraneoplastic pemphigus. Oral Maxilofacial Surg Clin North Am
2008;20(4):57784.
717
Treatment
Pemphigus vulgaris requires aggressive immunosuppression
with high-dose corticosteroids, and frequently cyclophosphamide or mycophenolate.
Failure to control disease with topical corticosteroids,

and severe disease with extensive ulceration and blisters,
will necessitate the addition of oral corticosteroids, and/or
immunosuppressive agents such as azathioprine.
Bullous pemphigoid
Clinical features
Bullous pemphigoid presents predominantly in the
elderly.
It features large, tense, not easily broken, sometimes hemorrhagic bullae, on an erythematous base
(Figure23-5).
There is a predilection for flexures.
Oral ulcers are rare.
Bullous pemphigoid is infrequently associated with
malignancy.
Clinical features
Pathology
Skin biopsysubepidermal vesicles with IgG or IgM,
and complement, in a linear pattern along the basement
membrane zone.
Immunofluorescence reveals IgG anti-basementmembrane zone antibodies in 70% of patients.
Circulating anti-basement-membrane zone antibodies
do not correlate with disease activity.
Skin biopsy shows subepidermal vesicles, beneath which

are found neutrophils in dermal papillae.
Immunofluorescence reveals IgA in a granular pattern,
and complement in the dermal papillae and along the
basement membrane zone of involved and uninvolved
skin.
Serum IgA tissue transglutaminase antibodies are present in the majority of cases, and may be helpful to monitor disease activity.
Treatment
Treatment
High-dose, high-potency topical corticosteroids may be

effective for localized or milder disease.
A gluten-free diet is the cornerstone of therapy. Skin disease that does not respond to the gluten-free diet, or patients
without celiac disease, should be treated with dapsone.
Dermatitis herpetiformis presents with intensely pruritic

vesicles, or excoriations, on knees, elbows and buttocks
(Figure 23-6). Mucosal involvement is not seen.
It usually presents in the 3rd or 4th decade.
Celiac disease (often asymptomatic) is almost always
present.
HLA DQw2 and DR3 are associated in >90% of cases.
Pathology
CLINICAL PEARL
Any skin change noted by a patient, or detected by the
physician, should prompt consideration of whether it
represents a cutaneous manifestation of a systemic
illness.
Figure 23-5 Bullous pemphigoid
Figure 23-6 Dermatitis herpetiformis
From Brinster NK et al. Dermatopathology: a volume in the Highyield Pathology series. Philadelphia: Elsevier, 2011.
From Krpti S. Dermatitis herpetiformis. Clin Dermatol

2012;30(1):569.
718
Livedo reticularis
Livedo reticularis is a spidery or lattice-like appearance that
can be red or blue in coloration (Figure 23-7), and affects
the skin of the limbs. It represents sluggish venular blood
flow. A number of diseases may be associated with livedo
reticularis (Box 23-2).
SKIN PROBLEMS ASSOCIATED

WITH UNDERLYING SYSTEMIC
DISEASE
Clinical features
Acanthosis nigricans is characterized by hyperpigmentation and velvety thickening of the intertriginous areas
(Figure23-8).
Causes
Malignancyadenocarcinoma, lymphoma
Endocrine disease, e.g. acromegaly, Cushings syndrome, hypothyroidism, diabetes mellitus and insulin
resistance states, lipodystrophies (especially leprechaunism), SteinLeventhal syndrome
Obesity
Congenital
Pyoderma gangrenosum
This is a serious, painful, ulcerating disease of the skin and
soft tissue, often affecting the lower legs.
Causes
Paraproteinemia, e.g. IgA myeloma
Box 23-2
Diseases associated with livedo

reticularis
Autoimmune disease
Dermatomyositis
Scleroderma
Sjgrens syndrome
Vasculitides
Neoplastic disease
Pheochromocytoma
Carcinoid
Myeloma
Polycythemia vera
Leukemia
Essential thrombocytosis
Infection
Parvovirus B-19
Syphilis
Hepatitis C
Tuberculosis
Drug reactions
Amantadine
Warfarin
Quinidine
Vascular disease
Cryoglobulinemia
Cholesterol emboli
Endocarditis
Thrombotic thrombocytopenic purpura
Figure 23-7 Livedo reticularis on the inner thigh
Figure 23-8 Acanthosis nigricans
From Jorquera-Barquero E et al. Oxalosis and livedo reticularis. Actas

Dermo-Siliogrcas (Engl ed) 2013;104(9):81518.
From Lebwohl MG et al (eds). Treatment of skin disease:

comprehensive therapeutic strategies, 4th ed. Elsevier, 2014.
719
Idiopathic
Clinical features
Pyoderma causes pustules and sterile abscesses, which
rupture and leave denuded, ulcerated lesions that may
necrose.
The edges of the ulcers are characteristically purple, and
undermined (Figure 23-9).
Lesions are painful.
Patients often experience pathergy, where new lesions
appear at the sites of new or previous trauma.
Without intervention, the disease often progresses and
can be life-threatening.
There is no diagnostic test for pyoderma. Diagnosis is
made on appearance of the skin lesions and exclusion
of other causes of blistering, pustular or necrotic lesions
byother tests or skin biopsy.
Treatment
Aggressive systemic immunosuppression is required.
Corticosteroids are often effective, but moderate to high
doses are required.
Anti-TNF therapy or cyclosporine (ciclosporin) may be
effective in some cases.
Identified underlying disease should be treated.
Sweets syndrome (acute febrile neutrophilic

dermatosis)
This rare syndrome causes painful, erythematous plaques in
association with fever.
Causes
It is more common in women, and in those who are
pregnant.
A significant minority of patients have an associated
malignancy, infection, or an autoimmune or inflammatory disorder.
Drugs including furosemide, trimethoprim-sulfamethoxazole, hydralazine, retinoic acid and minocycline have been implicated in this disorder.
Clinical features
The cutaneous eruption has a predilection for the dorsa
of the hands, and the head, neck and upper limbs, but
can affect any part of the skin.
Lesions are generally tender, erythematous, and papular
or plaque-like (Figure 23-10). Vesiculation and pustulation can occur.
Along with fever, multiple systemic features have been
described, including malaise, arthralgia, myalgia and
ocular involvement.
Diagnosis
Leukocytosis and elevated acute phase reactants are generally evident, but diagnosis depends on histopathology.
Treatment
Although spontaneous resolution is usual over time, the
severity of the symptoms requires the use of oral corticosteroids in moderate to high doses in most cases. This is generally effective for both cutaneous and systemic manifestations
in Sweets syndrome.
Pruritus
Any generalized persistent pruritus with scratch marks, that
is unrelieved by emollients and wakens the patient from
sleep, needs evaluation to exclude systemic disease. Systemic
causes, include:
cholestasis, e.g. primary biliary cirrhosis
pregnancy
lymphoma, myeloma
polycythemia rubra vera, mycosis fungoides
carcinoma, e.g. breast, stomach, lung
Figure 23-9 Pyoderma gangrenosum
Figure 23-10 Sweets syndrome
From Wall LB and Stern PJ. Pyoderma gangrenosum. J Hand Surg

2012;37(5):10835.
From Fazili T, Duncan D and Wani L. Sweets syndrome. Am J Med

2010;123(8):6946.
720
endocrine disease, e.g. diabetes mellitus, hypothyroidism, thyrotoxicosis, carcinoid syndrome

iron deficiency
medication.
Pigmentation
There are multiple causes of skin pigmentation:
liver disease, e.g. hemochromatosis, Wilsons disease,
primary biliary cirrhosis, porphyria
malignancy (related to cachexia, or ectopic adrenocorticotropic hormone [ACTH] production)
endocrine disease, e.g. Addisons disease (Figure
23-11), Cushings syndrome, acromegaly, pheochromocytoma, hyperthyroidism
systemic autoimmune disease, e.g. SLE, scleroderma,
dermatomyositis
drugs, e.g. neuroleptics, hydroxychloroquine, busulfan,
gold, lead, amiodarone, minocycline, heavy metals
radiation
malabsorption
chronic infection, e.g. infective endocarditis
increased levels of female hormonespregnancy, oral
contraceptive pill.
tender pustules; Figure 23-13), toxic shock syndrome,

hand, foot and mouth disease (linear or oval vesicles)
erythema multiforme
Reiters syndrome (erythematous pustular eruptions
keratoderma blennorrhagica)
atopic dermatitis
scabies
pustular psoriasis
drug reaction
mercury or arsenic poisoning.
Red person syndrome (erythroderma

or exfoliative dermatitis)
This refers to a confluent, generalized erythamatous rash
that can be the result of any etiology. An example is shown
in Figure 23-14 (overleaf).
Causes are:
malignancy
mycosis fungoides (infiltration of the skin by T cells)
Photosensitivity
Causes of photosensitivity include:
drugs, e.g. neuroleptics, antibiotics (sulfonamides, tetracycline), sulfonylureas, NSAIDs, diuretics
porphyria cutanea tarda (Figure 23-12)
SLE
pellagra.

Differential diagnosis of such rash:
syphilis
acute infections, e.g. infectious mononucleosis (nonspecific macular erythema), gonococcemia (purpuric
Figure 23-11 Pigmentation of scars in Addisons

disease
From Ferri FF. Ferris Clinical advisor 2014. Philadelphia: Elsevier,
2014.
Figure 23-12 Porphyria cutanea tarda

Figure 23-13 Pustular lesion on foot from

gonococcal infection
Courtesy of the Graham International Dermatopathology Learning
Center.
721
The phakomatoses
Neurobromatosis
Figure 23-14 Erythroderma of red person syndrome

From Gawkrodger DJ and Ardern-Jones MR. Dermatology: an
illustrated colour text, 5th ed. Elsevier, 2012.
lymphoma, leukemia
carcinoma (rare)
drugs, e.g. phenytoin, allopurinol
generalization of a pre-existing dermatitis, e.g. psoriasis,
atopic dermatitis.
Regardless of cause, patients may present with edema
(hypoalbuminemia from skin loss), loss of muscle mass, and
extrarenal water loss.

Causes of excessive sweating include:
thyrotoxicosis
pheochromocytoma
acromegaly
hypoglycemia
autonomic dysfunction, e.g. RileyDay syndrome
physiological causes, e.g. emotional stress, fever,
menopause.
Type I (von Recklinghausens disease: chromosome 17)

This is characterized by:
neurofibromas of peripheral nerves.
more than six v1.5cm caf-au-lait spots (Figure 23-15)
hamartomas of the iris (Lisch nodules)
axillary freckling (Crowes sign)
pseudo-arthrosis of the tibia.
Patients are predisposed to nervous system neoplasms,
including plexiform neurofibromas, optic gliomas, pheochromocytomas, ependymomas, meningiomas, astrocytomas, and change to sarcoma.
Type II (chromosome 22q)
Type II neurofibromatosis is characterized by bilateral
acoustic schwannomas.
Patients are predisposed to meningiomas, gliomas, and
schwannomas of peripheral and cranial nerves.
The most common presentation is unilateral deafness. If
detected early, surgery can preserve the auditory nerve.
Tuberous sclerosis
the disease is autosomal dominant, or sporadic
it presents with a triad of convulsions, mental retardation (with calcification in the temporal lobes), and adenoma sebaceum (fibromas on the cheeks and forehead)
other features may include the shagreen patch (thick
yellow skin on the lower back), cardiac rhabdomyoma,
renal angioleiomyoma, and pulmonary fibrosis.
Facial ushing
Causes of facial flushing include:
menopause
rosacea
mastocytosis
carcinoid syndrome
medullary carcinoma of the thyroid
drugs, e.g. alcohol.
GENETIC OR CONGENITAL
SKIN DISEASES
Figure 23-15 Caf-au-lait spots
Skin lesions may be manifestations of genetic or congenital

diseases.
From Boyd KP, Korf BR and Theos A. Neurobromatosis type 1. J Am

Acad Dermatol 2009;61(1):114.
722
Von HippelLindau disease

autosomal dominant
hemangioblastomas of the retina, cerebellum and spinal
cord
cysts in the kidney, epididymis or pancreas
hemangiomas elsewhere (e.g. liver, pancreas, kidney)
pheochromocytoma
renal and pancreatic cancer.
SturgeWeber syndrome
a congenital, non-hereditary disorder
capillary hemangiomas (port wine stains) in a cranial
nerve V distribution, upper or middle branch, with an
intracranial venous hemangioma of the leptomeninges
association with seizures, glaucoma, and mental
retardation.
Ataxiatelangiectasia
Clinical features are a triad of cerebellar ataxia, oculocutaneous telangiectasia on the bulbar conjunctiva and skin,
and immunodeficiency (decreased IgA and IgE, and thymic
atrophy).
SKIN DISEASE ASSOCIATED

WITH MALIGNANCY
Figure 23-16 Mycosis fungoides

topical nitrogen mustard

systemic chemotherapy.
Szary syndrome
Clinical features
Generalized erythroderma
Keratoderma of the palms and soles
Pruritus
Lymphadenopathy
Szary cell count of >1000/mm3 in the peripheral blood
Skin lesions may at times represent primary or secondary

malignancy, other than those that are typically a result of
ultraviolet radiation exposure.
Diagnosis
Biopsy reveals monoclonal CD4+ T-lymphocytes in the
epidermis and dermis (Szary cells).
Cutaneous T-cell non-Hodgkin lymphoma
Treatment
Mycosis fungoides
Clinical features
Initially, discrete plaques or nodules on the skin. Plaques
may be scaly and erythematous (Figure 23-16).
These may progress to coalescent lesions.
Lymph nodes and viscera may become involved in time.
Diagnosis
Biopsy reveals monoclonal CD4+ T-lymphocytes in the
epidermis and dermis (Szary cells).
Treatment
This depends on the stage of disease. It may require:
topical therapy with corticosteroids and retinoids
radiotherapy
narrow-band UVB therapy with or without oral retinoids
Topical therapy with corticosteroids and retinoids

Radiotherapy
Extracorporeal photopheresis
Systemic chemotherapy
Malignancies which metastasize to the skin include:
carcinomas of the:
breast
gastrointestinal tract
lung
kidney
ovary
melanomas
leukemias (especially acute myeloid leukemia).
Clues to underlying malignancy are outlined in Table 23-1,
overleaf.
723
Table 23-1 Cutaneous clues to underlying malignancy
SKIN CHANGE
POSSIBLE UNDERLYING MALIGNANCY
Extramammary Pagets disease
Genitourinary or gastrointestinal
Gastrointestinal, especially stomach
Pyoderma gangrenosum
Leukemia
Necrolytic migratory erythema
Glucagonoma
Torres syndrome (multiple sebaceous tumors of the skin)
Carcinoma of the colon, breast
Cowdens syndrome (trichilemmomas, verrucous papules,

oral bromas)
Carcinoma of the breast, thyroid
Gardeners syndrome (soft-tissue tumors, sebaceous cysts)
Carcinoma of the colon
Acquired ichthyosis
Hodgkin lymphoma
Hirsutism
Adrenal or ovarian tumor
Hypertrichosis
Carcinoid; carcinoma of the breast, gastrointestinal,

lymphoma
Erythema gyratum repens (concentric erythematous bands)
Carcinoma of the lung, breast
Sweets syndrome (acute febrile neutrophilic dermatosis)
Leukemia
Dermatomyositis
Especially gastrointestinal
Multiple mucosal neuromas
Medullary carcinoma of the thyroid
Cutaneous amyloidosis
Myeloma
Tylosis (palmarplantar keratoderma)
Carcinoma of the esophagus
Pemphigus
Thymoma
Paraneoplastic pemphigus (associated with erythema

multiforme)
Lymphoma, leukemia
Epidermolysis bullosa acquisita
Myeloma
724
1
A 47-year-old woman complains of ushing for the past 18 months. Her menstrual periods have been irregular for
12months, and she has been amenorrheic for the past 3 months. Her past medical history is unremarkable. The patient
also complains that her bowel habit has changed over that period, with watery diarrhea occurring up to several times
per day. On physical examination you observe signs of facial rosacea. What would be the most appropriate next step in
this case?
A Order 24-hour urinary collection for 5-HIAA (5-hydroxyindoleacetic acid) quantitation.
B Commence hormone replacement therapy.
C Commence topical antibiotics for treatment of rosacea.
D Perform serum tryptase to exclude systemic mastocytosis.
A 45-year-old male presents with painful lesions on the lower limbs. On examination you observe tender, indurated
lesions, predominantly over the pretibial area. On further questioning, the patient also has a dry cough. What further
investigations would be appropriate at this stage?
A Biopsy of lesion, anti-neutrophil cytoplasmic antibodies
B Anti-neutrophil cytoplasmic antibodies, computed tomography (CT) mesenteric angiogram
C CT mesenteric angiogram, chest radiograph
D Chest radiograph, serum angiotensin-converting enzyme (ACE) level
E Serum ACE level, biopsy of lesion
A 25-year-old female patient presents with extremely pruritic vesicles on the limbs, predominantly around the elbows,
shoulders and knees. There is no mucosal involvement. This has been present for 2 months. The likely appropriate
treatment in this case would be:
A A gluten-free diet
B High-dose oral corticosteroids
C Liberal application of potent topical steroid creams
D Oral valacyclovir (valaciclovir)
ANSWERS
1
A.
This patient has carcinoid syndromethis is an example of a skin manifestation being the rst sign of a systemic disease.
It is important to take a thorough history with any new symptom, even if menopause is by far the most common cause
of ushing in a female of this age. The symptom of new-onset watery diarrhea is always concerning, and must not be
ignored. Systemic mastocytosis can certainly cause diarrhea, but the skin rash is urticarial and pruritic.
D.
Erythema nodosum is generally very characteristic in appearance, so biopsy can be avoided in most cases and a
clinical diagnosis made. With the presence of a dry cough, one needs to be suspicious of sarcoidosis, and if bilateral
hilar lymphadenopathy is present, with or without interstitial lung changes, this becomes more likely. A positive serum
ACE level is moderately specic for sarcoidosis in this situation, but lacks sensitivity. An important differential diagnosis
is tuberculosis, in which case a chest radiograph is also very important. The history would be important to screen for
inammatory bowel disease. Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is not associated with
erythema nodosum, but cutaneous polyarteritis nodosa can look similar in appearance.
A.
Dermatitis herpetiformis is the most likely diagnosis here, given the signicant pruritus, the lack of mucosal involvement
and the lack of bullae. Chickenpox would not last for 2 months and would be more generalized. Pemphigus vulgaris
always involves the mucous membranes, and bullous pemphigoid results in large bullae and is usually seen in older age
groups. A gluten-free diet is the rst-line therapy for dermatitis herpetiformis.
725
CHAPTER 24
MEDICAL OPHTHALMOLOGY
Michael Hennessy and Brad Frankum
CHAPTER OUTLINE
INTRODUCTION
OCULAR HISTORY
OCULAR EXAMINATION

Visual acuity
Field of vision
Pupils
Color vision
Ocular motility
Ophthalmoscopy
Auscultation
PATHOLOGICAL CONDITIONS

Hypertension
INTRODUCTION
Eye examination is an essential part of a comprehensive general
medical consultation. Ocular symptoms and/or signs can:
help determine an accurate diagnosis
indicate disease severity when the diagnosis is established (e.g. a patient with diabetes mellitus)
reveal ocular changes related to treatment.
Non-arteritic anterior ischemic optic neuropathy

Arteritisarteritic acute anterior ischemic optic
neuropathy
UVEITIS
RETINITIS
SCLERITIS AND SCLERO-UVEITIS
THYROID-RELATED ORBITOPATHY
DRY EYE
NEOPLASIA AND THE EYE
NEURO-OPHTHALMOLOGY
Optic neuritis (ON)
Papilledema
PHAKOMATOSES
OCULAR EFFECTS OF SYSTEMIC
MEDICATION
Performing an accurate eye exam is based on understanding:
the structure and function of the eye and visual system,
recognizing that light is transmitted through living,
effectively transparent tissues and optically clear extracellular material (aqueous and vitreous) to then activate
the photoreceptors in the retina
that the manifestations of disease are determined by the
unique features of the anatomy and physiology of
727
theeye, and how these result in patients symptoms and

the examination signs.
Key concepts include:
Transparency.
To be transparent, a healthy cornea and lens are free
of intrinsic blood vessels, and the tissue structure
renders it transparent.
The inner cellular layers of a healthy retina are transparent. Retinal vessels supply the inner retina in all
but the central 0.5-mm-diameter foveal area, and
the arterioles and venules are visible with the ophthalmoscope. The color seen in the fundus is due to
the retinal pigment epithelium (RPE) and choroid.
This can be altered when the vascular, non-foveal
inner retina becomes opaque from the ischemia
resulting from retinal arterial occlusion, and the
normal fundus color is masked.
Manifestations of disease in the eye are directly visible
at a cellular level with imaging techniques that involve
illumination and magnification, as is achieved even with
a basic tool such as the direct ophthalmoscope.
OCULAR HISTORY
Common ocular symptoms are:
altered vision
pain, including photophobia
lacrimation
discharge
changed appearance including redness
diplopia
ptosis
anisocoria
leukocoria.
The timing or tempo of symptoms, and how they developed or changed with time, should be explored carefully
and the patient asked to describe altered vision in detail.
Blurry vision can mean many things.
The need to use distance-vision spectacles or contact lenses
should be clarified, and high levels of ametropia could be
relevant to ocular clinical problems such as hyperopia for
angle-closure glaucoma risk, and myopia for glaucoma,
retinal detachment and myopic retinal degeneration.
The open question Do you have any problem with your
vision? can illicit complaints because of the need to wear
spectacles. Is that with or without your glasses?, How
old are your glasses? and Do you need to use reading
glasses? can be useful clarifying questions. The improved
close vision without reading glasses can result from the
myopic shift induced by a nuclear sclerotic cataract.
A comprehensive systemic history is essential, and
should include:
allergies
drug reactions
medications, including use of eye drops
trauma to or near the eye
general medical history
and both specific ocular and general surgical history.
728
OCULAR EXAMINATION
Bedside eye examination techniques include the following.

This can include, where relevant:
measurement of ptosis
exophthalmos or enophthalmos
areas of altered sensation.
The clarity of the cornea and the depth of the chamber can
be assessed by gross inspection, directional illumination, and
with minimal magnification. A blue filter for the light and
the instillation of fluorescein stain can be used to detect corneal ulcers as part of a magnified external eye exam.
CLINICAL PEARL
Where corneal sensitivity and the blink reex need to
be tested, this should be performed before any eye
examination drops are used.
Visual acuity
Standard visual acuity assessment is performed at a distance of 6 m, with a 6m chartwhere the letter sizes on
the test chart are standardized for the testing distance.
Alternative test-chart sizes and test distances, e.g. a
hand-held visual acuity card, can be used.
One eye is tested at a time with the other thoroughly
covered, e.g. with the palm of the patients hand.
If distance glasses are used, visual acuity is tested with
the glasses worn.
Visual acuity is recorded for each eye as a fraction, with
the test distance being the numerator and the smallest
size letter achieved being the denominator (e.g. RVA
[right eye visual acuity] with glasses: 6/6).
If the vision is subnormal, a pinhole (PH) is used to
check for improvement. Improvement indicates that the
problem is refractive.
Near vision is tested with a reading card with fonts of
different sizes. Both eyes are tested together for near
vision acuity unless the symptoms indicate a need to
check each separately.
Formal intraocular pressure readings are recorded with
a tonometer.
Gross estimation of intraocular pressure (hard, normal
or very soft) is gained by palpation of the globe through
the eyelid.
Palpation should be avoided if there is a possibility
of globe injury, and employed gently to judge ocular tenderness if there is ocular pain.
Field of vision
The visual field of each eye is tested by confrontation with
the count fingers technique, each eye in turn.
Chapter 24 Medical ophthalmology
The examiner faces the patient at about a 1m distance,

and systematically tests, equidistant between examiner
and patient, the four quadrants in each eye in turn,
while the other eye is covered. The eye being tested
looks at the examiners opposite eye (e.g. patients right
to examiners left).
The patient is asked first to describe whether any parts
of the examiners face are missing when looking at the
center of the examiners face. This technique will determine large field defects such as quadrantinopias, hemianopias, or superior and inferior monocular hemi-field
defects.
Visual field defects are interpreted by following the path
first of the light onto the retina, and then of the nerve
fibers from the eye to the visual cortex. Light from the
right side of fixation in each eye reaches the left side of
the retina in each eye (relative to the fovea); that is, the
nasal retina in the right eye and the temporal retina in
the left, and vice versa.
There are eight key features of visual field defects:
Retinal and optic nerve lesions on one eye produce
field defects for that eye, and may follow upper or
lower field patterns for, respectively, lower or upper
retinal pathologies.
A bi-temporal hemianopia is caused by a lesion of the
optic chiasm that affects the nasal fibers crossing from
the optic nerve to the contralateral optic tract.
Lesions posterior to the chiasm (retro-chiasmal) cause
homonymous field defects:
anterior retro-chiasmal lesions cause incongruous
homonymous field defects
posterior retro-chiasmal lesions cause congruous
homonymous field defects
temporal lobe lesions involving the optic radiation cause upper quadrantinopiasoften slightly
incongruous
complete homonymous hemianopias cannot be
specifically localized along the contralateral retrochiasmal visual pathway
unilateral homonymous hemianopia does not
reduce visual acuity. In cortical blindness, the visual
acuity should be equal in both eyes. If not, there is
an additional cause for the difference in acuity.
Pupils
Pupil size and the response to light stimuli are determined
by the combination of:
nerve distribution in the afferent and efferent paths
the central connections that establish the reflex arc
the activity from higher brain centers
the effects of some drugs.
The normal neurological reflex arc (optic nerve, midbrain,
oculomotor nerve) function determines that:
1 the pupils will be the same size under any particular
level of room illumination
2 the direct and consensual pupil responses are equal
from the same torchlight stimulation on each side.
The elements of the reflex arc are: retina q optic nerve q

optic chiasm (partial decussation) q superior brachium of
the midbrain q EdingerWestphal subnucleus (bilateral,
equal innervation of both subnuclei by each side) q oculomotor nerve pre-ganglionic nerve fiber q post-ganglionic
nerve q iris sphincter muscle.
Pupil size
Pupil size is first observed and compared between the
two sides, and with the patients gaze directed to a specific point in the distance.
Unexpectedly tiny pupils can indicate the effect of narcotic drugs.
The pupils should be of equal size and concentric with
the limbus, and constrict briskly in a smooth motion
in response to a light stimulus from a torch directed
through the pupil.
Pupils of equal size will usually be first tested with
the torchlight test. Alternatively, when unequal-sized
pupils are present, the size difference of the pupils is
first compared between bright and dim levels of room
illumination.
Direct pupillary response

To test the direct pupil response to light, relatively dim room
lighting is used with the torchlight directed into the pupil,
and then the timing and characteristic of the pupil response
of the tested eye is observed. The direct response for the
other eye is tested the same way.
Swinging ashlight test

The pupil responses to light for the pair of eyes are best compared by using the swinging torch (swinging flashlight) test:
The torch light is directed at one eye for about 3 seconds, then switched instantly to the other eye, and the
illuminated pupil is observed over the next 3 seconds to
determine whether the pupil dilates.
When the light first arrives after the switch, the pupil
size is the result of the consensual response from the
other eye, and the response that becomes evident after
3 seconds of illumination shows any relative change for
the direct light response.
Dilatation of the pupil after the switch of the torchlight
signifies a relative afferent pupillary defect (RAPD) on
the side that dilates (see the clinical pearl overleaf).
If the size of one pupil does not change from either room
illumination or direct light response, then rather than
watching the pupil where the light shines, the examiner
observes the responses of the pupil that has a reaction,
including with instantaneous switches of the torchlight.
Pupil accomodation response

The pupil response to the effort of accommodation should
be tested with slightly dimmed room lighting:
The patient looks into the distance with both eyes, then
switches to read small print within an arms length, and
then switches fixation back to the distant object.
729
CLINICAL PEARL
CLINICAL PEARL
A relative afferent pupillary defect (RAPD) is interpreted

in relation to the visual acuity and the eld of vision. An
RAPD is a very sensitive sign of optic nerve pathology
and can be present with relatively normal direct light
responses. Thus if the pupils are the same size in room
illumination and the direct response on each eye looks
normal, the swinging torch test is essential and needs
to be performed accuratelythat is, distance xation
on a specic point in dim room lighting, then a quick
switch and observe the pupil size for change over
3seconds of illumination. For example, after recovery
from a unilateral episode of optic neuritis, the affected
eye might regain essentially normal acuity, have a very
subtle visual eld defect, have a subtle sense of color
desaturation and a subjective sense of reduced brightness, and demonstrate an RAPD.
Red desaturation is interpreted in conjunction with

visual acuity and visual eld test results, and usually signies optic neuropathy.
Sustained pupil constriction from near effort in the

absence of normal pupil light responses is called a light
near dissociation.
When the sign is present it usually occurs with normal vision. It signifies pathology of the dorsal midbrain
affecting the afferent nerve fibers passing through the
superior brachium, or aberrant regeneration of postganglionic parasympathetic nerve fibers from pathology
of the ciliary ganglion.
Unequal pupils
If the pupil sizes are unequal, signs of localized anterior eye
and iris trauma should be noted, and the difference in size is
compared between normal and dim room lighting:
A pupil that fails to dilate in the dark has a defect of
sympathetic innervation, or a miotic agent has been
used (e.g. pilocarpine) in the affected eye.
A pupil that is not as constricted as its fellow, especially
in brighter light, has a defect of parasympathetic innervation, or the eye shows the effect of a mydriatic agent
(e.g. atropine).
Unequal pupil size is interpreted relative to the level of
consciousness:
In the conscious patient, associated signs should be
noted such as ipsilateral ptosis in sympathetic paresis,
or ipsilateral ptosis, diplopia and the unilateral downand-out ocular deviation noted with oculomotor nerve
palsy.
When seen in an unconscious patient, and without the
effect of a mydriatic agent in one eye, this sign indicates
compression or injury of the 3rd cranial nerve and the
upper brain stem, caused either by an extending intracranial mass lesion or by diffuse brain injury.
Color vision
Color vision is tested using a pin with a large red-colored
head. Each eye is tested separately, and the patient is asked
to compare the brightness of the red color between the two
eyes.
730
Ocular motility
Each eye is moved within the bony orbit by the action of the
four recti and two oblique muscles of each eye.
The oculomotor nerve (cranial nerve [CN] III) supplies
the medial, superior and inferior recti, and the inferior
oblique muscles.
The trochlear nerve (CN IV) supplies the superior
oblique muscle.
The abducens nerve (CN VI) supplies the lateral rectus
muscle.
The lateral and medial rectus muscles in each eye control ocular abduction and adduction, respectively.
The ocular ductions are the monocular movements, including abduction and adduction, elevation, depression and cyclotorsion.
The ocular versions are the movements of both
eyes together, and the movement is conjugate when
the movement of both is coordinated to maintain
visual fixation. Extraocular muscle action is controlled through voluntary and automatic ocular
motility neural-control mechanisms that are manifest through the horizontal and vertical gaze centers, and then the respective brain stem cranial
nerve motor nuclei.
The horizontal yoked pairs are controlled by the
horizontal gaze center at the pontomedullary
junction near the 6th cranial nerve nucleus, with
interneurons travelling in the medial longitudinal fasciculus to the medial rectus nucleus in the
midbrain.
CLINICAL PEARL
The primary gaze position refers to the straight-ahead
direction of gaze for both eyes, toward the horizon.
Loss of alignment of the two eyes will result in diplopia,
which will be visible objectively as different positions
of the corneal reection of a torchlight on each eye
called the corneal light reex.
Pursuit eye movements are used so that vision tracks a moving object. This voluntary movement is also coordinated by
the cerebellum, acting on the horizontal and vertical gaze
centers.
Involuntary eye movements can be initiated by:
an optokinetic stimulus, whereby rapid movement of
an object across the field of vision elicits physiological
nystagmus
a vestibular stimulus, whereby movement of endolymph
in the semicircular canals of the inner ear provokes vestibular nystagmus.
Testing eye movement

Eye position, extraocular muscle action, and extraocular
movement control are tested as part of a cranial nerve and
cerebellar examination.
Eyelid position and movement, and the extent of the
sclera visible between the eyelids, should be observed in
conjunction with eye movement.
Ocular motility is tested by first observing the alignment of the eyes in the primary gaze position. The corneal light reflex is a useful aid to assess ocular alignment.
Pursuit movement is used to test movement into the cardinal positions of gaze (H pattern), where the patient
may describe increased object separation when there is
diplopia. The ductions of each eye and the versions of
the pair are observed.
When strabismus is present, the cover test is used in the
primary and cardinal positions of gaze to test extraocular
muscle action.
The fixating eye (central corneal light reflex) is covered
to test for movement of the eye that remains uncovered.
Any movement of the eye that remains visible where
it attempts to regain object fixation when the cover is
applied confirms the under-action of the muscle responsible for the direction of movement of the visible eye.
No movement indicates no paresis, a scotoma preventing appreciation of the stimulus in its new position,
or complete paralysis of the muscle responsible for the
refixation movement.
The uncover test reveals the position that had been taken by
the covered (non-paretic) eye when the eye with a paretic
muscle action was being used for fixation. The uncover
test makes evident the dramatic ocular deviation of the eye
which has normal muscle actions, because of the extra drive
needed for the paretic muscle of the fixating eye; that is, the
yoked pair innervation means the same drive required for
the weak muscle is also delivered to the normal mate of
the pair.
Vertical movement of both eyes is observed for:
relative changes in eyelid position during pursuit, as can
occur with lid lag in thyroid-related eye disease
vertical gaze defect.
The mydriatic drop tropicamide, an antimuscarinic

agent which also produces cycloplegia, has about a
10-minute onset with 4- to 8-hour duration.
Rarely, tropicamide can precipitate an acute attack of
very high intraocular pressure from anterior chamber
angle closure, with the associated risk of severe optic
nerve damage (= glaucoma).
The examiner should first check for the red reflex (Figure
24-1). The examiners focus is then directed to the disc, retinal vessels and macula, which are systematically inspected.
If there is a defect of the red reflex, adjusting the focus of
the ophthalmoscope can help establish the anteroposterior
position of any loss of optical clarity and establish a diagnosis
for reduced visual acuity, e.g. a corneal scar, cataract, vitreous hemorrhage, or retinal detachment.
Causes of cataracts are listed in Box 24-1.
Auscultation
Unilateral proptosis, or a symptom such as hearing a buzzing sound synchronous with the pulse, requires auscultation
over the orbit to detect a bruit, as might be present in an
arterial carotido-cavernous sinus fistula.
Figure 24-1 Loss of red reex on ophthalmoscopy in

the right eye of a child with cataract
From Hoyt CS and Taylor D. Pediatric ophthalmology and
strabismus, 4th ed. Elsevier, 2013.
CLINICAL PEARL
Generalized ophthalmic muscle paresis occurs from
reduced muscle action in multiple planes of action and
can result from myopathies, such as chronic progressive external ophthalmoplegia, neuromuscular junction disease such as myasthenia gravis, and muscular
dystrophies such as myotonic dystrophy.
Ophthalmoscopy
To facilitate ophthalmoscopy, mydriatic drops paralyze the
pupil constriction to light and improve the examiners field
of view, although a limited view of the patients optic nerve
head and macular can be obtained without a dilated pupil.
Box 24-1
Causes of cataract
Idiopathic, especially with aging

Congenitalfamilial, or due to maternal infection
e.g. rubella, cytomegalovirus
Metabolicdiabetes mellitus, hypothyroidism
Drugscorticosteroid therapy (systemic, topical, highdose inhaled), quetiapine, miotics
Trauma
Genetic disorders, e.g. Down syndrome, Turner
syndrome, myotonic dystrophy
Secondary to other ocular disease, e.g. uveitis
731
PATHOLOGICAL CONDITIONS
Occlusion of retinal circulation results from systemic
vascular disease, where there are usually associated cardiovascular disease risk factors, and is a common and
important cause of vision loss.
Systemic hypertension, dyslipidemia, diabetes mellitus,
and tobacco smoking contribute to the risk of retinal
vascular occlusive disease, namely central and branch
retinal arterial and venous occlusion, and non-arteritic
anterior ischemic optic neuropathy.
Diabetic retinopathy (DR) is usually bilateral and is a
common cause of visual loss.
The retinal effects of other vascular diseases are generally
unilateral, with less impact on overall visual impairment.
Hypertension
The signs described below are evident by ophthalmoscopy
(Figure 24-2).
Arteriolosclerosis
A sign of chronic systemic hypertension, this is evident in
the main retinal arterioles:
copper and silver wire changes of the normal light reflex
from the vessel
attenuation of arteriolar caliber, either generalized or
focal
arteriovenous (AV) crossing changesAV nipping
(hourglass shape), venous banking, increased vascular
tortuosity
retinal hemorrhages.
Acute hypertensive retinopathy

Severe acute hypertension without preceding chronic hypertension affects terminal retinal arterioles, where acute-onchronic hypertension will give a mixed picture of changes of
the terminal and main retinal arterioles:
focal intra-retinal peri-arteriolar transudatessmall,
white, focal oval dots deep in the retina, associated with
major arterioles
cottonwool spotsfocal inner retinal ischemia, usually
taking up to 6 weeks to fade
capillary damage leading to microaneurysms, shunt
vessels and collaterals.
Acute hypertensive optic neuropathy

Bilateral optic disc swelling indicates papilledema.
Acute hypertensive choroidopathy

Focal retinal pigment epithelium (RPE) white dot
changes
Serous neurosensory retinal detachment, often in the
macular region, and cystoid macular edema
Chronic hypertensive choroidal changes

Diffuse RPE changesgranularity that looks motheaten
RPE clumping and atrophy (Elschnig spots)
Larger atrophic patches
Linear hyperpigmented flecks along choroidal vessels
(Siegrist streaks)
Chronic optic disc changes

Optic disc pallor may be observed.
Figure 24-2 Retinal changes due to hypertension. (A) Acutearterioles show silver wiring, vascular tortuosity,
generalized reduced arterial caliber, and ame hemorrhage is evident. (B) Chroniccottonwool spots, preretinal hemorrhage, ame and blotch hemorrhages, hard exudates, irregular venous caliber, venous banking,
and arteriovenous crossing changes with arteriolar deviation
From: (A) Yanoff M and Duker JS (eds). Ophthalmology, 4th ed. Saunders, 2014. (B) Rogers AH and Duker JS. Rapid diagnosis in
ophthalmology series: retina. Elsevier, 2008.
732
Retinal arterial occlusion is a spectrum of clinical presentations, from amaurosis fugax to central retinal arterial occlusion, and visible retinal arterial emboli may or may not be
evident.
Amaurosis fugax is the painless, transient monocular
loss of vision akin to a cerebral transient ischemic attack.
Residual emboli may be visible with the ophthalmoscope. Irreversible retinal ischemia occurs after at least
100 minutes of occlusion.
A central retinal arterial occlusion (CRAO) is painless
and occurs with permanent monocular loss of vision.
The retinal pallor from ischemia develops within about
an hour of the onset of symptoms, and fades within a
few days. The characteristic feature is the cherry red spot
(Figure 24-3). A central spot of the macular remains the
normal choroidal color because there is no inner retinal
circulation of the thin foveal-pit area. This is an ophthalmic emergency.
Embolism may occur from known or occult conditions such as atrial fibrillation, ipsilateral carotid stenosis, cardiac valve vegetations, or patent foramen
ovale.
Urgent investigation and treatment will be required
to attempt to restore circulation, recover vision, and
avoid other embolic events. There is a poor prognosis, but some chance of visual recovery from early
intervention.
In addition to emboli, CRAO can be due to thrombotic occlusion of atherosclerotic lesions, inflammatory arteritis (e.g. giant cell arteritis), vascular spasm,
and occlusion secondary to low perfusion pressure.
Branch retinal arterial occlusion (BRAO) arises from
embolic occlusion of more-distal retinal vessels, often in
the temporal retinal circulation. It may produce a defect
in the field of vision that can be permanent.
Retinal venous occlusion is a common retinal vascular

disorder, with a variable pattern of monocular vision loss.
Severe central retinal vein occlusion (CRVO) has devastating consequences, such as rubeotic glaucoma and painful
monocular total blindness. The severity is usually related to
the extent of retinal capillary non-perfusion; and the severity can change, becoming ischemic over time, making exact
classification difficult.
The characteristic findings in CRVO are (Figure 24-4):
retinal hemorrhages in all four quadrants
dilated, tortuous retinal veins
cottonwool spots
macular edema
optic disc swelling.
Ischemic CRVO is associated with a greater risk of proliferative retinopathy, vitreous hemorrhage and rubeotic
glaucoma, and the diagnosis is based on:
severe vision loss at presentation
the presence of an RAPD
extensive retinal hemorrhages and cottonwool spots
(CWS)
non-perfusion on a fluorescein angiogram.
The non-ischemic form is usually milder, with less
severe loss of vision, no RAPD, fewer hemorrhages and
CWS, and good perfusion on a fluorescein angiogram.
If it does not then progress to the ischemic form, nonischemic CRVO can resolve and the patient achieves a
relatively good visual outcome.
CRVO is associated with a range of factors that impinge
on the central retinal vein at the optic disc head, especially where the vein passes through the lamina cribrosa:
external compression of the vein from structural
changes of the lamina cribrosa, as can occur associated with glaucomatous cupping, from swelling of
the optic nerve, or from pressure originating in the
orbit from orbital swelling
Figure 24-3 Central retinal arterial occlusion.

Diffuse retinal pallor, except at the fovea, where the
normal retinal (choroidal) colour looks cherry red by
comparison with the sick pale surrounding retina
From Duker JS, Waheed NK and Goldman D. Handbook of retinal
OCT. Elsevier, 2014.
Figure 24-4 Diffuse retinal hemorrhages secondary to

central retinal vein occlusion, predominantly involving
the retinal nerve ber layer, resulting in the arch-shaped
pattern of hemorrhage. Retinal veins are tortuous. Optic
disc swelling is present, with detail obscured. Macular
edema is present
From Ryan SJ et al. (eds). Retina, 5th ed. Elsevier, 2013.
733
inflammation of the vessel wall in vasculitis

changes in the blood, such as deficiency of thrombolytic factors and increase in clotting factors
blood flow disturbances, either hyperdynamic or
sluggish circulation from hyperviscosity.
The patient history should address the following areas:
hypertension
diabetes mellitus
cardiovascular disorders
bleeding or clotting disorders
vasculitis
autoimmune disorders
use of oral contraceptives
closed-head trauma
alcohol consumption
amount of physical activity
primary open-angle glaucoma or angle-closure glaucoma.

Diabetes mellitus, whether type 1 or type 2, is associated
with the risk of developing DR.
In general, DR occurs as a consequence of the duration
of diabetes and the severity of the associated microvascular structural changeswhether the microvascular
changes are due to accumulated effects of suboptimally
controlled blood glucose levels per se, or to the complex
metabolic changes as a consequence of diabetes.
DR is essentially a capillary disease of the eye, manifesting as either proliferative retinopathy or diabetic
macular edema.
Asymptomatic yet clinically important DR can be
detected by ophthalmoscopy.
Vision loss or disturbance associated with diabetes includes
a range of pathological changes in addition to DR and its
sequelae. Examples of non-DR complications include cataract, isolated cranial nerve palsies, and the consequences of
ocular and periocular infection.
There is proven benefit from optimal systemic control
of diabetes to delay or prevent the onset and reduce the
severity of retinopathy.
Screening eye examination allows early detection of
retinopathy, and institution of effective preventative
treatment.
In simple practical terms, the actual onset of type 2 diabetes may be difficult to pinpoint. In some circumstances,
vision-threatening but asymptomatic DR may be present
when the diagnosis of diabetes mellitus is made. Conversely, vision loss may be the reason the patient seeks
treatment and diabetes mellitus is subsequently found.
Grading of DR (see below) establishes its severity and the
presence of diabetic macular edema.
The grade of retinopathy is used to set intervals for
screening eye examinations, and the criteria for referral
to an ophthalmologist.
734
Management by an ophthalmologist is required when

there is imminent risk of loss of vision, where either a
shorter-interval screening schedule or ocular treatment
is indicated.
Prompt referral to an ophthalmologist is usually required
where there are symptoms of altered vision, or reduced
visual acuity is found during the screening examination.
Pregnancy where there is an established diagnosis of
diabetes mellitus requires special attention.
Features and grading of DR

Accurate classification of DR guides clinical management.
No retinopathynormal visual acuity and no retinopathy in a patient with diabetes mellitus. This usually
requires 2-yearly visual acuity checks and a follow-up
dilated fundus examination. In such a setting, there is a
low risk of rapid progression of retinopathy by the next
eye examination.
Minimal non-proliferative diabetic retinopathy (NPDR)
normal visual acuity and a few retinal microaneurysms. Minimal NPDR requires a 12-month follow-up
eye examination performed by a practitioner able to
accurately detect retinopathy.
Any of the more severe grades of retinopathymoderate
NPDR, severe NPDR, proliferative DR (Figure 24-5) and
high-risk DRwill usually require referral to an ophthalmologist. Features of more severe DR that require referral include:
microaneurysms and intra-retinal hemorrhages in all
four retinal quadrants
venous beading in more than two retinal quadrants
any prominent intra-retinal microvascular abnormalities
(IRMAs)
the presence of neovascularization either at the optic
disc or elsewhere in the retina
vitreous or pre-retinal hemorrhages.
Diabetic macular edema will be suspected from the presence
of ophthalmoscopically detectable retinal thickening or any
hard exudates.
Non-arteritic anterior ischemic optic

neuropathy
Anterior ischemic optic neuropathy (AION) is the most
common acute optic neuropathy in older patients. It is characterized by:
sudden monocular visual loss associated with relatively
pale disc swelling
Associated flame hemorrhage at the disc or in the nerve
fiber layer (Figure 24-6)
CWS in some cases.
Vision loss is usually permanent, with some recovery possible within weeks to months. A degree of optic atrophy
results.
Cardiovascular risk factors will usually be present,
although the diagnosis is usually one of exclusion of the arteritic form, which occurs in giant cell arteritis (see below).
Figure 24-5 (A) Severe non-proliferative diabetic retinopathy, macular hard exudates, microaneurysms, dot and
blotch hemorrhages, and venous beading. (B) Proliferative diabetic retinopathy that has had laser treatment: laser
scars, new vessels at disc and elsewhere, retinal hemorrhages, and brosis overlying vessels superior to disc
From: (A) Ryan SJ et al. (eds). Retina, 5th ed. Saunders, 2013. (B) Rakel RE and Rakel DP. Textbook of family medicine, 8th ed. Elsevier, 2011.
CLINICAL PEARL
Sudden monocular visual loss, associated with pale
disc swelling, in a patient aged 50 years or older will
require consideration for urgent systemic corticosteroid treatment, and possibly anticoagulation, because
of the risk of imminent involvement of the second eye
from giant cell arteritis, and thus the risk of sudden
acute total blindness.
Figure 24-6 Anterior ischemic optic neuropathy;

note the pale, diffuse optic nerve edema and retinal
ischemia evidenced by pallor
From Kidd DP, Newman NJ and Blousse V (eds). Neuroophthalmology. Blue Books of Neurology, issue 32. ButterworthHeinemann, 2008.
Arteritisarteritic acute anterior

ischemic optic neuropathy
Giant cell arteritis (GCA) is important because of the risk
of developing acute AION, which can be bilateral, and
becomes clinically apparent in a short timeframe.
Patients with symptoms of polymyalgia rheumatica
(PMR) can develop GCA (15%), and half of those with
GCA will have preceding PMR.
GCA has a range of ocular effects, including external
ophthalmoplegia and central or branch retinal artery
occlusion.
A localized headache of recent onset, with a high erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP), in conjunction with AION can be highly suggestive of the diagnosis and the need for urgent treatment.
The diagnosis is formally confirmed by a temporal

artery biopsy that exhibits a chronic granulomatous
inflammatory cell infiltrate of the arterial wall, and fluorescein angiography demonstrating markedly delayed
and patchy perfusion of the choroid from the short posterior ciliary arteries.
The symptoms and signs are related to the reduced perfusion caused by the vasculitis of the external carotid,
and the ophthalmic arteries and their branches.
UVEITIS
The uveal tract of the eye is separated anatomically into the
iris, ciliary body and choroid. Inflammation of any of these parts
is collectively called uveitis, or more specifically iritis, cyclitis or pars planitis for the ciliary body, or choroiditis.
Alternative systems of classification include anterior,
intermediate, posterior or pan-uveitis, based on the site of
most severe inflammation.
Uveitis is also described by whether one or both eyes are
involved.
The onset, whether acute or chronic, and the duration
and time course can be relevant.
Uveitis is an important differential diagnosis in any case
of red eye (Figure 24-7, overleaf).
735
RETINITIS
Figure 24-7 Anterior uveitis. Diffuse perilimbal

vascular congestion; cornea is clear
From Phelps K and Hassad C. General practice: the integrative
approach. Sydney: Elsevier Australia, 2011.
The most common form of retinitis is produced by cytomegalovirus (CMV) infection, usually seen in immunocompromised patientseither from leukemia, systemic
immunosuppressive treatment, or associated with human
immunodeficiency virus (HIV) infection.
Symptoms can vary depending on the area of the retina involved, with reduced visual acuity, a scotoma, or
floaters.
It may be asymptomatic during the early stages of
peripheral retinal lesions.
Low CD4+ cell counts (<50 cells/mL) can justify routine dilated fundus examination to screen for retinitis, because CMV infection is common in previously
healthy adults, and the retinitis is the result of reactivation of infection in the setting of immunosuppression.
Systemic and intraocular antiviral treatments, which are
virostatic, are required to treat the retinitis, in conjunction with treatment of the underlying immunodeficiency.
CLINICAL PEARL
The symptoms of uveitis include acute pain, redness,
photophobia, lacrimation, reduced vision, and oaters.
Slit-lamp examination is generally required to make the

diagnosis; in this, the protein and cellular exudate of
acute inflammation, or the intraocular signs of the consequences of chronic inflammation, are seen directly.
While a single, unilateral and mild attack of anterior
uveitis is often idiopathic, injury, systemic infections
and systemic autoimmune disorders can trigger an episode so should be considered and excluded.
A dilated retinal fundus examination is required in all
cases of uveitis, and can establish whether there are
intraocular features of previous uveitissuch as a posterior synechia, or a well-established chorio-retinal scar,
with possibly acute reactivation of the scar, or retinal
vasculitis.
CLINICAL PEARL
Common systemic conditions associated with uveitis
include seronegative arthropathy, sarcoidosis, systemic
lupus erythematosus, rheumatoid arthritis, juvenile
rheumatoid arthritis, herpesvirus group infections,
toxoplasmosis, syphilis, tuberculosis, ANCA-associated
vasculitis, and Behets disease.
Uveitis treatment will target any underlying systemic

condition, the intraocular inflammation, and the
consequences in the eye of inflammation, including
steroid-induced problems such as secondarily elevated
intraocular pressure.
Intensive topical steroids, and non-steroidal antiinflammatory eye drops, through to local steroid injections and glaucoma treatment, require supervision by
an ophthalmologist in conjunction with the physician
treating the underlying systemic condition.
736
SCLERITIS AND SCLEROUVEITIS

Scleritis usually occurs as a unilateral painful red eye. This is
a potentially blinding chronic inflammatory condition characterized by:
cellular infiltrates and edema of the sclera, and episclera
the effects of inflammation that secondarily involve the
uveal tract (sclero-uveitis).
Scleritis may be:
anterior with an acute painful red eye
posterior with altered vision, pain, tenderness and
orbital edema.
Involvement of the sclera can be diffuse, nodular, necrotizing
or necrotizing without inflammation. The diffuse and nodular
forms of scleritis tend to be the most common.
Scleritis is associated with systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis,
relapsing polychondritis, the spondyloarthropathies, polyarteritis nodosa, and giant cell arteritis.
The acute ocular presentation may be the first manifestation of these severe systemic conditions. An early, accurate ocular and systemic diagnosis, with systemic and ocular
treatment, can reduce the damage to the eye and prolong
patient survival.
THYROID-RELATED
ORBITOPATHY
Orbital involvement can occur as part of Graves disease.
The orbital involvement can precede, coincide with, or
follow thyrotoxicosis.
The ocular symptoms include tearing, through to
epiphora, gritty dry eye symptoms, more severe ocular
pain manifesting as both surface and deep ache, photophobia, proptosis, diplopia, and reduced vision.
The autoimmune cellular infiltrate and associated edema
of the orbital tissues is the underlying cause of the symptoms, and can threaten vision a number of ways.
The increased orbital volume that develops as a consequence of edema interferes with ocular motility,
causes posterior orbital pressure with compression
of the optic nerve at the orbital apex, restricts eyelid movement, and reduces corneal coverage with
closure, and thus reduces ocular surface protection
(Figure 24-8A).
The raised orbital pressure leads to increased intraocular pressure, and can cause glaucomatous optic
neuropathy.
The eyes can be red, resulting either from the orbital
inflammation or from dryness.
A staring, startled look (Figure 24-8B) arises from superior sclera show from eyelid retraction, which in part
occurs because of sympathetic eyelid elevator overactivation, as well as proptosis.
Lid lag can be evident on downward-pursuit eye
movement.
Diplopia arises from the restricted extra-ocular muscle action, which is also evident from ocular motility
testing.
DRY EYE
Dry eye symptoms usually describe ocular surface irritation and grittiness, and commonly are accompanied by a
sense of mild visual disturbance.
The composition of tears can be thought of in terms of
the components that originate from different ocular adnexal
structures:
the superficial lipid layer derived from the eyelid meibomian glands
Figure 24-8 (A) Thyroid eye disease secondary to

Graves disease; convergent strabismus, conjunctival
congestion, right palpebral aperture greater height
than left. (B) Bilateral proptosis, left eyelid retraction,
inferior scleral show, right > left
From Levin LA and Albert DM. Ocular disease: mechanisms and
management. Elsevier, 2010.
an aqueous layer derived from the main and accessory

lacrimal glands
a hydrophilic mucin layer derived from the surface epithelium and conjunctival goblet cells.
Normal tears contain water, electrolytes, proteins such as
immunoglobulin G (IgG) and secretory IgA, lysozyme, lactoferrin and lipocalin, as well as lipids, mucins and a range of
other small molecules.
The dry eye syndrome results from a variety of ocular
surface conditions which alter the overall tear film composition and function.
Conditions ranging from blepharitis and rosacea, to
keratoconjunctivitis sicca will lead to the dry eye syndrome, with multiple factors often simultaneously
atplay.
The hallmarks of the dry eye syndrome include increased
osmolarity of the tear film and associated ocular surface
inflammation, which exacerbates the instability of the
tear film, and this diminishes the lubricating, protective
effect of the tears for the mucosal ocular surface, and
impairs the function of the epithelial cells.
Sjgrens syndrome is the triad of ocular and oral sicca, with
autoimmune connective tissue disease.
Dry eye will be prominent in both the primary and secondary form of the disease.
Schirmers test will prove the reduction in tear production in Sjgrens syndrome.
Biopsy of lacrimal or salivary glands will reveal lymphocytic infiltration, but is usually not required in the
setting of typical clinical symptoms and autoimmune
serological abnormalities.
Treatment of dry eye syndrome is usually multifaceted,
and addresses the range of underlying causative factors.
Aqueous tear deficiency is remedied by the use of eyedrop lubricant supplements, and occlusion of lacrimal
drainage with plugs placed into the nasolacrimal puncta.
Topical cyclosporine A (ciclosporin A) is used to
improve aqueous tear production and normalize the
reactive increased goblet cell density.
Severe dry eye can lead to filamentous strands of mucous
and epithelium attached to the ocular surface that need
to be removed with forceps and treated with acetylcysteine eye drops.
Surgical treatment may be required if severe corneal
ulceration occurs.
Severe dry eye syndrome can lead to a disabling level of
ocular surface discomfort, through to a risk of blindness
from corneal ulceration and infective keratitis, making early
recognition and prompt treatment of dry eye syndrome
essential.
NEOPLASIA AND THE EYE

Neoplasia can affect the eye as primary ocular disease:
eyelid carcinomas
rare ocular surface neoplasia
737
primary melanoma in any of the melanin-pigmentcontaining tissues (conjunctiva and uveal tract)
retinoblastoma
optic nerve glioma
optic nerve sheath meningioma
orbital tissue tumors such as pleomorphic lacrimal gland
adenomas, and orbital tissue sarcomas.
Secondary tumor metastases can develop within the eye,
typically the uveal tract, or in the orbit.
Tumors developing within the eye cause visual disturbance, and tumors external to the eye cause visual
disturbance, proptosis, diplopia, and pain. The diagnosis is
usually made through a systematic ocular and general clinical examination addressing the presenting symptom.
NEURO-OPHTHALMOLOGY
Optic neuritis (ON)
Optic neuritis is a demyelinating inflammation of the optic
nerve. Occasionally it occurs in association with orbital
or paranasal sinus infections, or following a systemic viral
infection.
The onset of ON is usually unilateral, with retro-orbital
or ocular painespecially associated with eye movement. The first attack of ON may occur in previously
healthy young adults. Other visual symptoms such as
altered color vision (dyschromatopsia) may precede
reduced visual acuity.
The diagnostic work-up of ON will also address conditions with similar ocular signs, such as anterior ischemic optic neuropathy, compressive optic neuropathy,
or nutritional or hereditary optic neuropathy.
ON can be a primary demyelination, or occur in association with multiple sclerosis (MS) or neuromyelitis
optica (NMO).
Optic neuritis that occurs in young adults (2045
years) can be the first clinical manifestation of MS.
It can also occur in older patients.
In childhood, bilateral ON has a lower risk of
progressing to MS.
Detecting antibodies to aquaporin 4 can differentiate NMO from MS.
ON that occurs with other, sometimes previous, neurological symptoms suggests a diagnosis of
either MS or NMO.
A male with bilateral optic neuropathy, and relatively
little recovery of vision, suggests Lebers hereditary optic
neuropathy, and a family history with affected maternal
uncles may be present.
Ophthalmoscopy may reveal diffuse optic disc swelling. The absence of swelling does not rule out ON,
as two-thirds of cases can have retrobulbar optic nerve
involvement.
Various patterns of visual field defects can be evident,
with altitudinal and arcuate defects being present as well
as central scotoma.
Severe bilateral ON with chiasmal patterns of field
defects (e.g. bi-temporal field loss) suggests NMO.
Magnetic resonance imaging (MRI) of the brain and
orbits with contrast will usually be needed to exclude
compressive optic neuropathy, and detect central nervous system (CNS) lesions in MS.
Spinal cord and brainstem MRI will be indicated where
there are spinal cord signs, or NMO is a possibility.
Intravenous steroid treatment will usually be considered
for ON. The potential benefit is quicker recovery from the
acute episode, with little benefit in 5-year visual outcomes.
Papilledema
Bilateral optic disc swelling and well-preserved vision associated with raised intracranial pressure (ICP) is termed
papilledema (Figure 24-9).
Associated symptoms will be determined by the primary
cause of raised ICP, and will commonly be accompanied by symptoms of headache, nausea and vomiting,
and pulsatile tinnitus.
The possibility of underlying severe systemic hypertension, with raised ICP, should be borne in mind.
The visual symptoms that may be present with papilledema
include:
transient visual changes (obscurations) such as gray out
of vision associated with posture change to a more elevated position, or transient visual flickering
blurred vision associated with constricted visual fields
and altered color vision
diplopia due to a 6th nerve palsy.
Urgent CT or MRI neuro-imaging is required to identify
intracranial causes for raised ICP, and magnetic resonance
venography may need to be performed to detect venous
sinus thrombosis.
CLINICAL PEARL
In assessing optic neuritis, the vision assessment includes
testing visual acuity, visual elds, pupil responses to light
including the swinging torch test for a relative afferent
pupillary defect, and color vision testing.
738
Figure 24-9 Papilledema: bilateral optic disc swelling

(right > left); loss of disc margins, increased visibility
of small capillaries crossing disc, peri-papillary
hemorrhages (right)

Paralysis of the extraocular muscles arises from pathology
affecting the oculomotor, trochlear or abducens nerves. The
primary symptom is diplopia:
Oculomotor palsy has combined horizontal and vertical diplopia, with ipsilateral ptosis and dilated pupil,
reflecting the combined extraocular motor and parasympathetic motor functions of the oculomotor nerve.
The most common pathologies involve all fascicles of
the nerve, and thus isolated under-action of individual
extraocular muscles is uncommon.
Trochlear nerve palsy gives vertical, torsional or oblique
diplopia, especially on down-gaze and looking to the
side away from the side of the affected superior oblique
muscle (down and in).
Abducens nerve palsy gives horizontal diplopia that is
worse looking to the side of the weak lateral rectus muscle, with esotropia in primary gaze, and a compensatory
head turn to the side of the weak muscle.
The diagnosis of cranial nerve palsy causing extraocular
muscle paralysis with symptoms of diplopia is primarily
anatomical, and is achieved from identifying the symptoms

and signs that arise from involvement of the nerve and associated structures along the path of each nerve from the brain
stem nucleus to the muscle(s).
PHAKOMATOSES
The phakomatoses are a group of disorders where hamartomas are present in the nervous system (central or peripheral),
and the eye, skin and viscera. Ocular features are given in
Table 24-1.
OCULAR EFFECTS OF SYSTEMIC

MEDICATION
Visual disturbance may result from the side-effects of medication, necessitating a careful drug history in any patient
with such a symptom. Table 24-2 (overleaf) lists some ocular
complications of systemic pharmacotherapy.
Table 24-1 Ocular features in the phakomatoses
NEUROFIBROMATOSIS
TUBEROUS
SCLEROSIS
VON
HIPPEL
LINDAU
SYNDROME
ATAXIA
TELANGIECTASIA
STURGE
WEBER
SYNDROME
Inheritance
Autosomal dominant
Autosomal
dominant
Autosomal
dominant
Autosomal recessive
Sporadic
Ocular
complications
Lisch nodules
(hamartoma of iris
melanocytes)
Eyelid neurobromas
Prominent corneal
nerves
Optic nerve and
chiasmal gliomas
Retinal and optic
disc hamartomas
Compressive optic
neuropathy
Bony deformities
Cataracts
Retinal and
optic nerve
hamartomas
Retinal
angiomata
Retinal
detachment
Conjunctival
telangiectasia
Oculomotor apraxia
Hamartomatous
angiomata of
eye
Glaucoma
739
Table 24-2 Important ocular effects secondary to systemic medication
MEDICATION
OCULAR EFFECTS
Corticosteroids
Cataract, raised intraocular pressure
Hydroxychloroquine
Retinopathy (color vision and eld defects)
Amiodarone
Multiple: corneal deposits, optic neuropathy, lens deposits
Desferrioxamine
Retinopathy
Vigabatrin
Retinopathy
Ethambutol
Optic neuritis
Isoniazid
Optic neuritis
Fingolimod
Macular edema
Minocycline
Papilledema
740
1
A 45-year-old man presents with a painful, red left eye. Physical examination reveals reduced visual acuity, and an
irregular pupil. He complains of a dry cough for the past 6 weeks. Which of the following investigations would be a
priority in this case to ascertain the diagnosis? More than one answer may be correct.
A Thyroid function tests, thyroid autoantibodies
B Blood sugar level, uorescein retinal angiography
C Chest X-ray, serum angiotensin-converting enzyme (ACE) level
D Antineutrophil cytoplasmic autoantibodies (ANCA), erythrocyte sedimentation rate (ESR)
E C-reactive protein (CRP), rheumatoid factor (RF)
A 60-year-old woman presents with painful monocular blindness. Physical examination reveals a relative afferent pupil
defect, and extensive retinal hemorrhages. Which of the following underlying illnesses may have led to this problem?
More than one answer may be correct.
A Antiphospholipid syndrome
B Type II diabetes mellitus
C Warfarin therapy for recent pulmonary embolus
D Low-molecular-weight heparin thromboprophylaxis for recent orthopedic surgery
E Nephrotic syndrome
You see a 22-year-old male who has had type I diabetes mellitus since the age of 5. Which of the following clinical
ndings would prompt you to refer him to an ophthalmologist for urgent review? More than one answer may be
correct.
A Mild reduction in the red reex in the right eye
B Detection of neovascularization near the macula but no change in vision
C Intermittent visual blurring after recent introduction of insulin-pump therapy
D Painful red eye with mucopurulent ocular discharge
E Three new microaneurysms in the right eye
4 A 71-year-old woman presents with transient monocular visual loss. Which of the following may be a risk factor for this
condition? More than one answer may be correct.
A Multiple sclerosis
B The presence of aquaporin-4 antibodies
C Atrial brillation
D Commencement of vasodilator therapy for hypertension
E Giant-cell arteritis
5
Which of the following may explain a sudden deterioration of vision in a patient as a consequence of hypertension?
More than one answer may be correct.
A Retinal hemorrhage
B Serous retinal detachment
C Acute (closed-angle) glaucoma
D Papilledema
E Arteriovenous nipping of retinal vessels
ANSWERS
1
C.
A painful red eye with an irregular pupil and reduced vision is suggestive of uveitis. Sarcoidosis is a known cause of
uveitis, and the presence of a dry cough must raise the possibility of this diagnosis. The presence of bilateral hilar
lymphadenopathy or interstitial changes on a chest X-ray would strengthen the clinical suspicion. Serum ACE is only
moderately sensitive and specic for sarcoidosis. An elevated result would, however, increase the likelihood of this
diagnosis.
ANCA-positive vasculitis, especially granulomatosis with polyangiitis, can certainly cause a variety of ocular conditions, as
well as lung disease, so answer D is not unreasonable. However, the ESR is too nonspecic in this situation to help narrow
the diagnosis. Thyroid eye disease may cause proptosis and ophthalmoplegia, but should not produce uveitis. Rheumatoid
arthritis can also be associated with autoimmune ocular complications and with pulmonary inammation, but the RF and
CRP are lacking in specicity. Diabetes mellitus should not be the cause of uveitis.
A, B, E.
The clinical scenario is describing central retinal vein occlusion. Any cause of hypercoagulability is a risk factor in this
instance. Therefore, antiphospholipid syndrome due to the presence of anti-cardiolipin antibodies, and nephrotic
syndrome due to loss of antithrombotic proteins in the urine, can lead to this problem. Diabetes mellitus is also a risk
factor, probably through multiple mechanisms such as hypercoagulability associated with severe hypoglycemia with
dehydration, or nephropathy with nephrotic syndrome. Anticoagulant therapy is not a cause of retinal vein occlusion.
741
B and D.
Features of severe diabetic retinopathy that require referral to an ophthalmologist include:
i microaneurysms and intra-retinal hemorrhages in all four retinal quadrants
ii venous beading in more than two retinal quadrants
iii any prominent intra-retinal microvascular abnormalities (IRMAs)
iv the presence of neovascularization either at the optic disc or elsewhere in the retina
v vitreous or pre-retinal hemorrhages.
In the above scenario, it would be important to arrange urgent ophthalmological assessment for option B, as the patient
with proliferative retinopathy is at risk of hemorrhage and sudden loss of vision, which often can be prevented by laser
photocoagulation therapy. Similarly, a longstanding diabetic with an infection in the eye, such as in option D, can lose the
eye very quickly through development of endophthalmitis if prompt treatment is not instituted with appropriate
anti-microbial therapy.
Early cataract (option A), transient changes in visual acuity secondary to lens distortion from rapid blood sugar level
changes (option C), and background diabetic retinopathy (option E) are not emergencies.
4 C and D.
This scenario describes amaurosis fugax. Amaurosis fugax is usually the consequence of embolic occlusion of the central
retinal artery, with subsequent dissolution and dislodgement of the clot. Atrial brillation with the formation of left atrial
thrombus, as in option C, is therefore an important risk factor. It can, however, result from hypoperfusion due to a transient
drop in blood pressure in the setting of pre-existing cerebral vascular disease, such as in option D.
Multiple sclerosis and neuromyelitis optica (NMO) can cause optic neuritis, which can result in reduced visual acuity, but
not transient loss of vision. NMO is associated with aquaporin-4-antibodies. Giant-cell arteritis can cause arteritic retinal
arterial occlusion or anterior ischemic optic neuropathy. The blindness is usually not transient.
5
A, B, D.
Hypertension, both acute and chronic, has multiple effects on the eye, and can affect the vasculature, optic nerves and
retina, including the choroid. Some of these can acutely threaten the vision, such as retinal hemorrhage (option A), serous
retinal detachment (option B), and papilledema (option D). Papilledema can result from acute severe hypertension. Acute
(closed-angle) glaucoma does not result from hypertension. Arteriovenous nipping of vessels is a sign of hypertensive
vascular change, but per se will not affect the vision.
742
CHAPTER 25
WOMENS HEALTH FOR THE PHYSICIAN

Andrew Korda
CHAPTER OUTLINE
INFERTILITY
Age and infertility

Hyperprolactinemia
Infertility due to anatomical abnormalities of
the reproductive tract
CONTRACEPTION
MENOPAUSAL SYMPTOMS
PREMENSTRUAL SYNDROME
ABNORMAL UTERINE BLEEDING

Diagnosis
Management
DYSMENORRHEA
VULVAR CONDITIONS
Management
Conditions with abnormalities on examination
SEXUALLY TRANSMITTED INFECTIONS

(STIs)
Chlamydia
Gonorrhea
PELVIC INFLAMMATORY DISEASE (PID)

Clinical features
Treatment
SEXUAL PROBLEMS
Treatment
INFERTILITY
CLINICAL PEARL
Infertility is the failure of a couple to conceive:
after 12 months of regular intercourse without use
of contraception in women less than 35 years of
age
after 6 months of regular intercourse without use
of contraception in women 35 years and older.
Primary infertility implies no previous pregnancy; secondary

infertility is defined by an inability to conceive following a
history of any antecedent pregnancy, including abortion,
and ectopic pregnancies.
Overall, the great majority (8090%) of apparently normal couples will conceive within the first year of trying.
The prevalence of infertility is approximately 7% in the
general population.
In developed countries, the various sources of infertility
are classified as shown in Table 25-1 (overleaf).
743
Table 25-1 Types of infertility
TYPE
PREVALENCE
Female factor infertility
4055%
2540%
Both male and female factor infertility
10%
10%
Age and infertility

An increasing number of women older than 35 years will
seek treatment for infertility, as a womans fertility is known
to decline with age, and the number of women wishing to
conceive between 35 and 45 years old is increasing.
The possibility for oocytes to be fertilized and develop
naturally is compromised with increasing age.
There is a clear inverse relationship between fertility
and female age, and spontaneous pregnancies are rarely
reported after the age of 45.
Significant changes in ovarian and uterine physiology
also occur with advancing age, specifically loss of oocyte
integrity and decreased uterine receptiveness.
As women age, there is also an increase in the prevalence
of gynecological and systemic disease, such as endometriosis, pelvic infection, fibroids, diabetes, obesity,
hypertension and smoking-related diseases.
In women older than 35 who seek infertility treatment,
prompt and complete investigation of fertility should be
offered so that any correctible conditions can be treated
as soon as possible.
Some causes of infertility, such as azoospermia, longstanding amenorrhea, or bilateral tubal obstruction, are easy to
determine. However, the situation is often less clear: sperm
may be reduced in number, but not absent; there may be oligomenorrhea with some ovulatory cycles; the woman may
have partial tubal obstruction; or a menstrual history may
suggest intermittent ovulation.
In general terms, the likelihood of causes is as given in
Table 25-2.
Table 25-2 Causes of infertility
CAUSE
APPROXIMATE
INCIDENCE
Male factor hypogonadism, posttesticular defects, seminiferous

tubule dysfunction
26%
Ovulatory dysfunction
21%
Tubal damage
14%
Endometriosis
6%
Coital problems
6%
Cervical factor
3%
Unexplained
744
28%
Investigation of infertility should commence in couples

who have not been able to conceive after 12 months of
unprotected and frequent intercourse, but earlier assessment (after 6 months) can be started in women over
35years of age.
The timing of the initial investigation into infertility
also depends on the couples risk factors.
Infertility is stressful for most couples. It is important to
appreciate that couples may have multiple factors contributing to their infertility; therefore, a complete initial diagnostic evaluation, including a detailed history and physical
examination, should be performed. This will detect the
most common causes of infertility. Evaluation of both partners should be performed concurrently.
The following tests are valuable in most couples with
infertility:
menstrual history
semen analysis
assessment of LH (luteinizing hormone) surge prior to
ovulation
a hysterosalpingogram to assess tubal patency and the
uterine cavity
day 3 serum FSH (follicle-stimulating hormone) and
estradiol levels
serum prolactin estimation
evaluation of thyroid function
pelvic ultrasound examination to determine the presence of uterine fibroids and ovarian cysts
diagnostic laparoscopy to identify endometriosis, or
other pelvic pathology such as tubal disease t hydrotubation for tubal patency
assessment of ovarian reserve in women over 35 years of
age, which may involve a clomiphene (clomifene) challenge test, ultrasound for early follicular antral follicle
count, day 3 serum inhibin B12 levels, or anti-Mllerian
hormone measurements.
The utility of measurement of anti-sperm antibodies is not
established.
Once the cause of infertility is identified, therapy is
aimed at correcting reversible causes and overcoming irreversible factors.
The couple should also be counseled on lifestyle modifications to improve fertility, such as cessation of smoking,
reducing excessive caffeine and alcohol consumption, loss
of weight (especially in overweight women), and the appropriate timing and frequency of intercourse (every 12 days
around the expected time of ovulation).
Ovulatory dysfunction and anovulation affect 1525% of all
infertile couples seeking therapy.
Treatment of ovulation disorders, if isolated, remains
one of the most successful of all infertility treatments.
Post-treatment conception at 2 years is between 78%
and 96%.
Chapter 25 Womens health for the physician
Initial treatment is most commonly with clomiphene

citrate (clomifene), a selective estrogen receptor modulator which stimulates ovulation induction.
Patients with some degree of insulin resistance might
require some adjuvant therapy to clomiphene. Correction of hyperinsulinemia will increase the rate of
spontaneous ovulation, and also increase the response
to clomiphene. This is best achieved by the use of metformin, an insulin-sensitizing agent.
Prior to metformin treatment, a patient should be
screened for insulin resistance.
In the event that patients do not conceive on clomiphene citrate and metformin, other medications have
been useful; such as adrenal steroid therapy, and gonadotropins, with or without gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists.
Hyperprolactinemia
Hyperprolactinemia is present in 23% of patients with
amenorrhea, and 8% of patients with oligomenorrhea. Elevated prolactin is believed to be a cause of anovulation by
impairing gonadotropin pulsatility, and the arrangement of
the estrogen-positive feedback effect of LH secretion.
CLINICAL PEARL
Prolactin can be increased by physiological events, such
as stress, or a normal breast or pelvic examination.
Patients who have elevated prolactin levels should also

be screened for hypothyroidism and for a pituitary gland
mass.
Treatment is usually with bromocriptine, an ergot-alkaloid
dopamine-receptor agonist, which directly inhibits prolactin secretion.
Infertility due to anatomical

abnormalities of the reproductive tract
In the event of tubal pathology, surgical treatment
of tubal disease or assisted conception to overcome
thetubal obstruction are the treatments of choice.
If fibroids involve a significant portion of the endometrium or obstruct the tubal ostium, their removal
is warranted. Additionally, a submucous fibroid larger
than 2cm needs to be removed as it is associated with
increased risk of abortion.
Ashermans syndrome, a condition characterized by
adhesive scarring of the endometrium, needs to be
treated with hysteroscopic resection of adhesions.
Endometrial polyps, if diagnosed by imaging studies,
should be removed.
Endometriosis, if minimal to mild, should be treated
surgically. There is no supportive literature to undergo
surgical treatment for moderate to severe endometriosis,
and therefore these women should be offered fertility
treatments.

Only 6% of infertile men have conditions for which therapy
of confirmed benefit is available.
Treatment of most infertile men mostly involves techniques that use available sperm, rather than fruitless
efforts to improve sperm concentration or motility.
There is some evidence that repairing a varicocele may
improve pregnancy rates.
Intra-uterine insemination will sometimes be used in
cases of asthenospermia.
Use of a sperm donor bank will sometimes be chosen by
a couple after a few attempts at conception.
CLINICAL PEARL
At least 2540% of infertility is attributable to abnormalities in male reproductive function. It is, therefore,
important to evaluate the male partner as an integral
part of the infertility work-up.
Unexplained infertility is diagnosed when other causes have
been excluded. It is a term applied to an infertile couple for
whom standard investigations yield normal results.
Without treatment, up to 60% of couples with unexplained infertility will conceive within 3 years.
After 3 years of infertility, the pregnancy rate without
treatment decreases by 2% every month of infertility.
The most sensible option for unexplained infertility is
assisted conception such as IVF (in-vitro fertilization).
It is important to understand that women who use
infertility therapies such as IVF appear to have a small
but statistically significant increase in risk of pregnancy
complications, such as pre-term birth and abnormal
placentation.
Compared with the general population, an increased
risk of poor pregnancy outcomes has been observed
among untreated subfertile women who conceive
naturally.
CONTRACEPTION
About half of all pregnancies in the United States are
unplanned and almost a half of these occur in women using
contraception. About half of women aged 1544 years have
experienced an unwanted pregnancy.
Fertility control is an important contributor to reproductive health. It has been well documented that fertility
regulation has significantly decreased maternal mortality.
An understanding of the available contraceptive methods
allows clinicians to advise women about the methods that
are most consistent with their routine and viewpoint, and
therefore most likely to be successful.
The most popular contraceptive methods are given in
Table 25-3 (overleaf).
745
Table 25-3 Methods of contraception
CONTRACEPTIVE METHOD
APPROXIMATE
RATE OF USE
Oral contraception
31%
Female sterilization
27%
Condoms
18%
Injectables/implants/patch
9%
Male sterilization
9%
Other
8%
No method of contraception is perfect. The effectiveness of contraception is often quantified by the Pearl index,
which is defined as the number of unintended pregnancies
per 100 women per year of use (i.e. the number of pregnancies in 1200 observed months of use).
The most effective contraceptive methods are intrauterine contraception, contraceptive implants, and sterilization.
The next most effective methods are injectables, oral
contraceptives, transdermal contraceptive systems, and
the vaginal ring.
The least effective contraception systems are diaphragms, cervical caps, condoms, spermicides, and
withdrawal.
Natural family planning, also known as the rhythm
method, has a high failure rate of around 2030% per
year.
One of the newer methods is the hysteroscopic sterilization of the fallopian tubes (e.g. Essure).
Oral contraceptives
The development and widespread use of the oral contraceptive pill was a major breakthrough in reproductive health in
the 20th century.
Cerebrovascular disease
Oral contraceptives are contraindicated in the presence of
cerebrovascular disease, as they increase the risk of stroke in
women with other underlying risk factors.
Migraine and headache
Patients with a history of migraine and headache should use
oral contraceptives circumspectly.
It has been traditionally thought that women who have
a history of classic focal migraines have an increased potential for strokes when using oral contraceptives. However, the
evidence for this is poor. Women with a history of migraines
have a two- to threefold increased risk of ischemic stroke
regardless of oral contraceptive use.
Epilepsy
Oral contraceptives have no impact on the pattern or frequency of fits; however, some anticonvulsants decrease
serum concentrations of estrogen and thus increase the likelihood of intermenstrual bleeding, and pregnancy. Women
with epilepsy should start on a high-dose oral contraceptive
formulation.
Cardiovascular disease
Women who are older than 35 years, and who smoke,
should not use oral contraceptives, as in this group there is
an increased incidence of cardiovascular complications such
as myocardial infarction.
Deep vein thrombosis
There is controversy surrounding the use of oral contraceptives in women who have deficiencies in protein C, protein
S, or anti-thrombin 3. There is no evidence that women
with a factor V Leiden mutation who use oral contraceptives have an increased incidence of venous thromboembolic
disease.
Women with a body mass index of >29 kg/m2 have an
independent increased risk of venous thromboembolic disease, and in such women oral contraception should only be
used if they are 35 years of age or younger.
Benets of oral contraception

Known benefits of oral contraception include:
the very low likelihood of extrauterine pregnancies
a reduction in pelvic inflammatory disease, ovarian
cysts, and iron-deficiency anemia
a decrease in the rate of ovarian and endometrial cancers.
Hypertension
Oral contraceptives have a potential to aggravate hypertension, hence blood pressure should be controlled prior to
their commencement. If blood pressure is controlled and no
vascular disease is present, the use of oral contraceptives is
not contraindicated.
A history of pregnancy-induced hypertension is not a
contraindication to the use of oral contraceptives, provided
the blood pressure returns to normal after delivery.
Side-effects of oral contraception

Side-effects are a major source of patient non-adherence
and discontinuation. Estrogen commonly produces breast
tenderness and nausea; these symptoms usually decline after
3 months of use. Caution should be exercised when prescribing oral contraceptives to patients with certain underlying conditions.
Dyslipidemia
All oral contraceptives increase triglyceride levels to some
extent. If a womans triglycerides are v350 mg/dL (v3.95
mmol/L), or in patients with familial hypertriglyceridemia,
oral contraceptives should be avoided because they may precipitate pancreatitis or increase the risk of cardiovascular
disease.
746
Angina
Oral contraceptives do not stimulate the atherosclerotic process, and may actually inhibit plaque formation. On the other
hand, they are contraindicated in the presence of coronary
disease. There is an increased incidence of cardiovascular
disease secondary to atherosclerosis in past oral contraceptive
users. Smoking, when combined with oral contraceptive use,
markedly increases the risk of atherosclerosis.
Women with known angina and suspected atherosclerosis, but with no history of prior myocardial infarcts
or additional risk factors, may safely use low-dose oral
contraceptives.
Mitral valve prolapse
In general, oral contraceptives can be used in women with
mitral valve prolapse who are symptom-free.
Diabetes mellitus
Women with diabetes mellitus who do not have retinopathy, nephropathy or hypertension can use lowdose oral contraceptives.
Women with a history of gestational diabetes during
their last pregnancy can safely take low-dose oral
contraceptives.
Sickle-cell disease
The risk of pregnancy in this condition is much greater than
the risk posed by the use of oral contraceptives.
Cancer risk with oral contraception
Breast cancer
There is no association between oral contraceptive use and
an increased relative risk of breast cancer. The risk of breast
cancer in women who take oral contraceptives up until the
age of 55 is no different to that of the rest of the population.
Oral contraceptive use in women with a history of breast
cancer in a first-degree relative does not increase the risk of
breast cancer.
Cervical cancer
There is no association between the use of oral contraceptives and the development of cervical cancer, except maybe
for the potential higher exposure to human papillomavirus
(HPV).
Endometrial cancer
It is well established that combined oral contraceptive use is
protective against endometrial cancer.
Ovarian cancer
Oral contraceptive use is thought to be protective for ovarian
cancer, and the degree of protection is related to the duration
of use. Women who use oral contraceptives for 10 years or
more have an 80% reduction in their risk of ovarian cancer.
Estrogen dose
When choosing an oral contraceptive, the higher the dose of
estrogen then the better the cycle control.
In general, oral contraceptives with 25 microg of estrogen have an 11% incidence of intermenstrual bleeding,
while 3035 microg of estrogen reduces intermenstrual
bleeding to 4%.
The use of oral contraceptives containing 50 microg of
estrogen should be reserved for women requiring additional estrogen to prevent intermenstrual bleeding, or
women who have recurring functional ovarian cysts in
order to significantly suppress ovarian function.
Breastfeeding
Breastfeeding women should avoid the use of combined
oral contraceptive medications, as small amounts of steroids
are excreted in the milk, and estrogen may suppress milk
production.
Progesterone-only contraceptive pill
These pills are an excellent choice for breastfeeding women,
and for women with medical conditions where the use of
estrogen is contraindicated. Their efficacy is decreased compared with combined oral contraceptives, so rigorous timing
of their intake is important.
They also often cause breakthrough bleeding.
Interaction with other drugs
Certain antibiotics, particularly penicillins and tetracyclines,
may diminish the effectiveness of oral contraceptives.
Discontinuation of an oral contraceptive
Conception is rapid after cessation of oral contraceptives.
Injectable contraceptivesdepot
medroxyprogesterone acetate
Injectable contraception is highly effective, reversible, and
reduces the need for adherence. One injection is given
every 12 weeks. Additionally, progestin injections reduce
the risk of endometrial cancer and the volume of menstrual
bleeding.
There is no proven relationship between depot medroxyprogesterone acetate and weight gain.
Women with sickle-cell anemia, congenital heart disease, or those older than 35 are excellent candidates for
contraception with depot medroxyprogesterone acetate.
Women with a history of long-term use of depot
medroxyprogesterone acetate have reduced bone density.
Depot medroxyprogesterone acetate is not teratogenic,
and is safe during lactation.
Contraceptive implants
Implanon
This is a single-rod progestin implant releasing etonogestrel over a 3-year period. It is well tolerated and effective
and has a very minimal reported failure rate. No pregnancies have been reported in 70,000 cycles of use.
Side-effects are irregular bleeding and amenorrhea.
747
Implanon has no major impact on lipid profile, carbohydrate metabolism, coagulation factors or liver function.
Contraceptive vaginal ring

Contraceptive vaginal rings are based on the principle
that the vaginal epithelium can absorb steroids released
from the silicone elastomer at a constant rate.
The ring releases minimal amounts of estrogen into
the circulation, yet maintains efficacy and cycle control
comparable to that of oral contraceptives.
The vaginal ring has an outside diameter of 54 mm, and
is inserted by the woman and worn continuously for
3 weeks, after which time it is removed for 1 week to
allow for withdrawal bleeding. After this week, a new
device is inserted.
A disadvantage of the ring is that some 1830% of men
report feeling the ring during intercourse and some
women report an increase in leukorrhea. If this is a
problem, the ring can be removed for intercourse but
must be replaced within 3 hours. If the ring remains
outside the vagina for longer than 3 hours, its effectiveness is compromised.
Pregnancy rates are reported to be 12 per 100 women
years of use.
Transdermal contraception
Transdermal drug delivery provides continuous, sustained release of hormonal contraception over several
days, thereby avoiding fluctuations in hormone levels
and the need for daily patient action.
The benefits, risks and contraindications of transdermal contraception are similar to those of combined oral
contraceptives, except that the transdermal device is
associated with more estrogen-related adverse events,
including venous thromboembolism.
Obese women should be counseled about reduced efficacy but obesity is not a contraindication.
Intrauterine contraception
Intrauterine contraception is safe and effective.
Currently, intrauterine contraceptives release either
copper or a synthetic progestin.
The progestin-releasing intrauterine contraceptives
have additional advantages such as decrease in menstrual blood loss, relief of dysmenorrhea, and cure of
endometriosis.
Modern intrauterine devices are not associated with a
higher rate of expulsion, or the risk of pelvic inflammatory disease that was caused by previous models.
Intrauterine devices decrease the probability of pregnancy; however, if it occurs, the incidence of ectopic
pregnancy rates increase. It is therefore important to
determine the site of pregnancy when, and if, it occurs.
748
Barrier methods
Barrier methods of contraception such as a diaphragm, cervical cap, male condom and female condom have a much
higher pregnancy rate than hormonal methods. They are
not recommended for women with serious medical conditions in whom pregnancy is life-threatening. Such women
should be advised about the availability of emergency
contraception.
Emergency contraception is also known as post-coital contraception. Women who have had unprotected intercourse,
including those who have had a failure of another method,
are potential candidates for this intervention. It has the
potential to reduce abortion rates.
This method of contraception is indicated after unprotected intercourse and for couples who experience, and
recognize, a failure of a barrier method.
Emergency contraception utilizing progestin-only pills
is available without a prescription in many countries.
The mechanism of emergency contraception is uncertain, and may vary depending upon the day of the menstrual cycle and the drug administered. It is likely to
inhibit or delay ovulation, interfere with fertilization or
tubal transport, prevent implantation by altering endometrial receptivity, and may cause regression of the
corpus luteum.
CLINICAL PEARL
A routine follow-up visit with a pregnancy test is essential after emergency contraception to ensure that, if
bleeding has not occurred, an intrauterine or ectopic
pregnancy is not present.
MENOPAUSAL SYMPTOMS
Post-menopausal hormone treatment continues to play a
role in the management of menopausal symptoms such as
hot flushes, vaginal atrophy and mood changes.
While it is no longer recommended that hormone
therapy in women over the age of 60 should be used
to prevent illness, the use of hormone therapy to treat
menopausal symptoms is not inappropriate. This
should, however, be re-evaluated after 5 years of use
because of the increased risks of complications after
this period.
There is evidence for a benefit of unopposed estrogen
use in women who have undergone hysterectomy,
in that the incidence of breast cancer in this group is
reduced.
Hormone therapy results in a definite reduction of
recurrent urinary tract infection, and improves quality
of life and balance.
The risks of stroke, venous thromboembolism, breast
cancer, and cholecystitis are increased.
As a result of the mixture of risks and benefits, postmenopausal hormone therapy is currently only recommended for the short-term management of moderate to
severe vasomotor symptoms.
If there is no history of breast cancer, coronary heart
disease, or a previous thromboembolic event, estrogen
therapy is appropriate. Active liver disease and migraine
headaches are also contraindications.
If a patient has not had a hysterectomy then a progestin
should be added, as endometrial hyperplasia and endometrial cancer can develop after as little as 6 months of
unopposed estrogen therapy.
The best preparation to use is a combined preparation of
conjugated estrogen and a synthetic progestin. The drugs
can be delivered either orally or transdermally, as they are
equally effective for the treatment of vasomotor symptoms.
The treatment should involve the lowest possible dose of
estrogen and progestin that controls the symptoms.
In addition to vasomotor symptoms, vaginal atrophy
often needs treatment.
Vaginal atrophy results in vaginal dryness, itching, and
dyspareunia.
It can be treated with systemic hormone replacement
therapy, but intravaginal estrogen in either a cream, tablet or ring form is the most effective therapy and can
be administered indefinitely, as systemic absorption is
negligible.
PREMENSTRUAL SYNDROME
Premenstrual syndrome is characterized by symptoms that
occur monthly in the second half of the menstrual cycle.
Although most women experience mild emotional and
physical symptoms just prior to the onset of menstrual periods, the term premenstrual syndrome implies that these
symptoms lead to economic or social dysfunction that occurs
for at least 5 days before the onset of menstrual periods, and
includes:
symptoms such as depression, anger, irritability, anxiety,
breast pain, bloating, and headaches
an impairment in quality of life, a decrease in productivity, and increased absenteeism.
There are no physical signs associated with premenstrual
syndrome. Diagnosis is made when there is at least one
symptom, either psychological or behavioral, that impairs
functioning in some way.
If untreated, premenstrual symptoms can last throughout
reproductive life and only disappear with the menopause.
Treatment with selective serotonin reuptake inhibitors
such as fluoxetine has been demonstrated to be better
than placebo. These agents are usually administered
during the luteal phase, and discontinued after the onset
of the menstrual period.
There is no evidence that other antidepressants and lithium have any benefit in the treatment of premenstrual
syndrome.
Benzodiazepines such as alprazolam are effective, but

side-effects limit their use.
GnRH agonists and danazol (an androgen) suppress
ovulation and therefore control symptoms, but sideeffects preclude their use on a prolonged basis.
Hormonal oral contraceptives can also be effective.
ABNORMAL UTERINE BLEEDING

CLINICAL PEARL
Abnormal uterine bleeding is responsible for as many
as one-third of all outpatient gynecological visits. The
majority occurs just after the menarche or in the perimenopausal period.
Most cases of abnormal uterine bleeding are related to pregnancy, structural uterine pathology, anovulation or, rarely,
disorders of hemostasis or neoplasia.
Symptoms of ovulation should be noted, as well as the
commencement of abnormal bleeding. As an example,
menorrhagia since the menarche suggests a coagulation
disorder, while anovulation as a cause is more common
around the menarche and the perimenopause.
Any precipitating factor such as trauma should be
sought, as well as a family history of bleeding or systemic disorders. The possibility of pregnancy should be
considered.
Changes in bodyweight should be elicited, as eating disorders, excessive exercise, illness or stress may interfere
with ovulation.
The amount of bleeding is difficult to evaluate, as a patients
self-reports are often inaccurate indicators of the quantity of
blood loss:
around 25% of women with normal periods consider
their blood loss excessive
around 40% of women with excessive bleeding consider
their periods as light or moderate
only about 33% of women who consider that their periods are heavy have blood loss which is truly excessive.
Diagnosis
Physical examination should involve a general examination
to detect systemic illness, and then a gynecological examination which should determine any obvious bleeding sites on
the vulva, vagina, cervix, urethra or anus.
Suspicious findings such as a mass, ulceration, laceration
or foreign body should be noted, and the size, contour
and tenderness of the uterus as well as the possibility of
an adnexal mass should be determined.
All women of reproductive age should have a pregnancy
test to exclude either an intrauterine or an ectopic
pregnancy.
Cervical cytology should be obtained to exclude cervical
cancer, and any visible cervical lesion should be biopsied.
749
After a pregnancy is excluded, an endometrial sample

should be obtained to exclude endometrial cancer or
hyperplasia.
Both transabdominal and transvaginal ultrasound
examinations should be performed to demonstrate
any subserosal or intramyometrial pathology such as
fibroids, adenomyosis or neoplastic change. An ultrasound examination can also detect ovarian neoplasm.
Hysteroscopy provides excellent visualization of the
endometrial cavity. It also allows targeted biopsy or
excision of lesions.
Other investigations such as thyroid function tests,
coagulation profile, full blood count, serum prolactin, and androgen levels may be indicated. The initial
approach to the management involves treatment of
underlying conditions such as fibroids, polyps or arteriovenous malformations, often with surgery.
Secondary dysmenorrhea is due to pathological processes

such as endometriosis, adenomyosis, fibroids, ovarian
cysts, intrauterine or pelvic adhesions, chronic pelvic
inflammatory disease, obstructive endometrial polyps,
cervical stenosis, an intrauterine device, or pelvic congestion syndrome.
Inflammatory bowel disease, irritable bowel syndrome, and various psychogenic disorders can also
generate secondary dysmenorrhea.
The goal of treatment of dysmenorrhea is to provide adequate relief of pain.
In primary dysmenorrhea, the treatment is empirical.
NSAIDs are the most effective agents.
In secondary dysmenorrhea, the associated pathological
entities will need to be specifically treated.
Hormonal contraception to suppress ovulation is also
effective.
Management
Estrogenprogestin contraceptives are usually the first
line of medical therapy in most women. In addition to
reducing blood flow, they regulate cycles, provide contraception, prevent the development of hyperplasia in
anovulatory patients and treat dysmenorrhea.
The second line of therapy is the insertion of a levonorgestrel intrauterine device, which releases a high
local concentration of progestin which thins out the
endometrium. This treatment is more effective than
hormonal oral contraception, and is as effective as systemic progestogens. It is superior to non-hormonal
medical therapy.
Non-steroidal anti-inflammatory drugs (NSAIDs)
reduce the volume of menstrual blood loss by 2050%,
via reduction of the rate of prostaglandin synthesis in the
endometrium, leading to vasoconstriction and reduced
bleeding.
Antifibrinolytic agents such as tranexamic acid reduce
menstrual flow 3050% from baseline. The risk of
thrombosis with these drugs is controversial, so they
should be used when other therapies have failed in
women who have a low thrombosis risk.
If medical treatment fails, then surgery can be used; this
involves either endometrial ablation or a hysterectomy.
DYSMENORRHEA
Dysmenorrhea is a common problem experienced by
women of reproductive age. When severe, it interferes with
the performance of daily activities, often leading to absenteeism from school, work or other responsibilities.
Primary dysmenorrhea, defined as abdominal pain during
menses without any identifiable pathology, is mainly a
clinical diagnosis.
It is likely to be due to the release of prostaglandins
from the endometrium during menstrual periods.
Symptoms usually begin during adolescence, after
ovulatory cycles become established.
750
CLINICAL PEARL
The prevalence of dysmenorrhea is very high; between
50% and 90% of women describe some degree of dysmenorrhea. The majority of these women are young,
and have primary dysmenorrhea. The prevalence of
primary dysmenorrhea decreases with age.
VULVAR CONDITIONS
CLINICAL PEARL
Benign conditions of the vulva and vagina are common. About one-fth of women have signicant vulval
symptoms lasting for >3 months at some time in their
lives.
Symptoms of vulvar conditions are common, often chronic,

and can cause significant sexual dysfunction.
Itch is a common symptom. If itching is worse before or
during menstrual periods, then recurrent vulval candidiasis is likely.
Various dermatoses can also be intermittent, with flareups associated with precipitant factors.
The history is sometimes difficult to elicit because of anxiety and frustration about ineffective treatment. A thorough
examination with good illumination is vital. Key features of
the history and examination can pinpoint diagnosis. Investigations will ultimately deliver the diagnosis.
A vaginal or vulval swab for culture and sensitivity
should be taken in all patients.
If fissures or ulcers are present, testing for herpes simplex virus (HSV) should be performed.
Biopsy is required for any abnormal findings that persist
without a clear diagnosis, and is mandatory to rule out
malignancy.
Management
It is important to advise the woman that vulval conditions respond slowly to treatment, usually over weeks
to months, and that the aim of treatment is to control
symptoms rather than to cure the condition.
Sometimes a multidisciplinary approach is required, such
as a physiotherapist with experience in biofeedback, and
sexual counselors, especially in the case of vulvodynia.
Good vulval skin care should be part of the treatment of
all conditions. This involves the avoidance of irritants,
including soap, and moisturizing the skin with creams
such as sorbolene or aqueous cream. If there is incontinence or a vaginal discharge, a barrier cream should
be used. Scratching can be reduced by applying cold
compresses.
Conditions with abnormalities on

examination
Dermatitis
Dermatitis is common, and is present in about half of women
who present with chronic vulval symptoms. It is even more
common in individuals with vulval atrophy, in whom the
skin is less able to tolerate environmental insults.
Clinical signs may be subtle and are associated with erythema, scale, fissures, lichenification, and excoriation.
Itch is a common presenting symptom, although burning can occur if the mucosa is involved.
Contact allergens such as deodorant soaps, bubble-bath
products, or perfumed feminine hygiene products can
be irritating, and can intensify symptoms. Ongoing
avoidance of irritants is helpful.
If urinary incontinence is present it should be addressed,
as urine is a major vulval irritant.
Initial treatment involves identification and elimination of
the irritating agent, the use of cotton underwear washed in
a bland detergent, the taking of sitz baths using plain tepid
water twice a day, and applying a thin, plain petrolatum film
or zinc oxide 1020% ointment after bowel movements.
Tricyclic antidepressants such as doxepin may be considered for treatment of pruritus.
Topical corticosteroids may be used for 23 weeks to
reduce inflammation and to promote healing.
Methylprednisolone aceponate is useful until symptoms
have resolved, after which a weaker corticosteroid such
as 1% hydrocortisone can be continued for a further
3months. The cycle can be repeated if disease activity
flares.
also common. It is common for symptoms to worsen

before menstrual periods.
Examination usually reveals erythema of the vulva,
with some swelling and occasional longitudinal fissures
(Figure 25-1); a discharge is a common association.
Some 50% of women have negative microscopy on
swabbing.
Most cases are caused by Candida albicans, but C. glabrata,
C.tropicalis and C. parapsilosis can also occur and may be difficult to treat.
90% of uncomplicated cases respond to topical
antifungals.
Resistant cases may respond to oral fluconazole or
ketoconazole.
If there is significant dermatitis, the addition of 1%
hydrocortisone cream may be useful.
Women who have C. glabrata are usually not sensitive to
standard antifungal treatment, and respond to intravaginal boric acid.
There is no clinical evidence that dietary modification
for the elimination of Candida spp. from the gastrointestinal tract, or the treatment of asymptomatic male sexual
partners, is useful.
Low-dose oral contraceptives can be used to prevent
recurrence.
CLINICAL PEARLS
Vaginitis due to bacterial vaginitis from Gardnerella
vaginalis has a shy odor when mixed with potassium hydroxide, and clue cells are present (epithelial
cells with bacteria adhering).
Trichomonas vaginalis causes a frothy, shy-smelling
discharge that is yellow-green, and a strawberrycolored cervix.
Recurrent vulvo-vaginal candidiasis

Vulvo-vaginal candidiasis is considered to be recurrent
if at least four discreet documented episodes occur in
12months. The pathophysiology of recurrent infections
is unclear.
Recurrent vulvo-vaginal candidiasis presents primarily
with itch; but burning, especially after intercourse, is
Figure 25-1 The most common presentation for

acute vaginal candidiasis is a red inamed vulva and
vagina, and a white, thick discharge
From Habif TP. Clinical dermatology, 5th ed. St Louis: Elsevier, 2009.
751
Lichen sclerosis
Lichen sclerosis is a common vulval disorder. The mean age
of onset is 50 years, although it can occur in children and
pre-pubertal girls. The etiology is unknown.
Lichen sclerosis presents most commonly with an itch;
burning and dyspareunia can also occur.
There is an association with autoimmune disease in
20% of patients.
Lichen sclerosis is characterized by thinning and whitening of the perianal and perivaginal skin, with an
accompanying loss of mucocutaneous markings and
skin elasticity. There is atrophy of the involved tissues
and a loss of vulval architecture (Figure 25-2).
There may be associated purpura, hyperpigmentation, erosion, fissures and edema.
Routine vulvar biopsy for diagnosis is debated. Biopsy
only after failure of empirical treatment is acceptable.
Treatment should aim to control symptoms, minimize scarring, and detect malignant change early.
Potent topical corticosteroids are symptomatically
effective in more than 90% of women, providing rapid
symptomatic relief.
Betamethasone dipropionate ointment 0.05% should
be used initially twice daily for a month, then daily for
2months, and gradually tapered to use as needed.
Annual follow-up is recommended, as the lifetime risk of
squamous cell carcinoma within the affected area is about
4%. Annual biopsy of the vulva is prudent.
Psoriasis
mistaken for atopic dermatitis. One-third of patients with

psoriasis have a family history of the disease.
Clinically, psoriasis on the vulva lacks the typical silver
scale, and usually appears as red or reddish yellow pustules on the intertriginous areas (Figure 25-3).
Genital psoriasis often appears in the mons and the labia.
Treatment usually requires mid- to high-potency topical
steroids, injectable corticosteroids, as well as weak-potency
preparations such as 3% liquor picis carbonis in aqueous
cream twice daily. This helps to provide a break from prolonged corticosteroid use.
Vulvar intraepithelial neoplasia

Vulvar dysplasia, or vulvar intraepithelial neoplasia (VIN),
is reported as VIN I, II or III. VIN III is synonymous with
carcinoma-in-situ.
The incidence of VIN has increased significantly in
women who are young, and those who smoke. This
increased incidence reflects the higher prevalence of the
human papillomavirus in women.
The most common symptom of VIN is localized
itching and burning, although some 60% of cases are
asymptomatic.
VIN is usually multifocal and looks like raised or keratinized skin, or a macule usually on mucosal areas.
VIN III can progress to vulvar cancer.
A biopsy is necessary for any raised hyperpigmented
lesion.
The treatment for VIN is wide local excision, or laser
therapy.
Psoriasis of the vulva occurs in about 5% of women who

present with chronic vulval symptoms. It can be easily
Figure 25-2 Vulvar lichen sclerosis. The crease

areas are atrophic and wrinkled, the labia is
hyperpigmented, and the introitus is contracted
andulcerated
From Habif TP. Clinical dermatology, 5th ed. St Louis: Elsevier, 2009.
752
Figure 25-3 Psoriasis of perineum and vulva. Flexural

psoriasis often lacks the typical parakeratotic scale
ofpsoriasis on other body sites. Painful erosion of the
natal cleft is common
From Robboy SJ, Anderson MC and Russell P (eds). Pathology of the
female reproductive tract. Edinburgh: Elsevier, 2002.
Erosive vulvovaginitis
Chronic painful erosions and ulcers with superficial bleeding can be seen in the vulvar vestibule. Causes include:
Crohns disease
Behets syndrome
neurofibromatosis
cicatricial pemphigoid
pemphigus vulgaris
vulvar pyoderma gangrenosum
desquamative inflammatory vaginitis.
As vulvar and vaginal adhesions can occur in these conditions if they are not properly managed, specialist referral is
recommended.
Atrophic vaginitis
Estrogen deficiency causes the vaginal epithelium to become
thin, pale and dry. Symptoms include dyspareunia, minor
vaginal bleeding, and pain from splitting caused by friction.
Topical vaginal estrogen creams are useful.
Vulvar vestibular syndrome (vulvodynia)

Apart from dyspareunia, these patients usually have focal
erythema and localized vulvar dysesthesia. Many women
have associated urinary symptoms such as frequency and
bladder irritability.
This condition may be associated with the presence of
interstitial cystitis.
Diagnosis is usually made by the touch test. A cottontip swab is used to firmly touch the labia majora, the
sulci and the lateral labia minora. This is followed by
firmly touching the ostia of the Skenes glands, and the
major and minor vestibular glands. Women with vulvodynia classically have a heightened sensitivity associated
with the touch of the gland openings.
Management is difficult and very often prolonged, and
involves both behavioral and medical interventions that are
common in many pain syndromes.
Dysesthetic vulvodynia
Dysesthetic vulvodynia, also known as generalized vulvodynia, occurs mainly in older patients.
The etiology is unclear. Neuropathic pain, pudendal
neuralgia, chronic reflex pain syndrome, pelvic floor
abnormalities, and referred visceral pain have been suggested as causes.
The predominant symptom is chronic, localized burning or pain in the vulva, with no abnormalities on
examination but hypersensitivity and altered perception
to light touch.
Patients with this condition often have psychosexual
dysfunction.
Treatment with low-dose tricyclic antidepressants can
be helpful.
SEXUALLY TRANSMITTED
INFECTIONS (STIs)
CLINICAL PEARLS
The sexually transmitted infections that present with
vulvar ulceration are lymphogranuloma venereum,
chancroid, herpes simplex, primary syphilis, and
granuloma inguinale.
The sexually transmitted infections that present
with cervicitis are chlamydia, gonorrhea, and pelvic
inammatory disease.
Sexually transmitted infections are more common in:

the young
the unmarried
women who have recently had a new sexual partner
those with multiple sexual partners
women with a previous sexually transmitted
infection
recreational drug users
women who have contact with sex workers
women who meet partners on the internet.
All patients who seek screening for STIs should receive
testing and counseling for human immunodeficiency
virus (HIV) and hepatitis B and C infection.
The optimal interval for screening is uncertain, but
rescreening at three months after a diagnosed infection
is recommended.
Other sexually transmitted diseases and infections
include condylomata acuminata (genital warts), molluscum contagiosum, and pediculosis pubis.
Complications of sexually transmitted infections include
upper genital tract infections, infertility, cervical and
vulvar cancer, and enhanced transmission of HIV.
Chlamydia
Chlamydia trachomatis is a small Gram-negative intracellular
bacterium, and is the most common bacterial agent of sexually transmitted infections.
A large percentage of women are carriers of C. trachomatis and are asymptomatic, thereby providing an ongoing
reservoir. Rates of chlamydial infection are highest in
adolescent women.
The incubation period of symptomatic disease ranges
from 7 to 14 days.
Symptoms of chlamydial infection include cervicitis,
discharge and urethritis.
Cervicitis causes a vaginal discharge, and intermenstrual and post-coital bleeding.
Cervical discharge is frequently mucopurulent.
Urethritis commonly accompanies cervicitis, with
concomitant symptoms such as urinary frequency
and dysuria.
Infants born to mothers who have an infected birth
canal may develop conjunctivitis and pneumonia.
753
Chlamydia cannot be cultured on artificial media; traditionally, tissue culture has been required to establish a diagnosis.
Although tissue culture is the gold standard in identifying
chlamydial infection, rapid diagnostic testing using nucleic
acid amplification technology is now readily available, and
reasonably accurate.
The natural history of chlamydial infection is not clearly
established. Rates of spontaneous resolution, persistence
and progression are difficult to establish.
Occasionally patients with chlamydial infection develop
peri-hepatitis and inflammation of the liver capsule and
adjacent peritoneal surfaces, known as Fitz-Hugh
Curtis syndrome.
Approximately 30% of women with chlamydial infection develop upper genital tract involvement such as
pelvic inflammatory disease and, if left untreated, this
results in infertility.
Treatment
Chlamydia trachomatis is highly susceptible to tetracyclines
and macrolides. The first-line agents are doxycycline and
azithromycin.
The recommended regimen is 100 mg of doxycycline
orally twice daily for 7 days, or azithromycin 1 g orally
in a single dose.
Alternative regimens include erythromycin, ofloxacin,
or levofloxacin.
Except in pregnant women, it is not recommended that
patients have a test-of-cure 3 weeks after completing treatment if the recommended or alternative regimens were used.
Gonorrhea
Gonorrhea is the second most commonly reported communicable disease in the United States, accounting for more
than 300,000 cases annually. It is estimated that an equal
number of cases are unreported.
Although men are often symptomatic, and usually present early for therapy, symptoms in women may not be
apparent until complications such as pelvic inflammatory disease develop.
In women, the most common complaints are a vaginal
discharge, dysuria and/or abnormal vaginal bleeding.
Infection of Skenes glands, Bartholins glands, the anus
and the pharynx are common.
Disseminated gonococcal infection occurs in 12% of
women.
Untreated gonorrhea is a common cause of infertility,
chronic pelvic pain and an increased incidence of ectopic pregnancy.
Diagnosis of gonorrhea is made by either culture or nucleic
acid amplification tests. Rapid diagnostic tests are highly
sensitive, detecting up to 98% of infections. However,
nucleic acid amplification tests of swabs taken from the rectum and pharynx yield poor results.
Culture for Neisseria gonorrhoeae is processed on ThayerMartin agar, which prevents the overgrowth of other
endogenous flora.
754
Swabs should be obtained from the urethra, cervix, rectum and pharynx for culture. Culture with sensitivity
testing is particularly important for detection of resistant
organisms.
Treatment needs to have an efficacy rate of greater than
95%, as treatment failure has significant public health
implications.
Approximately 20 drugs within the cephalosporin,
quinolone, macrolide and tetracycline classes of antibiotics demonstrate high rates of gonococcal eradication
with single-dose therapy. Single-dose therapy decreases
the reliance on patient adherence.
The preferred therapeutic agents are cefixime 400 mg
orally in a single dose, ceftriaxone 250 mg intramuscularly in a single dose, ciprofloxacin 500 mg orally in a
single dose, ofloxacin 400 mg orally in a single dose, or
levofloxacin 250 mg orally in a single dose.
Treatment should also include antibiotics for chlamydial
infection, as coexistence of C. trachomatis is common.
PELVIC INFLAMMATORY
DISEASE (PID)
Pelvic inflammatory disease is defined as sexually transmitted pelvic infection, between the menarche and the menopause. It does not include vulvar or vaginal infections. It is
often used synonymously with salpingitis, but in fact is the
infection of the uterus, uterine tubes, adjacent parametrium
and overlying pelvic peritoneum.
The list of causative organisms is long, but includes
C.trachomatis, Gram-negative bacilli, Haemophilus influenzae, group B and D streptococci, Mycoplasma hominis,
and various anaerobic organisms including anaerobic
Gram-positive cocci and bacteroides species. Polymicrobial infection is common.
It is possible that viruses including coxsackievirus B5,
echovirus 6, and HSV may cause PID, but their role
is not clearly established. Mycobacteria have also been
implicated.
Pelvic infection is found more frequently in some sectors of the community than others. It is most common
between 15 and 19 years of age.
Approximately 25% of women with PID will experience long-term complications such as infertility, chronic
pelvic pain, dyspareunia, and an increased incidence of
ectopic pregnancy.
PID is never seen in prepubertal females, and very rarely
seen after the menopause.
Clinical features
The most important presenting feature is abdominal pain.
The pain is continuous and bilateral, involving both lower
abdominal quadrants.
While pain is usually present in patients with PID, not
all patients with lower abdominal pain will have an
infection.
Pain is increased with movement and coitus.

The pain is also present during menstruation and
micturition.
Some 35% of patients also have irregular bleeding, but
this feature is not helpful when considering a differential
diagnosis.
Many patients have increased vaginal discharge.
Those with severe infection have nausea, vomiting,
malaise, and fever.
Examination may reveal pyrexia, tachycardia, abdominal
tenderness and, during pelvic examination, pain on moving
the cervix. An adnexal mass may be palpable.
An increasing number of women with PID will not
have classic features. It is estimated that cases of silent
PID now outnumber clinically apparent cases by a ratio
of 3:1.
Abdominal ultrasound is useful to differentiate an ectopic pregnancy or complications of early pregnancy from
PID.
Laparoscopy is the gold standard for diagnosis.
CLINICAL PEARL
A pregnancy test is essential to exclude ectopic pregnancy in women with abdominal pain, in the reproductive age, even if pelvic inammatory disease is the
suspected cause.
To establish the diagnosis of PID, all three of the following

clinical features must be met:
1 abdominal tenderness (and/or rebound)
2 tenderness with movement of the cervix and uterus
3 adnexal tenderness
and one or more of the following can be included:
1 Gram stain of the endocervix positive for Gramnegative intracellular diplococci
2 temperature greater than 38C
3 leukocytosis greater than 10,000/mm3
4 purulent material (white cells present) from the peritoneal cavity by laparoscopy or laparotomy
5 pelvic abscess of inflammatory complex on bimanual
examination or observed by pelvic ultrasound.
Treatment
The aim of treatment is to prevent infertility, ectopic
pregnancy, and other long-term sequelae. If the patient is
extremely ill, hospitalization will be necessary.
Treatment regimens include levofloxacin 500 mg orally
once daily for 14 days, with metronidazole 500 mg
twice a day for 14 days to enhance anaerobic coverage.
If the patient is an inpatient, then intravenous cefotetan
2g 12-hourly, and doxycycline 100 mg orally or intravenously every 12 hours, with intravenous metronidazole 500 mg every 8 hours should be administered.
SEXUAL PROBLEMS
Sexual problems are common. Approximately 40% of
women have sexual concerns, and some 12% have distressing sexual problems.
Although it is thought that the frequency of sexual
activity declines with age, population-based studies
indicate that sexual activity continues in women aged
between 66 and 71 years, and in a third of women over
the age of 78. With the advent of treatment of male sexual dysfunction, the likelihood that women will continue sexual activity well into their 80s will be a feature
of modern life.
The average frequency of sexual activity is 6 times per
month for women compared with 7 for men, with vaginal intercourse the most common sexual practice and
oral sex a distant second.
An understanding of normal sexual response is necessary
for the evaluation and treatment of sexual dysfunction. The
sexual response is complex, involving social, psychological,
neurological, vascular and hormonal processes, and includes
complex interactions of sexual stimulation with the central
nervous system, the peripheral neurovascular system, and
hormonal influences that are not completely understood.
The female sexual response is divided into four phases:
1 Desirethe desire to have sexual activity, including
sexual thoughts, images and wishes.
2 Arousalwhich includes physiological changes such
as genital vascular congestion, and systemic changes
such as tachycardia, elevation in blood pressure, and
increased respiratory rate.
3 Orgasmwhich is a peaking of sexual pleasure and a
release of sexual tension with rhythmic contractions of
the perineal muscles and reproductive organs.
4 Resolutionwhich involves both emotional and physical satisfaction.
Within this framework, for many women there is a difference in sequence.
Most women report inability to achieve orgasm with
vaginal intercourse, and require direct stimulation of the
clitoris. About 20% have coital climaxes, and 80% climax
before or after vaginal intercourse when stimulated. Only
30% of women almost always, or always, achieve orgasm
with sexual activity, in contrast to 75% of men.
Female sexual dysfunction can be classified into four
areas:
1 Sexual arousal disorderthe persistent inability to reach
sexual excitement.
2 Orgasmic disorder difficultyinability to reach orgasm
after sexual stimulation and arousal.
3 Sexual desire disorderthe lack of desire for sexual activity and/or the absence of sexual thought and fantasy,
as well as a fear of and avoidance of sexual thought and
situations.
4 Sexual pain disorder, including dyspareunia, vaginismus,
or genital pain that occurs with any type of sexual
stimulation.
755
Female sexual dysfunction is multifactorial, often with several different etiologies contributing to the problem.
Patients should be evaluated for associated physical or
psychological issues.
The medical history is important, as certain illnesses
or medications affect sexual function. For instance,
spinal cord injuries, thyroid disease, diabetic neuropathy, surgical or medical castration with accompanying
decreased estrogen and testosterone levels, and depression may interfere with sexual function.
Antidepressants, antipsychotics and sedatives alter the
blood flow to the genitals, decreasing arousal and/or
lubrication.
Recreational drugs and alcohol are often associated with
sexual dysfunction.
Excessive smoking may lead to vascular insufficiency
and decreased genital blood flow.
A previous vaginal delivery or vaginal surgery may result
in interference with nerve supply, and dyspareunia.
Vaginal blood flow and vaginal secretions are estrogendependent. Low estrogen levels are associated with
significant decreases in clitoral, vaginal, and urethral
blood flow, and thinning of the mucosa in the genital region. Any medical condition or medication that
interferes with estrogen levels can contribute to sexual
dysfunction.
Women with urinary incontinence, fecal incontinence,
or uterovaginal prolapse often have difficulty with sexual function.
When assessing women with sexual dysfunction, routine
laboratory testing is not recommended unless endocrinopathy is suspected.
Treatment
The treatment of sexual dysfunction is complex and timeintensive, and requires special expertise.
A team approach with the use of psychotherapists, sex
therapists and physiotherapists is sometimes needed to
address specific aspects of treatment.
If associated medical conditions are found, these should
be treated before or during sexual dysfunction therapy.
For instance, a woman with depression may require an
antidepressant.
Relationship problems often exacerbate or underlie
sexual dysfunction in women. Couples counseling may
be effective when there is relationship conflict or poor
communication.
756
Hormone therapy
Estrogen improves vaginal and clitoral blood flow,
increasing lubrication. Dyspareunia caused by atrophy
is treated best by vaginal estrogens. The ability of systemic estrogens to enhance sexual function has not been
established.
Testosterone has been linked to increased libido,
although the data on testosterone use for the treatment
of female sexual function is poor, partly because of the
side-effect profile.
Dehydroepiandrosterone (DHEA) has been shown to
improve sexual interest and satisfaction in some women.
It is important to counsel patients that androgen therapy
can result in androgenic, metabolic and adverse endocrine
effects, and therefore should be used with caution in women
who are at risk of cardiovascular disease, hepatic disease,
endometrial hyperplasia or cancer, or breast cancer. Additionally, women should be warned of the possibility of significant hirsutism, acne, voice deepening and clitoromegaly.
Pelvic-oor disorders
Pelvic-floor disorders such as urinary and fecal incontinence
and pelvic organ prolapse are common, and have a negative
impact on the sexual function of women. Multiple studies
have shown that surgical treatment of the underlying disorder, such as repair of prolapse and treatment of urinary or
fecal incontinence, improves sexual function.
Hysterectomy
There is no evidence that hysterectomy alters sexual
function. Multiple studies have demonstrated a positive
effect from total and subtotal abdominal and vaginal
hysterectomy on sexual function.
There is no benefit for sexual function by preservation
of the cervix during hysterectomy.
Pregnancy and childbirth

Sexual dysfunction is very common after childbirth; up
to 86% of women report sexual problems in the first
3months after vaginal delivery.
Most women resume normal sexual function 6 months
after childbirth.
Continued breastfeeding, and severe genital tract trauma
sustained during childbirth, may lead to prolonged sexual problems.
1
A 55-year-old woman is having hot ushes and is requesting hormone replacement therapy. She has a history of a
previous deep vein thrombosis in her right calf. Which of the following statements is true for managing this patient?
A This patient could use unopposed estrogen therapy for 5 years.
B The best preparation to use is a combined preparation of conjugated estrogen and synthetic progestin.
C Hormone therapy is recommended for the prevention of cardiovascular disease.
D With a history of previous thromboembolic disease, hormone replacement is inappropriate.
A 70-year-old woman, a smoker with a previous history of cervical cancer, presents with vulval itching, burning and
irritation. On examination of her vulva there is a raised hyperpigmented lesion visible on the labium majus. Which of
the following statements is true for this woman?
A A vulval biopsy should be performed to determine the exact pathology.
B She should be treated with topical antifungal agents.
C She should be treated with topical corticosteroids.
D She should be encouraged to use oatmeal baths.
A 60-year-old obese woman who has hypertension and type 2 diabetes mellitus develops vaginal bleeding for the rst time
since the menopause 9 years previously. Which of the following statements is true for the management of this woman?
A The most likely explanation for this womans symptoms is the presence of an arteriovenous malformation in the
uterine wall.
B She probably has broids.
C She has engaged in energetic sexual intercourse.
D She needs to be evaluated with a pelvic examination and transvaginal ultrasound, and needs referral for
endometrial sampling.
4 Which four of the following options are the investigations that are valuable in most couples with infertility?
A Semen analysis
B Measurement of testicular volume
C Day 3 serum FSH (follicle-stimulating hormone)
D Papanicolaou smear
E Serum prolactin estimation
F Magnetic resonance imaging of the brain
G Thyroid function tests
5
Which four of the following can inuence the measurement of serum prolactin level in the evaluation of infertility?
A Sexual intercourse an hour before the measurement
B Hyperthyroidism
C Adenoma of the pituitary gland
D Psychological stress
E Breast examination
F Pelvic examination
6 Which two from the following list are the most common causes of infertility?
A Male factors
B Tubal pathology
C Fibroids
D Endometrial polyps
E Unexplained
7
Which four of the following options may be side-effects of hormonal oral contraceptive agents?
A Cardiovascular disease
B Migraine headaches
C Epilepsy
D Deep vein thrombosis
E Worsening hypertension
F Angina
G Mitral valve disease
H Diabetes mellitus
I Stroke
8 Which of the following explains the mechanism of action of emergency contraception?

A Inhibits or delays ovulation
B Interferes with fertilization
C Interferes with tubal transport
D Prevents implantation
E Causes regression of the corpus luteum
F All of the above.
757
ANSWERS
1
D.
If there is a history of a previous thromboembolic event, the use of estrogen therapy is inappropriate. Unopposed estrogen
therapy in a woman who still has a uterus is dangerous as it can predispose to endometrial cancer. There is no evidence
that hormone replacement prevents any disease process except osteoporosis.
A.
Any woman with a history of previous papillomavirus infection, as evidenced by the diagnosis of cervical cancer, is at risk
of developing vulvar intraepithelial neoplasia, and when this is associated with a raised hyperpigmented lesion the risk of
malignancy is signicant.
D.
In a postmenopausal woman, especially with diabetes, obesity and hypertension, the risk of endometrial cancer is high and
needs to be excluded.
4 A, C, E, G.
5
C, D, E, F.
6 B, E.
7
B, D, E, I.
8 F.
While the mechanism is not fully known, all or any are possibly correct.
758
CHAPTER 26
OBSTETRIC MEDICINE
Annemarie Hennessy
CHAPTER OUTLINE
GENERAL PRINCIPLES OF MEDICAL
OBSTETRIC CARE
DIABETES IN PREGNANCY
HYPERTENSION IN PREGNANCY
RESPIRATORY DISEASE IN PREGNANCY

Pneumonia
Asthma
VENOUS THROMBOEMBOLISM (VTE) IN

PREGNANCY
THYROID DISORDERS IN PREGNANCY
Hypothyroidism
Hyperthyroidism
COMMON GASTROENTEROLOGICAL AND
LIVER DISORDERS IN PREGNANCY

Constipation and irritable bowel syndrome (IBS)
VIRAL INFECTION IN PREGNANCY

Viral hepatitis
IMMUNOLOGICAL AND HEMATOLOGICAL

DISEASE IN PREGNANCY

CARDIAC DISEASE IN PREGNANCY

cardiomyopathy
OBESITY IN PREGNANCY
NEUROLOGICAL CONDITIONS IN
PREGNANCY
759
GENERAL PRINCIPLES OF
MEDICAL OBSTETRIC CARE
Pregnancy is commonly associated with several major medical problems. The most common of these are diabetes and
high blood pressure, but respiratory disease, viral infections,
thyroid disease and gastrointestinal disturbance are also not
uncommon.
There are fundamental principles for considering any
acute medical illness in pregnancy; these are outlined in
Table 26-1.
The safety of medication treatment is defined by a classification system based on evidence of risk in pregnancy. This
is applied to all medications and should be discussed in detail
with any patient requiring medical management of their disease in pregnancy. There is some variation in classification
systems throughout the world, but the following categories
are widely used.
Asafe in pregnancy, and have been used by a large
number of pregnant women without harmful effect.
Banimal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and
well-controlled studies in pregnant women; or animal
studies have shown an adverse effect, but adequate and
well-controlled studies in pregnant women have failed
to demonstrate a risk to the fetus in any trimester.
Canimal reproduction studies have shown an adverse
effect on the fetus and there are no adequate and wellcontrolled studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite
potential risks. The adverse event is a reversible effect
on the human fetus.
Ddrugs which have caused human fetal malformations or irreversible damage.
Xstudies in animals or humans have demonstrated fetal

abnormalities and/or there is positive evidence of a human
fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in
use of the drug in pregnant women clearly outweigh the
potential benefits. These should not be used in pregnancy
or where there is a possibility of pregnancy.
In Australia the B category is subdivided, and this has been
adopted by some other countries also.
B1used by a limited number of women who are
pregnant or of child-bearing age without an increase in
malformation or other harmful effect, and no effect
inanimal studies.
B2as for B1 but where animal studies are lacking or
inadequate.
B3as for B1, with an increase in fetal damage seen in
animals, the significance of which is considered uncertain in humans.
The complexity of the diseasepregnancy interaction indicates that specialist care needs to be provided, and where
possible this should include a fetomaternal specialist and an
obstetric physician, or a specialist physician with particular
knowledge of physiological and pathophysiological processes
and treatments in pregnancy. For the most common conditions (diabetes mellitus, hypertension and thyroid disease),
most major centers conduct high-risk clinics which combine midwifery, obstetric, fetomaternal specialist and physician care, with the appropriate tertiary support as required.
DIABETES IN PREGNANCY
Diabetes is one of the most common medical complications of pregnancy, and is increasing in incidence due to
higher rates of obesity and type 2 diabetes, and also a rise
Table 26-1 Principles relating to acute medical illness in pregnancy
QUESTION
RELEVANCE
What is the potential adverse impact of

being pregnant on the course of the
disease?
Pregnancy q Disease
Example: Increased possibility of maternal disability or death due to H1N1
inuenza occurring in a pregnant woman
What is the potential adverse effect of

the disease on the pregnancy?
Disease q Pregnancy
Example: Increased risk of premature labor in a patient with genital infection or
renal disease causing preeclampsia
What is the likely effect of either disease

or pregnancy on the fetus/neonate?
Disease/Pregnancy q Fetus/Neonate
Example: Increased risk of macrosomia in the fetus when a pregnant woman
has diabetes mellitus
What are the likely implications of

the necessary investigations on the
pregnancy?
Investigations q Pregnancy
Example: The danger from radiation exposure to the fetus, particularly in the
1st trimester, needs to be carefully considered if a pregnant woman needs
radiological tests in the setting of a serious illness
What are the likely implications of the

necessary treatment on the pregnancy?
Treatment q Pregnancy
Example: An acute attack of asthma may require oral corticosteroid therapy,
but early in pregnancy this would impart a very slight increased risk of
congenital abnormality in the fetus (such as cleft lip)
760
Chapter 26 Obstetric medicine
in maternal age at pregnancy. Current rates of gestational

diabetes are approximately 58% depending on race, family history and high-risk comorbidities, but the changing
demographics of women, higher screening rates and tighter
criteria for diagnosis are likely to lead to greater numbers
of women being diagnosed in pregnancy. Diabetes in pregnancy is classified as:
gestational diabetes
pre-existing diabetes, either:
type 1 diabetes in pregnancy or
type 2 diabetes in pregnancy.
The White classification, used to assess maternal and fetal
risk, classifies diabetes as follows.
Gestational diabetes:
Class A1gestational diabetes controlled with diet
Class A2gestational diabetes controlled with
insulin.
Pre-existing diabetes:
Class Bonset at age 20 or older or with duration
of <10 years
Class Conset at age 1019 or duration of 1019
years
Class Donset before age 10 or duration >20 years
Class Eovert diabetes mellitus with calcified
pelvic vessels
Class Fdiabetic nephropathy
Class Rproliferative retinopathy
Class RFretinopathy and nephropathy
Class Hischemic heart disease
Class Tprior kidney transplant.
The diagnosis of gestational diabetes mellitus (GDM) is
made on the basis of elevated blood glucose concentrations
in pregnancy only. This condition is largely discovered on
screening blood tests in the target population, although
universal screening is recommended. Risk factors for gestational diabetes are given in Box 26-1.
Box 26-1
Risk factors for gestational diabetes

Women at greatest risk of gestational diabetes mellitus
include those:
over 30 years of age

with a family history of type 2 diabetes mellitus
who are overweight (dened as pre-pregnancy body
mass index of >25 kg/m2)
of racial background including Chinese, Middle
Eastern, Polynesian, Melanesian or Maori, AfricanAmerican, and Indigenous Australian
with a previous history of gestational diabetes
with a previous adverse obstetric outcome such as
macrosomia, shoulder dystocia or polyhydramnios
with glycosuria.
Mechanisms
The metabolic derangement that leads to higher maternal blood glucose concentrations is insulin resistance
conferred by the placenta, through production of cortisol and progesterone, as well as human placental lactogen, prolactin and estrogen.
It is also thought that increases in fat deposits mediate
some of the hormonal responses.
There is a clear genetic component to these responses,
with genetic risk tracking with insulin receptor, insulinlike growth factor and glucokinase gene variations.
There is a prevailing view that there is pancreatic betacell impairment.

and diagnosis
The majority of presentations are asymptomatic, and therefore diagnosis is determined by screening serum and urine
biochemical tests. First-trimester testing for overt disease can
include fasting plasma glucose or random plasma glucose, and
then glycosylated hemoglobin (HbA1C) if glucose is elevated.
Screening typically occurs at 2428 weeks of gestation
for all pregnancies in some countries, and is recommended
at 14 weeks of gestation for those at highest risk. The defining blood sugar concentrations for diagnosis are:
1-hour plasma glucose level of v7.8 mmol/L after a 50g
glucose load (morning, non-fasting) or v8.0 mmol/L
after a 75g glucose load (morning, non-fasting).
Confirmation of diagnosis after a positive screening test:
a 75g oral glucose tolerance test (fasting) with venous
plasma glucose at 0 hours of v5.5 mmol/L or at 2 hours
of v8.0 mmol/L (although some countries use 7.09.1
mmol/L).
Women at high risk of GDM should proceed straight to
a glucose tolerance test instead of a screening polycose
test to expedite early diagnosis and intervention.
If symptoms and signs occur, they can be maternal, fetal or
neonatal.
Maternal (although these can be nonspecific symptoms
of pregnancy):
thirst
polyuria
constant hunger.
Fetal:
macrosomia
polyhydramnios, or olighydramnios (uncommon).
Neonatal:
hypoglycemia
hyperbilirubinemia
polycythemia.
However, it is more common that the diagnosis is made on
biochemical screening.

Evidence-based targets for GDM require close attention
to detail (diagnosis and treatment), and a multidisciplinary
model of care.
761
Early detection of gestational diabetes is optimal, from

either universal or targeted screening at either 14 or
28weeks of gestation.
Patient education is very important, and a multidisciplinary team approach including midwives, dietitians,
diabetic educators, obstetricians, and endocrinologists
or obstetric physicians, if available, is beneficial.
Dietary therapy is essential, with oral hypoglycemic agents
or insulin added where required to achieve the minimum goals for glycemic control: fasting blood glucose
<5.5 mmol/L, 1-hour postprandial <8.0 mmol/L, or
2-hour postprandial <7.0 mmol/L.
Careful antepartum fetal surveillance is essential. Continuation of the pregnancy in uncomplicated GDM
not on insulin and with controlled glycemia to 10 days
beyond term is acceptable, provided that indications
from fetal monitoring are reassuring. This may include
regular fetomaternal assessment of fetal growth parameters and other markers of fetal wellbeing (amniotic fluid
index, non-stress test, biophysical profile, and umbilical
artery flow characteristics).
Close neonatal monitoring is important, particularly for
the detection of hypoglycemia.
CLINICAL PEARL
Maternal follow-up, with an oral glucose tolerance test,
should be performed 68 weeks postpartum and then
at least every 2 years, because of the increased risk of
developing permanent diabetes.

Classes ET of the White classification (overt diabetes
mellitus with calcified pelvic vessels; diabetic nephropathy; proliferative retinopathy; retinopathy and nephropathy;
ischemic heart disease; and prior kidney transplant) are associated with greater maternal and fetal adverse outcomes, and
require great care in the pre-pregnancy planning phase as
well as careful monitoring during the pregnancy.
Of particular note, women with diabetic proliferative retinopathy should consider having their retinal vessels treated
with photocoagulation on specialist advice early in pregnancy
to reduce the risk of retinal hemorrhage, which is increased
in pregnancy. This is especially important in those being considered for prophylaxis with aspirin (for preeclampsia).

A pre-pregnancy consultation should be undertaken,
with appropriate specialist referral.
Patients with diabetic nephropathy (White classes F
and RF) are likely to be treated with renal protective antihypertensives such as angiotensin-converting
enzyme inhibitors (ACEIs) and angiotensin II receptor
antagonists (ATRAs), which are contraindicated in all
trimesters of pregnancy; they are usually ceased once
pregnancy is detected. These drugs are associated with
increased fetotoxicity (drug category D). They should
be substituted with drugs that are safe in pregnancy.
762
Other organ pathologies resulting from diabetes, such

as ischemic heart disease, cardiac autonomic neuropathy
or gastric autonomic neuropathy, can cause significant
symptoms in pregnancy. These need to be carefully
managed with optimal treatment and care for the course
of the pregnancy.
Early identification and treatment of diabetic ketoacidosis and acute hypoglycemia are major considerations in
those on insulin. With early diagnosis and appropriate
care, fluid management and insulin, the incidence of
fetal death has now decreased to below 10%. Women
should be taught signs and symptoms that require medical attention.
The risk of preeclampsia in these women is of the
order of 30%, but relates to the degree of blood pressure control and renal function prior to the onset of the
pregnancy.

The most common form of established diabetes seen in
pregnancy (>90% of cases) is type 2 diabetes mellitus.
These women are generally overweight or obese, and
have a familial and genetic tendency to diabetes.
Insulin resistance is the hallmark of this disorder, which
is worsened by the metabolic changes of pregnancy.
Pregnancy may be the first time women have been tested
for diabetes, so it may not be clear whether a woman has
underlying type 2 diabetes or GDM.
The presence of microalbuminuria (albumin/creatinine
ratio of >15 mg/mmolCr) can also increase the chance
of additional renal dysfunction, and preeclampsia in the
pregnancy.

In addition to the targets set above for gestational diabetes,
weight control and ongoing dietary advice are important in
the management of those with type 2 diabetes in pregnancy.
CLINICAL PEARL
Dramatic weight loss is not a target for the management of type 2 diabetes in pregnancy, but a focus on
healthy diet, maintenance of weight, and a concerted
effort not to gain signicant weight during pregnancy
are important in the overall management.
Pre-conceptual care includes:

weight loss
education in diet, and self-monitoring of blood glucose
diagnosis and management of target organs affected by
diabetes
a target of HbA1C of <7% to decrease risk of fetal
malformations.
Pregnancy care requires:
fetal surveillance
tight glycemic control, including with oral hypoglycemic agents or subcutaneous insulin.
HYPERTENSION IN PREGNANCY
Hypertensive disorders of pregnancy (HDP) are classified as those that are present only in pregnancy (usually
appearing after 20 weeks of gestation), and those present
prior to, or after, pregnancy.
The risk factors (Table 26-2) for gestational hypertension, preeclampsia and superimposed preeclampsia (in a
patient with chronic hypertension) reflect the prevailing
theories that preeclampsia is related to placental mass,
placental dysfunction and some level of immunological activation in the presence of a toxic antiangiogenic
response from the placenta.
The epidemiological association noted in women who
have been using barrier contraception, have short
cohabitation times, new partners, and who use artificial
reproductive techniques (and therefore non-exposed
tissues) has sparked investigation into immunological
mechanisms as a cause of preeclampsia. It is yet to be
determined how this knowledge will affect the capacity
to prevent preeclampsia.
Our understanding of preeclampsia has been greatly
enhanced by the recent discovery of abnormalities in
the antiangiogenic molecules (soluble fms-like tyrosine
kinase-1), and their regulators (placental growth factors,
vascular endothelial growth factor) which arise from
the placenta as important causal molecules. The link
between these molecules, alterations in innate immunity
Table 26-2 Risk factors for preeclampsia
RISK FACTOR
RISK
and regulation of innate immunity by cytokines has also

advanced our understanding of preeclampsia, and the
likelihood that focused treatment may be offered in the
future.

and diagnosis
While much attention has been paid in the past to the classification of the hypertensive disorders in pregnancy, the
more recent classification into four categories has significantly simplified our understanding and capacity to determine risk and prognosis in any given pregnancy:
1 Gestational hypertension.
2 Preeclampsia related to pregnancy.
3 Chronic hypertension and superimposed preeclampsia where blood pressure is elevated before or prior to
20weeks of pregnancy or persists 3 months after delivery.
4 Chronic hypertension, either primary (essential) or
secondary, and including white coat hypertension.
This group has an increased risk of superimposed preeclampsia which can be severe, occurring early in the
pregnancy and leading to significant maternal and perinatal mortality and morbidity.
Gestational hypertension
Gestational hypertension is any increase in blood pressure (BP) after 20 weeks of gestation which is resolved by
3 months post-delivery. Any prior history, even of a transient increase in BP in the setting of oral contraceptive use,
excludes women from this classification. Gestational hypertension requires two BP readings of 140 mmHg systolic
or 90 mmHg diastolic taken more than 6 hours apart; an
elevation in either is required.
Preeclampsia/eclampsia
Renal transplant recipient, with

an elevated creatinine, high
blood pressure, and on highrisk immunosuppression such as
Approaching
100%
APS (antiphospholipid syndrome)

severe, untreated
85%
Also at risk of
miscarriage
Renal disease
30%
Chronic hypertension
30%
Donor ovum
30%
Triplet pregnancy
22.7%
Twin pregnancy
14%
Primiparity
10%
New partner, donor sperm
10%
Preeclampsia/eclampsia is any increase in blood pressure

after 20 weeks gestation associated with at least one of the
following:
proteinuria >300 mg per 24 hours or a protein:
creatinine ratio of 30 mg protein/mmoL Cr
serum creatinine >0.09 mmol/L; oliguria
elevated liver enzymes, a >30% reduction in platelet
count or <100 w 109/L; hemolysis or disseminated intravascular coagulation (DIC)
pulmonary edema
persistent and/or severe headache; convulsions (eclampsia); persistent visual disturbance; stroke
epigastric pain
hyper-reflexia/clonus
fetal growth restriction
placental abruption.
Interpregnancy interval >10 years
10%
Issues in diagnosis
Second pregnancy to a partner

without preeclampsia
2%
Considerable discussion arises about the sensitivity and

specificity of the urine testing regimen. However, a urinary
protein excretion of ++ or more (+++ and ++++) on a dipstick
763
test is reliable to diagnose significant proteinuria. Once

identified, proteinuria, regardless of its progress, establishes
the diagnosis of preeclampsia/eclampsia.
The usual pattern is for the proteinuria to increase with
time, although a sudden severe proteinuria (often within
hours) is very well described in preeclampsia.
The difficulty rests with the diagnosis of no proteinuria
on a dipstick test, and low-range proteinuria (trace and
+), which has a false-negative rate of up to 9%. Here
the sensitivity and specificity range from 27% to 89%.
Normal urinary protein excretion is <300mg/day in the
3rd trimester.
The screening nature of this test can be improved by
requesting a laboratory (or point of care) urine protein/
creatinine ratio, which takes into account the concentration of the urine at the time of testing. A ratio of >30
mg/mmolCr is considered significant.
Ultimately, the 24-hour collection for urine quantification is the gold standard, but it needs to be recognized
that up to 50% of the actual tests end in inaccurate collection, especially if done at home.
Proteinuria confers additional risk of poor obstetric outcome but, in and of itself, does not confer severity.
Blood pressure discussions are similarly vexed.
When the BP is >170/110 mmHg there is universal
agreement about the diagnosis and need for treatment.
When BP is under 140/90 mmHg, women do not reach
the diagnostic threshold.
The identification of at-risk women, particularly those
in a younger age group, by a rise in systolic BP of
25mmHg or a rise in diastolic BP of 15 mmHg should
prompt the need for greater monitoring. BP readings
between 140/90 and 170/110 mmHg (either systolic or
diastolic; both are not needed) meet the criteria for gestational hypertension or preeclampsia.
The investigation for secondary hypertension in those with
chronic hypertension, or occasionally in those with de novo
hypertension, should be reserved for those with signs or
symptoms suggestive of secondary disease:
very high BP early in the 2nd trimesterpheochromocytoma
radio-femoral delaysuggestive of coarctation of the
aorta
a renal bruit or discrepant renal sizesuggestive of renal
artery stenosis
hypokalemiasuggestive of mineralocorticoid excess
hypercalcemiasuggestive of hyperparathyroidism as a
potential cause
under- and over-active thyroid functionsuggests thyroid disease as a target for treatment
Overlap syndromes with diabetes and diabetic nephropathy
are also important contributors to the risk of preeclampsia.
seizures. It decreases both the rate of cerebral palsy in

the extremely premature neonate (<30 weeks of gestation) and the rate of maternal mortality. It is used in any
woman with severe-range hypertension, or at lower BP
readings when there is neurological irritability or seizure.
For those with a BP under 140/90 mmHg, even if this
represents an increase in BP, treatment is not routinely
recommended.
Considerable debate exists about the need for treatment in the group with BP of 140169/90109
mmHg. Those who favor antihypertensive treatment
recognize the worsening prognosis of hypertension
with respect to risk of intracerebral hemorrhage and
placental abruption. Those who oppose antihypertensive treatment identify risks to fetal weight gain and
neonatal safety.
Treatment of hypertension in pregnancy is important to
allow safe progression of the pregnancy, timely and controlled delivery where possible, and a decrease in maternal and fetal morbidity and mortality.
There is also increasing evidence that preeclampsia
affects future cardiovascular risk.
CLINICAL PEARL
Treatment of severe hypertension in pregnancy (especially if the blood pressure is above 170/110 mmHg)
requires rapid blood pressure control and immediate
fetal monitoring. Antihypertensive therapy including
intravenous treatment is indicated in this group of
women.
Antihypertensive drug choices in pregnancy are outlined in

Table 26-3.

There is increasing evidence that acetylsalicylic acid can be
used prophylactically to decrease the risk of preeclampsia in
the highest risk groups: those with renal disease, diabetes
and chronic hypertension. The usual dose is 100 mg (low
dose) per day, started in the 1st trimester and ceasing at
34weeks of gestation.
RESPIRATORY DISEASE IN
PREGNANCY
Pneumonia
CLINICAL PEARL
Pneumonia is not more common in pregnancy, but the
consequences of some forms of pneumonia, notably
varicella pneumonia, include extremely high mortality
in pregnancy.

The use of magnesium sulfate is safe for babies and
mothers and has a proven benefit in preventing maternal
764
Risk factors for pneumonia in pregnancy include asthma

and anemia.
Table 26-3 Antihypertensive drug choices in pregnancy
DRUG
MECHANISM OF ACTION
CATEGORY IN PREGNANCY
Alpha-methyldopa
Centrally acting
Clonidine
Centrally acting
B3
Labetalol
Non-selective beta-blocker
C (fetal bradycardia)
Oxprenolol
Non-selective beta-blocker
C (fetal bradycardia)
Nifedipine
Calcium-channel blocker
C (fetal distress)
Diazoxide
Peripheral vasodilator
C (neonatal hyperglycemia)
Hydralazine
C (fetal distress)
Prazosin
B2
The bacterial pneumonias are typically those that are

commonly seen outside of pregnancy; streptococci, Haemophilus influenzae and Mycoplasma pneumoniae. These are
easily treated with both beta-lactam and macrolide antibiotics, which are considered safe in pregnancy.
Viral infections, including varicella, and influenzas
including avian influenza, severe acute respiratory syndrome (SARS) and more recently swine influenza, can
be complicated by maternal pneumonia and have an
increased mortality in pregnancy. The increased mortality in the swine influenza epidemic of 2009 was contributed to by obesity and increased susceptibility in
some ethnic groups.
Treatments include the rapid use of antiviral medication, and support for respiratory failure such as
ECMO (extracorporeal membrane oxygenation).
Apart from maternal respiratory failure, the other complications of pneumonia in pregnancy are premature
labor and the increased risk of low-birthweight infants.
Early recognition of pneumonia is therefore critically
important in pregnancy. The increasing availability of vaccination, particularly for influenzas, may decrease the associated morbidity and mortality in pregnancy.
Asthma
Asthma is a common disorder, and therefore flares may
occur in pregnancy. The consequences of uncontrolled
asthma can have significant and surprising consequences on
the fetus (increased risk of hypoxic injury) and the mother
(increased risk of preeclampsia).
The respiratory rate is essentially unchanged in pregnancy, but the increase in tidal volume, minute ventilation and minute oxygen uptake, and therefore the
decrease in functional residual capacity and residual volume, can appear as a hyperventilatory state in the latter
part of the pregnancy.
The effect of pregnancy on partial pressure of carbon dioxide (pCO2; a decrease), serum bicarbonate (a
decrease), and pH (an increase) reflect a chronic respiratory alkalosis which needs to be taken into account
when interpreting blood gases and biochemistry results

in pregnant women.
CLINICAL PEARL
In the setting of asthma, a normal partial pressure of
carbon dioxide (pCO2) in a pregnant patient may signal
impending respiratory failure.

and diagnosis
The diagnosis of asthma in pregnancy uses the same criteria as in the non-pregnant state: breathlessness, cough, and
wheeze. The demonstration of airway reactivity reversible
with beta-mimetics is the pathognomonic feature of the
disease.
Given that dyspnea is common in pregnancy, it is a challenge to sort out the physiological breathlessness in pregnancy from potentially dangerous diagnoses including:
airway obstruction
amniotic fluid embolism
acute congestive heart failure (CHF), secondary to peripartum cardiomyopathy
pulmonary thromboembolism.
The time of greatest risk for asthma flares is in the 3rd trimester when mechanical factors, such as diaphragmatic
splinting and decreased functional reserve, limit respiratory
reserve.
The complications for the mother at this stage can
include respiratory failure, barotrauma, and adverse
effects of treatment including corticosteroids, causing,
for example, pathological rib fractures secondary to
osteoporosis.
Left untreated, severe maternal morbidity and mortality
can result (Box 26-2, overleaf).
The use of standard asthma medication is recommended
in pregnancy when required. The net effect of untreated
asthma outweighs any perceived problems based on the
use of regular anti-asthma medications. Women need to be
765
Box 26-2
Adverse outcomes from severe

and poorly controlled asthma in
pregnancy
Preeclampsia and gestational hypertension

Uterine hemorrhage
Pre-term labor
Premature birth
Congenital anomalies (especially related to drugs
taken in the 1st trimester)
Intrauterine growth restriction
Low birthweight percentile
Neonatal hypoglycemia, seizures, tachypnea, and
neonatal intensive care unit admission
encouraged to have their asthma adequately treated, including with the assistance of regular respiratory review and airflow testing.
VENOUS THROMBOEMBOLISM
(VTE) IN PREGNANCY
Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is an uncommon but potentially life-threatening disorder in pregnancy.
Pregnancy is associated with a 10-fold increase in the incidence of VTE due to an increase in several coagulation
factors, increase in venous stasis and possible endothelial
injury.
CLINICAL PEARL
Accurate diagnosis of venous thromboembolism is
essential, and clinical symptoms alone should not
be used in place of objective radiological diagnostic
tests.
Objectively diagnosed VTE, whether DVT or PE,

requires immediate anticoagulation, with therapeuticdose low-molecular-weight heparin preferred over
unfractionated heparin given its increased bioavailability, its more predictable dose effect, and its better sideeffect profile. Unfractionated heparin is associated with
a risk of heparin-induced thrombocytopenia (HIT) and
osteoporosis if used over several weeks.
Warfarin should not be used to treat acute VTE during
pregnancy due to its teratogenicity profile.
Risk factors for VTE in pregnancy may be pregnancyspecific, such as preeclampsia, caesarean section and postpartum hemorrhage; or general maternal risk factors, such
as a personal or family history of thrombosis, increased
body mass index (BMI), immobility or smoking.
Thrombophilic patients are at risk, and pelvic surgery is
an additional risk factor in the pregnancy setting.
766
Women at increased risk of developing pregnancyassociated VTE may require antepartum and/or postpartum thromboprophylaxis, but there are very few data
from clinical trials to give clear guidelines.
Management of the bleeding risk in the peri-delivery
period is particularly challenging. Anticoagulation
should be discontinued for the shortest time possible in
women at increased risk of developing thrombosis. Vaginal delivery should be the goal unless caesarean section
is indicated for obstetric reasons and a safe plan for anticoagulation can be formulated.
THYROID DISORDERS IN
PREGNANCY
All thyroid disease can present in pregnancy, but from the
fetal wellbeing point of view the most important consideration is the functional thyroid hormone level.
Generally, thyroid function tests in pregnancy need to
be considered in the context of the following normal physiological changes.
Altered thyroid-hormone-binding globulin (TBG) production and sialylation from 2 weeks to 20 weeks of
gestation.
Increased triiodothyronine (T3) and thyroxine (T4) produced to match TBG increases.
Iodine deficiency:
increased renal clearance due to hyperfiltration of
pregnancy
reactive increase in thyroid uptake (may increase
the size of the gland)
direct competition by which the thyroid overrides
fetal uptake of iodine.
Increased beta human chorionic gonadotropin
(beta-hCG):
shares an alpha subunit with thyroid-stimulating
hormone (TSH)
stimulates the TSH receptor and decreases transiently the TSH concentration (may lead to false
diagnosis of hyperthyroidism).
Hypothyroidism
Hypothyroidism occurs in 9/1000 of the young female
population prior to pregnancy, and another 3/1000 are diagnosed during pregnancy.
Symptoms can be very difficult to define in pregnancy,
as the hormonal effects of pregnancy per se can lead to
tiredness, lethargy, weight change, and cold intolerance.
The usual pattern for recognition is biochemical, and
includes elevated TSH and low free T4.
The most common cause is Hashimotos thyroiditis.
Pituitary causes of hypothyroidism are rare.
Treatment is directed at adequately replacing thyroid
hormone, with increases in dose especially in the second
half of the pregnancy.
There are special concerns for the treatment of hypothyroidism relating to the possibilities of thyrotoxicosis
or hypothyroidism in the neonate, with the attendant
concerns for neurodevelopmental delay if not treated.
Neonatal encephalopathy can be a complication of
either hypothyroidism or its treatments.
COMMON
GASTROENTEROLOGICAL
AND LIVER DISORDERS IN
PREGNANCY
Hyperthyroidism
Gastroesophageal reux disease

(GERD)
Hyperthyroidism occurs in 2/1000 pregnancies.

This is most likely (95%) to be due to autoimmune
thyroiditis/Graves disease, due to production of immunoglobulin G (IgG) thyrotropin-receptor-stimulating
autoantibodies, also known as thyroid-stimulating
immunoglobulins (TSIs).
It can rarely be due to multinodular goiter, a functioning solitary nodule, subacute thyroiditis, or a thyroid
carcinoma.
CLINICAL PEARL
The most common explanation for apparent hyperthyroidism in pregnancy, as evidenced by low levels of
thyroid-stimulating hormone, is simply the artifactual
biochemical result induced by beta human chorionic
gonadotropin (beta-hCG).
It is essential to assess women for tremor, tachycardia, nodular thyroid disease, and proptosis, and then
test for functional thyroid concentrations and thyroid
antibodies.
Thyroid disease often decreases in the 2nd and 3rd
trimesters due to changes in maternal immunity, but
worsens again in the puerperium.
As with thyroid disease in non-pregnant individuals, the
mainstay of treatment is with drugs which block the organification of iodine and the coupling of iodotyrosyl molecules.
Propylthiouracil, and carbimazole are the most commonly used drugs.
Both of these agents cross the placenta, although
propylthiouracil seems to do so less readily.
Propylthiouracil also decreases the conversion of T4
to T3, in both the mother and the fetus. As deiodinases II and III are preserved, as long as iodine is
sufficient then fetal brain development is not usually affected.
Monitoring for side-effects is just as important in pregnancy as in the non-pregnant state. Methimazole has
been reported to be associated with esophageal or choanal atresia as well as aplasia cutis when given in early
pregnancy.
As would be the principle in treating any chronic disease in pregnancy, a minimum dose should be used to
control symptoms and signs, with close monitoring and
dose reductions wherever possible.
Control of thyroid function assists with managing
hypertension, and thereby reduces the risk of superimposed preeclampsia.
Dyspepsia in pregnancy is an almost universal symptom.

Some risk factors are independent of pregnancy (e.g. obesity), but include the increase in production of relaxin, estrogen and progesterone in combination, and other relaxing
hormones, which predispose the gastroesophageal junction
to dysfunction resulting in symptoms of heartburn, hunger
pains and chronic chest pain.
Treatment of GERD is problematic, as many treatments, other than delivery of the pregnancy, are not
effective.
Antacid medications are commonly prescribed.
Increasingly, safety around the use of proton-pump
inhibitors is being accumulated. Some studies have
shown a non-significant increase in congenital abnormalities related to omeprazole. The advice at present is
to reserve these medications for those with peptic ulceration and, perhaps, proven blood loss, and to give as late
as possible in the pregnancy.
Constipation and irritable bowel

syndrome (IBS)
The contribution of cyclical hormones to bowel motility is well known, and in pregnancy the effects of sex steroids and known physiological phenomena such as fluid
shifts and increased bowel transit time contribute to clinical
constipation.
Constipation also possibly contributes to the increased
rates of anal fissure, hemorrhoids and anal bleeding
which occur in pregnancy.
IBS is common in women of reproductive age, but there
is no clear evidence of increased rates in pregnancy.
Symptoms can be worse, better or the same in pregnancy. No other complications or sequelae from IBS
have been described in pregnancy.

Inflammatory bowel disease, especially Crohns disease, has
an important impact in pregnancy. Symptoms of Crohns
disease that can be exacerbated by pregnancy include:
chronic diarrhea
rectal bleeding
weight loss
fever
abdominal pain and tenderness (often on the right side
of the lower abdomen)
feeling of a mass or fullness in the lower, right abdomen.
767
Taking into account the lack of predictability of the condition in pregnancy, general wisdom would be to embark
on a pregnancy when the disease is quiescent, when treatment is stable and/or while taking minimal, non-teratogenic
medication. Joint counseling and care between obstetricians
specializing in high-risk obstetrics, gastroenterologists or
obstetric physicians, and colorectal surgeons is often necessary in preparing for and managing a pregnancy. Consideration needs to be given to:
the state of disease activity at the time of the pregnancy
the likelihood that the pregnancy will exacerbate the
condition and what action will be taken if this occurs
the possible effects of the disease on the pregnancy
the possible effects of the disease and treatments on the
baby, including likely prematurity
the possibility of superimposed complications such as
preeclampsia or gestational diabetes if the woman is on
corticosteroids.
Box 26-3
Differential diagnosis of jaundice

in pregnancy
Drug hepatotoxicity (can be seen with alphamethyldopa)

Viral hepatitis
Autoimmune hepatitis (screen for antimitochondrial
antibodies)
Hyperemesis gravidarum (severe)
Cholelithiasis
Cholangiocarcinoma (extremely rare)
Overlap syndromes:
preeclampsia (HELLP syndrome) (liver rupture, and
infarction in rare cases)
acute fatty liver of pregnancy
CLINICAL PEARL
Acute or intrahepatic cholestasis of pregnancy is the
most common cause of jaundice in pregnancy.
This is a condition related to the estrogen glucuronides that

inhibit the bile salt export pump, and thus lead to a cholestatic pattern of liver function test abnormalities. There is an
increased sensitivity of the bile tract membranes and hepatocytes to estrogen and progesterone. There are links to a diet
low in selenium, and it is seen in the winter in temperate climates, in those with HLA-B8/BW16 haplotypes, and with
changes in the ABCB4 phosphatidylcholine bile transporter
gene. This can have effects on bile transport across the placenta, and is thought to contribute to the potential fetotoxicity of the disease.
The condition is more common in those with thyroid
disorders in pregnancy, and with multiple gestation.
It occurs in 2% of all pregnancies, and in those who
have had it once it recurs in 4570% of subsequent
pregnancies.
Any jaundice in pregnancy should provoke a search for
other diagnostic possibilities (Box 26-3).
The diagnosis is confirmed by an increase in bilirubin
concentration, and an increase in the transaminases to
approximately twice normal concentrations.
There is an increase in serum bile acids.
There is often a prolongation of the prothrombin time,
which is responsive to vitamin K.
In interpreting liver function test results in pregnancy,
it is important to remember that they are usually low,
as there is a mild dilutional effect in the 1st and 2nd
trimesters.
The fetal complications are the most worrying feature, and it
is unclear whether sudden fetal demise (stillbirth) is related.
768
For this reason there is a tendency to monitor carefully and

induce delivery at the safest possible time for the baby, usually no later than 38 weeks, although there is no clear consensus. This can occur at an earlier gestation if the jaundice
is severe and the mother intensely symptomatic.
The other complications include preterm labor, fetal
distress, fetal clotting, and meconium aspiration.
It is recommended that fetal monitoring is increased to
twice weekly from 30 weeks of gestation on the advice
of a fetomaternal specialist.
The only proven treatment for the associated pruritus is
ursodeoxycholic acid (UDCA). UDCA reduces sulfated
metabolites of progesterone in serum and stimulates biliary
transport, thereby increasing bile acid clearance.
Other treatments have included guar gum, S-adenosylmethionine, activated charcoal and cholestyramine, but
have been less effective in relieving the itch.
There is no effect of these treatments on improving fetal
outcome.

This is a much rarer, but potentially life-threatening liver
failure, specific to pregnancy.
Risk factors include obesity, abnormal thyroid function, primiparity, multiple pregnancy, and male fetus.
There are crossover syndromes, where acute liver failure
in the setting of hypertension and proteinuria creates
confusion with preeclampsia as an alternative diagnosis.
The condition is due to a defect of intramitochondrial fatty acid oxidation, more specifically longchain 3-hydroxyacyl-CoA dehydrogenase deficiency
(LCHAD) deficiency.
The discovery of these fatty acid oxidation pathway
abnormalities in the offspring of the related pregnancy
has indicated a potential genetic basis for the disease.
CLINICAL PEARL
Presentation of acute fatty liver of pregnancy (AFLP)
is usually with right upper quadrant pain, fever, vomiting, headache, and jaundice. Itch occurs in 30%. Ascites develops in 43%, and necrotizing enterocolitis can
occur, as well as pancreatitis.
The diagnosis is assumed when there is an elevated

white cell count in the setting of jaundice, with elevated
alkaline phosphatase (ALP) in excess of a rise in uric
acid or aspartate transaminase.
The transaminases are typically 310 times the upper
limit of normal, and the serum bilirubin levels are also
elevated.
The identification of hypoglycemia, and its rapid treatment, is an essential part of the treatment.
The maternal mortality is 18% and the fetal mortality
23%, and therefore this condition requires the highest
level of tertiary care and multidisciplinary input. It is
usually managed in an intensive care unit.
Mortality is due to decreased level of consciousness,
liver failure, renal failure, bleeding, and coma.

BuddChiari syndrome (1/1,000,000 pregnancies) is due to
occlusion of the hepatic arteries, and presents in pregnancy
as abdominal pain, ascites and hepatomegaly.
The presentation can be acute, fulminant, chronic, or
asymptomatic.
Approximately 1020% of women also have hepatic
vein thrombosis.
This rarely occurs in the setting of thrombophilia, and
only limited screening for antiphospholipid antibodies
and hematological malignancy is recommended.
CLINICAL PEARL
Any palpable liver is abnormal in pregnancy, as the liver
is normally displaced upwards and to the right, and is
not palpable.
Thrombophilia investigation in pregnancy should include

testing for:
protein S deficiency
protein C deficiency
antithrombin III deficiency
activated protein C resistance (from the factor V Leiden
mutation)
antiphospholipid syndrome (coagulation profile, anticardiolipin antibody and lupus anticoagulant)
prothrombin gene mutation
paroxysmal nocturnal hemoglobinuria (in rarer cases
where clinically indicated).
Treatment requires transfer to a liver treatment hospital/unit
which offers liver transplantation as an option. The mainstay
of initial treatment is anticoagulation, but managing the

pregnancy in the context of progressive liver failure requires
a multidisciplinary team, including a high-level neonatal
nursery in the event of premature delivery.
VIRAL INFECTION IN
PREGNANCY
Although viral infections are no more likely to occur in
pregnancy, they are conditions that require special
consideration.
The effect of the disease on the pregnancy relates to prematurity, usually due to pre-term delivery (spontaneous).
The effects of the infection on the fetus can include
increased rates of stillbirth and congenital abnormality. This is particularly relevant with cytomegalovirus
(CMV) maternal infection, which is second only to
parvovirus and herpes simplex virus (HSV) as the major
viral cause of stillbirth.
Viral hepatitis
In the case of viral hepatitis, the effect of pregnancy on
the disease is the tendency for more severe disease.
The fetal effects can include intrauterine growth restriction (IUGR), except for hepatitis A.
Hepatitis A appears to have no increased rate of spontaneous abortion or stillbirth.
No increase in congenital abnormalities has been
described with viral hepatitis, except CMV where the
complex syndrome includes IUGR, jaundice, hepatosplenomegaly, petechial rash, thrombocytopenic rash,
chorioretinitis and encephalitis. CMV screening is an
important part of 1st trimester pregnancy screening for
this reason.
CLINICAL PEARL
The typical viral screening strategies for early pregnancy include:
T Toxoplasmosis
O Other infections (including syphilis)
R Rubella
C Cytomegalovirus
H Herpes simplex virus and human immunodeciency
virus.
Vertical transmission to the fetus is of major concern,

with other agents as well as CMV. Hepatitis B transmission is of particular public health interest due to a
high burden of disease, and its contribution to lifelong
risk for chronic hepatitis and hepatocellular carcinoma
(HCC).
Investigation of maternal serology is harmless to the fetus,
and is the mainstay of diagnosis of the different possible viral
agents.
Confirmation of neonatal infection is usually undertaken after birth.
769
Diagnostic liver biopsy is no more likely to develop

complications than in the non-pregnant state, but
should only be considered in severe cases where there is
significant diagnostic uncertainty.
Most antiviral treatments are relatively contraindicated in
pregnancy.
IMMUNOLOGICAL AND
HEMATOLOGICAL DISEASE IN
PREGNANCY
Systemic lupus erythematosus is a common disease in the
reproductive-age female population.
The immediate aspects of most relevance to pregnancy
are renal disease, antiphospholipid syndrome, and respiratory complications of the disease.
Functional status of the various organ components in
SLE is essential to determine obstetric risk. The level of
renal dysfunction is especially important.
Creatinine clearance below 30 mL/min/1.73 m2 and
uncontrolled hypertension increase the likelihood of a
poor pregnancy outcome. This level of chronic kidney
disease is more likely with those who have had class 3 and
4 lupus nephritis, and who may have responded initially
to treatment but progressed to renal scarring with time.
The diagnosis of either of these forms of aggressive
inflammatory lupus nephritis during pregnancy creates
the ultimate dilemma for the parents and caring team:
that of the need to terminate the pregnancy in order to
treat the progressive renal disease.
Generally, it would not be considered safe to
administer alkylating agents, nor high-dose corticosteroids, in pregnancy.
In a similar way, chronic pulmonary fibrosis and
poor respiratory reserve would be a relative contraindication to pregnancy, given the need to increase
respiratory function in pregnancy.
Symptomatic relief of lupus arthritis becomes problematic in pregnancy due to the intrinsic unsafe fetal
profile of high-dose continuous corticosteroids (prednisone generally does not cross the placenta but has been
implicated as a contributor to cleft palate in very high
doses), antimetabolites, and even the non-steroidal antiinflammatory drugs (NSAIDS) (premature closure of
the ductus arteriosus, renal adverse drug reactions). For
hydroxychloroquine there is conflicting advice, and the
recommendation is to take only if absolutely essential.

Miscarriage can be a feature of SLE, APS and other thrombophilias, uncontrolled hypertension, chronic kidney disease, infectious diseases, diabetes, drug and alcohol use, as
well as some obstetric and genetic causes which lead to pregnancy loss.
770
CLINICAL PEARL
Late miscarriage (>10 weeks of gestation), 2ndtrimester loss and recurrent miscarriage as well as
early severe preeclampsia are all indicators of possible
antiphospholipid syndrome and should be investigated
accordingly.
The mechanism of pregnancy loss or complication

(miscarriage or preeclampsia) is through antiphospholipid antibody binding to trophoblast in the placenta,
causing microthrombi, which decreases placental perfusion and leads to placental insufficiency. These placentas are smaller, and consist of areas of small infarcts and
calcification.
The placental failure leads to loss in the 2nd trimester
(weeks 1228 weeks of gestation), IUGR, preeclampsia, and placental abruption.
APS is a clinical diagnosis supported by laboratory tests. The
diagnostic criteria include one or more of the following clinical criteria:
arterial, venous or small-vessel thrombosis without
vessel inflammation and not in a superficial vessel
v3 unexplained consecutive miscarriages (<10 weeks of
gestation), excluding anatomical, genetic, infective or
hormonal causes
v1 unexplained death(s) of a morphologically normal
fetus at or after 10 weeks of gestation
v1 premature birth(s) of a morphologically normal neonate at or before 34 weeks of gestation, associated with
severe preeclampsia or severe placental insufficiency,
including IUGR.
Treatment
Pregnant patients with confirmed APS should be fully
anticoagulated.
The risk of recurrent miscarriage in the patient with
APS can be reduced by prophylactic-dose unfractionated heparin, or prophylactic-dose low-molecularweight heparin plus low-dose aspirin.
Idiopathic thrombocytopenic purpura

(ITP)
The normal physiological response to pregnancy is up to
a 30% reduction in platelet count from baseline. An acute
decline of platelet count within the setting of hypertension
or proteinuria is supportive of a diagnosis of preeclampsia. In
the absence of preeclampsia and with >30% drop in platelet
count, ITP should be considered.
The incidence of ITP is 1 in 10,000 pregnancies.
Mild decreases in platelet count are not thought to be
threatening to mother or baby, and can be just watched
carefully.
The neonatal effect of maternal antiplatelet antibodies is largely minimal, and has in some places led to an
increased use of delivery by caesarean section with perception of greater fetal safety. This is not proven.
ITP is only diagnosed with the exclusion of SLE, lupus
anticoagulant and anti-cardiolipin antibody, and in a
setting not suggestive of viral thrombocytopenia.
The risk of bleeding with ITP is very low, and the risk
of neonatal thrombocytopenia is minimal.
In the absence of bleeding, the goal should be monitoring and anticipation of potential bleeding risk.
The general rule of the platelet count needing to be >80
w 109/L does not totally hold up in women with chronic
ITP, and it is likely that 50 w 109/L is sufficient for
delivery and >70 w 109/L for regional anesthesia.

Anemia is common in pregnancy and is contributed to by
the following physiological responses to pregnancy:
iron deficiency in the 1st trimester leads to an increase
in iron absorption in the 2nd and 3rd trimesters
an increased iron requirement in the 2nd and 3rd trimesters (50% increase) due to an increase in fetal uptake
of iron.
The consequences of IDA in any pregnancy are:
preterm delivery
infant small for gestational age (SGA)
inferior neonatal health
reduced ability to withstand the adverse effects of excessive blood loss should they occur during delivery
bleeding during childbirth
a higher risk of requiring transfusion in the postpartum
period
Anemia in multiple sequential pregnancies becomes a compounding problem, with progressive depletion of total body
iron stores. The non-pregnant recommended daily intake
of iron is 18 mg for menstruating women of reproductive
age. In pregnancy the dietary requirement for iron increases
to 27mg/day, which is difficult to achieve by diet alone.
It is routine to measure hemoglobin concentration in
the 1st trimester and then repeat that test at 18 weeks,
28 weeks and 36 weeks of gestation (depending on
the country), in order to monitor the increasing iron
requirements in the latter half of pregnancy and intervene if anemia is progressive.
Appropriate levels of iron supplement (up to 100 mg/
day) are recommended and can be titrated against the
level of anemia.
CARDIAC DISEASE IN
PREGNANCY
Overall, although heart disease is relatively uncommon,
it remains a great concern in pregnancy due to the risk
of maternal death. It is still the biggest contributor of any
chronic medical condition to maternal mortality. The specific entities which are of concern are as follows.
Acquired conditions such as:

cardiomyopathy
postpartum cardiomyopathy
aneurysm/dissection
myocardial infarction
valvular heart disease/rheumatic heart disease.
Congenital disease:
Congenital heart disease is a concern now that children are reaching reproductive age after corrective
surgery.
Non-structural heart disease in the form of arrhythmia is a common feature of pregnancy. Palpitations,
most usually due to a sinus tachycardia, are common in pregnancy. In the absence of any structural
abnormality these do not typically lead to increased
risk of maternal mortality.
The risk of a congenital cardiac lesion in the fetus is
also increased.

Valvular heart disease can be congenital, or acquired through
rheumatic fever.
The most common congenital abnormalities seen in
the pregnant population are patent ductus arteriosus,
atrial septal defect, pulmonary stenosis and ventricular
septal defect.
The rates of these conditions are similar to those seen in
the general female population.
In the advent of corrected major heart disease, such as
tetralogy of Fallot, pregnancy outcomes can be very complicated, depending on the severity of the underlying
heart condition. Treatment strategies should include preconceptual investigation to establish the level of left and
right ventricular function, and history of arrhythmia.
Occasions of heart failure from congenital abnormalities are rare in pregnancy.
Heart failure at the time of delivery is of special concern, and fluid shifts in the immediate postpartum
period need to be carefully monitored.
Rheumatic heart disease is common in some parts of
the world by reason of socioeconomic disadvantage, as
well as other infective factors. Rates have rapidly dropped
in the past 40 years in many developed countries.
The most common valvular lesion of concern is mitral
stenosis, and this is the most frequent cause of heart failure in the setting of chronic rheumatic heart disease in
pregnancy.
The reasons for the increased risk of pulmonary edema
in mitral stenosis are common to all pregnancies, but are
exaggerated in stenotic valvular disease.
CLINICAL PEARL
Contributors to acute pulmonary edema in pregnancy:
increased heart rate preventing ventricular relling
increase in cardiac output
increase in pulmonary blood volume
increase in circulating blood volume.
771
As with congenital heart disease, pre-conceptual care, and

assessment of left and right atrial and ventricular function
and the degree of valve stenosis need to be determined prior
to pregnancy.
The appearance of pulmonary edema is potentially lifethreatening and can be intractable, so needs to be identified and treated early.
Mitral valve stenosis may require surgical intervention
in the pregnancy, and this may be achieved by closed
valvuloplasty.
The other issue with valvular heart disease and the care of
pregnant women who have had artificial valves is prophylaxis for thromboembolism, and endocarditis in selected
cases, especially at delivery, and identification and treatment
of arrhythmias.
The general principle in heart disease is that it is a
pregnancy effect on the disease, with the increasing
fluid volumes, increased cardiac output, and heart
rate that are part of the normal response to pregnancy
causing a risk that the heart with valvular heart disease
canfail.
This is especially true of stenotic valvular lesions, with
the regurgitant lesions faring better in pregnancy.

Arrhythmias are more common in pregnancy, and palpitations occur in 50% of pregnant women although this rate is
close to that in the normal population under 40 years of age.
There is an increased awareness of even the benign
arrhythmias such as sinus tachycardia in pregnancy,
which increases the frequency of complaint.
Sustained arrhythmias are less common and occur in
23/1000.
As indicated above, it is the arrhythmia in the presence
of a structural cardiac abnormality that increases the risk
of maternal morbidity.
Treatment decisions depend on the diagnosis, but also
the duration, frequency and tolerability of the arrhythmias to the mother.
The management of arrhythmias with pharmacotherapy is generally safe, with no clear contraindications.
Some of the highly selective beta-blockers (atenolol) have been associated with a marked reduction in birthweight, and should be replaced by
non-selective beta-blockade unless there is no
alternative.

Other vascular conditions likely to have cardiac consequences in pregnancy relate to those which cause chronic
severe hypertension, such as coarctation of the aorta
(Figure26-1) and reno-vascular disease.
In coarctation of the aorta:
identification of concentric left ventricular hypertrophy
and appropriate pre-pregnancy treatment of hypertension is essential in management of a pregnancy
there needs to be a clear pattern of BP-taking that is
manageable in the pregnancy, with discrepant readings
in the arms or legs identified early
where the coarctation is corrected prior to the pregnancy, sometimes leaving a limited defect, a better outcome can be expected.
Reno-vascular disease causes an early and aggressive form of
preeclampsia.
This can be managed by correction of the stenosis
by arterioplasty of fibromuscular dysplasia in young
womenand can dramatically improve the prognosis
for pregnancy and reduce the risk of preeclampsia.
The only clinical clues for reno-vascular disease are discrepant renal size (detected on renal ultrasound), and a
renal bruit. However, a renal bruit is very difficult to
ascertain in a pregnant abdomen, and sounds of uterine
souffl can confuse the sign.

cardiomyopathy
Biventricular cardiac failure is an uncommon complication of pregnancy.
The most common time for heart failure seen in pregnancy is in the immediate post-partum period, and
relates to a dilated, progressive and aggressive form of
cardiomyopathy.
772
Figure 26-1 Coarctation of the aorta in a pregnant

woman, seen on magnetic resonance imaging. AA,
ascending aorta; DA, descending aorta
From Creasy RK, Resnik R et al. (eds). Creasy and Resniks Maternal
fetal medicine, 7th ed. Philadelphia: Elsevier, 2014.
OBESITY IN PREGNANCY
A special mention needs to be made about the increasing
worldwide trend for obesity in women of reproductive age.
Obesity is a major contributor to conditions which have
altered prognoses for pregnancy:
anovulatory infertility
increased rate of miscarriage
metabolic syndrome and diabetes mellitus
gestational diabetes
chronic hypertension
risk for preeclampsia/gestational hypertension
reduced respiratory function, primary hypoventilation
obstructive sleep apnea and other forms of sleepdisordered breathing
risk of venous thrombosis and pulmonary embolism
increased infective risk
increased risk of hemorrhage
increased risk of caesarean-section-related complications including wound dehiscence
increased rate of obstetric complications
increased intraoperative risk if caesarean section is

required
increased birth risksmacrosomia, shoulder dystocia
and birth trauma, increased rates of congenital abnormalities, fetal death.
NEUROLOGICAL CONDITIONS
IN PREGNANCY
The most common neurological comorbidity managed in
pregnancy is epilepsy.
Although epilepsy does not seem to have an effect on
the course of the pregnancy, it has been associated with
an increased risk of caesarean delivery.
Pregnancy per se can lower the seizure threshold and
increase the frequency of seizures in some patients.
By far the most significant issue is that of appropriate
drug use in pregnancy. There are a significant number
of new anticonvulsants with little long-term data about
their safety in pregnancy.
773
1
Mrs K is a 29-year-old with a history of hypertension since the age of 20 years, who is taking the oral contraceptive
pill. She is admitted to the obstetric ward at 30 weeks of gestation with a decrease in fetal movements, and is noted to
have a blood pressure (BP) of 240/140mmHg. She is otherwise asymptomatic. Mrs K is noted to have 300 mg/day of
proteinuria. Her usual medications are alpha-methyldopa 250 mg three times daily, and labetalol 100 mg three times
daily. Which of the following would not indicate the need to consider delivery of the pregnancy immediately?
A Inability to control the BP with additional intravenous antihypertensive, and magnesium sulfate.
B An increase in urinary protein excretion to 1500 mg/day.
C Sudden onset of headache and neurological irritability (clonus and hyper-reexia) requiring magnesium sulfate.
D Elevation in serum creatinine and transaminases above the normal range.
E A baby that has not grown since the last fetal assessment scan 2 weeks prior to this admission.
A 26-year-old known asthmatic is now pregnant. She has noted an increase in exertional dyspnea in the 3rd trimester
of her pregnancy (she is at 29 weeks of gestation). Her usual medication consists of inhaled budesonide twice daily,
and inhaled salbutamol as required. She has considered changing to combined uticasone/salmeterol, as per her
doctors recommendation. Which additional features of her lung function and capacity, in pregnancy, will inuence
your interpretation of her peak ow, forced expiratory time and FEV1/FVC ratio?
A Peak ow remains unchanged, forced expiratory time is unchanged, and the FEVI/FVC ratio is the same as nonpregnant readings.
B The decrease in respiratory muscle strength and decrease in functional residual volume make the peak ow and
forced expiratory time unhelpful, but increase the reliability of the FEV1/FVC ratio.
C Increase in respiratory rate and decreased residual volume make the partial pressure of carbon dioxide (pCO2) a
much more reliable marker.
D The increase in tidal volume and minute ventilation, make the FEV1/FVC ratio unreliable.
Jennifer is at 24 weeks of gestation in her second pregnancy. In her rst she was noted to have increased blood
pressure (BP) from week 12 and had been treated with labetalol; she is not asthmatic. Her BP remained managed in
that pregnancy, and the delivery was uncomplicated by preeclampsia. In this, her second pregnancy, she has elected to
try alpha-methyldopa for BP control, as she has heard that it is the only category A (i.e. safe) medication in pregnancy.
She has a body mass index of 39 kg/m2 and is known to have had a gallstone identied during an episode of right upper
quadrant (RUQ) abdominal pain 3 months after the birth of her rst child. An attempt to have this surgically corrected
was halted when it was found that she was pregnant again. She now has new-onset RUQ pain and tenderness, and the
results of liver function tests are shown in the following table. Her blood pressure is 130/80 mmHg and her urine shows
190 mg of protein. Her platelet count is 150 w 109/L.
Bilirubin
26 micromol/L
Reference range (RR) 315

micromol/L
Albumin
31 g/L
RR 3647 g/L
201 IU/L
RR 30150 U/L
Gamma glutamyl transpeptidase (GGT)
42 IU/L
RR 30115 U/L
222 IU/L
RR 130 IU/L
260 IU/L
RR 140 IU/L
Which is the most likely diagnosis, and what course of action would be indicated?
A This is an episode of cholecystitis and she needs an abdominal ultrasound.
B This is likely to be an episode of alpha-methyldopa liver toxicity and the drug should be stopped immediately.
C Sclerosing cholangitis is likely, and urgent biliary tract stenting is indicated.
D She has preeclampsia and requires urgent delivery irrespective of the prematurity of the pregnancy.
ANSWERS
1
B.
The markers of severity in terms of deciding the need to deliver urgently at any gestation in preeclampsia are:
i Inability to control the BP to <170/110 mmHg and preferably to at or below 140/90 mmHg.
ii Increase in maternal symptoms, especially seizure.
iii Increase in liver enzymes, indicating cytotoxic edema of the liver (often associated with liver pain and enlargement,
which can lead to liver rupture).
iv Rapidly decreasing platelet count (note whether the platelet count is <30% of baseline).
v Any signicant increase in serum creatinine (remember that serum creatinine is below the normal range in pregnancy
774
(3060 micromol/L). A rise to within the (non-pregnant) reference range can be highly signicant and represent a
serious decrease in glomerular ltration rate (Figure 26-2).
vi A baby that is failing to grow.
vii A baby that shows acute distress (ultrasound criteria and cardiotocographic criteriaconsultation with obstetrician and
neonatologist is required).
Although proteinuria is a marker of disease, i.e. a dening feature for the diagnosis of preeclampsia, it is not a criterion for
delivery per se. Delivery may be required for the rapidly rising creatinine even though the absolute value is still within the
normal range.
Creatinine
90
Generalized normal high
80
mol/L
70
60
50
Generalized normal low
40
01/06/2010 31/08/2010 30/11/2010 01/03/2011 31/05/2011 30/08/2011 29/11/2011 28/02/2012 29/05/2012 28/08/2012
Figure 26-2 Note the dramatic rise in serum creatinine in this graph from a patient with preeclampsia. The
maximum level remains within the normal laboratory reference range, but the change indicates a rapid fall
in glomerular ltration rate
2
A.
Respiratory rate is essentially unchanged in pregnancy, but the increase in tidal volume, minute ventilation and minute
oxygen uptake, and therefore the decrease in functional residual capacity and residual volume, can appear as a
hyperventilatory state in the latter part of the pregnancy. The effect of pregnancy on pCO2 (a decrease), serum bicarbonate
(a decrease) and pH (an increase) reect a chronic respiratory alkalosis which needs to be taken into account when
interpreting blood gases and biochemistry results in pregnant women.
Asthma needs to be identied and treated in pregnancy, and the usual monitors of peak ow, FEV1/FVC ratio and forced
expiratory time remain reliable indicators of disease state in pregnancy. Uncontrolled asthma has been associated with
poor neonatal outcomes and with preeclampsia. Episodes of severe asthma in pregnancy are more likely in those with
initial poor control, and infants small for gestational age are more common in this severe group.
B.
Many women who are fertile are at risk of cholecystitis, and this should be monitored in pregnancy. However, the pattern
of liver function test abnormality, just as in non-pregnant cases, should reect an obstructive jaundice. Her pattern of
hepatocellular damage is consistent with a drug toxicity reaction as is seen in 1/200 cases with alpha-methyldopa. For
this reason the drug should be stopped immediately, and another antihypertensive drug chosen, such as labetalol. It is
unlikely that a new-onset cholangial disease is present in this case, as she has no risk factors (e.g. inammatory bowel
disease). Although she is at risk for preeclampsia, her current investigations are not diagnostic, and she should be watched
for proteinuria (>300 mg/day) symptoms and fetal growth signs of placental dysfunction. Remember that the placenta
produces alkaline phosphatase, which is always elevated in pregnancy.
775
CHAPTER 27
GERIATRIC MEDICINE
Will Browne and Kichu Nair
CHAPTER OUTLINE
INTRODUCTION
EPIDEMIOLOGY OF AGING
AGING AND DISEASE
Theories of aging
PHYSIOLOGY OF AGING
Cardiac changes
Renal changes
Skin changes
PATHOLOGY: DISEASE IN OLDER PEOPLE
INTRODUCTION
The 20th and 21st centuries have been characterized both
by dramatic advances in medical knowledge and by the rapid
growth in the number of people living into old age. Once
a rarity, survival beyond the age of 70 years is now commonplace. Because of the relatively high burden of illness
THE GIANTS OF GERIATRICS

The six Is
The six Ss
ELDER ABUSE
OSTEOPOROSIS
COMPREHENSIVE GERIATRIC ASSESSMENT
HEALTHY AGING

Diet
Exercise
Alcohol use
Adapting to reduced function and independence
FACING THE INEVITABLE WITH DIGNITY

in older people, our hospitals and clinics are looking after
an increasing number of older patients. Hence, all doctors
involved in the care of adult patients need to recognize the
syndromes and presentations of illness in older people.
The special needs of older patients require an understanding of the changes in physiology with advancing age,
and the protean manifestations of disease in this population.
777
AGING AND DISEASE

Both the incidence and the prevalence of diseases
increase with aging.
While congenital and genetic disorders that are associated with premature death are relatively uncommon
among older people, the rates of chronic disease and
degenerative disorders are very high.
Many chronic diseases which develop over adult life are
carried into old age. Consequently, many older people
have a combination of acquired, chronic and degenerative disease that make their medical care complex and
challenging, and therefore rewarding.
A degenerative disease can be thought of as any disease
in which deterioration of the structure or function of tissue occurs. This description would apply to many of the
problems considered common in older people, including some forms of dementia, arteriosclerosis, cancer, and
osteoarthritis.
While much is being learnt about the mechanisms that
underlie these important processes, our ability to treat
them is, in most cases, limited.
Recognition of symptomatic degenerative disorders
allows patients to plan and adapt to changes, and to
weigh up the therapeutic options.
Because degenerative processes occur concurrently in
many tissues and organ systems, degenerative disease
seldom occurs in one system in isolation.
Total fertility rate (children per women)
There is a global shift toward an older population due to

declining fertility rates and increasing life expectancy. This
is known as the demographic shift. Figure 27-1 illustrates
this process.
While more advanced in developed countries, the same
factors drive demographic transition in developing countries, where this represents a significant economic burden.
80
6
60
5
4
40
3
2
1
20
Total fertility rate
Life expectancy at birth
Life expectancy at birth (years)
EPIDEMIOLOGY OF AGING
0
195055 197580 200005 202530 204550
Figure 27-1 Total fertility rate and life expectancy at

birth: world, 19502050
From Population Division, DESA, United Nations. World Population
Ageing 19502050. Geneva: United Nations, 2007.
described below, as well as the increased susceptibility of

many older individuals to a wide variety of pathological
processes.
Evolution and aging

It is likely that some of the diseases and degenerative changes
seen in aging result from the failure of natural selection to
act upon genes and traits that manifest after reproductive life.
As evolutionary processes act largely only until the
conclusion of childbearing, there is little selective pressure
against processes that cause disease in the 50s, 60s, 70s and
beyond. An example might be seen in the case of Alzheimer
diseasea disease with at least some component determined
by genetic factors. While this disease places a heavy burden
on older people, it almost invariably occurs long after reproductive life has concluded, greatly limiting its adverse effects
on natural selection.
Theories of aging
Telomere shortening and mitochondrial

dysfunction
Processes underlying aging
It has been known since the 1960s that human cells in

culture will divide a specific number of times, and then
stop. This process results in progressive shortening of
telomeres in somatic cells.
There is a definite functional link between mitochondria and telomeres. The latter are protective segments
at the ends of chromosomes that shorten with repeated
cellular divisions.
Telomeres have long been thought to play some role in
the senescence of rapidly dividing tissues. The suggestion of a link between them and mitochondria implicates both in some aspects of aging.
Telomere failure may result in impaired mitochondrial
function.
Aging is a complex process, and it has proved challenging to

determine which of the features associated with advanced
age reflect accumulation of the effects of disease, and which
reflect a distinct process caused by tissue senescence and
degeneration. In many cases, both degeneration related to
aging and damage due to disease interact in the same organ
and tissues.
Homeostenosis
Homeostenosis refers to the aging-related loss of reserve
capacity in maintaining homeostasis.
This gradual decline in homeostatic reserve explains
the typical presentation of the geriatric syndromes
778
Chapter 27 Geriatric medicine
Insulin-like growth factor 1 (IGF1) and aging
PHYSIOLOGY OF AGING
Hereditary factors contribute to aging processes, and

there is evidence that IGF1 levels may have an inverse
effect on the rate of aging.
IGF1 pathways are important regulators of lifespan in
animal models. It is likely that IGF1 plays a similar role
in humans, and hence in human aging.
While there is compelling evidence that the process of

homeostenosis (diminished reserve, and compensatory failure) occurs in the absence of specific disease, understanding
changes in normal aging physiology is made more challenging by the problem of distinguishing disease from normal
aging changes.
The changes discussed in the following sections might
be expected to occur in a healthy older individual.
Inammation and aging

Inflammatory conditions are often associated with diseases common in older people, and contribute to sarcopenia and to other phenotypic changes characteristic of
the syndrome of aging.
Inflammation is correlated with diseases of aging, and
markers of inflammation carry some value in stratifying risk for a number of conditions, including heart
disease.
Free radicals and aging

The production of oxyradicals (also called free radicals)
in many tissues, as well as their accumulation, increases
with aging.
Oxyradicals are potentially damaging to cellular structures. They are produced during mitochondrial metabolism, and are scavenged by a number of cellular systems.
Superoxide dismutase, glutathione and catalase all play a
role in the detoxification of oxygen, and variations in the
efficiency of these repair systems may underlie some of
the variable changes of aging seen between individuals.

These disorders, although rare, suggest a genetic role for at
least some aspects of the human aging process. The bestdescribed disorders are Werners syndrome and progeria
(HutchinsonGilford) syndrome. Patients suffering from
these genetic disorders exhibit outward features suggestive
of early aging, including degeneration in numerous tissues,
and a shortened lifespan.
The progeria patient survives to their teens, the Werners patient often to their early 40s.
The genetic basis of these rare disorders has been
elucidated.
Progeria relates to mutation in the nuclear membrane protein Lamin A.
Werners syndrome is caused by mutation to a single
gene named after the syndrome (WRN), which is
both a DNA helicase and an endonuclease.
These disorders are associated with graying of the hair,
osteoporosis, atherosclerosis, and cataracts. However, these
patients do not exhibit all of the diseases or degenerative
changes typical in normal aging, and therefore it seems
likely that they are a facsimile rather than an acceleration of
the aging process itself.
In older individuals there are changes to many aspects of
cardiac and vascular structure and function.
In addition to the changes caused by disease, there is an
increase in heart weight, left ventricular wall thickness,
and hypertrophy in healthy aging.
Of particular importance are the aging-related changes
contributing to the very high prevalence of hypertension among the elderly. These include:
changes in endothelial function
low plasma renin
increasing arterial wall stiffness
changes in body fat percentage and distribution
changes in metabolism and insulin resistance.
Cardiac changes
These include:
left ventricular diastolic dysfunction related to changes
in the extracellular matrix
changes in the mechanical properties of myocytes
increases in mass, weight, and wall thickness of the heart
altered connective tissue, with increased proportions of
collagen and fibrinogen
degenerative changes in the cardiac valves, including
calcification and fatty changes
fibrotic changes of the conducting system
thickening and increasing tortuosity of many of the
major blood vessels.
While these changes generally have only a modest impact
on day-to-day cardiac function, they result in a lowered
threshold for the development of disease. For this reason,
cardiovascular disease is among the most important causes
of serious illness in older people.
Renal changes
There is a progressive decline in renal reserve with
advancing age, which can become clinically important
when an acute illness occurs.
The same changes may have an impact on drug clearance.
The effect of age on glomerular filtration is embodied in
the CockroftGault calculation for estimated creatinine
clearance (eClCr):
eCrCl =
(140 age) mass (in kg) (0.85 if female)

72 serum creatinine (in mg/dL)
779
The decline in renal function with aging is greatly accelerated by the presence of hypertension, diabetes, vascular disease and a variety of nephrotoxic environmental
exposures, including excessive use of analgesics.
Atherosclerotic disease and heart failure are closely associated with decline in renal function in older people,
and it is probable that at least part of the decline in renal
function with aging is due to renal atherosclerosis.
Sarcopenia or progressive loss of muscle mass is typical
in aging, and is one of the components of the important
concept of frailty.
Part of this loss of skeletal muscle tissue is driven by falling levels of androgen.
IGF-1 levels also fall with aging, and interestingly in this
context are associated with greater sarcopenia.
Bed rest is particularly concerning, resulting in an
average loss of 5% of muscle mass per week. The skeletal muscle of aged individuals is particularly likely to
undergo apoptosis or atrophy.
Inflammation is probably contributory to the loss of
muscle mass in many people, and possibly to the aging
process itself.
Numerous neurological changes associated with aging have
been proposed.
At a structural level there is loss of nerve cells, changes in
dendritic function, and alterations in glial cell reactivity.
Some of these changes may relate to accumulation of
protein metabolites. Amyloid-beta accumulates in hippocampal and medial temporal structures in normal
aging but to a far greater extent in Alzheimer disease.
Cognitive changes do occur with aging and can be measured with neuropsychological tests. When severe, such
changes are usually associated with a neurodegenerative
disorder. Milder changes in speed of processing, executive functioning, and memory changes are common and
are usually unassociated with serious dysfunction.
Skin changes
Overlooked perhaps by physicians but seldom by patients,
the skin undergoes important changes with aging.
Even in the absence of drugs like corticosteroids that
accelerate skin thinning, the epidermis becomes progressively thinner with aging.
The inner surface of the skin is normally characterized
by an undulating appearance to microscopy, with projections of epidermal tissue called rete ridges extending
downward into the dermal layer. This distinctive undulation is progressively lost as aging advances.
The epidermis has fewer melanocytes and Langerhans
cells.
The dermis undergoes atrophy. There are fewer fibroblasts, mast cells and blood vessels.
780

The metabolic changes with aging are diverse, and include
changes in tissue turnover, glucose utilization and endocrine function. Despite this, normal function in the absence
of stressors is generally maintained in normal aging. Under
stress, however, reserve capacity is reduced and important
clinical consequences arise accordingly.
Plasma glucose levels are well maintained in normal
aging, while a glucose load causes a substantially higher
plasma glucose level than in younger people.
The production of some hormones may be increased to
compensate for this waning in endocrine function. For
example, levels of follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) increase in healthy older
males in order to maintain serum testosterone.
These are complex, and their association with symptoms
such as constipation is not clear.
Fewer neurons are found in the myenteric plexus, as well
as a reduced response of the bowel to direct stimulation.
Progressively higher collagen deposition is seen in the
left colon, associated with lower rectal compliance.
There is reduced colonic segmental motor coordination.
There is greater binding of plasma endorphins to intestinal receptors.
Fibro-fatty change, and thickening of the internal anal
sphincter, is found.

Reduced physiological reserve, and attenuation of
homeostatic and immunological responses to disease,
can result in significant differences between the presentation of disease in older and younger persons.
Diverse disorders may present with falls, confusion
and other somewhat restricted symptoms, which can
be pragmatically grouped together as the geriatric
syndromes.
PATHOLOGY: DISEASE IN
OLDER PEOPLE
Generally, the numerous diseases that afflict younger patients
exact a burden (often a greater burden) in older people.
Additionally, due to the process of aging and the consequent
degenerative dysfunction and disease, many diseases rare in
the young become important causes of ill health in older
patients (Table 27-1).
THE GIANTS OF GERIATRICS

While the spectrum of disease known to occur in the elderly
person is vast, there are a number of characteristic geriatric
syndromes.
Table 27-1 Important pathologies more common in

older people
ORGAN
SYSTEM
DISEASE
Gastrointestinal
tract
Gastric cancer
Colon cancer
Constipation
Gastroparesis
Pancreatic insufficiency
Intestinal bacterial overgrowth
Diverticulosis
Renal tract

Acute kidney injury
Neurological
system
Delirium
Dementia
Cardiovascular
system
Ischemic heart disease

Hypertension
Dysrhythmias
Congestive heart failure
Peripheral vascular disease
Respiratory
system

Pulmonary brosis
Bone
Osteoporosis
Pagets disease
Endocrine
Skin
Actinic damage
Skin cancer
CLINICAL PEARL
The giants of geriatric syndromes can be remembered
as the 6 Is and as the 6 Ss.
The 6 Is
Infection
Instability
Immobility
Incontinence
Impaired cognition
Iatric
The 6 Ss
Stability
Sarcopenia
Sad (depression)
Sepsis
Sore (pain)
Social isolation
The six Is
Infection
See below under sepsis.
Instability/dizziness
One of the most important symptoms an older person may
bring to a physician is that of instability, or dizziness.
There are four broad groups of disorders which should

be considered when encountering the complaint of
dizziness:
1 Vertigothis symptom predominantly arises from
disorders of the peripheral vestibular symptom,
although important but less common central nervous
system (CNS) disturbances are known.
2 Cerebral hypoperfusionthis symptom arises due
to cardiovascular disturbance or blood pressure dysregulation that causes reduction in cerebral perfusion pressure. This is an extremely common symptom in older
people and is frequently exacerbated by pharmacotherapy for cardiac or other disease.
3 Dysequilibriuma sense of imbalance that occurs
while walking, this presentation is often associated
with gait abnormalities and subcortical movement
disorders.
4 Nonspecific dysequilibriummany older patients
develop considerable anxiety associated with mobilizing, and a fear of falling. The anxiety itself may be the
primary cause of a complaint of dizziness. Sometimes
such symptoms are coupled with other mechanisms
of dizziness. They may be part of a more generalized
anxiety disorder, or a problem that arises after falls have
occurred. The experience of a long period before being
discovered after falling is particularly frightening and
traumatic.
Postural stability is of particular importance in older people,
and waning postural stability should be sought on examination in all older people (Figure 27-2, overleaf). Declining postural stability is particularly a feature of Parkinsons disease,
other disorders of the basal ganglia, and cerebellar disease.
Immobility
Waning mobility is a common syndrome seen in older
people, and most typically is associated with disease.
Changes in mobility are minimal in uncomplicated
aging, and their onset should raise consideration of a
treatable disease.
The frequency of neurodegenerative and musculoskeletal disease results in important changes in gait, postural
reflexes and balance that impair mobility and raise the
frequency of falls.
Impaired mobility may result in the development of
pressure areas (Figure 27-3, overleaf).
Incontinence
Urinary and fecal incontinence are common problems
among older people. Although extremely disruptive to
quality of life, many patients are reluctant to discuss continence problems with their physician. Specific enquiry is an
important part of history taking in the older person.
After identifying the presence of urinary incontinence
on history, further inquiry as to the nature of the symptoms is of diagnostic importance.
Three common presentations of urinary incontinence
are urge, stress and mixed.
781
1. Start here! Previously healthy

person presents following a
fall or falls.
2. History When did the falls occur? Were there

any precipitating factors? Any associated
symptoms? Loss of consciousness? Any concurrent
illness or symptoms? What medications is the
patient taking?
3. Examination General appearance. Can the

patient walk? Any abnormality of gait? Any
truncal or appendicular ataxia? Abnormality of
Rhombergs test? Impairments of vision or
hearing? Cognitive impairment? Neurological
deficits? Abnormalities of peripheral sensation? Is
there orthostatic hypotension?
1. Investigations this is determined by history and

examination. Commonly useful investigations
include: an electrocardiogram, blood count and
film, serum electrolytes, renal function, liver
chemistry, serum 25-hydroxy vitamin D (calcidiol),
serum hydroxycobalamin (B12), serum folate,
thyroid stimulating hormone (TSH), chest X-ray,
bone densitometry.
Figure 27-2 Falls ow diagram
Urge incontinence
This form of incontinence is associated with the urge
to void, which if not expeditiously relieved is associated
with the involuntary loss of large volumes of urine.
Detrusor overactivity is thought to be part of the pathogenesis, but this abnormality can also be found in
asymptomatic older people so does not constitute the
entire explanation for the problem. It can be due to central neurological degeneration, with loss of inhibition to
the bladder, resulting in bladder spasm.
Treatment is with a combination of bladder re-training,
and anticholinergic drugs such as oxybutynin.
Stress incontinence
Possibly the most common form of urinary incontinence, and much more common in women than in
men, this is a problem of loss of urine associated with
activities that raise intravesical pressure.
Activities involving exercise, coughing, laughing or
lifting may be associated with stress incontinence.
It usually results from local tissue damage that results in
loss of support for the urethra.
Treatment is with pelvic floor exercises, or in some cases
surgery.
Figure 27-3 Heel pressure areas, in this case in an
83-year-old woman following an ischemic stroke,
are more frequent in frail patients and those with
impaired mobility
782
Mixed incontinence
Commonly both urge and stress symptoms occur concurrently. While this may represent an overlap disorder, the
underlying pathogenesis remains to be fully elucidated.
Fecal incontinence
This important and disabling symptom rises sharply with
aging, and again requires empathic history-taking to come
to the physicians attention.
Impaired cognition
This broad description incorporates the distinct, though
related, forms of cognitive disorder delirium and dementia.
Cognitive evaluation is an essential component of the
assessment of any older person.
While some less experienced clinicians might shy away
from such an undertaking, fearing that it might be perceived as insulting or threatening to a patient, a good
result is reassuring for both patients and their families.
If the result suggests cognitive impairment, further management including interventions can be implemented.
The Mini Mental Status Examination (MMSE) is the most
commonly used tool. Most importantly, however, the diagnosis of dementia is based on an accurate and corroborative
history.
Delirium
This common condition is defined as an acute disorder of
attention and cognition. The clinical features of delirium are
shown in Box 27-1.
It occurs with high frequency in hospitalized older people, and is also prevalent among many older persons living at home or in residential facilities. So common is
the problem that anybody above the age of 65 with a
medical condition should be considered at risk.
Reports of the incidence of the condition in various environments vary widely, but delirium is probably in excess of 20% among hospitalized persons, and
up to 50% in surgical wards. Frequently, delirium is
unrecognized and hence under-treated, with grave
consequences.
Like dementia, delirium is a clinical diagnosis and investigations, while useful in identifying causes of the delirious state, cannot be used to make a diagnosis of the
syndrome.
Box 27-1
Clinical features of delirium
Acute onset in most cases

Fluctuating level of consciousness
Patients often appear agitated and distracted
Difficulty with concentration, orientation, and attention
Impairment of other cognitive functions such as
memory, visuospatial orientation and language may be
prominent
Patients may have perceptual disturbance, e.g. visual
hallucinations
A wide variety of predisposing causes may be present,
such as febrile illness, drug toxicity, or organ failure
A number of screening tools exist that aid the clinician

in identifying delirium and distinguishing it from other
disorders of awareness and cognition in older people.
If a patient has delirium, the best way to manage the condition is with multicomponent non-pharmacological
intervention. If that fails, a small dose of haloperidol is
effective, and the newer generation of antipsychotics are
not superior to this. However, the drug should be used
in the minimum dose, for the minimal time, with constant review.
Dementia
Progressive decline in cognitive function associated with
disturbance of memory and functional impairment are the
characteristic features of dementia. This disorder of cognition is closely associated with aging, although is not inevitable, even in advanced age.
By far the most common cause of dementia is Alzheimer
disease (see Chapter 19).
Iatric
The waning physiological reserve that is characteristic of the
aging state renders individuals at high risk of disease and of
symptoms that are induced by treatments intended to treat
other disease.
While examples of iatric disease in older people are innumerable, they can be hard to identify, and it is often the
responsibility of the physician with knowledge of the care
of the elderly to identify and manage these problems.
Important examples of iatric conditions of the elderly
are included in Table 27-2 (overleaf). It should be
pointed out that all of the interventions mentioned may
be appropriate, necessary and even life-saving under the
right circumstances. Recognition of iatric complications
remains important, as does the avoidance of unnecessary
interventions and the removal of treatments/medicines
after the need for them has resolved.
The 6 Ss
Stability
Postural instability in the older person may be contributed
to by:
changes in cutaneous sensation
orthostatic hypotension
impaired vision
reduced muscle strength
vestibular disturbance
medications
acute illness
impulsivity/risk-taking behavior.
Changes in stability represent an important risk factor for
falling.
Stability when mobilizing can be assessed by many clinical tools. Two commonly used tests include:
the timed up and go test (Box 27-2, overleaf)
783
Table 27-2 Complications of therapeutic intervention in the elderly
INTERVENTION
IATRIC COMPLICATION
Drugs
SSRIs
Hyponatremia (SIADH), serotonin toxicity
Delirium, urinary retention, prolonged QT interval
Dopamine agonists
Psychosis, compulsive behavior
Antipsychotics
Extrapyramidal effects, prolonged QT interval, lowered seizure threshold
Opiates
Vomiting, constipation, delirium, falls
Edema, constipation
Benzodiazepines
Falls, sedation, worsening delirium, habituation
Cholinesterase inhibitors
Nausea, bradycardia
Loop diuretics
Dehydration, hypokalemia, renal failure, orthostatic hypotension, falls
Thiazide diuretics
Dehydration, hyponatremia, renal failure, orthostatic hypotension, falls
Other
Surgery (any type)
Delirium, urinary retention, falls, de-conditioning, myocardial infarction, stroke, cardiac

arrhythmia, malnutrition, constipation, pressure ulcer, DVT, PE, increased risk of death
Bed rest
De-conditioning, pressure ulcers, pneumonia, increased risk of death, DVT, PE
Indwelling catheter
Urosepsis, delirium, local irritation of the urethra
DVT, deep vein thrombosis; PE, pulmonary embolism; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; SSRIs,
selective serotonin reuptake inhibitors.
Box 27-2
Timed up and go test

1 Equipmentarmchair, tape measure, tape, stop
watch.
2 Begin the test with the patient sitting correctly in a
chair with arms; the patients back should be resting
on the back of the chair.
3 Place a piece of tape or other marker on the oor
3 m away from the chair.
4 Give the instructions On the word GO you will stand
up, walk to the line on the oor, turn around and walk
back to the chair and sit down. Walk at your regular
pace.
5 Start timing on the word GO and stop timing when
the patient is seated again correctly in the chair, with
their back resting on the back of the chair.
6 Normal healthy elderly people usually complete the
task in 10 seconds or less. Very frail or weak elderly
people with poor mobility may take 2 minutes or
more.
A score of v14 seconds has been shown to indicate a
high risk of falls.
the functional reach testa patient with one shoulder

near the wall is asked to extend a fist as far forward as
possible. The patient then tries to lean as far forward
aspossible without taking a step or losing balance. The
patient should be able to bring his or her fist forward by
15 cm (6 inches) or more.
Sarcopenia
Sarcopenia refers to the loss of skeletal muscle mass and
strength associated with aging, and affects about 30% of
people aged 60 and over.
By the 7th/8th decades, maximum muscle strength
decreases by 2040%.
A major loss of skeletal muscle fibers relates to decreased
numbers of motor neurons.
Other factors include:
reduced physical activity
reduced hormone levels, e.g. testosterone
protein/energy malnutrition
chronic inflammatory states.
Sad (depression)
Depression is a common cause of morbidity and mortality
in the elderly.
784
Table 27-3 Treatment of depression in the elderly
MODE OF THERAPY
COMMENT
Psychotherapy, e.g. cognitivebehavioral therapy

Interpersonal therapy
Problem-solving therapy
Started at diagnosis, and continued for 612 months after induction

of remission
Second-line agents
Include venlafaxine, duloxetine or mirtazapine
Have a poor side-effect prole, and should be avoided
St Johns wort
Causes numerous interactions, photosensitivity and hypomania, and

should be avoided
ECT (electroconvulsive therapy)
Is generally safe and effective

Should be considered if drugs not safe/ tolerated/effective, if rapid
response is needed, with psychotic depression, or with catatonia
Olanzapine
Can be added to SSRIs for psychotic depression (ECT is rst-line

therapy)
Risk factors include:

female gender
loss or adverse life experiences
medical disorders, e.g. stroke, cardiovascular disease
prior depression/mental illness.
Neurodegenerative disease is associated with depression.
Temporal lobe atrophy and white matter lesions visible
on magnetic resonance imaging may be associated with
major depression.
Depression in the elderly can resemble dementia (this is
known as pseudo-dementia).
Treatment includes the options listed in Table 27-3.
Sepsis (infection)
Sepsis is common in the older patient population, and has
more serious consequences than in younger people.
Severe sepsis in older people is independently associated
with substantial and persistent new cognitive impairment, and functional disability among survivors.
Alterations in immune function, changes in the efficiency of mucosal barriers, alterations in urinary excretion, and changes to swallowing function all predispose
the older patient to the risk of infection. The alterations
in immune response, however, may make diagnosis of
this problem more difficult. Fever and leukocytosis may
be absent, and the patient may present with a fall, delirium or malaise.
Immunosenescence refers to changes in innate and
adaptive immune responses with aging:
aging results in alterations in the function of Tolllike receptors (TLRs), a pattern-recognitionreceptor family of the innate immune system
human TLR function is impaired in the context of

aging
there is inappropriate persistence of TLR activation
in sepsis
advanced age leads to functional changes in the
neutrophil, macrophage, dendritic cell, natural
killer cell, and cytotoxic T-cell populations.
Important causes of sepsis in older people include:
pneumonia
urinary tract infection
influenza
diverticulitis
biliary tract infection
tuberculosis (this remains important worldwide).
Sore (pain)
Pain is a frequent problem in older people and should be
specifically sought in each patient encounter.
Many older people are reluctant to discuss problems of
pain and may feel these are normal consequences of
aging. Pain should not, however, be ignored in patient
care.
The management of pain is similar to that in younger
people and includes remediation of underlying disease if
possible.
Older patients have significantly greater risk of adverse
reactions to analgesic medications, and the patients
individual needs, preferences and risk factors for complications from treatment should be incorporated in
selection of pharmacotherapy.
785
High rates of renal and hepatic impairment in older

persons may limit the use of certain medications or the
doses needed for effective relief.
will experience an osteoporotic fracture over their lifetime, and 20% of Caucasian men.
Rates of osteoporosis and fracture rise progressively
with age.
Social isolation
Social isolation represents an important barrier to independence and maintaining healthcare.
Factors contributing to social isolation in older people
include:
reduced mobility
inability to drive
hearing and visual impairment
death of spouse, friends
retirement from work
cognitive impairment.
Encouraging and facilitating older people to participate
in group activities can improve the quality of life and
sense of wellbeing.
The use of personal alarms is valuable in older people
who live at home and who may be unable to obtain help
in the event of a fall or sudden illness.
ELDER ABUSE
This is a far more common occurrence than is often appreciated, and like child abuse is often insidious and hidden.
However, unlike child abuse where systems (albeit imperfect) exist for identification of the problem, older victims of
abuse are vulnerable and in many cases a legal channel for
their protection does not exist.
Physical abuse certainly occurs, but far more often there
is financial abuse with the patients assets and control over
the patients own affairs removed by others. Often the victims of this abuse have cognitive impairment or are dependent upon their abusers for some form of assistance. Like
many victims of abuse they are often ashamed, and fearful of
the situation in which they find themselves.
Clinicians should be vigilant for the possibility of abuse,
and should consider asking patients directly whether they
feel safe, and whether they feel they have lost control of their
lives. Relatives or friends behaving in an odd or inappropriate way to hospital staff during a patients stay, placing
unreasonable or dangerous demands on the patient, or providing conflicting information about the patients situation
and function, can be clues to an abusive relationship.
OSTEOPOROSIS
Osteoporosis is a common disorder of older people.
The prevalence is higher in women than in men, but is
common among older persons of both genders.
Frequent sites of osteoporotic fractures are the hips,
radius of the forearm, and the vertebrae. Half of women
786
COMPREHENSIVE GERIATRIC
ASSESSMENT
This refers to a comprehensive clinical evaluation of an older
person, incorporating elements of history and examination
that address the geriatric syndromes outlined earlier in this
chapter.
Such evaluations incorporate an assessment of cognition,
mobility, self-care, social supports and a review of medication use. Functional assessment is the principal focus of such
reviews.

While physicians working in any area of medicine attest to
the enduring importance of physical examination in diagnosis and care, this is more true of the care of the older patient
than under any other circumstance.
The protean nature of the presentation of geriatric disease, as depicted by the syndromic geriatric giants, the
extraordinarily high rates of undiagnosed and clinically relevant pathology, and the broad nature of differential diagnosis for many of the syndromes mentioned mandate physical
examination as the tool by which a rational plan of investigation, diagnosis and treatment may be formulated.
The key is a methodical and thorough approach that
includes examination of the joints, oral mucosa, fundus, ear
canal, visual acuity, a thorough neurological examination
including observation of gait, screening tests of mood and
cognitive function, and cardiovascular, respiratory and gastrointestinal examinations. The measurement of pulse and
blood pressure should be attempted in lying and standing as
well as seated positions.
All older people should have a functional assessment, regardless of the setting in which they are seen.
By convention, this assessment is typically divided into
two distinct areas of functional performance. These
are the activities of daily living (ADLs; Box 27-3) and the
instrumental activities of daily living (IADLs; Box 27-4).
Assessing these abilities is vital to assisting patients and
their families to organize support at home as, and when,
needed.
This form of assessment also serves as a guide when providing advice regarding whether a person is safe to stay
at home, and in particular whether they need help with
ADLs.
Box 27-3
attributable to disease is both common and potentially

remediable.
Activities of daily living

This important group of functional skills may be
conveniently remembered with the somewhat ironic
acronym DEATH:
D Dressing
E Eating
A Ambulating
Diet
In Western societies the problems of overnutrition and obesity are common, and the focus of popular concern and
attention.
While obesity remains a serious problem among older
people, the incidence of malnutrition becomes increasingly
important.
T Toileting
H Hygiene

Box 27-4
Instrumental activities of daily living

The IADLs are best remembered with the acronym
SHAFT:
S Shopping
H Housework
A Accounting
F Food
T Transport
HEALTHY AGING
Healthy aging refers to the avoidance of preventable diseases, the maintenance of function, adaptation to age-related
reduction in function, and compression of morbidity to the
final period of life.
This is the principle objective of geriatric medicine,
rather than life extension per se.

Attention to lifestyle factors which influence the prevalence
and progression of disease remains very important throughout life.
Even in older people, avoidance of smoking coupled
with good diet, exercise and sleep habits can have an
important influence on survival and quality of life.
These issues should be addressed in all older patients.
Smoking cessation remains important even in older
patients, and the notion among patients and physicians
that its too late to matter is incorrect.
Smoking-related illness is very frequently encountered
in clinical practice, and significant functional limitation
Nutritional deficiencies occur with greater frequency in

the elderly in comparison with younger populations.
This greater risk results from the increased metabolic
demands of chronic disease and the reduced intake of
food due to poor health, dental disease, depression, cognitive impairment and reduced appetite due to medications and concurrent illness.
Deficiencies in macronutrients, protein and energy
contribute to sarcopenia and frailty in the elderly.
Social isolation and poverty also contribute to nutritional problems in older persons.
Micronutrient deficiencies result from malabsorption,
poor diet, and altered metabolic demands.
A nutritional assessment should be considered in all
older persons.
Exercise
Exercise is beneficial in older people and is associated
with improved management of chronic disease and
quality of life.
Both aerobic activities (which place demand on the
cardiovascular and respiratory systems, such as walking
and swimming) and resistance exercises (such as weight
training) have been shown to be beneficial. Such benefits include reduced risk of depression, improved cognitive performance, fewer falls, and improvement in
balance and bone density.
Tai chi has been shown to be associated with a reduced
risk of falls in older people.
Alcohol use
Alcohol misuse in older people is not rare, and is compounded in its adverse effects by the effects of aging and
comorbid illness on cognition and mobility.
Specific questions regarding alcohol intake should form
part of the evaluation of older people, and counseling
and support is often needed to assist older people to successfully address problem drinking.
787

The use of habituating prescribed drugs represents a serious
threat to the safety of older people.
Temazepam and other benzodiazepines are known to
increase falls risk. Such medications are frequently associated with dependency, and withdrawal can be complicated by serious adverse effects including seizures,
agitation and delirium.
Drugs with known psychotropic effects should be
avoided wherever possible due to the risk of falls and
other adverse effects on cognition.
FACING THE INEVITABLE

WITH DIGNITY
End-of-life issues often arise during the care of older
people, and the thoughtful management of care for
patients with a terminal illness should be seen as part of
the normal scope of geriatric medical practice.
While the general approach to the dying older person is
similar to that of other patients, changes in drug metabolism and other degenerative changes make adequate
management of symptoms especially challenging.
Adapting to reduced function and

independence
Successful aging incorporates the adaption of patients

to changes in health and function as a consequence of
growing older.
The preference of many patients is to remain in their
own homes rather than enter into residential care
facilities.
Healthcare providers can assist patients in a variety
of ways to make the required adaptations. Examples
include:
the use of walking aids such as sticks and walking
frames, which should preferably be provided with
the assistance of an experienced mobility therapist
the use of rails for stairways and in toilet and bathroom environments
avoidance of clutter, floor covers, etc., that pose a
tripping hazard
the use of appropriate footwear and vision aids
the use of a shower chair
the provision of services assisting with meal preparation, cleaning, shopping and self-care.
It is important where possible to discuss end-of-life issues

with patients, and this is especially applicable to older patients
who may have specific wishes regarding their end-of-life
care and any limits to care they might wish to be enforced.
While physicians and sometimes families may be reticent regarding discussion of dying and related issues,
many older people welcome the opportunity and prefer
to be involved in decisions relating to this issue.
An advance care plan communicates a patients wishes
with regard to medical care in the event that they should
be unable to express these. It is intended to prevent the
administration of treatments at odds with the patients
wishes and values. Such a plan may be expressed verbally
or in writing.
A living will is a form of advance care plan detailing a
persons wishes with regard to treatment under a variety
of circumstances. Many countries have laws that cause
this document to be legally binding to various degrees.
Physicians have an ethical responsibility to respect a living will where possible.
788
1
A 75-year-old male presents with worsening self-care. He is brought in by his daughter. Symptoms began 18 months
ago when his daughter noticed that her father was not remembering details of conversations. He has neglected to
attend medical appointments recently, and his blood pressure control has deteriorated. He denies low mood. His blood
pressure is 170/80mmHg. Over the past 6 months, the patients daughter has taken over payment of his bills. Which of
the following statements is correct in this case?
A Magnetic resonance imaging (MRI) of the brain should allow diagnostic conrmation.
B The patient should be commenced on a low-dose selective serotonin reuptake inhibitor (SSRI) antidepressant.
C Aggressive blood pressure control will reverse the cognitive decits.
D The patient should be commenced on risperidone 0.5 mg at night.
E Discussion of strategies to manage current and future deterioration in memory is indicated.
An 80-year-old woman undergoes elective hip replacement for the management of disabling osteoarthritis. She
has a background of diet-controlled type 2 diabetes mellitus, hypertension, and mild cognitive impairment/minor
neurocognitive disorder. Two days after her surgery she becomes agitated, attempting to hit nursing staff attending
to her care, and refusing food and medications. She claims the nursing staff are trying to poison her. Symptoms of
confusion are noticeably worse at night, and have improved by morning. She sleeps and is drowsy and confused for
much of the following day, but becomes agitated and aggressive again late in the afternoon. Her family say that she
was forgetful at times before her surgery, but she was able to function essentially as normal. What is the most likely
diagnosis?
A Lewy body disease
B Psychotic depression
C Alzheimer disease
D Manic phase of bipolar disorder
E Acute delirium
A 79-year-old man is reviewed in the clinic because of recurrent falls. He has depression and was recently started on a
selective serotonin reuptake inhibitor (SSRI) antidepressant with signicant improvement in his symptoms and quality
of life. He still experiences sleep disturbance. His serum 1,25-dihydroxycholecalciferol level is 65 pg/mL (156 pmol/L).
His only medications are the antidepressant and a vitamin D supplement (1000 IU/day). Physical examination reveals
the absence of orthostatic hypotension, a blood pressure of 130/70 mmHg, a normal cardiovascular examination, mild
proximal weakness, and difficulty rising from a seated position without the use of the arms. He has impaired standing
balance. He walks with a narrow-based, cautious gait, and tends to reach for furniture to steady himself. Which of the
following interventions is most likely to reduce the risk of a subsequent fall in this patient?
A A program that integrates balance and strength training into everyday home activities (functional exercise).
B Increase in the dose of serum vitamin D supplementation to 2000 IU/day.
C Commencement of low-dose benzodiazepine at night to improve sleep quality and duration.
D Stopping the SSRI and commencing a tricyclic antidepressant.
E A trial of levodopa/carbidopa combination.
4 A 70-year-old woman presents to her family physician with the complaint of new-onset urinary incontinence. She
describes the sudden strong urge to urinate and nds that if she is unable to quickly reach a toilet she will involuntarily
void a large volume of urine. She is embarrassed by this problem, and has stopped attending her local church and
caring for her grandchildren as a consequence. She has the background problems of hypertension, ischemic heart
disease, and type 2 diabetes mellitus. Her blood sugars have been well controlled on her current medication and with
the implementation of a modied diet and exercise program. Her current medications include indapamide, aspirin,
metoprolol, metformin, perindopril and atorvastatin. She is an ex-smoker of some 20 pack-years, and consumes a
glass of wine most evenings. She was recently widowed, and has three supportive adult children. On examination
she is a well-looking woman. Her body mass index is 31 kg/m2. Her blood pressure is 120/80 mmHg and heart rate is
65 beats/min. The remainder of her physical examination is normal. Urinalysis is normal. What is the next step in the
management of this patients incontinence?
A Commence oxybutynin.
B Ask the patient to complete a voiding and uid intake diary.
C Refer patient for pelvic-oor exercises.
D Refer patient for urodynamic studies.
E Counsel patient to lose weight by diet modication and exercise.
789
ANSWERS
1
E.
The utilization of memory strategies in the setting of milder degrees of dementia can be helpful. In this case, the use of
medication dosing devices, calendars, residential nursing support and automated reminder messages can assist patient
safety. One possible reason for the patients worsening blood pressure is the loss of adherence due to worsening memory
impairment.
This patient most likely has Alzheimer dementia. While MRI can be helpful to rule out alternative diagnoses, it is not
possible to make a specic diagnosis on imaging alone. Antidepressant medications can be helpful in the management
of major depression in the elderly, with SSRIs currently considered the agents of choice. Depression can also mimic
the features of a dementing illness in some patients. However, this patient does not have clinical features supporting a
diagnosis of depression. Management of hypertension is an important goal of care, but is unlikely to reverse the patients
cognitive disturbance. Risperidone can be useful for managing psychotic symptoms complicating a dementing illness.
However, this patient does not have a history suggesting psychosis.
E.
This patients presentation is most consistent with an episode of acute agitated delirium. This common neurological
disturbance is frequent in hospitalized patients. The CAM (Confusion Assessment Method) is a validated tool for identifying
cases. Diagnostic features captured in this clinical tool include:
i acute onset and uctuating course
ii inattention
iii altered level of consciousness
iv disorganized thinking.
Psychotic depression can be associated with altered behavior and delusions. However, the acute nature of this change
in the setting of recent surgery suggests this is not the most likely cause of this patients symptoms. Alzheimer disease is
frequently associated with psychotic symptoms. This is seldom the presenting feature of this form of dementia, however.
Furthermore, the acuity of the patients behavior change argues against the more indolent progression of a pure dementia.
An underlying cognitive disorder, perhaps mild Alzheimer disease or mild cognitive impairment, is a major risk factor for
the development of delirium. Mania is associated with agitation and altered behavior, but its manifestation for the rst time
in an elderly person would be unlikely.
A.
Strength and balance training integrated with daily activities, also called functional training, has been demonstrated to
lower the risk of falls in community-dwelling older people by as much as 30%.
While treating vitamin D deciency has been shown to reduce the risk of falls, this patients level is already acceptable
and is unlikely to improve with the provision of further supplementation. Benzodiazepines can increase the risk of falls
and should be avoided if possible. Tricyclics are generally less well tolerated than SSRIs. This patients depressive illness is
responding to his current agent and there is no indication for a change at this time. This man has a cautious and unsteady
gait and does not have features of Parkinsons disease. The use of levodopa/carbidopa is therefore not indicated.
4 B.
The next step in the evaluation of this patients new-onset symptoms is asking the patient to complete a voiding and
uid intake diary. Correlation of the timing of episodes of incontinence with the amount and type of uids consumed,
and association or otherwise with activities and medications, can often yield potential strategies to reduce or prevent the
problem.
This patients symptoms suggest the onset of urge incontinence, associated with detrusor instability and increased bladder
sensation. Oxybutynin and other anticholinergic agents can be useful in managing these symptoms, but their use should
not precede evaluation of the problem. Pelvic oor exercises can improve symptoms in patients with mixed or stress
incontinence. They are less likely to be helpful in this patient with predominant urge symptoms, and their use should not
precede evaluation of the complaint. Urodynamic studies are helpful in the evaluation of selected patients with urinary
incontinence, but are time-consuming and expensive. They would be indicated in patients with prior or planned surgery
to the urogenital system, or in patients where the diagnosis remained unclear after an appropriate evaluation. Weight loss
with diet and exercise is a desirable goal in this patient with a body mass index of 31, and can improve urinary incontinence
symptoms. However, this patient has already engaged in such a program.
790
INDEX
A
A1AT deficiency see alpha-1 anti-trypsin
deficiency
Aa gradient 118
abdominal computed tomography
initial image review with 87
key image review with 87, 889t
patient demographics in 86
principles of interpretation in 86, 86b
review areas for 90
systematic review with 90
technical review for 867, 87t
techniques of examination using 856, 85t
abnormal uterine bleeding 74950
ABPA see allergic bronchopulmonary
aspergillosis
abscess 671t
Absidia 667
absolute effect 9
absolute risk reduction 9, 10f
AC see allergic conjunctivitis
acalculous cholecystitis 401, 401b
acanthosis nigricans 719, 719f
accuracy 5, 11
ACEIs see angiotensin-converting enzyme
inhibitors
acetaminophen (paracetamol) 394
toxicology of 445, 45f, 46t
acetazolamide 601
achalasia 3201
acid toxicology 49
acidbase disorders 114
pulmonary 120
Acinetobacter 676
acne 715
acquired immune deficiency syndrome
(AIDS) 5449, 546b, 547b, 547f, 548t,
550t
acquired kidney cystic disease 2348, 235b,
236b
acral lentiginous melanoma 480
acromegaly 2734, 274f
activities of daily living (ADLs) 787b
acute coronary syndromes
management of NSTEACS/NSTEMI
1801
management of STEMI 17980, 179f
pathophysiology of 1789
pharmacological therapy in 181
terminology 1778, 177f, 178b
acute disseminated encephalomyelitis
(ADEM) 634
acute dystonias 656
acute fatty liver of pregnancy (AFLP) 7689
acute fever
common causes of 682t
management of 681t
acute intermittent porphyria (AIP) 400
acute interstitial nephritis (AIN) 258
acute interstitialground-glass opacity, chest

X-rays for 78t
acute kidney injury (AKI) 257
acute liver failure (ALF) 3923, 392b
acute low back pain 5857, 585t, 586b, 587b,
587f
acute lymphoblastic leukemia (ALL) 429
acute myeloid leukemia (AML) 4268, 427f,
427t, 428t
acute pericarditis 21112
acute promyelocytic leukemia (APML)
4289
acute pulmonary edema, chest X-rays for 79t
acute renal failure 257
acute respiratory distress syndrome (ARDS)
1457, 145f
acyclovir 34t, 664, 678
AD see Alzheimer disease; atopic dermatitis
Addisonian crisis 465
Addisons disease 288, 288f, 315, 721f
ADE see adverse drug event
ADEM see acute disseminated
encephalomyelitis
adenovirus 666
ADLs see activities of daily living
ADPCKD see autosomal dominant polycystic
kidney disease
ADR see adverse drug reactions
adrenal disorders
adrenal insufficiency 2879, 288f
congenital adrenal hyperplasia 2923, 293f
cortisol excess 28990, 290f, 315
incidentaloma 2934, 294f
pheochromocytoma 2912
physiology and assessment of 287, 287f
primary hyperaldosteronism 2901
adult-onset Stills disease 569
advance care planning 788
adverse drug event (ADE) 38
adverse drug reactions (ADR) 389
DoTS and EIDOS for describing 39b
Naranjo score for assessing 40b
type A (augmented) 39
type B (bizarre) 39
aeration, chest X-rays for 73b, 74
AF see atrial fibrillation
AFLP see acute fatty liver of pregnancy
aging
acceleration of 779
disease and 7789
free radicals and 779
healthy 7878
infertility and 744
inflammation and 779
physiology of 77980
theories of 7789
see also elderly care
agonist 35
AICA infarction 622

AIDS see acquired immune deficiency
syndrome
AIH see autoimmune hepatitis
AIN see acute interstitial nephritis
AIP see acute intermittent porphyria;
autoimmune pancreatitis
air bronchogram 80t
airway cilia 123
airways diseases
ABPA 126, 126f
asthma 1246, 150, 765
bronchiectasis 1267, 127f
bronchiolitis 1278, 128f
COPD 115, 117, 1289, 150, 151
cystic fibrosis 127
granulomatous ILD 1323
interstitial lung disease 12930, 130b
occupational lung disease 1301, 131f
akathisia 656
AKI see acute kidney injury
alcohol 637t
elderly use of 787
liver and 394, 395b
alcoholic cardiomyopathy 190t, 191
aldosterone deficiency 287
ALF see acute liver failure
alkalis toxicology 49
ALL see acute lymphoblastic leukemia
allergic bronchopulmonary aspergillosis
(ABPA) 126, 126f
allergic conjunctivitis (AC) 51012, 511b,
511f, 512b
allergic disease
allergic rhinitis and allergic conjunctivitis
51012, 511b, 511f, 512b
anaphylaxis 50910, 509b
atopic dermatitis 51315, 514f
chronic rhinosinusitis 51213, 513b
drug allergy 51920, 520f, 520t
food allergy 51516, 515b, 704
insect venom allergy 5201
urticaria and angioedema 51619, 516f,
517b, 517f, 518t
allergic rhinitis (AR) 51012, 511b, 511f,
512b
allergy
beta-lactams 6723
egg 704
allopurinol 34t
alpha-1 anti-trypsin (A1AT) deficiency 397
alpha-hemolytic streptococci 663
Alports disease 239
alteplase 603
Alzheimer disease (AD) 608
amantadine, for Parkinsons disease 626
ambulatory reflux monitoring 321
amebic liver abscess 3323
aminoglycosides 34t, 673, 674t
791
Index
amitriptyline, for migraine 599
AML see acute myeloid leukemia
amoxycillin 672t
amphetamines 478, 48t
ampholenes 681
amphotericin B 666
ampicillin 672t
anaphylactoid reaction 45
anatomical shunt 119
androgen deficiency 287
androgen replacement therapy 298
anemia
anemia of chronic disease 442
approach to iron-deficiency 4402, 442b
drug-induced hemolysis 450
hemolytic anemias 44550, 446t, 447t,
448f, 449t
iron-deficiency 358, 771
laboratory tests for 440, 441t
macrocytic anemias 4435, 444f
management of iron deficiency 442
mechanisms of 440, 440f
non-immune acquired hemolytic anemias
450
sideroblastic anemias 443
thalassemias 4423
angina 747
angiodysplasias 3578
angioedema 51619, 516f, 517b, 517f, 518t
angiomyolipomas 234
angiotensin-converting enzyme inhibitors
(ACEIs) 175, 181
ankylosing spondylitis (AS) 5667, 566f, 567f
anorexia 4967, 654
anovulatory infertility 7445
antagonist 35, 675
anterior ischemic optic neuropathy 735f
anterior-to-posterior position (AP) 72, 74t
anthrax 702t
anti-anginal agents 176
antibiotics 6717
choice of 670
judicious use of 697
resistance 677, 677t
anticholinergics 628
for Parkinsons disease 626
syndrome 657t
anticonvulsant therapy 6556
for epilepsy 616, 617t
antidepressants 6567
antiemetics 622
antifibrinolytic agents 750
antifungals 67981, 680t
anti-GBM disease 244, 244b
antigen detection 661
anti-infective agents 67181
anti-infective treatment 66871
anti-inflammatory agents 141
antiphospholipid syndrome (APS) 41213,
533, 533b, 770
antiplatelet agents 174, 181
antipsychotics
atypical 656
typical 656
antiretrovirals 637t
antiviral agents 678
anxiety disorders 652
aorta, coarctation of 772f
aortic arch, chest CT of 82b, 83t, 84
aortic regurgitation (AR) 182t, 1878, 189t
aortic stenosis (AS) 182t, 1857, 189t
AP see anterior-to-posterior position
APML see acute promyelocytic leukemia
792
apneas
central sleep 143
obstructive sleep 122, 1423
apomorphine, for Parkinsons disease 626
apoproteins 16870, 169t
APS see antiphospholipid syndrome
AR see allergic rhinitis; aortic regurgitation
ARCM see arrhythmogenic right-ventricular
cardiomyopathy
ARDS see acute respiratory distress syndrome
arrhythmias 772
ventricular 2001, 201f
see also cardiac arrhythmias
arrhythmogenic right-ventricular
cardiomyopathy (ARCM) 193t, 194
arteritis 735
giant-cell 5346, 535b
PAN 535b, 536, 536b
Takayasu 535b, 536
AS see ankylosing spondylitis; aortic stenosis
asbestosis 130, 131f
ascites 3857, 386t
Ashermans syndrome 745
Aspergillus 667
aspirin 174, 181
asplenia 706
asthma
definition 124
differential diagnosis 1245
intermittent 125
management of chronic 125
in pregnancy 765
signs of severe exacerbation of 125, 150
treatment of 1256
asymptomatic myeloma 438
ataxiatelangiectasia 723
atelectasis, chest X-rays for 76t
atenolol 34t
atopic dermatitis (AD) 51315, 514f
atrial appendage occlusion devices 199
atrial fibrillation (AF) 197200, 197f, 198f,
200t, 602
atrial flutter 1967, 197f
atrophic vaginitis 753
atypical pneumonias 137t
aura, migraine 597
auscultation 731
autocrine action 268
autoimmune hepatitis (AIH) 398
autoimmune pancreatitis (AIP) 3623, 363b
autoimmunity 507
autoimmune diseases of skin 71522
autoimmune liver diseases 3989, 399t
pancreatitis 3623, 363b
PGA syndromes 303
thyroid 276
autoinflammatory disorders 5401
autosomal dominant 62
autosomal dominant polycystic kidney disease
(ADPCKD) 2324, 233f
autosomal recessive 62
autosomal recessive polycystic disease 234
azithromycin 674t, 675
azoles 67981
aztreonam 671
B
back pain
acute lower 5857, 585t, 586b, 587b, 587f
chronic lower 5878, 588b
baclofen 34t, 628
bacterial pulmonary infections 133b, 134
bacterial vaginosis 690
Bacteroides fragilis 664

balance 61823
Barretts esophagus 322
barrier methods of contraception 748
Bartter syndrome 291
basal ganglia, head CT for 95b, 100t, 101
basilar-type migraine 598
BBB see bundle branch block
BCS see BuddChiari syndrome
Beggs pharmacokinetic triangle 31f
Behets disease 535b, 53940, 540f, 635
benign paroxysmal positional vertigo (BPPV)
6201
benzodiazepines 628, 656
toxicology of 47
berylliosis 1301
beta-adrenergic blockers 175
beta-adrenoceptor agonists 141
beta-blockers 656
antidote for poison from 44t
for migraine 599
betahistine 622
beta-interferons 633t
beta-lactams 6713
activity of 672t
allergy 6723
BHR see bronchial hyper-responsiveness
bi-level positive airway pressure (BPAP) 147
biliary tree 4001, 401b
bilirubin metabolism 3747, 375b, 376f, 377t
biological agents 51, 52b
BL see Burkitts lymphoma
bladder tumors 46970
Blastomyces dermatitidis 668
bleeding disorders
causes of 414b
clinical presentation of 414t
coagulation factors deficiencies causing
417
ecchymoses and hemarthrosis with 414f
hemophilia A 41617, 416t
hemophilia B 417
von Willebrand disease 41415, 415t
blinding 7
blood pressure lowering, stroke prevention
and 605
blood vessels, hypertensions effects on 222
body temperature 6601
bone and mineral metabolism disorders
hypercalcemia 2813, 283b
hypocalcemia 2834, 284b, 284f
mineral homeostasis 281
osteomalacia and rickets 2856, 285t, 286t
osteoporosis 2845, 284b
Pagets disease 2867
booster doses 704, 705
Borrelia burgdorferi 693
botulinum toxin 599
botulism 707
bowel cancer screening 3535, 355f
BPAP see bi-level positive airway pressure
BPPV see benign paroxysmal positional
vertigo
bradykinesia 624
brain
hypertensions effects on 224
tumors 47980, 480t
brain CT see head computed tomography
breast cancer 4824, 482t, 747
breastfeeding 704, 756
bronchial hyper-responsiveness (BHR) 124
bronchitis, chronic 129
bronchodilators 141
Index
BuddChiari syndrome (BCS) 396, 396b
bulimia nervosa 654
bullous lesions 71718
bullous pemphigoid 718, 718f
bundle branch block (BBB) 2012, 202f
Burkitts lymphoma (BL) 435
bystander drug exposure 36
C
CA see cardiac arrest
cachexia 4967
CAD see coronary artery disease
caf-au-lait spots 722f
CAH see congenital adrenal hyperplasia
calcium scoring 160t, 1678, 167f
calcium-channel blockers 176
for migraine 599
caloric reflexes 596
Calymmatobacterium granulomatis, diagnostic
tests for 689t
canalith repositioning maneuvers (CRMs)
622
cancer see oncology; specific cancer
cancer with unknown primary (CUP)
4667, 487
Candida 666
candidiasis 690
recurrent vulvo-vaginal 751
cannabinoids, synthetic 49
carbamazepine 617t
carbapenems 34t, 671, 672t
carbimazole 767
carbuncles 683
carcinoid 326
carcinoid syndrome 301
carcinoma
chest X-rays for 77t
hepatocellular 4789, 478t
cardiac arrest (CA) 144
cardiac arrhythmias 162
atrial fibrillation 197200, 197f, 198f, 200t
sick sinus syndrome 195
sinus node disturbances 1945, 194f
supraventricular premature complexes 195
supraventricular tachycardia 1956
ventricular arrhythmias 2001, 201f
cardiac auscultation 158, 158t, 159t, 160
cardiac catheterization 160t, 1667, 166f,
167f
cardiac disease
investigation
cardiac catheterization 160t, 1667,
166f, 167f
chest X-ray 160t, 163, 163f
coronary angiography 160t, 1667,
166f, 167f
coronary CT angiography 160t, 1678,
167f
echocardiography 160t, 1636
electrocardiography 1603, 160t, 161t
magnetic resonance imaging 160t, 168
radionuclide myocardial perfusion
imaging 160t, 166, 166f
in pregnancy 7712
cardiac failure
causes 204, 204b
definition 2034, 203b
devices 2078
diagnosis of 2045, 205t
treatment 2057, 207t
cardiac resynchronization therapy (CRT) 207

cardiac tamponade 4645, 464f
cardiogenic shock 144, 145t
cardiology 153215
acute coronary syndromes
management of NSTEACS/NSTEMI
1801
management of STEMI 17980, 179f
pharmacological therapy in 181
terminology 1778, 177f, 178b
aortic valve disease
aortic regurgitation 182t, 1878, 189t
aortic stenosis 182t, 1857, 189t
cardiac arrhythmias
atrial fibrillation 197200, 197f, 198f,
200t
supraventricular premature complexes
195
supraventricular tachycardia 1956
cardiac disease investigation
cardiac catheterization 160t, 1667,
166f, 167f
chest X-ray 160t, 163, 163f
coronary angiography 160t, 1667,
166f, 167f
coronary CT angiography 160t, 1678,
167f
electrocardiography 1603, 160t, 161t
magnetic resonance imaging 160t, 168
radionuclide myocardial perfusion
imaging 160t, 166, 166f
cardiac failure 2038, 203b, 204b, 205t,
207t
cardiomyopathies
alcoholic 190t, 191
arrhythmogenic right-ventricular 193t,
194
chemotherapy-induced 190t, 191
cirrhotic 392, 392b
diabetes and obesity 1934, 193t
dilated 1901, 190t
familial/genetic 190, 190t
hypertrophic 1912
idiopathic 190, 190t
restrictive 1923
Takotsubo 193t, 194
ventricular non-compaction 193t, 194
viral myocarditis 190t, 191
clinical evaluation for
history taking 1546, 155t
physical examination 15660, 157f,
157t
conduction defects
atrioventricular blocks 203
bundle branch block 2012, 202f
fascicular blocks 2023
coronary artery disease 172
dyslipidemia
cholesterol, lipoproteins, apoproteins
16870, 169t
CVD 1701, 170t
ischemic heart disease mortality with
168f
lipid-modifying treatments 1712
infective endocarditis 208f
diagnosis 209
management 20910
microbiology 2089
prevention 21011, 210b, 211t
mitral valve disease
mitral regurgitation 182t, 1835, 189t
mitral stenosis 1823, 182t, 189t
mitral valve prolapse syndrome 182t,
185, 189t
pericardial diseases
chronic 213
pericardial effusion and tamponade
21213
pulmonary valve disease 182t, 189
stable coronary artery disease
improving prognosis 1745
investigation 1724, 173f
management of refractory angina 1767
management of symptoms in 1756
tricuspid valve disease
tricuspid regurgitation 182t, 189, 189t
tricuspid stenosis 182t, 1889, 189t
valvular heart disease 1812, 182t
cardiomyopathies
alcoholic 190t, 191
arrhythmogenic right-ventricular 193t,
194
chemotherapy-induced 190t, 191
cirrhotic 392, 392b
diabetes and obesity 1934, 193t
dilated 1901, 190t
familial/genetic 190, 190t
hypertrophic 1912
idiopathic 190, 190t
peripartum 193t, 194
in pregnancy 772
restrictive 1923
Takotsubo 193t, 194
cardiopulmonary resuscitation (CPR),
end-of-life decision-making with 22,
788
cardiothoracic ratio 80t
cardiovascular disease 746
Carney complex 303
carotid stenosis 606
case-control studies 8
CASP see Critical Appraisal Skills Programme
cataract 731b
catechol-O-methyl transferase (COMT) 625
cathinones, synthetic 49
CD see Crohns disease
CDI see clostridium difficile infection
CECT see contrast-enhanced CT
cefazolin 672t
cefepime 672t
cefotaxime 672t
cefotetan 672t
cefoxitin 672t
cefpirome 672t
ceftazidime 672t
ceftriaxone 672t
celiac disease 3278, 327f, 328b
cellular immunodeficiency 686
opportunistic pathogens in 687t
cellulitis 684t
central sleep apnea (CSA) 143
cephalexin 672t
cephalosporins 34t, 671, 672t
cerebellar stroke 622
cerebrospinal fluid (CSF), in multiple sclerosis
632
cervical cancer 747
cervicitis 690
793
Index
CF see cystic fibrosis
chancroid 691
channels 35
chemical agents 51, 51b
chemical toxicology 49
chemotherapy
adjuvant 460, 475
breast cancer treatment with 483
cardiomyopathy induced by 190t, 191
gastric cancer treatment with 475
hepatocellular carcinoma treatment with
479
high-dose 473
lung cancer treatment with 468
principles of 4601
residual masses after 473
responsiveness of 462
sarcoma treated with 4812
toxicity of cytotoxic 461
chest CT see thoracic computed tomography
chest pain 117, 154, 155t
chest X-ray (CXR)
advantages and disadvantages of 72b
anatomical review for 745, 74b
cardiac disease investigation with 160t,
163, 163f
lines, tubes and implants with 74
patient demographics with 72
patient position for 723, 74t
review areas for 75
signs of chest disease in 7680t
systematic interpretation of 73b
technical assessment of 724, 74t
CheyneStokes respiration 115
childbirth 756
childhood absence seizures 614
ChildsPughTurcotte (CPT) score 384t
chlamydia 7534
Chlamydia trachomatis 675, 7534
diagnostic tests for 688t, 689t
chloramphenicol 674t, 676
chlorine toxicology 49
cholera 702t
cholestasis, of pregnancy 768
cholesterol 16870, 169t
HDL 168, 169t
LDL 168, 169t
lowering, stroke prevention and 6056
non-HDL 168
total 168
chorea 628
causes of 629b
chromosomes 57
genetic conditions of
Down syndrome 65, 68
Klinefelter syndrome 66
Turner syndrome 65
mechanisms for forming abnormal 64f
chronic dysequilibrium 623
chronic idiopathic intestinal
pseudo-obstruction (CIIP) 337
chronic interstitialreticular, chest X-rays
for 78t
chronic kidney disease (CKD)
classification systems for 2534
clinical presentations of stage 3 254
clinical presentations of stages 4 and 5
2545
definitions 254
early stages of 254, 254f
end-stage renal disease 2557, 256t, 257b
renal replacement therapy 2557, 256t,
257b
targets in management of 255t
794
chronic low back pain 5878, 588b

chronic lymphocytic leukemia (CLL) 4314,
434f
chronic myeloid leukemia (CML) 4301
chronic obstructive pulmonary disease
(COPD) 115, 117, 1289, 150, 151
chronic pericardial disease 213
chronic tubulo-interstitial disease 258
ChurgStrauss syndrome (CSS) 535b, 538
cidofovir 678
CIIP see chronic idiopathic intestinal
pseudo-obstruction
ciprofloxacin 674t, 675
circle of care 37, 37f
cirrhosis 3835, 384b, 384t, 385t
cirrhotic cardiomyopathy 392, 392b
CIS see clinical isolated syndrome
CJD see Creutzfeldt-Jakob disease
CKD see chronic kidney disease
CL see clearance
cladribine 633t
clarithromycin 675
clavulanate 672t
clearance (CL)
drug excretion 301, 30f
drug metabolism 2930
variation in 31
clindamycin 674t
clinical isolated syndrome (CIS) 632
CLL see chronic lymphocytic leukemia
clobazam 617t
clonazepam 617t
clonidine 34t
clopidogrel 174, 605
Clostridium difficile 675, 696t
Clostridium difficile infection (CDI) 3345,
334f
clozapine 656
clubbing 116, 116b
cluster headache 600
CM see cutaneous mastocytosis
CML see chronic myeloid leukemia
CMV see controlled or continuous mechanical
ventilation; cytomegalovirus
CNV see copy number variation
coagulation 40910, 409f
coal-workers pneumoconiosis (CWP) 130
coarctation of aorta 772f
cocaine 48
Coccidioides immitis 668
cochlear anatomy 620f
Cogans syndrome (CS) 535b, 540
cohort studies 7, 8b
colchicine 637t
colistin 674t, 676
colon polyps 3513, 354t
color vision 730
colorectal cancer 475 7, 476t
coma
causes of 594, 594b
Glasgow Coma Scale 595t
complicated migraine 599
computed tomography (CT) 667f
abdominal 8590, 85t, 86b, 889t
chest 804, 81t, 82b, 834t
head 94101, 95b, 96100t
myasthenia gravis testing 640
COMT see catechol-O-methyl transferase
confidence intervals 11
confidentiality 201
conflict of interest 23
confounding 6b
confusion 594
congenital adrenal hyperplasia (CAH)

2923, 293f
congestive cardiac failure, chest X-rays for 79t
Conns syndrome see primary
hyperaldosteronism
consciousness disorders
definitions 594
patient assessment in 5956
consent 212
consequentialism 18, 18b
constipation 3434, 343t, 344t, 498
in palliative medicine 498
in pregnancy 767
continuous murmurs 160
contraception 7458
barrier methods of 748
emergency 748
implants 7478
injectable 747
non-steroidal 748
oral 746
transdermal 748
vaginal ring 748
contrast-enhanced CT (CECT) 94, 95t
controlled or continuous mechanical
ventilation (CMV) 147
conversion disorder 653
COP see cryptogenic organizing pneumonia
COPD see chronic obstructive pulmonary
disease
copy number variation (CNV) 61
corneal reflexes 595
coronary angiography 160t, 1667, 166f, 167f
coronary artery disease (CAD)
improving prognosis for 1745
investigation of 1724, 173f
management of refractory angina with
1767
management of symptoms in stable 1756
coronary CT angiography (CTCA) 160t,
1678, 167f
coronary revascularization 175
correlation 11
corticobasal syndrome 6278
corticosteroids 141, 622, 637t
cortisol deficiency 287
cortisol excess (Cushings syndrome) 28990,
290f, 315
co-trimoxazole 674t, 675
cough, chronic 116, 150
cough reflex 122
cover-up method 75
CPR see cardiopulmonary resuscitation
CPT score see ChildsPughTurcotte score
crescendo/decrescendo murmur 159
CREST syndrome 5312, 531b, 532b
Creutzfeldt-Jakob disease (CJD) 60910
Critical Appraisal Skills Programme (CASP) 6
critical care medicine
cardiac arrest 144
diagnosis and disease management
acute respiratory distress syndrome
1457, 145f
shock 1445, 145t
mechanical ventilation of lungs
extracorporeal membrane oxygenation
148, 149b
invasive positive-pressure ventilation
148
non-invasive positive-pressure
ventilation 1478
resuscitation 144
CRMs see canalith repositioning maneuvers
Crohns disease (CD) 3456, 345b, 345f, 366
Index
cross-sectional studies 8
CRT see cardiac resynchronization therapy
Cryptococcus 6667
cryptogenic organizing pneumonia (COP)
133
crystal arthropathies 56973, 569f, 570b,
570f, 571f, 573b, 573t
CS see Cogans syndrome
CSA see central sleep apnea
CSF see cerebrospinal fluid
CSS see ChurgStrauss syndrome
CT see computed tomography
arterial phase CT abdomen 85t, 86
head 94
CTCA see coronary CT angiography
Cullens sign 358, 358f
Cunninghamella 667
CUP see cancer with unknown primary
Cushings syndrome 637t
Cushings syndrome see cortisol excess
cutaneous leukocytoclastic angiitis 535b,
539, 539b, 540f
cutaneous lymphomas 436
cutaneous mastocytosis (CM) 522
cutaneous T-cell non-Hodgkin lymphoma
723
CVD see dyslipidemia and cardiovascular
disease
CWP see coal-workers pneumoconiosis
CXR see chest X-ray
cyanide, antidote for poison from 44t, 54
cystic fibrosis (CF) 127
genetics of 67
cytogenetic studies 64, 64f, 65f
cytomegalovirus (CMV) 6656
immune globulin 707
D
dabigatran 34t
DAH see diffuse alveolar hemorrhage
daptomycin 674t
DBS see deep brain stimulation
DCM see dilated cardiomyopathy
death 788
decolonization 697
deep brain stimulation (DBS), for Parkinsons
disease 6267
deep vein thrombosis (DVT) 746
ultrasound for 934, 94b
delayed CT abdomen 85t, 86
deliberate self-harm (DSH) 6545
delirium 4989, 499f, 502, 594
criteria for 783b
in elderly 783
dementia 60711
diagnosis 6078
in elderly 783
frontotemporal 608
with Lewy bodies 608, 627
pathology work-up for 610t
vascular 609
demyelinating neuropathy 643
demyelination 622
deontology 18, 18t
deoxyribonucleic acid (DNA) 57, 58f
deprescribing 38, 39f
depression 6512
in elderly 7845, 785t
major 652
dermatitis 751
dermatitis herpetiformis 718, 718f
dermatomyositis 529, 529f, 637t
DES see diffuse esophageal spasm
DH lymphomas see double hit lymphomas

DI see diabetes insipidus
diabetes
carbohydrate metabolism and 3045, 304f,
305b, 305t
cardiomyopathy with 1934, 193t
complications of 31011, 310b, 311b, 311t
energy excess disordersobesity 313,
313b, 313t
energy metabolism overview 3034, 304f
hypoglycemia 31112, 312b, 312t
metabolic syndrome 31314, 314b, 314t
diabetes insipidus (DI) 2745
diabetes mellitus 248, 249b, 249f, 747
gestational 312, 7612
type 1 3067, 306b, 306t, 307t, 762
type 2 30710, 308b, 308t, 309f, 309t,
310t, 762
diaphragm
chest CT of 82b, 84, 84t
chest X-rays for 73b, 74t
diarrhea
acute 32830, 329b, 329t, 354
chronic 3302, 330b, 331b, 331t
Clostridium difficile infection 3345, 334f
colonic and small bowel 328b
Entamoeba histolytica 332, 333f
factitious 3334
Giardia lamblia 332
non-watery 331, 331b
watery 331
diastolic murmurs 15960
DIC see disseminated intravascular
coagulation
diet, in elderly 787
diffuse alveolar hemorrhage (DAH) 1334,
133b
diffuse esophageal spasm (DES) 321
diffuse large B-cell lymphoma (DLBCL)
4345, 435b
diffusing capacity for carbon monoxide
(DLCO test) 122, 123t
diffusion-weighted imaging (DWI) 1036,
103t, 105t
digoxin 34t
dilated cardiomyopathy (DCM) 1901, 190t
dimethyl fumarate 633t
dimorphic fungi 6678
diphtheria 702t, 705t
direct pupillary response 729
disseminated intravascular coagulation (DIC)
41920, 420b, 420t, 465
distribution 31
distributive shock 144, 145t
diuretic therapy 622
diverticular bleeding 357
diverticular disease 344
DixHallpike test 621f
dizziness 61823
in elderly 781
hemodynamic 619
DLBCL see diffuse large B-cell lymphoma
DLCO test see diffusing capacity for carbon
monoxide
DNA see deoxyribonucleic acid
DNR (do not resuscitate) 22
donovanosis 691
doodling punding 625f
dopa-dysregulation 6245
dopamine agonists, for Parkinsons disease
626
dose 29, 53
DoTS 39b
double hit (DH) lymphomas 435

Dravet syndrome 615
drink spiking 49
drug concentrationtime curves 32f
drug excretion 301, 30f
drug fever 685
drug interactions, types of 3940
drug metabolism 2930
drug profile 37, 37f
drug regulation 401
drug research 412
drug transport 312, 32f
drug-induced parkinsonism 656
drugs of abuse
cocaine and crack cocaine 48
drink spiking 49
GHB 48
opioids 489
prescription drug abuse 49, 788
synthetic cannabinoids 49
synthetic cathinones 49
dry eye 7378
DSH see deliberate self-harm
Duchenne muscular dystrophy 638
Duodopa, for Parkinsons disease 626
DVT see deep vein thrombosis
DWI see diffusion-weighted imaging
dysesthetic vulvodynia 753
dyslipidemia 746
cholesterol, lipoproteins, apoproteins
16870, 169t
CVD 1701, 170t
ischemic heart disease mortality with 168f
dyslipidemia and cardiovascular disease
(CVD) 1701, 170t
dysmenorrhea 750
dyspepsia 3245, 325t, 364
dysphagia 320, 320f
dyspnea 11415, 115b, 154, 4978, 497t
dystonia 6278
E
early diastolic murmur 159
eating disorders 6534
EBV see Epstein-Barr virus
ecchymoses 414f
echinocandins 681
eclampsia 7634
ECMO see extracorporeal membrane
oxygenation
ectopics see supraventricular premature
complexes
edrophonium test 640
EDS see excessive daytime sleepiness
efficacy 34
effusion
pericardial 21213
pleural 1368, 138t
EGE see eosinophilic gastroenteritis
egg allergy 704
EGPA see eosinophilic granulomatosis with
polyangiitis
EhlersDanlos syndrome 578t
EIDOS 39b
EKG see electrocardiography
elderly care
abuse in 786
alcohol use 787
795
Index
elderly care (continued)
comprehensive assessment 786
delirium in 783
dementia in 783
depression in 7845, 785t
diet in 787
disease and 7806
dizziness in 781
elder abuse 786
ethics and dignity with 223
exercise in 787
iatric disease in 783
immobility in 781
impaired cognition in 783
incontinence in 7813
malnutrition in 787
pain in 7856
physical examination in 786
prescription drug abuse in 788
sarcopenia in 784
sepsis in 785
social isolation in 786
therapeutic intervention complications
784t
see also aging
electrocardiography (EKG) 1603, 160t, 161t
electrolyte disorders 25961, 259t, 260b,
261f
electrophysiology, in multiple sclerosis 632
emergency contraception 748
emphysema 129
empyema 663f
EN see erythema nodosum
endocarditis 671t
endocrine action 268
endocrinology 267318
adrenal disorders
congenital adrenal hyperplasia 2923,
293f
cortisol excess 28990, 290f, 315
incidentaloma 2934, 294f
physiology and assessment of 287, 287f
primary hyperaldosteronism 2901
bone and mineral metabolism disorders
hypercalcemia 2813, 283b
osteomalacia and rickets 2856, 285t,
286t
osteoporosis 2845, 284b
Pagets disease 2867
diabetes
carbohydrate metabolism and 3045,
304f, 305b, 305t
complications of 31011, 310b, 311b,
311t
energy excess disordersobesity 313,
313b, 313t
energy metabolism overview 3034,
304f
gestational diabetes mellitus 312, 7612
insipidus 2745
type 1 diabetes mellitus 3067, 306b,
306t, 307t, 762
type 2 diabetes mellitus 30710, 308b,
308t, 309f, 309t, 310t, 762
feedback control in 2689, 268f
796
female reproductive endocrinology

anatomy and physiology for 298, 298f,
299b
clinical and laboratory evaluation 2989
female hypogonadism 300
hirsutism 299
polycystic ovary syndrome 299300
pregnancy 300
growth and puberty 2945, 296f
hormonal systems function in 269
hormones, transport and action in 268
male reproductive endocrinology
erectile dysfunction causes 297
gynecomastia 2978
infertility 745
male hypogonadism 297
testicular function 2957
multiple endocrine systems disorders
Carney complex 303
McCuneAlbright syndrome 303
multiple endocrine neoplasia 3023
PGA syndromes 303
neuroendocrine tumors
differential diagnosis of 302
overview 3001, 301f
treatment of 302
pathogenic mechanisms of disorders in
26970
pituitary and hypothalamus disorders
anatomy and physiology 2701, 270f,
271t
diabetes insipidus 2745
hypopituitarism 2723, 272t
inflammatory and infiltrative disorders
274
pituitary mass lesions 271, 271f
surgery and radiotherapy for tumors of
274
syndromes of hypersecretion 2734,
274f
thyroid disorders
goiter and thyroid nodules 27980, 279f
hyperthyroidism 2768, 277b
hypothyroidism 2789
physiology and assessment of 275, 275t
in pregnancy 280, 7667
thyroid autoimmunity 276
thyroid cancer 280
thyroid disease in pregnancy 280
thyroid imaging 2756, 276f
end-of-life 788
ethics for 22
endometrial cancer 486, 747
endometriosis 745
end-stage renal disease (ESRD) 2557, 256t,
257b
enhancers 58
entacapone, for Parkinsons disease 626
Entamoeba histolytica 332, 333f
Enterococcus 6634
enteroviruses 666
enzymes 35
EoE see eosinophilic esophagitis
eosinophilia 521, 521b
eosinophilic esophagitis (EoE) 322
eosinophilic gastroenteritis (EGE) 337, 337t
eosinophilic granulomatosis with polyangiitis
(EGPA) 535b, 538
eosinophilic pneumonia 133
eosinophilic pulmonary disorders 133
epilepsies 61118, 746
acquired cortical injury and 616
anticonvulsant therapy for 616, 617t
focal 61516
historical classification of 613b
idiopathic generalized 61415
temporal lobe 615
treatment 61618
EpsteinBarr virus (EBV) 665
erectile dysfunction 297
erosive vulvovaginitis 753
ertapenem 672t
ERV see expiratory reserve volume
erysipelas 684t
erythema migrans 693f
erythema nodosum (EN) 717, 717f
erythromycin 674t
ESBL see extended-spectrum beta-lactamases
ESCAPPM 664
Escherichia coli 664
ESE see exercise stress echocardiography
esophageal cancer 4734, 474f
esophageal infections 322
esophagitis (not acid reflux caused) 3213
esophagus
dysphagia 320, 320f
esophagitis (not acid reflux caused) 3213
motor disorders 3201
ESRD see end-stage renal disease
essential thrombocytosis (ET) 4235, 424b,
424t, 425f
essential tremor 6234
estrogen 747, 756
ET see essential thrombocytosis
ethics
cardiopulmonary resuscitation 22
clinical 19, 20b
confidentiality in 201
conflict of interest with 23
consent in 212
dignity and elderly care 223
end-of-life 22
evidence, decision-making and 1819
futility and 22
internal medicine 1718
law and 18
mental competence in 21
meta 18
non-competent people in 212
normative 18
pharmaceutical industry 23
physicianpatient relationships in 19
practical 18
professionalism in 19
teaching about 19
theories 18
truth-telling in 1920
virtue 18
ethylene glycol/methanol, antidote for poison
from 44t
evidence-based medicine 515
assessing 5
biases in study designs with 6
case-control studies in 8
cohort studies in 7, 8b
cross-sectional studies in 8
pseudo-randomized trials in 7
randomized trials in 67, 7b
screening in 13
sources of errors with 56
statistical analysis interpretation for 1011
study findings interpretation for 910
evolution 778
Ewing sarcoma 482
excessive daytime sleepiness (EDS) 142
excessive sweating 722
exercise, in elderly 787
Index
exercise stress echocardiography (ESE) 1656
expiratory reserve volume (ERV) 120
extended-spectrum beta-lactamases (ESBL)
696t
extracorporeal membrane oxygenation
(ECMO) 148, 149b
extraocular muscle paralysis 739
eye movement
abnormalities 596t
tests 731
eye neoplasia 7378
ezetimibe 171
F
facial flushing 722
falls 782f
famciclovir 678
familial adenomatosis polyposis (FAP) 3534
familial hemiplegic migraine 598
familial Mediterranean fever (FMF) 5401
familial/genetic cardiomyopathy 190, 190t
FAP see familial adenomatosis polyposis
fatigue 493, 493b
febrile neutropenia 464
fecal incontinence 783
fecal occult blood testing (FOBT) 353
female reproductive endocrinology
anatomy and physiology for 298, 298f,
299b
clinical and laboratory evaluation 2989
hirsutism and hyperandrogenism 299
polycystic ovary syndrome 299300
pregnancy 300
fever
acute
common causes of 682t
management of 681t
drug 685
familial Mediterranean 5401
Q 705t
Rocky Mountain spotted 696f
yellow 703t
fibrates 171
fibroids 745
fibromyalgia 5824, 582b, 583f
fingolimod 633t
FISH see fluorescence in situ hybridization
fissures, chest X-rays for 73b, 74
FL see follicular lymphoma
flowvolume loops 122, 122f, 122t
flucloxacillin 672t
fluconazole 679
fluorescence in situ hybridization (FISH)
645, 65f
FMF see familial Mediterranean fever
FOBT see fecal occult blood testing
focal sclerosing glomerular nephropathy
(FSGN) 24851, 250t
folate antagonists 675
follicular lymphoma (FL) 4356
folliculitis 684t
food allergy 51516, 515b, 704
foramen magnum, head CT for 95b, 98t, 101
foscarnet 6789
fosfomycin 674t, 677
frameshift mutation 62
FRC see functional residual capacity
free radicals, aging and 779
frontotemporal dementia (FTD) 608
frozen shoulder 580, 580b
FSGN see focal sclerosing glomerular
nephropathy
FTD see frontotemporal dementia

functional residual capacity (FRC) 120
fungal pulmonary infections 133b, 134
fungi 6668
dimorphic 6678
pulmonary infections from 133b, 134
furuncles 683
fusidic acid 674t, 676
futility 22
G
GABA see gamma-aminobutyric acid
gabapentin 34t
gadolinium-enhanced (GAD) 103t, 105t,
1067
gait disorder 624
gall bladder calculi, abdominal ultrasound
of 92t
gallstones 4001, 401b
gamma-aminobutyric acid (GABA) 656
gammahydroxybutyrate (GHB) 48
ganciclovir 678
Gardner syndrome 354
Gardnerella vaginalis, diagnostic tests for 689t
gastric cancer 4745
gastrinomas 326
gastritis 325
gastroenterology 31969
bowel cancer screening 3535, 355f
esophagus
dysphagia 320, 320f
esophagitis (not acid reflux caused)
3213
gastrointestinal bleeding 3558, 355f, 357f
large bowel
constipation 3434, 343t, 344t, 498,
767
inflammatory bowel disease 34451,
345t
Crohns disease 3456, 345b, 345f,
366
pregnancy and 351, 352t, 7678
ulcerative colitis 345b, 345f, 34651,
34750t, 365
irritable bowel syndrome 330b, 3423,
342b
nutritional deficiency
assessment in end-stage liver disease
341, 341t
clinical clues to 338
enteral and parenteral nutrition 3412
vitamin 33840t, 340f
pancreas
acute pancreatitis 35861, 358f, 359b,
359f, 360t, 361t
autoimmune pancreatitis 3623, 363b
chronic pancreatitis 3612, 362f
pancreatic cysts 363
pregnancy with disorders in 7679
small bowel
CIIP 337
diarrhea 32831b, 32835, 329t, 331t,
333f, 334f, 354
eosinophilic gastroenteritis 337, 337t
malabsorption 3356
microscopic colitis 336
short bowel syndrome 3378
small-intestinal bacterial overgrowth
3367
tropical sprue 336
stomach
dyspepsia and its management 3245,
325t, 364
gastritis and gastropathy 325
gastroparesis 327
peptic ulcer disease 325
physiology of acid secretion 3234,
323f, 323t
post-gastrectomy complications 3267
tumors 326, 326b, 326f
gastroesophageal reflux disease (GERD)
3212
in pregnancy 767
gastrointestinal bleeding 3558, 355f, 357f
gastrointestinal stromal tumors (GISTs) 326
gastroparesis 327
gastropathy 325
GBM see glioblastoma multiforme
GBS see GuillainBarr syndrome
GCA see giant-cell arteritis
GCTs see germ cell tumors
GDM see gestational diabetes mellitus
generalized anxiety disorder 652
genetic connective tissue disorders 578, 578t
genetics 5769
chromosomal conditions common in
Turner syndrome 65
cystic fibrosis from 67
disease risk calculation 634
information flow in
regulation 601, 61f
transcription 589, 59f
translation 5960, 59f, 60f
lung disease 124
medical testing
cytogenetic studies 64, 64f, 65f
FISH 645, 65f
PCR 65
sequencing 65
Mendelian diseases 623, 63f
skin diseases and 7223
variation 612, 62f
genital ulceration 6901
genome 57
GERD see gastroesophageal reflux disease
germ cell tumors (GCTs) 471, 472
gestational diabetes mellitus (GDM) 312,
7612
gestational hypertension 763
GFR see glomerular filtration rate
GHB see gammahydroxybutyrate
giant-cell arteritis (GCA) 5346, 535b
Giardia lamblia 332
GISTs see gastrointestinal stromal tumors
Gitelman syndrome 291
Glasgow Coma Scale 595t
glatiramer acetate 633t
glioblastoma multiforme (GBM) 480
glomerular filtration rate (GFR) 313, 33f
glomerulonephritis (GN)
classification 239
primary glomerular inflammatory disease
23945, 240f, 242b, 243f, 244b, 245b,
265
secondary glomerular inflammatory disease
2458, 246t, 247b
glucagonoma 301, 301f
glucose metabolism disorders 637t
glycopeptides 34t, 673
GN see glomerulonephritis
goiter 27980, 279f
golfers elbow 581
797
Index
Gmri trichrome staining 638f
gonorrhea 7534
gout 56972, 569f, 570b, 570f, 571f
GPA see granulomatosis with polyangiitis
gradient echo (GRE) 103t, 105t, 106
granulomatosis with polyangiitis (GPA)
535b, 5378, 537b
GRE see gradient echo
ground-glass opacity, chest X-rays for 7880t
GuillainBarr syndrome (GBS) 6434
gynecomastia 2978
H
Haemophilus ducreyi, diagnostic tests for 689t
Haemophilus influenzae type b 702t, 705t
hairy cell leukemia (HCL) 4334, 434f
half-life 31, 31f
Hardy-Weinberg distribution 63
HBIG see hepatitis B immune globulin
HCC see hepatocellular carcinoma
HCL see hairy cell leukemia
HCM see hypertrophic cardiomyopathy
HDCT see high-dose chemotherapy
HDL cholesterol see high-density lipoprotein
cholesterol
head and neck cancer 473
head computed tomography (brain CT)
brain protocols for 945, 95b
clinical utility of 94b
initial image review with 96, 968t
key image review with 98100t, 98101
technical review for 96
headache
assessment and management algorithm
597f
pain pathways in 598f
primary syndromes 596601
menstrual migraine 600
migraine 596600, 746
tension 600
tension headache 600
secondary
intracranial pressure and 6001
low pressure 601
heart
chest CT of 82b, 83t, 84
chest X-rays for 73b, 74t, 75
see also cardiology
Helicobacter pylori 3245, 325t
hemarthrosis 414f
hematology 40754
anemia
anemia of chronic disease 442
approach to iron-deficiency 4402,
442b
drug-induced hemolysis 450
hemolytic anemias 44550, 446t, 447t,
448f, 449t
iron-deficiency 358, 771
laboratory tests for 440, 441t
macrocytic anemias 4435, 444f
management of iron deficiency 442
mechanisms of 440, 440f
non-immune acquired hemolytic
anemias 450
sideroblastic anemias 443
thalassemias 4423
antiphospholipid syndrome 41213
798
bleeding disorders
causes of 414b
clinical presentation of 414t
coagulation factors deficiencies causing
417
ecchymoses and hemarthrosis with 414f
hemophilia B 417
von Willebrand disease 41415, 415t
cancer and thrombosis in 41314
coagulopathy in intensive care patients
421, 421f, 421t
disseminated intravascular coagulation
41920, 420b, 420t
hemostasis 40810, 409f
Hodgkin lymphomas 4368, 437b
leukemia
acute lymphoblastic leukemia 429
acute myeloid leukemia 4268, 427f,
427t, 428t
acute promyelocytic leukemia 4289
chronic lymphocytic leukemia and
B-cell disorders 4314, 434f
chronic myeloid leukemia 4301
hairy cell 4334, 434f
myelodysplastic syndrome 42930, 430t
prolymphocytic 433
myeloproliferative disorders
essential thrombocytosis 4235, 424b,
424t, 425f
polycythemia rubra vera 4213, 422f,
423b
primary myelofibrosis 4256, 426b
non-Hodgkin lymphomas 4346, 434t,
435b
plasma cell disorders 4389, 438t, 439b
platelet disorders
hemolytic uremic syndrome 419
idiopathic thrombocytopenic purpura
41718
thrombotic thrombocytopenic purpura
41819
portal vein thrombosis 413
pregnancy with disease in 7701
venous thrombosis
diagnosis of 411
post-thrombotic syndrome 412
predisposition to 41011, 411b, 411t
venous thromboembolism 412
hematopoietic stem-cell transplant (HSCT)
705
hemicraniectomy 604
hemochromatosis 3978, 398f
hemodynamic dizziness 619
hemolytic uremic syndrome (HUS) 2512,
419
hemophilia B 417
hemoptysis 11617
hemostasis 40810, 409f
Henoch-Schnlein purpura (HSP) 535b,
5389, 539f
heparin/enoxaparin 181
hepatitis A 375t, 377
hepatitis A immune globulin 707
hepatitis B 375t, 37781, 378f, 379f, 379t,
381f
hepatitis B immune globulin (HBIG) 707
hepatitis C 375t, 3812, 382b, 382f
hepatitis D, E and G 3823
hepatitis viruses 692, 702t, 705t
hepatitis-C-related glomerulonephritis
2478
hepatocellular carcinoma (HCC) 4789, 478t
hepatolenticular degeneration see Wilsons

disease
hepatology 371405
acute liver failure 3923, 392b
alcohol and 394, 395b
ascites 3857, 386t
autoimmune liver diseases
autoimmune hepatitis 398
primary biliary cirrhosis 399, 399t
primary sclerosing cholangitis 399, 399t
bilirubin metabolism and jaundice 3747,
375b, 376f, 377t
cirrhosis 3835, 384b, 384t
cirrhotic cardiomyopathy 392, 392b
drugs and 394, 395t
gallbladder and biliary tree
acalculous cholecystitis 401, 401b
gallstones 4001, 401b
hepatopulmonary syndrome 3912
hepatorenal syndrome 387
hyponatremia 3878
liver diseases
A1AT deficiency 397
BuddChiari syndrome 396, 396b
non-alcoholic fatty liver disease 3967,
397b
non-alcoholic steatohepatitis 3967,
397b
Wilsons disease 397
liver function tests for
serum enzymes 372
synthetic function tests 372
liver transplantation 3934, 393f, 394f
patient approach for 3724, 372b, 373f,
374b, 375t
porphyrias
acute intermittent porphyria 400
porphyria cutanea tarda 400
portal hypertensive bleeding 3889, 389f
portopulmonary hypertension 391
portosystemic encephalopathy 38991,
389b, 390f, 391t
pregnancy and disease of 400, 400t
spontaneous bacterial peritonitis 388
systemic disease and 400, 400b
viral hepatitis
hepatitis A 375t, 377
hepatitis B 375t, 37781, 378f, 379f,
379t, 381f
hepatitis C 375t, 3812, 382b, 382f
hepatitis D, E and G 3823
tests for other viruses causing 383t
hepatopulmonary syndrome (HPS) 3912
hepatorenal syndrome (HRS) 387
hereditary non-polyposis colon cancer see
Lynch syndrome
hereditary spherocytosis 4489, 448f
heroin 489
herpes simplex virus 1 (HSV-1) 664, 6901
diagnostic tests for 688t
herpes simplex virus 2 (HSV-2) 664, 664f,
6901
HES see hypereosinophilic syndrome
high-density lipoprotein (HDL) cholesterol
168, 169t
high-dose chemotherapy (HDCT) 473
hila, chest CT of 82b
hilum, chest X-rays for 73b
hippocampus 616f
hirsutism and hyperandrogenism 299
histone modification 60
Histoplasma capsulatum 6678
Index
HIV see human immunodeficiency virus
HNPCC see Lynch syndrome
Hodgkin lymphomas 4368, 437b
holosystolic murmur see pansystolic murmur
homeostenosis 778
hopelessness 655
hormone resistance 270
hormone therapy 756
HPS see hepatopulmonary syndrome
HPV see human papillomavirus
HRS see hepatorenal syndrome
HSCT see hematopoietic stem-cell transplant
HSP see Henoch-Schnlein purpura
HSV-1 see herpes simplex virus 1
HSV-2 see herpes simplex virus 2
human immunodeficiency virus (HIV)
5449, 546b, 547b, 547f, 548t, 550t, 692
human papillomavirus (HPV) 691, 703t,
705t
human parvovirus B19 666
humoral immunodeficiency 686
HUS see hemolytic uremic syndrome
hyperandrogenism 299
hypercalcemia 2813, 283b, 465
hypercapnia 118
hypereosinophilic syndrome (HES) 521
hyperkalemia 260, 260b
hyperkinetic movement disorders 6289
hypernatremia 2589
hyperprolactinemia 273, 745
hypersecretion syndromes 2734, 274f
hypertension 746
clinical presentations and investigations
into 2212
definitions of 2201, 220b, 221f
epidemiological evidence for 21819, 220f
gestational 763
malignant 252
management of 227b
mechanisms of 21718, 218b, 219b, 219t
in pregnancy 7634
drug choice 765t
target-organ effects of
blood vessels 222
brain 224
cardiac effects 222, 223f
renal changes 2234
retinopathy 2223, 224f
treatment and targets for control of 2245
treatment for chronic primary
higher stages of hypertension 226, 226b,
226t, 227b
high-normal 225
normal adult 225
stage 1 hypertension 2256
treatment in acute setting 226
in pregnancy 767
hypertrophic cardiomyopathy (HCM) 1912
hypochondriasis 653
hypogammaglobulinemia 328b
hypoglycemics, oral, toxicology of 47
hypogonadism
female 300
male 297
hypokalemia 2601, 261f
hypokalemic alkalosis 261
hyponatremia 25960, 259t, 3878, 465
hypopituitarism 2723, 272t
hypothalamus disorders 2705, 270f, 271f,

271t, 272t, 274f
hypothesis testing 10
hypothyroidism 2789, 637t
in pregnancy 7667
hypoventilation 124
hypovolemic shock 144, 145t
hypoxemia 118
hysterectomy 756
I
IADLs see instrumental activities of daily
living
iatric disease, in elderly 783
IBD see inflammatory bowel disease
IBD-associated spondyloarthropathy 569
IBS see irritable bowel syndrome
ICD see implantable cardioverterdefibrillator; impulse-control disorders
ICE see intracardiac imaging
ICP see raised intracranial pressure
IDA see iron-deficiency anemia
idiopathic cardiomyopathy 190, 190t
idiopathic generalized epilepsies 61415
idiopathic intracranial hypertension (IIH)
601
idiopathic pulmonary fibrosis 132
idiopathic thrombocytopenic purpura (ITP)
41718, 7701
IgA disease see immunoglobulin A disease
IgA vasculitis (IgAV) 535b, 5389, 539f
IGF1 see insulin-like growth factor 1
IgG4-related disease 5334
IIH see idiopathic intracranial hypertension
ILD see interstitial lung disease
iliac crest, abdominal CT of 86b, 89, 89t
imaging 71111
abdominal computed tomography
review areas for 90
technical review for 867, 87t
techniques of examination using 856,
85t
abdominal ultrasound
background principles for 90, 91b
contraindications for 90b
lower limb duplex ultrasound 934, 94b
principles of interpretation in 91, 913t
cardiac disease investigation 1608, 160t,
161t, 163f, 166f, 167f
chest X-rays
anatomical review for 745, 74b
lines, tubes and implants with 74
patient position for 723, 74t
review areas for 75
signs of chest disease in 7680t
systematic interpretation of 73b
technical assessment of 724, 74t
head computed tomography
brain protocols for 945, 95b
initial image review with 96, 968t
key image review with 98100t, 98101
head MRI 10111

principles of interpretation in 10711,
108b
protocols for 1027, 1036t
review areas for 111
safety considerations for 102b
sequences in 103t
positron emission tomography 111, 111f
thoracic computed tomography
review areas for 84
thyroid 2756, 276f
immobility, in elderly 781
immune system
innate 123
respiratory tract 1234
immunization
of adults 707, 708f, 709f, 710f
immunocompromised hosts 7045
oncology patients 705
pregnancy and 704
solid-organ transplant patients 705
in specific populations 7047
see also vaccines
immunizing agents 702
immunoassay 269
immunodeficiency 507, 5414, 541t, 542b,
543t, 544t, 545f
immunogenicity 7034
immunoglobulin A (IgA) disease 2401, 265
immunological disease, in pregnancy 7701
immunology 50355
allergic disease
allergic rhinitis and allergic
conjunctivitis 51012, 511b, 511f,
512b
atopic dermatitis 51315, 514f
food allergy 51516, 515b
urticaria and angioedema 51619, 516f,
517b, 517f, 518t
autoimmunity in 507
autoinflammatory disorders 5401
eosinophilia 521, 521b
HIV/AIDS 5449, 546b, 547b, 547f, 548t,
550t
hypersensitivity in 507, 507t
immune system manipulation in 5089,
509t
immunity, inflammation and tissue repair
in 508
immunobiology in 508
immunodeficiency 507, 5414, 541t, 542b,
543t, 544t, 545f
immunological memory in 5067, 506t
innate and adaptive immunity with 5045,
504t, 505b, 505f
799
Index
immunology (continued)
mast cell disorders 522, 522f
specificity and diversity in 5056
systemic autoimmune disease
antiphospholipid syndrome 533, 533b
IgG4-related disease 5334
inflammatory myopathies 52931, 529f,
530f, 530t
mixed connective tissue disease 5323
scleroderma and CREST syndrome
5312, 531b, 532b
Sjgrens syndrome 5279, 528t
systemic lupus erythematosus 5237,
523f, 5245b, 526t, 527t
vasculitis
classification of 534b
large-vessel vasculitis 5346, 535b
medium-vessel vasculitis 535b, 5367,
536b, 537b
single-organ vasculitis 535b, 539
small-vessel vasculitis 535b, 5379, 537b
variable-vessel vasculitis 535b, 53940,
539f, 540f
impetigo 684t
implantable cardioverter-defibrillator (ICD)
207
impulse-control disorders (ICD) 6245
IMV see intermittent mandatory ventilation
incidence 9
incidence rate 9
incidentally found adrenal masses
(incidentaloma) 2934, 294f
incidentaloma see incidentally found adrenal
masses
inclusion-body myositis 6368, 637t
incontinence
in elderly 7813
fecal 783
mixed 782
stress 782
urge 782
infections
airway 114
bacterial pulmonary 133b, 134
clostridium difficile 3345, 334f
esophageal 322
fungal pulmonary 133b, 134
kidney 238, 239b
parasitic 193t, 194
pulmonary 137t
mycobacterial 1346, 135f, 136t
sexually transmitted, in women 7534
skin 71922
viral, in pregnancy 76970
viral pulmonary 133b, 134
infectious diseases
analytical considerations 661
antibiotic choice 670
antigen detection 661
anti-infective treatment 66871
failure of 671t
host factors 670t
clinically important organisms 6628,
662t
common causes 669t
diagnostics in 661
examination 660
history in 660
in immunosuppressed patients 6856
likeliness of 669
nucleic acid detection 661
pathogens 669
physical signs 6601
post-analytical considerations 661
800
pre-analytical considerations 661

prevention and control 6967
antibiotic use 697
environmental measures 697
serology 661
sexually transmitted infections 68692
systemic viral infections 6926
infective endocarditis 208f
diagnosis 209
management 20910
microbiology 2089
prevention 21011, 210b, 211t
infertility 7435
age and 744
anatomical abnormalities and 745
causes of 744t
male factor 745
types of 744t
unexplained 745
infiltrative disorders, peripartum
cardiomyopathy 193t, 194
inflammation, aging and 779
inflammatory bowel disease (IBD) 34451,
345t
Crohns disease 3456, 345b, 345f, 366
34750t, 365
inflammatory myopathies 52931, 529f,
530f, 530t
inflammatory myopathy 636
information bias 6b
inherited cystic kidney disease
ADPCKD 2324, 233f
autosomal recessive polycystic disease 234
medullary cystic disease 234
MSK 234, 234f
inherited renal basement membrane disease
2389
innate immune system 123
INO see internuclear ophthalmoplegia
insomnia 142, 499500
inspiratory reserve volume (IRV) 120
instrumental activities of daily living (IADLs)
787b
insulin, toxicology of 47
insulin-like growth factor 1 (IGF1) 779
insulinoma 301
intention-to-treat (ITT) analysis 7
interferons 678
intermittent mandatory ventilation (IMV)
147
internal medicine
diagnosis importance in 2
specialization in 12
21st century 13
internuclear ophthalmoplegia (INO) 6301
interstitial lung disease (ILD) 12930, 130b
granulomatous 1323
intestinal ischemia 3567, 357f
intracardiac imaging (ICE) 164
intracerebral hemorrhage 606
intracranial pressure, headaches and 6001
intraocular pressure 7289
intravascular imaging (IVUS) 164
invasive positive-pressure ventilation (IPPV)
148
inversion 64
inversion recovery (IR) 103, 103t, 104t
IPPV see invasive positive-pressure ventilation
IR see inversion recovery
iron, antidote for poison from 44t
iron-deficiency anemia (IDA) 358, 771
irritable bowel syndrome (IBS) 330b, 3423,

342b
in pregnancy 767
IRV see inspiratory reserve volume
ischemic colitis 357
ischemic heart disease mortality 168f
ischemic penumbra 603f
ischemic stroke, causes of 602t
ITP see idiopathic thrombocytopenic purpura
itraconazole 679
ITT analysis see intention-to-treat analysis
ivabradine 176
ivory wave 49
IVUS see intravascular imaging
J
Janeway lesions 208, 208f
Japanese encephalitis 703t, 705t
jaundice 3747, 375b, 376f, 377t
JME see juvenile myoclonic epilepsy
joint pain 55860, 558b, 559t
jugular venous pulse ( JVP) 1556, 156f
juvenile myoclonic epilepsy ( JME) 61415
JVP see jugular venous pulse
K
K2 49
karyotyping 64f
Kawasaki disease (KD) 535b, 5367, 537b
ketoconazole 679
kidney
abdominal ultrasound of 93t
infection 238, 239b
see also nephrology
kidney cystic disease
acquired 2348, 235b, 236b
inherited 2324, 233f, 234f
kidney stones 2358, 235b, 236b
Klebsiella 664
L
labyrinthitis 61920
lacosamide 617t
lamotrigine 617
large bowel
constipation 3434, 343t, 344t, 498, 767
inflammatory bowel disease 34451, 345t
Crohns disease 3456, 345b, 345f, 366
34750t, 365
irritable bowel syndrome 330b, 3423,
342b
lateral ventricles, head CT for 95b, 100t, 101
LBBB see left bundle branch block
LDL cholesterol see low-density lipoprotein
cholesterol
lead poisoning 49
antidote for 44t
left bundle branch block (LBBB) 202
LennoxGastaut syndrome (LGS) 615
lentigo maligna melanoma 480
leukemia
acute lymphoblastic leukemia 429
acute myeloid leukemia 4268, 427f, 427t,
428t
acute promyelocytic leukemia 4289
chronic lymphocytic leukemia and B-cell
disorders 4314, 434f
chronic myeloid leukemia 4301
hairy cell 4334, 434f
Index
myelodysplastic syndrome 42930, 430t
prolymphocytic 433
levetiracetam 34t, 617
levodopa 628
for Parkinsons disease 6256
Lewy bodies, dementia with 608, 627
LGS see LennoxGastaut syndrome
LGV see lymphogranuloma venereum
Lhermittes phenomenon 631
lichen sclerosis 752
vulvar 752f
Liddles syndrome 291
LiFraumeni syndrome 463
likelihood ratio (LR) 12, 12f
lincosamides 6734
linezolid 674t
lipid-lowering agents 175
lipopeptides 673
lipoproteins 16870, 169t
literature appraisal 89, 8b
lithium 34t
lithium carbonate 655
livedo reticularis 719, 719b, 719f
liver
abdominal CT of 86b, 87, 88t
acute liver failure 3923, 392b
alcohol and 394, 395b
amebic liver abscess 3323
cirrhosis, abdominal ultrasound of 92t
damage 45
dilated biliary ducts, abdominal ultrasound
of 92t
end-stage liver disease 341, 341t
function tests 372
hemangioma, abdominal ultrasound of 91t
metastases, abdominal ultrasound of 91t
pregnancy with disorders of 7679
transplantation 3934, 393f, 394f
liver diseases
A1AT deficiency 397
autoimmune 3989, 399t
BuddChiari syndrome 396, 396b
non-alcoholic fatty liver disease 3967,
397b
non-alcoholic steatohepatitis 3967, 397b
Wilsons disease 397
living wills 788
loading dose 31
lobar anatomy, chest X-rays for 73b
low pressure headaches 601
low-density lipoprotein (LDL) cholesterol
168, 169t
lower limb duplex ultrasound 934, 94b
low-molecular-weight heparins 34t
LR see likelihood ratio
lungs
abdominal CT of lung bases 86b, 87, 88t
cancer 4679, 467t, 468f, 468t
chest X-rays for 73b, 74, 74t
genetic disease of 124
ILD 12930, 130b
measurement of function of
DLCO test 122, 123t
interpretation of 122, 123t
lung volumes interpretation 122
spirometry 1201, 121f
mechanical ventilation of 1478, 149b
total capacity of 120, 123t
transplantation 1401, 140t
see also airways diseases
lupus nephritis 2457, 246t, 247b
Lyme disease 693

lymphadenopathy 661
lymphogranuloma venereum (LGV) 691
Lynch syndrome 3545, 463
M
macrolides 6734
magnetic resonance angiography (MRA)
103t, 106t, 107
magnetic resonance gated intracranial
cerebrospinal dynamics (MR-GILD)
103t, 107
magnetic resonance imaging (MRI) 101
cardiac disease investigation with 160t,
168
head in 10111, 102b, 1036t, 108b,
10911t
T1 MRI protocol 102, 103t, 104t
magnetic resonance venography (MRV)
103t, 106t, 107
major depression 652
malabsorption 3356
malaria 668
male factor infertility 745
male reproductive endocrinology
erectile dysfunction causes 297
gynecomastia 2978
infertility 745
malignant hyperthermia 657t
malnutrition, in elderly 787
mantle-cell lymphoma (MCL) 436
MAO see monoamine oxidase
Marfan syndrome 578t
marine envenomation 50
mast cell disorders 522, 522f
maximum mid-expiratory flow rate
(MMFR) 123t
MBL see metallo-beta-lactamase; monoclonal
B-cell lymphocytosis
McCuneAlbright syndrome 303
MCD see minimal change disease
MCL see mantle-cell lymphoma
MCTD see mixed connective tissue disease
MDS see myelodysplastic syndrome
measles 703t
mechanical ventilation of lungs 1478, 149b
mediastinal masses 117, 117b
mediastinum, chest X-rays for 73b, 74t, 75
medullary sponge kidney (MSK) 234, 234f
melanoma 4801
memantine 34t
membranous nephropathy 2412, 242b
MEN see multiple endocrine neoplasia
Mendelian diseases 623, 63f
Mnires disease 621
meningococcus 705t
Meniscus sign 80t
menopausal symptoms 7489
mental competence 21
meropenem 672t
mesangio-capillary glomerulonephritis 242
mesenteric venous thrombosis 357
messenger RNA (mRNA) 589, 59f
meta-analysis 9, 9b
meta-ethics 18
metallo-beta-lactamase (MBL) 696t
metastases
liver, abdominal ultrasound with 91t
metformin 34t
methicillin-resistant Staphylococcus aureus
(MRSA) 696t
methylation 61, 69
methysergide 599
metronidazole 674t
MG see myasthenia gravis
MGUS see monoclonal gammopathy of
uncertain significance
microscopic polyangiitis 244, 245b
mid-diastolic murmur 159
mid-pelvis, abdominal CT of 86b, 89, 89t
migraine 746
aura 597
basilar-type 598
complicated 599
familial hemiplegic 598
management 599600
acute-phase 599
amitriptyline for 599
beta-blockers 599
calcium-channel blockers 599
NSAIDs 599
pizotifen for 599
prophylactic 599
triptans 599
venlafaxine for 599
menstrual 600
pain pathways in 598f
postdrome period 598
presentation 5969
probable 599
prodromal syndromes 597
prophylaxis 622
retinal 599
sporadic hemiplegic 598
vertigo and 621
minimal change disease (MCD) 2445, 245b
Mini Mental State Examination (MMSE)
608
missense mutation 62
mitochondrial disorders 637t, 6389
mitral regurgitation (MR) 182t, 1835, 189t
mitral stenosis (MS) 1823, 182t, 189t
mitral valve 165
mitral valve prolapse (MVP) syndrome 182t,
185, 189t, 747
mixed connective tissue disease (MCTD)
5323
mixed incontinence 782
MMFR see maximum mid-expiratory flow
rate
MMSE see Mini Mental State Examination
MND see motor neuron disease
molds 667
molluscum contagiosum 691
monoamine oxidase (MAO) 625
monobactams 672t
monoclonal B-cell lymphocytosis (MBL) 433
monoclonal gammopathy of uncertain
significance (MGUS) 438
mononeuritis multiplex 642t
mononeuropathy 642t
morphine 489
morphine-6-glucuronide 34t
motor neuron disease (MND) 6413
motor neuropathy 642t
movement disorders 6239
801
Index
moxifloxacin 674t
MR see mitral regurgitation
MR spectroscopy (MRS) 103t, 107
MRA see magnetic resonance angiography
MR-GILD see magnetic resonance gated
intracranial cerebrospinal dynamics
MRI see Magnetic resonance imaging
mRNA see messenger RNA
MRS see MR spectroscopy
MRSA see methicillin-resistant Staphylococcus
aureus
MRV see magnetic resonance venography
MS see mitral stenosis
MSA see multisystem atrophy
MSK see medullary sponge kidney
Mucor 667
mucormycosis 667
mucositis 4923, 501
multiple endocrine neoplasia (MEN) 3023
multiple sclerosis 6305
classification 630
CSF examination 632
diagnosis 6312
dissemination in space 6312
dissemination in time 632
electrophysiology 632
management 6324
corticosteroids 6324
symptomatic 6334
primary-progressive 630
progressive-relapsing 630
relapsing-remitting 630
sensory symptoms 631
multi-resistant organisms in modern hospitals
696t
multisystem atrophy (MSA) 627
mumps 703t
mupirocin 674t
muscular dystrophies 637t
musculoskeletal medicine 55791
acute low back pain 5857, 585t, 586b,
587b, 587f
chronic low back pain 5878, 588b
crystal arthropathies 56973, 569f, 570b,
570f, 571f, 573b, 573t
fibromyalgia 5824, 582b, 583f
genetic connective tissue disorders 578,
578t
golfers elbow 581
joint pain 55860, 558b, 559t
osteoarthritis 5748, 575f, 576t, 577f
plantar fasciitis 5812, 582b
relapsing polychondritis 574, 574f
rheumatoid arthritis
clinical features and complications with
5613, 562f
diagnosis of 561, 561b, 562t
genetics and environmental contribution
to 5601, 560f
investigations into 563
pathology of 561
treatment for 5635, 564f, 565t, 568t
septic arthritis 5845, 584b
shoulder pain 57880, 579f, 579t, 580b
spondyloarthropathies 5659, 565f, 566f,
567f, 568t
tennis elbow 581
MVP syndrome see mitral valve prolapse
syndrome
myasthenia gravis (MG) 639f
clinical assessment 63940
diagnostic testing 640
pathophysiology 639
treatment 6401
802
mycobacterial pulmonary infections 1346,

135f, 136t
mycosis fungoides 723f
myelodysplastic syndrome (MDS) 42930,
430t
myeloproliferative disorders 4216, 422f,
423b, 424b, 424t, 425f, 426b
myoclonus 6289
causes of 629b
myopathy 6368
drug-induced 638
inflammatory 636
overview 637t
see also cardiomyopathies
N
N-acetylcysteine 445, 45f, 46t
nafcillin 672t
NAFLD see non-alcoholic fatty liver disease
nalidixic acid 674t
Naranjo score 40b
NASH see non-alcoholic steatohepatitis
NaSSAs see noradrenergic and specific
serotonergic antidepressants
natalizumab 633t
nausea 4936, 494f, 4956t, 501
NCCT see non-contrast CT
nedocromil sodium 141
negative in health (NIH) 11
negative predictive value (NPV) 11, 12f
Neisseria gonorrhea 687
Neisseria meningitidis 663
neoplasia, eye 7378
nephrology 23165
acquired kidney cystic disease
renal stones/kidney stones 2358, 235b,
236b
simple renal cysts 2345
acute kidney injury 2557
acute renal failure 257
chronic kidney disease
classification systems for 2534
clinical presentations of stage 3 254
clinical presentations of stages 4 and 5
2545
definitions 254
early stages of 254, 254f
end-stage renal disease 2557, 256t, 257b
renal replacement therapy 2557, 256t,
257b
targets in management of 255t
electrolyte disorders
hyperkalemia 260, 260b
hypernatremia 2589
hypokalemia 2601, 261f
hyponatremia 25960, 259t
glomerulonephritis
classification 239
primary glomerular inflammatory
disease 23945, 240f, 242b, 243f,
244b, 245b, 265
secondary glomerular inflammatory
disease 2458, 246t, 247b
hemolytic uremic syndrome 2512
inherited channelopathies
hypokalemic alkalosis 261
renal tubular acidosis 2612, 262t
inherited cystic kidney disease
ADPCKD 2324, 233f
autosomal recessive polycystic disease
234
MSK 234, 234f
inherited renal basement membrane disease

Alports disease 239
thin basement membrane disease 2389
kidney and urinary tract infection
clinical presentation 238
disease mechanisms for 238
treatment and targets for 238, 239b
malignant hypertension 252
pregnancy-related diseases
normal adaptations 2623
underlying renal disease 263
reflux nephropathy 253, 253b
scleroderma kidney 2523
sclerosing glomerular disease
FSGN 24851, 250t
2512
tubulo-interstitial diseases 2578, 258t
acute interstitial nephritis 258
chronic tubulo-interstitial disease 258
vascular renal disease
renal artery stenosis 251, 251f
treatment of renovascular disease 251
nerve conduction studies 640
NETs see neuroendocrine tumors
neuroacanthocytosis 629f
neuroendocrine tumors
overview 3001, 301f
treatment of 302
neurofibromatosis 722
neuroleptic malignant syndrome 656, 657t
neurological conditions, in pregnancy 773
neuromuscular disease 6359
neuromuscular disorders 63945
neuromyelitis optica (NMO) 634
neuronal migration disorder 61516
neuro-ophthalmology 7389
neuropathy
anterior ischemic optic 735f
demyelinating 643
laboratory investigation for 645t
mononeuropathy 642t
motor 642t
peripheral 6445, 644t
sensory 642t
neutropenia 686
neutrophilic dermatoses 71920
new oral anticoagulants (NOACs), for stroke
605
NFR (not for resuscitation) 22
nicorandil 176
NIH see negative in health
nitrates 176, 181
nitroimidazoles 677
NIV see non-invasive positive-pressure
ventilation
NMDA encephalitis 629
NMO see neuromyelitis optica
NNT see number needed to treat
NOACs see new oral anticoagulants
nodular melanoma 480
non-alcoholic fatty liver disease (NAFLD)
3967, 397b
non-alcoholic steatohepatitis (NASH) 3967,
397b
non-beta-lactams 673
non-competent people 212
non-contrast CT (NCCT)
abdomen 85t, 86
head 94
non-contrast CT KUB 85t, 86
non-epileptic seizures 618
Index
non-HDL cholesterol 168
non-hemolytic streptococci 663
non-Hodgkin lymphomas
Burkitts lymphoma 435
cutaneous lymphomas 436
diagnosis 434
diffuse large B-cell lymphoma 4345,
435b
double hit lymphomas 435
follicular lymphoma 4356
mantle-cell lymphoma 436
staging 434, 434t
non-invasive positive-pressure ventilation
(NIV) 1478
non-proliferative diabetic retinopathy 735f
non-seminomatous germ cell tumor
(NSGCT) 4712, 472t
nonsense mutation 62
non-small-cell lung cancer (NSCLC) 4678,
467t, 468f, 468t
non-ST-elevation acute coronary syndrome
(NSTEACS) 177f, 178, 1801
non-ST-elevation myocardial infarction
(NSTEMI) 177f, 178, 1801
non-steroidal anti-inflammatory drugs
(NSAIDs) 750
for migraine 599
toxicology of 46
non-steroidal contraception 748
noradrenergic and specific serotonergic
antidepressants (NaSSAs) 46
norepinephrine reuptake inhibitors (NRIs)
47
norfloxacin 675
normative ethics 18
not for resuscitation see NFR
NPV see negative predictive value
NRIs see norepinephrine reuptake inhibitors
NSAIDs see non-steroidal anti-inflammatory
drugs
NSCLC see non-small-cell lung cancer
NSGCT see non-seminomatous germ cell
tumor
NSTEACS see non-ST-elevation acute
coronary syndrome
NSTEMI see non-ST-elevation myocardial
infarction
nucleic acid detection 661
nucleoside analogues 678
null value 10
number needed to treat (NNT) 9, 10f
nutritional deficiency
assessment in end-stage liver disease 341,
341t
clinical clues to 338
enteral and parenteral nutrition 341
vitamin 33840t, 340f
O
OA see osteoarthritis
obesity 142
energy excess disordersdiabetes and 313,
313b, 313t
in pregnancy 773
obesity hypoventilation syndrome (OHS)
143
obstetric medicine 760
obstructive sleep apnea (OSA) 122, 1423
obtundation 594
occupational exposure, vaccines for 706t
ocular effects of systemic medication 739
ocular motility 730
oculocephalic reflexes 5956

oculomotor palsy 739
odds ratios (OR) 10, 10f
ofloxacin 674t
OHS see obesity hypoventilation syndrome
omega-3 fatty acids 1712
oncocytomas 235
oncology 45588
bladder tumors 46970
brain tumors 47980, 480t
breast cancer 4824, 482t, 747
cancer with unknown primary 4667, 487
chemotherapy principles for 4601
colorectal cancer 475 477, 476t
diagnosis 4589
elements of cancer 457, 457f, 458f
endometrial cancer 486
esophageal cancer 4734, 474f
familial cancers and cancer genetics 463
gastric cancer 4745
head and neck cancer 473
hepatocellular carcinoma 4789, 478t
lung cancer 4679, 467t, 468f, 468t
melanoma 4801
molecular targeted therapy 4623
oncological emergencies 4635
ovarian cancer 4845
pancreatic cancer 4778
paraneoplastic syndrome 466
pelvis tumors 46970
personalized medicine 462
prevention 4578
prognosis 459
prostate cancer 4701
radiotherapy principles for 4612
renal cancer 469
sarcoma 4812
testis cancer 4713, 472t
treatment principles 45960
treatment responsiveness 462
tumor markers in serum 4656, 487
ureter tumors 46970
ophthalmology
examination 72831
ocular history 728
pathological conditions 7325
ophthalmoscopy 731, 731f
opioids 44t, 489
optic neuritis 630, 738
OR see odds ratios
oral contraceptives 746
cancer risk and 747
oral hypoglycemics, toxicology of 47
organophosphorus insecticide poisoning 44t,
49, 50t
OSA see obstructive sleep apnea
oscillopsia 6223
oseltamivir 679
OslerWeberRendu syndrome 355, 355f
osteoarthritis (OA) 5748, 575f, 576t, 577f
osteogenesis imperfecta 578t
osteomalacia 2856, 285t, 286t
osteoporosis 2845, 284b, 786
ovarian cancer 4845, 747
oxygenhemoglobin associationdissociation
curve 119
P
p value see probability
PA see posterior-to-anterior position
Pagets disease (PD) 2867
pain
acute low back 5857, 585t, 586b, 587b,
587f
chest 117, 154, 155t

chronic low back 5878, 588b
in elderly 7856
joint 55860, 558b, 559t
pain pathways, headache 598f
pain pathways, migraine 598f
palliative medicine for 4902, 490f, 491t,
501
shoulder 57880, 579f, 579t, 580b
paliperidone 34t
palliative care 788
palliative medicine 489502
cachexia and anorexia 4967
constipation 498
delirium 4989, 499f, 502
dyspnea 4978, 497t
fatigue 493, 493b
insomnia 499500
mucositis 4923, 501
nausea and vomiting 4936, 494f, 4956t,
501
pain 4902, 490f, 491t, 501
palm, rash on 721
palpitations 154, 1578
in pregnancy 772
PAN see polyarteritis nodosa
panbronchiolitis 128
pancreas tumor, abdominal ultrasound of 93t
pancreatic cancer 4778
pancreatic cysts 363
pancreatitis
acute 35861, 358f, 359b, 359f, 360t, 361t
autoimmune 3623, 363b
chronic 3612, 362f
panic disorder 652
pansystolic (holosystolic) murmur 158
papilledema 7389, 738f
paracetamol see acetaminophen
paracrine action 268
paraneoplastic syndrome 466
parasitic infection, infiltrative disorders,
peripartum cardiomyopathy 193t, 194
Parkinsons disease (PD) 609
DBS for 6267
diagnosis 625
non-motor features 6245
treatment
amantadine 626
anticholinergics for 626
apomorphine 626
dopamine agonists 626
Duodopa for 626
entacapone 626
levodopa 6256
rasagiline for 626
patient assessment, in consciousness disorders
5956
patient profile 37, 37f
PBC see primary biliary cirrhosis
PCOS see polycystic ovary syndrome
PCR see polymerase chain reaction
PCT see porphyria cutanea tarda
PD see Pagets disease; Parkinsons disease
PE see pulmonary embolism
pelvic inflammatory disease 690, 7545
pelvic-floor disorders 756
pelvis tumors 46970
pemphigus vulgaris 71718, 717f
penicillins 34t, 53, 671, 672t, 692
PEP see post-exposure prophylaxis
peptic ulcer bleeding 356
peptic ulcer disease (PUD) 325
percussion 1578, 160
803
Index
percutaneous transluminal cerebrovascular
angioplasty and stenting (PTCAS) 606
perfusion 114
CT 95
radionuclide myocardial imaging with
160t, 166, 166f
pericardial diseases
chronic 213
pericardial effusion and tamponade 21213
pericardial effusion 21213
pericardial friction rubs 160
pericardiocentesis 21213
peripartum cardiomyopathy 193t, 194
peripheral nerve disorder 641
types and functions of 642t
peripheral neural axis 641
peripheral neuropathy 6445
common causes 644t
peripheral vestibular system 619
pertussis 702t, 705t
pertuzumab 484
pesticides toxicology 44t, 49, 50t
PET see positron emission tomography
PeutzJeghers (PJ) syndrome 355, 355f
PGA syndromes see polyglandular
autoimmunity syndromes
PH see pulmonary hypertension
phakomatoses 7223, 739
ocular features 739f
pharmaceutical industry, conflict of interest
and ethics with 23
pharmacodynamics
concentrationresponse relationships of
34, 35f
drug targets of 34, 356
health effects of 34
molecular effects of 34
patient characteristics with 36
physiological effects of 34, 36
therapeutic index of 345, 35b
pharmacoeconomics 41
pharmacoepidemiology 41
pharmacokinetics
administration 29
altered 324, 33f, 34t
bioavailability 29
clearance 2931, 30f
distribution 31
drug transport 312, 32f
patient size 345
pharmacology 2755
acute coronary syndromes 181
bystander drug exposure with 36
liver and 394, 395t
principles of 28, 28f
pulmonary 141
quality use of medicines in 3642, 37f,
38b, 39f, 39b
phenobarbitone 617t
phenytoin 617t, 618f
photosensitivity 721
phrenic angles, chest X-rays for 73b
physical examination
cardiology evaluation in 15660, 157f,
157t
elderly in 786
toxicology assessment in 43t
physical signs 6601
physician
patient relationships with 19
public health role of 2
as scholar 23
804
physiological tremor 623

PICA infarction 622
PID see positive in disease
pigmentation 721
piperacillin 672t
pituitary disorders 2705, 270f, 271f, 271t,
272t, 274f
pituitary fossa, head CT for 95b, 99t, 101
pituitary mass lesions 271, 271f
pizotifen, for migraine 599
PJ syndrome see PeutzJeghers syndrome
plantar fasciitis 5812, 582b
plasma cell disorders 4389, 438t, 439b
Plasmodium 668
platelet disorders 41719
platelets 4089
pleura, chest X-rays for 73b
pleural effusion 1368, 138t
plexitis 642t
plexopathy 642t
PMF see primary myelofibrosis
pneumococcal meningitis 671t, 702t
Pneumococcus 705t
pneumonia 137t
in pregnancy 7645
pneumothorax 138
point estimate 9
point prevalence 9
poison antidotes 44t
poliomyelitis 705t
poliovirus 703t
polyarteritis nodosa (PAN) 535b, 536, 536b
polycystic ovary syndrome (PCOS) 299300
polycythemia rubra vera (PV) 4213, 422f,
423b
polyglandular autoimmunity (PGA)
syndromes 303
polymerase chain reaction (PCR) 65
polymorphisms 61
polymyositis 529, 637t
POPH see portopulmonary hypertension
porphyria cutanea tarda (PCT) 400, 721f
porphyrias 400
porta hepatis, abdominal CT of 86b, 87, 88t
portal hypertensive bleeding 3889, 389f
portal vein thrombosis (PVT) 413
abdominal ultrasound of 92t
portal venous CT abdomen 85t, 86
portopulmonary hypertension (POPH) 391
portosystemic encephalopathy (PSE) 38991,
389b, 390f, 391t
posaconazole 681
positive in disease (PID) 11
positive predictive value (PPV) 11, 12f, 163
positron emission tomography (PET) 111,
111f
postdrome period, migraine 598
posterior fossa, head CT for 95b, 99t, 101
posterior-to-anterior position (PA) 72, 74t
post-exposure prophylaxis (PEP) 707
post-streptococcal glomerulonephritis
(PSGN) 23940, 265
post-thrombotic syndrome (PTS) 412
post-traumatic stress disorder (PTSD) 6523
potency 34, 35f
PPMS see primary-progressive multiple
sclerosis
PPV see positive predictive value
practical ethics 18
pragmatism 18
pramipexole 34t
prednisolone 600
preeclampsia 7634
risk factors for 743t
pregabalin 34t
pregnancy 756
acute fatty liver of 7689
asthma in 765
BuddChiari syndrome in 769
bystander drug exposure with 36
cardiac disease in 7712
cardiomyopathy in 772
cholestasis of 768
constipation in 767
diabetes in 312, 7602
endocrinology of 300
gastroenterological disorders in 7679
GERD in 767
hematological disease in 7701
hypertension in 7634
drug choice 765t
hyperthyroidism in 767
hypothyroidism in 7667
IBS in 767
immunization and 704
immunological disease in 7701
inflammatory bowel disease and 351, 352t,
7678
liver disease with 400, 400t
liver disorders in 7679
neurological conditions in 773
obesity in 773
pneumonia in 7645
principles relating to medical illness in 760t
renal disease related to 2623
respiratory disease in 7646
thyroid disorders in 280, 7667
venous thromboembolism in 766
viral infection in 76970
premenstrual syndrome 749
prescribing checklist 38, 38b
prescription drug abuse 49
in elderly 788
pressure-support ventilation (PSV) 147
prevalence 9
primary biliary cirrhosis (PBC) 399, 399t
primary gland dysfunction 269
primary headache syndromes 596601
migraine 596600
primary hyperaldosteronism (Conns
syndrome) 2901
primary myelofibrosis (PMF) 4256, 426b
primary sclerosing cholangitis (PSC) 399,
399t
primary-progressive multiple sclerosis
(PPMS) 630
primidone 617t
PRMS see progressive-relapsing MS
probability (p value) 11
probable migraine 599
proctitis 690
prodromal syndromes 597
professionalism in 19
progesterone 747
progressive supranuclear palsy (PSP) 627
progressive-relapsing MS (PRMS) 630
prolymphocytic leukemia 433
promoters 58, 59f
propylthiouracil 767
prostate cancer 4701
Proteus 664
pruritus 7201
PsA see psoriatic arthritis
Index
PSC see primary sclerosing cholangitis
PSE see portosystemic encephalopathy
pseudogout 5723, 573b, 573t
Pseudomonas aeruginosa 664, 676
pseudo-randomized trials 7
PSGN see post-streptococcal
glomerulonephritis
psoriasis 71617, 752
subtypes 716f
vulvar 752f
psoriatic arthritis (PsA) 566f, 5678, 568t
PSP see progressive supranuclear palsy
PSV see pressure-support ventilation
psychiatry 651
psychotropic agents 6557
PTCAS see percutaneous transluminal
cerebrovascular angioplasty and stenting
PTS see post-thrombotic syndrome
PTSD see post-traumatic stress disorder
puberty 2945, 296f
PUD see peptic ulcer disease
pulmonary arteries, chest CT of 82b, 83t, 84
pulmonary disorders 124, 124b
pulmonary edema 131
pulmonary embolism (PE) 79t, 13940
pulmonary fibrosis, idiopathic 132
pulmonary hypertension (PH) 1334, 133b,
1389, 139b
pulmonary infections
bacterial 133b, 134
environmental factors in 137t
fungal 133b, 134
pneumonia 137t
viral 133b, 134
pulmonary regurgitation 182t, 189
pulmonary stenosis 182t, 189
pulmonary valve 165
pulmonary valve disease 182t, 189
pulmonology 11352
acidbase disturbances in 120
airways diseases
ABPA 126, 126f
asthma 1246, 150, 765
bronchiolitis 1278, 128f
COPD 115, 117, 1289, 150, 151
cystic fibrosis 127
interstitial lung disease 12930, 130b
anatomy and physiology in
Aa gradient 118
gas exchange 118, 118f
right-to-left shunting 119
V/Q inequality 11819, 119f
breath control in 122, 123f
clinical clues with disease of
breathing patterns 115
chest pain 117
chronic cough 116, 150
clubbing 116, 116b
dyspnea 11415, 115b
hemoptysis 11617
mediastinal masses 117, 117b
solitary pulmonary nodule 117
stridor 118
wheeze 117
critical care medicine
cardiac arrest 144
diagnosis and disease management
acute respiratory distress syndrome
1457, 145f
shock 1445, 145t

mechanical ventilation of lungs
extracorporeal membrane
oxygenation 148, 149b
invasive positive-pressure ventilation
148
non-invasive positive-pressure
ventilation 1478
resuscitation 144
eosinophilic pulmonary disorders
acute eosinophilic pneumonia 133
chronic eosinophilic pneumonia 133
genetics of 124
lung function measurement in
DLCO test 122, 123t
interpretation of 122, 123t
lung volumes interpretation 122
lung transplantation 1401, 140t
pathophysiology
hypercapnia 118
hypoxemia 118
oxygenhemoglobin association
dissociation curve 119
pharmacology
anti-inflammatory agents 141
bronchodilators 141
pleural disease 1368, 138t
pleural effusion 1368, 138t
pneumothorax 138
pulmonary disorders
hypoventilation 124
respiratory failure 124, 124b
pulmonary hemorrhage 1334, 133b
pulmonary infections
bacterial 133b, 134
environmental factors in 137t
fungal 133b, 134
pneumonia 137t
viral 133b, 134
pulmonary vascular disease
pulmonary embolism 13940
pulmonary hypertension 1389, 139b
respiratory disease, clinical presentations of
114, 115b
respiratory sleep medicine
clinical clues for 142
disorders 1423
respiratory tract defenses in
immune system 1234
mechanical defenses 1223
ventilation disorders in 115b
pulse 1556, 156f, 156t
PUO see pyrexia of unknown origin
pupils
abnormalities 595t
accommodation response 72930
direct pupillary response 729
size 729
swinging flashlight test 729
unequal 730
purple glove syndrome 618f
PV see polycythemia rubra vera
PVT see portal vein thrombosis
pyoderma gangrenosum 71920, 720f
pyrexia of unknown origin (PUO) 6812
Q
Q fever 705t
quality use of medicines (QUM)
adverse drug reactions 389, 39b, 40b
circle of care with 367, 37f

deprescribing 38, 38f
drug interactions 3940
drug profile with 37, 37f
drug regulation with 401
drug research for 412
getting it right with 37, 37f
patient profile with 37, 37f
prescribing checklist 38, 38b
therapeutic drug monitoring for 40
quasi-experimental trials 7
quinolones 675
QUM see quality use of medicines
R
RA see rheumatoid arthritis
rabies 703t, 705t
rabies immune globulin (RIG) 707
radiculopathy 642t
radionuclide myocardial perfusion imaging
160t, 166, 166f
radiotherapy 4612
adjuvant 460
pituitary and hypothalamus disorders
treatment with 274
raised intracranial pressure (ICP) 465
random error 5
randomized trials 67, 7b
ranolazine 176
rapidly progressive glomerulonephritis
(RPGN) 2424, 243f, 244b, 245b
rasagiline, for Parkinsons disease 626
rash 661
RBBB see right bundle branch block
reactive arthritis (ReA) 566f, 5689
receptors 35
reciprocal translocation 64, 65f
recurrent vulvo-vaginal candidiasis 751
red person syndrome 7212, 722f
reflux nephropathy 253, 253b
refractory angina 1767
refractory hypertension 220, 220b
regulation 601, 61f
relapsing polychondritis (RP) 574, 574f
relapsing-remitting MS (RRMS) 630
relative risk 9, 10f
renal artery stenosis 251, 251f
renal cysts 2345
renal failure 637t
renal hilum, abdominal CT of 86b, 87, 88t
renal replacement therapy 2557, 256t, 257b
renal stones 2358, 235b, 236b
renal tubular acidosis 2612, 262t
residual volume (RV) 120, 123t
resistant hypertension 220
respiratory acidosis 120
respiratory alkalosis 120
respiratory failure 124, 124b
respiratory sleep medicine 1423
respiratory syncytial virus (RSV) 679
restrictive cardiomyopathy 1923
retinal migraine 599
retinitis 736
retinopathy 2223, 224f
rheumatoid arthritis (RA)
clinical features and complications with
5613, 562f
diagnosis of 561, 561b, 562t
genetics and environmental contribution to
5601, 560f
investigations into 563
pathology of 561
treatment for 5635, 564f, 565t, 568t
Rhizomucor 667
805
Index
Rhizopus 667
rhythm control 199
ribavirin 679
ribonucleic acid (RNA) 57, 67
messenger 589, 59f
ribosome 60
rickets 2856, 285t, 286t
rifampicin 674t, 676
rifamycin 676
RIG see rabies immune globulin
right bundle branch block (RBBB) 202
rigidity 624
RNA see ribonucleic acid
Rocky Mountain spotted fever 696f
rosacea 715, 716f
rotavirus 703t
Roth spots 208, 208f
route of administration 29, 53
roxithromycin 675
RP see relapsing polychondritis
RPGN see rapidly progressive
glomerulonephritis
RRMS see relapsing-remitting MS
RSV see respiratory syncytial virus
rubella 703t
RV see residual volume
S
Saksenaea 667
Salmonella enterica 675
sarcoidosis 132, 635
sarcoma 4812
sarcopenia, in elderly 784
SBP see spontaneous bacterial peritonitis
SCLC see small-cell lung cancer
scleritis 736
scleroderma 5312, 531b, 532b
scleroderma kidney 2523
sclerosing glomerular disease
FSGN 24851, 250t
sclero-uveitis 736
secondary headache
intracranial pressure and 6001
low pressure 601
secondary somatization 653
seizures 61118
appearance of 612t
causes 61213, 612t
childhood absence 614
focal 611
generalized 611
investigation of first 613, 614t
non-epileptic 618
partial 611
post-ictal 612
prodrome 612
types 61112
selection bias 6b
selective serotonin reuptake inhibitors
(SSRIs) 46, 47f, 6567
seminoma 471, 472
sensitivity 11, 12f, 163
sensory neuropathy 642t
sepsis, in elderly 785
septic arthritis 5845, 584b
sequencing 65
serotonin toxicity 46, 47f
differentiating 657t
serotoninnoradrenaline reuptake inhibitors
(SNRIs) 46, 657
sexual problems 7556
sexually transmitted infections (STIs)
68692
806

examination 688
management 688
in women 7534
Szary syndrome 723
shock 1445, 145t
shoulder pain 57880, 579f, 579t, 580b
SIBO see small-intestinal bacterial overgrowth
sickle cell disease 4478
signaling molecules 35
silhouette sign 80t
silicosis 130, 131f
single-nucleotide polymorphism (SNP) 61
sinus arrest 194f, 195
sinus arrhythmia 194
sinus bradycardia 194
sinus tachycardia 194
sitagliptin 34t
Sjgrens syndrome (SS) 5279, 528t, 737
skeleton
chest X-rays for 73b, 75
see also musculoskeletal medicine
skin disease
autoimmune 71522
genetic 7223
malignancy-associated 723, 724t
skin infections 6835, 684t
with underlying systemic disease 71922
SLE see systemic lupus erythematosus
SM see systemic mastocytosis
small bowel
CIIP 337
diarrhea 32831b, 32835, 329t, 331t,
333f, 334f, 354
eosinophilic gastroenteritis 337, 337t
malabsorption 3356
small-intestinal bacterial overgrowth 3367
tropical sprue 336
small-cell lung cancer (SCLC) 4689
small-intestinal bacterial overgrowth (SIBO)
3367
snake bites 50, 54
snoring 142
SNP see single-nucleotide polymorphism
SNRIs see serotoninnoradrenaline reuptake
inhibitors
social isolation, in elderly 786
sodium cromoglycate 141
sodium valproate 617t
sole, rash on 721
solid-organ transplant patients 705
immunization 705
solitary pulmonary nodule (coin lesion) 117
somatization, secondary 653
SPACE 664
specificity 11, 12f, 163
spice 49
spider bites 4950
spinal cord compression 4634, 464f
spine, chest X-rays for 73b, 74t
spleen metastasis, abdominal ultrasound of
93t
splenectomized patients 686
splice sites 62
splinter hemorrhages 208, 208f
spondyloarthropathies 5659, 565f, 566f,
567f, 568t
spontaneous bacterial peritonitis (SBP) 388

sporadic hemiplegic migraine 598
SS see Sjgrens syndrome
SSRIs see selective serotonin reuptake
inhibitors
stability, in elderly 7834
standardized rate 9
Staphylococcus aureus 662
methicillin-resistant 696t
statins 171, 181, 637t
status epilepticus 616
ST-elevation myocardial infarction (STEMI)
161t, 167f, 177, 177f, 17980, 179f
steroidal contraception 7467
STIs see sexually transmitted infections
stomach
dyspepsia and its management 3245,
325t, 364
gastritis and gastropathy 325
gastroparesis 327
peptic ulcer disease 325
physiology of acid secretion 3234, 323f,
323t
post-gastrectomy complications 3267
tumors 326, 326b, 326f
strabismus 731
Streptococcus pneumoniae 6623
Streptococcus pyogenes 663
stress incontinence 782
stridor 118
stroke 6016
acute assessment and management 6023
cerebellar 622
early secondary prevention 6056
antiplatelet therapy 605
blood pressure lowering 605
cholesterol lowering and 6056
new oral anticoagulants for 605
warfarin for 605
general care measures 6045
ischemic, causes of 602t
neurosurgical intervention 604
thrombolysis in 6034
TOAST classification 602b
vertigo and 6212
Strongyloides stercoralis 668
ST-segment depression 162
ST-segment elevation 162
stupor 594
SturgeWeber syndrome 723
subarachnoid hemorrhage 601
management 606
natural history 606
sub-specialty medicine, general versus 12
suicide 6545
risk assessment 655
sulfonamides 675
sumatriptan 600
superficial spreading melanoma 480
superior vena cava (SVC) obstruction 465
suprasellar, head CT for 95b, 99t, 101
supratentorial infarct 603f
supraventricular premature complexes
(ectopics) 195
supraventricular tachycardia (SVT) 1956
SVC obstruction see superior vena cava
obstruction
SVT see supraventricular tachycardia
Sweets syndrome 720, 720f
swinging flashlight test 729
symphysis pubis, abdominal CT of 86b, 89,
89t
symptomatic generalized epilepsies 615
symptomatic myeloma 4389, 438t
Index
syncope 155
synonymous change 61
syphilis 691
systematic error 5, 6b
systemic disease
liver and 400, 400b
skin infections with 71922
systemic lupus erythematosus (SLE) 5237,
523f, 5245b, 526t, 527t, 770
systemic mastocytosis (SM) 522
systemic medication, ocular effects of 739
systemic viral infections 6926
systolic murmurs 158
T
T wave changes 162
T1DM see type 1 diabetes mellitus
T2DM see type 2 diabetes mellitus
tachypnea 115
Takayasu arteritis (TAK) 535b, 536
Takotsubo cardiomyopathy 193t, 194
tamponade 21213
tardive dyskinesia (TD) 656
tazobactam 672t
TD see tardive dyskinesia
TDM see therapeutic drug monitoring
TEE see transesophageal echocardiography
teicoplanin 674t
telomere shortening 778
temporal lobe epilepsy (TLE) 615
tennis elbow 581
teriflunomide 633t
terrorism toxicology
testis cancer 4713, 472t
testosterone 756
tetanus 671t, 702t, 705t
tetanus immune globulin (TIG) 707
tetracycline 674t, 6756
thallium, antidote for poison from 44t
therapeutic drug monitoring (TDM) 40
thin basement membrane disease 2389
thoracic computed tomography (chest CT)
review areas for 84
thrombolysis 6034
(TTP) 2512, 41819
thyroid cancer 280
thyroid disease in pregnancy 280
thyroid disorders
goiter and thyroid nodules 27980, 279f
hypothyroidism 2789
physiology and assessment of 275, 275t
in pregnancy 280, 7667
thyroid cancer 280
thyroid imaging 2756, 276f
thyroid gland, chest CT of 82b, 83t, 84
thyroid nodules 27980, 279f

thyroid-related orbitopathy 7367
thyrotoxicosis 637t
TIA see transient ischemic attack
ticarcillin 672t
tick-borne encephalitis 703t
tics 628
tidal volume (TV) 120
TIG see tetanus immune globulin
tigecycline 674t, 6756
tizanidine 628
TLC see total lung capacity
TLE see temporal lobe epilepsy
TM see transverse myelitis
(TRAPS) 541
TOAST classification of strokes 602b
topiramate 34t, 617
total cholesterol 168
total lung capacity (TLC) 120, 123t
total parental nutrition (TPN) 3412
toxicology
chemicals 49
clinical assessment in
investigations 423
physical examination 43t
risk assessment 43
drugs of abuse or misuse
cocaine and crack cocaine 48
drink spiking 49
GHB 48
opioids 489
prescription drug abuse 49
synthetic cannabinoids 49
synthetic cathinones 49
epidemiology of poisoning in 42
information sources for 42
management of common poisons in
acetaminophen 445, 45f, 46t
benzodiazepines 47
insulin 47
NaSSAs 46
newer antipsychotics 47
NRIs 47
NSAIDs 46
oral hypoglycemics 47
poison antidotes 44t
SNRIs 46
SSRIs 46, 47f
tricyclic antidepressants 46
management principles of 434
marine envenomation 50
snake bites 50, 54
spider bites 4950
terrorism
TPN see total parental nutrition
TR see tricuspid regurgitation
trachea, chest X-rays for 73b, 74t
transcription 589, 59f
transdermal contraception 748
transesophageal echocardiography (TEE) 164
transient ischemic attack (TIA) 6067
investigation 607
pathophysiology 607
recurrent event risk 607
translation 5960, 59f, 60f
translocation 64
reciprocal 64, 65f
transplantation
liver 3934, 393f, 394f
lung 1401, 140t

renal 2557, 257b
transporters 32f, 35
transverse myelitis (TM) 6345
TRAPS see TNF-receptor-associated
periodic syndrome
trastuzumab emtansine 484
travel vaccines 7067
tremor
essential 6234
physiological 623
Treponema pallidum 691, 692
Trichomonas vaginalis 690
tricuspid regurgitation (TR) 182t, 189, 189t
tricuspid stenosis (TS) 182t, 1889, 189t
tricuspid valve 165
tricyclic antidepressants 657
toxicology of 46
triglyceride 168, 171
trimethoprim 675
triple-phase CT abdomen 85t, 86
triptans, for migraine 599
tropical sprue 336
truth-telling 1920
TS see tricuspid stenosis
TTP see thrombotic thrombocytopenic
purpura
tuberculosis 702t
tuberous sclerosis 722
tubulo-interstitial diseases 2578, 258t
tumor markers 4656, 487
Turner syndrome 65
Turners sign 358, 359f
TV see tidal volume
type 1 diabetes mellitus (T1DM) 3067,
306b, 306t, 307t
type 2 diabetes mellitus (T2DM) 30710,
308b, 308t, 309f, 309t, 310t
typhoid 702t, 705t
U
UC see ulcerative colitis
Uhthoff s phenomenon 631
ulcerative colitis (UC) 345b, 345f, 34651,
34750t, 365
uncoating inhibitors 678
unequal pupils 730
unexplained infertility 745
ureter tumors 46970
urethritis 690
urge incontinence 782
urinary tract infection
clinical presentation 238
disease mechanisms for 238
treatment and targets for 238, 239b
urticaria 51619, 516f, 517b, 517f, 518t
uveitis 7356
V
vaccines
booster doses 704, 705t
chemical and physical properties 7034
inactivated 702t
for occupational exposure 706t
in specific populations 7047
travel 7067
see also immunization
vaccinia 703t
VaD see vascular dementia
vaginal ring, contraceptive 748
vaginitis, atrophic 753
valaciclovir 678
807
Index
valganciclovir 678
valvular heart disease 1812, 182t, 7712
vancomycin 674t
vancomycin-resistant enterococci (VRE)
663, 696t
vanilla sky 49
varenicline 34t
varicella zoster immune globulin (VZIG) 707
varicella zoster virus (VZV) 665, 703t
vascular dementia (VaD) 609
vascular renal disease 2512, 251f
vascularity, chest X-rays for 73b, 74t
vasculitis 692
classification of 534b
large-vessel vasculitis 5346, 535b
medium-vessel vasculitis 535b, 5367,
536b, 537b
single-organ vasculitis 535b, 539
small-vessel vasculitis 535b, 5379, 537b
variable-vessel vasculitis 535b, 53940,
539f, 540f
VEBs see ventricular ectopic beats
venlafaxine, for migraine 599
venous sinus thrombosis (VST) 600
venous thromboembolism (VTE) 412
in pregnancy 766
venous thrombosis
diagnosis of 411
post-thrombotic syndrome 412
predisposition to 41011, 411b, 411t
venous thromboembolism 412
ventilation disorders 115b
ventricular ectopic beats (VEBs) 200
ventricular fibrillation (VF) 201
808
ventricular tachycardia (VT) 2001, 201f

vertex, head CT for 95b, 100t, 101
vertigo 61823
migraine and 621
stroke and 6212
treatment 622
vestibular anatomy 620f
vestibular neuritis 61920
vestibular rehabilitation 622
VF see ventricular fibrillation
VIN see vulvar intraepithelial neoplasia
VIPoma 301
viral infection, in pregnancy 76970
viral pulmonary infections 133b, 134
virtue ethics 18
vision
color 730
field of 7289
visual acuity 728
vital capacity 120, 123t
vitamin deficiency 33840t, 340f
vomiting 4936, 494f, 4956t, 501
Von HippelLindau disease 723
von Willebrand disease (vWD) 41415,
415t
voriconazole 667, 67981
V/Q inequality 11819, 119f
VRE see vancomycin-resistant enterococci
VST see venous sinus thrombosis
VT see ventricular tachycardia
VTE see venous thromboembolism
vulvar conditions 7503
vulvar intraepithelial neoplasia (VIN) 752
vulvar lichen sclerosis 752f
vulvar psoriasis 752f
vulvar vestibular syndrome 753

vulvovaginitis, erosive 753
vWD see von Willebrand disease
VZIG see varicella zoster immune globulin
VZV see varicella zoster virus
W
warfarin, for stroke prevention 605
Wegeners granulomatosis (WG) 535b,
5378
West syndrome 615
WG see Wegeners granulomatosis
wheeze 117
Whipples disease 3356
degeneration) 397
womens health
infertility 7434
sexual problems 7556
see also female reproductive endocrinology
X
X-linked dominant 62
X-linked recessive 623
Y
yellow fever 703t
Y-linked inheritance 63
Z
zanamivir 679
ZollingerEllison syndrome (ZES) 326
zoonoses 6923
history of 693
from specific animals 694t
zoster 703t

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ESSENTIALS OF

Sydney Edinburgh London New York Philadelphia St Louis Toronto

This edition 2015 Elsevier Australia

FOREWORD BY KENNETH DEVAULT

Internal medicine is the broadest of fields, and a textbook to

quick and approachable reference when faced with problems

FOREWORD BY NICHOLAS SAUNDERS

Both physician trainees studying for their college and board

Foreword by Kenneth DeVault

Brad Frankum, David Currow and Nicholas J Talley

General versus sub-specialty medicine

Jane Young and David Currow

Matt Doogue and Alison Jones

Ian Kerridge and Michael Lowe

Clinical ethics: theory and frameworks for

Calculating the risks of disease

David Arnold, Peter Wark, Michael Hensley and

Important clinical clues

Aortic regurgitation (AR)

Treatment for chronic primary hypertension

Chronic kidney disease (CKD)

Mark McLean and Sue Lynn Lau

Magnus Halland, Vimalan Ambikaipaker,

Robert Gibson, Magnus Halland and

Bilirubin metabolism and jaundice

Plasma cell disorders

Meera Agar and Katherine Clark

Christopher Levi, Thomas Wellings and

Dementia with Lewy bodies (DLB)

Michael Hennessy and Brad Frankum

Will Browne and Kichu Nair

Pathology: disease in older people

The definition of a specialist as one who knows more and

The editors would like to thank Teresa McIntyre for

Robert Gibson BMed, FRACP

David Arnold BMed, FRACP, FCCP

Magnus Halland BMed, BMedSci (Hons), MPH

John Attia MD, PhD, FRCPC, FRACP

Annemarie Hennessy MBBS, PhD, FRACP, MBA

Will Browne MBCHB, FRACP, MMed Sci

Michael P Hennessy BMedSc, MBBS, MBioMedE,

Christos S Karapetis MBBS, FRACP, MMedSc

and Public Health, Newcastle, NSW, Australia; Director,

Kristine Barlow-Stewart BSc, PhD, FHGSA

Rob MacGinley MBBS, BMedSci, MMedSci, MClin

E. Michael Shanahan BMBS MPH PhD FAFOEM

Jonathan Watson MA BMBCh FRCP PhD FRACP

Stephen Shumack OAM, MBBS, FACD

Tim Wigmore, MB, BCh, FRCA, FCICM, FFICM

Winnie Tong B.Sc (Med) MBBS FRACP FRCPA

Ingrid Winship MB ChB MD Cape Town FRACP

Elizabeth Verghese BSc(Hons), PhD,

Kwang Chien Yee B Med Sci (Hons), MBBS (Hons),

INTERNAL MEDICINE IN THE

expert and authoritative in very narrow fields. On the other

Essentials of internal medicine

treatment than removing them. Similarly, the care provided

Furthermore, the larger the number of investigations

THE PHYSICIANS ROLE IN

THE PHYSICIAN AS SCHOLAR

LR (<0.1). The hypothetical test meets this criterion,