Tarascon Adult Endocrinology

Tarascon Adult
Endocrinology
Pocketbook
Marc J. Laufgraben, MD, MBA, FACE, FACP

Associate Professor of Medicine,
Cooper Medical School of Rowan University and Chief,
Division of Endocrinology, Cooper University Hospital, Camden, NJ
Geetha Gopalakrishnan, MD
Associate Professor of Medicine
Director of Fellowship Program in Diabetes and Endocrinology
Alpert Medical School of Brown University, Providence, RI
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CONTRIBUTORS LIST
Shabina Ahmed, MD Johns Hopkins University, Division of Endocrinology
and Metabolism, Baltimore, MD
Erik K Alexander, MD Brigham and Women’s Hospital, Boston, MA
Bradley Anawalt, MD University of Washington Medical Center, Seattle, WA
Jennifer A Argumedo, MD Texas Diabetes Institute, San Antonio, TX
Stephen L Atkin FRCP, PhD Head, Academic Endocrinology, Diabetes
and Metabolism, Hull York Medical School, Michael White Centre,
Hull, UK
Richard J Auchus, MD MEND/Internal Medicine, University of Michigan,
Ann Arbor, MI
Theingi Aung, MD The Oxford Centre for Diabetes, Endocrinology, and
Metabolism The Churchill Hospital, Oxford, UK
Nupur Bahl, MD Rhode Island Hospital, E. Providence, RI
Guiseppe Barbesino, MD Massachusetts General Hospital, Boston, MA
Geetha Bhat, MD Cooper University Hospital, Division of Endocrinology,
Cherry Hill, NJ
Harikrashna Bhatt, MD Rhode Island Hospital, E. Providence, RI
Charlotte M Boney, MD Rhode Island Hospital, Department of Pediatrics,
Providence, RI
George A Bray, MD Boyd Professor, Chief, Division of Clinical Obesity
and Metabolism Professor, Pennington Biomedical Research Center, Baton
Rouge, LA
Gregory A Brent, MD UCLA, Department of Medicine, Los Angeles, CA
M Luiza Caramori, MD, MSc, PhD University of Minnesota, Department of
Medicine, Division of Endocrinology and Diabetes, Minneapolis, MN
Harold E Carlson, MD Professor of Medicine and Division Head, Stony
Brook University School of Medicine, Department of Endocrinology, Stony
Brook, NY
Kenneth Chen, MD Women and Infants’ Hospital of Rhode Island,
Providence, RI
Vicky Cheng, MD Rhode Island Hospital, E. Providence, RI
David S Cooper, MD The Johns Hopkins University School of Medicine,
Division of Endocrinology, Baltimore, MD
Mark S Cooper, MD Queen Elizabeth Hospital, Department of Endocrinology,
Birmingham, UK
Glenn R Cunningham, MD Baylor College of Medicine, Houston, TX
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iv Contributors List
Guari Dhir, MD Temple University Hospital, Philadelphia, PA
Kevin Donohue, DO Thomas Jefferson University Hospital, Department of
Endocrinology, Philadelphia, PA
Diana R Engineer, MD Baylor College of Medicine, Houston, TX
Azeez Farooki, MA Memorial Sloan-Kettering Cancer Center, New York, NY
Mark N Feinglos, MD Duke University Medical Center, Durham, NC
Natali Franzblau, MD Cooper University Hospital, Department of OB/
Gyn, Camden, NJ
Neil Gittoes, MD Queen Elizabeth Hospital, Department of Medicine,
Birmingham, UK
Ole-Petter Hamnvik Brigham and Women’s Hospital, Boston, MA
Amir H Hamrahian, MD Cleveland Clinic, Department of Endocrinology,
Cleveland, OH
Anthony Heaney, MD Gonda Diabetes Center, Los Angeles, CA
Mark Herman, MD Beth Israel Deaconess Medical Center, Boston, MA
Silvio E Inzucchi, MD Yale University, New Haven, CT
Serge Jabbour, MD, FACE, FACP Thomas Jefferson University Hospital,
Department of Endocrinology, Philadelphia, PA
William Jeffcoate, MRCP Consultant Endocrinologist, Diabetologist,
Nottingham University Hospitals, Department of Diabetes and Endocrinology,
Nottingham, UK
Tessey Jose, MD Yale University, New Haven, CT
Rajesh M Kabadi, MD Cooper University Hospital, Camden, NJ
Niki Karavitaki, MD The Oxford Centre for Diabetes, Endocrinology, and
Metabolism The Churchill Hospital, Oxford, UK
Laurence Katznelson, MD Professor of Medicine and Neurosurgery,
Stanford University, Stanford, CA
Steven Kaufman, MD Cooper University, Department of Endocrinology,
Cherry Hill, NJ
Aliya Khan, MD Professor of Clinical Medicine, McMaster University,
Oakville, ON, Canada
Maryam Khan, MD Cooper University Hospital, Division of Endocrinology,
Camden, NJ
Jaya Kothapolly, MD Cooper University Hostipal, Willingboro, NJ
Matthew H Kulke, MD Dana-Farber Cancer Institute, Boston, MA
Andre Lacroix, MD Centre hospitalier de l’Universite de Montreal
(CHUM), Division of Endocrinology, Montreal, QC, Canada
David Wing-Hang Lam, MD Mount Sinai School of Medicine, New York, NY
Rebecca Leboeuf, MD CHUM Hospital Notre-Dame, Montreal, QC, Canada
Lillian F Lien, MD Duke University Medical Center, Durham, NC
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Contributors List v
Ivana Lukacova-Zib, MD Rhode Island Hospital, E. Providence, RI
Eleftheria Maratos-Flier, MD Beth Israel Deaconess Medical Center,
Boston, MA
Jane V Mayrin, MD Einstein Medical Center, Elkin Park, PA
Rebecca McEachern Clinical Assistant Professor of Pediatrics, Pediatric
Endocrinology of Rhode Island, Providence, RI
Anna Milanesi, MD, PhD Cedars-Sinai Medical Center, Division of
Endocrinology, Los Angeles, CA
Mark E Molitch, MD Martha Leland Sherwin Professor of Endocrinology,
Northwestern University Feinburg School of Medicine, Division of
Endrocrinology, Metabolism and Molecular Medicine, Chicago, IL
Farah Morgan, MD Cooper University Hospital, Division of Endocrinology,
Diabetes and Metabolism, Cherry Hill, NJ
Harmeet Singh Narula, MD Assistant Professor of Clinical Medicine,
Stony Brook University School of Medicine, Department of Endocrinology,
Stony Brook, NY
Lawrence Nelson, MD National Institutes of Health (NIH), Bethesda, MD
Benjamin O’Donnell, MD Rhode Island Hospital, E. Providence, RI
Catherine J Owen, MRCP, PhD Royal Victoria Infirmary, Department of
Pediatric Endocrinology, New Castle upon Tyne, UK
Karel Pacak, MD, PhD, DSc Head, Section on Medical
Neuroendocrinology, National Institutes of Health (NIH), Bethesda, MD
Kevin M Panalone, MD Cleveland Clinic, Department of Endocrinology,
Cleveland, OH
Mohammed Zohair Rahman, MD McMaster University, Oakville, ON,
Canada
J Bruce Redmon, MD University of Minnesota, Minneapolis, MN
Raymond R Russell, MD Yale University, New Haven, CT
Chad D Sagnella, MD Resident, Yale University School of Medicine,
Emergency Medicine, New Haven, CT
Thokhukat Sathyapalan, MD, FRCP Michael White Centre for Diabetes
and Endocrinology, Hull, UK
Urvi Shah, MD Eunice Kennedy Shriver NICHD/NIH, Bethesda, MD
Jennifer Sipos, MD Ohio State University, Columbus, OH
Elias S Siraj, MD Temple University Hospital, Philadelphia, PA
Robert J Smith Professor of Medicine, Alpert Medical School of Brown
University, Providence, RI
Michael Stowasser, MD Endocrine Hypertension Research Centre,
University of Queensland School of Medicine, Brisbane, Queensland,
Australia
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vi Contributors List
Vin Tangpricha, MD Associate Professor, Emory College, Atlanta, GA
Pamela Taxel, MD Associate Professor of Medicine, University of
Connecticut Health Center, Farmington, CT
Joseph R Tucci, MD, FACP, FACE Roger Williams Medical Center,
Providence, RI
Joseph G Verbalis, MD Chief of the Division of Endocrinology and
Metabolism, Georgetown University, Washinton, DC
Wendy Vitek, MD University of Rochester Medical Center, Rochester, NY
Perry J Weinstock, MD Cooper University Hospital, Camden, NJ
Hilary Whitlatch, MD Rhode Island Hospital, E. Providence, RI
Robert T Yanagisawa, MD Program Director, Clinical Fellowship in
Encrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine,
New York, NY
Kevin CJ Yuen, MD Oregon Health and Science University, Portland, OR
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CONTENTS
Abbreviations in Text xiv Craniopharyngiomas 34
References 36
SECTION I: PITUITARY 1 7 Hypoosmolality and the
1 Pituitary Essentials 3 Syndrome of Inappropriate
Basic Facts 3 Antidiuretic Hormone
Pituitary Control 3 Secretion 37
Pituitary Function 5 Pathophysiology 37
References 6 Clinical Presentation 37
Diagnostic Evaluation 38
2 Hypopituitarism 7 Classification of
Background 7 Hypoosmolality
Pathophysiology 7 by ECF Volume Status 38
Clinical Presentation 7 Syndrome of Inappropriate
Diagnostic Evaluation 9 Antidiuretic Hormone
Hormone Replacement 9 Secretion (SIADH) 39
References 11 References 42
3 Prolactinemia 8 Diabetes Insipidus 43
and Prolactinoma 13 Definition 43
Pathophysiology of Etiologies 43
Hyperprolactinemia Clinical Manifestations 43
and Prolactinomas 13 Diagnosis 44
Clinical Presentation 13 References 45
Treatment 15
Follow-Up 16 SECTION II: THYROID 47
Pregnancy 16
References 17 9 Thyroid Essentials and
Thyroid Function Tests 49
4 Acromegaly 19 Anatomy 49
Pathophysiology 19 Histology 49
Clinical Presentation 19 Physiology 49
Diagnostic Evaluation 20 References 52
Management 21
References 24 10 Thyrotoxicosis
and Hyperthyroidism 53
5 Growth Hormone Etiology and Pathophysiology 53
Deficiency in Adults 25 Clinical Presentation 54
Pathophysiology 25 Diagnosis 54
Clinical Presentation 25 Management Options 57
Laboratory Evaluation 26 Thyroid Storm: Diagnosis
Imaging 29 and Management 60
Management 29 Subclinical Hyperthyroidism 60
6 Pituitary Incidentalomas, 11 Hypothyroidism 63
Nonfunctioning Pituitary Background 63
Adenomas, and Diagnosis 64
Craniopharyngiomas 31 Treatment 65
Pituitary Incidentalomas 31 Subclinical Hypothyroidism 66
Nonfunctioning Pituitary Myxedema Coma 66
Adenomas 32 References 67
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viii Contents
12 Nonthyroidal Illness Follow-Up 96
Syndrome 69 References 96
Background 69 17 Anaplastic Thyroid
Pathophysiology 69 Cancer and Poorly
Diagnostic Evaluation 70 Differentiated Thyroid
Management 71 Cancer 97
References 71 Pathophysiology 97
13 Drugs Affecting Thyroid Clinical Presentation 97
Function and Thyroid Diagnostic Evaluation 98
Hormone Replacement 73 Management 100
General Comments 73 Surgery 100
Drugs Affecting Thyroid External Radiation Therapy 100
Absorption 73 References 102
Drugs Affecting Thyroid 18 Thyroid Disorders
Hormone Metabolism 74 in Pregnancy 103
Drugs Directly Affecting Hypothyroidism in Pregnancy 103
Thyroid Function 75 Etiology and Pathophysiology 103
Drugs Causing Central Clinical Presentation 103
Hypothyroidism 77 Screening for Hypothyroidism
References 78 in Pregnancy 103
14 Thyroid Nodule Laboratory Evaluation 104
Evaluation 79 Diagnosis 104
Epidemiology and Management 104
Pathophysiology 79 Hyperthyroidism in
Clinical Presentation 79 Pregnancy 105
Diagnostic Evaluation 80 Etiology and Pathophysiology 105
Management 81 Clinical Presentation 106
References 82 Laboratory Evaluation 106
Diagnosis 106
15 Papillary and Follicular Management 107
Thyroid Carcinoma 85 Thyroid Nodules and
Definition 85 Thyroid Cancer 107
Epidemiology 85 Etiology and Pathophysiology 107
Risk Factors 85 Clinical Presentation 108
Pathogenesis 86 Diagnosis and Management 108
Pathological Features 86 History of Thyroid Cancer 109
Clinical Presentation Postpartum Thyroiditis 109
and Diagnosis 87 Etiology and Pathophysiology 109
Prognosis 87 Clinical Presentation 109
Tumor Node Metastasis Diagnostic Evaluation 109
(TNM) Classification 88 Treatment and Monitoring 110
Initial Treatment of DTC 89 References 110
Long-Term Management 90
Management of Persistent/
Recurrent Disease 91 SECTION III: ADRENAL 111
References 92 19 Adrenal Essentials 113
16 Medullary Thyroid Anatomy 113
Cancer 93 Histology 113
Pathophysiology 93 Hormone Synthesis 113
Clinical Presentation 94 Regulation of Adrenal
Diagnosis 94 Function 114
Clinical Features 95 Function of Adrenal
Staging 95 Hormones 115
Therapy 95 References 116
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Contents ix
20 Adrenal Insuffi ciency 117 25 Adrenal Incidentaloma 149
Causes of Adrenal Introduction 149
Insufficiency 117 Assessment for Hormone
Diagnosis of AI 118 Hypersecretion 149
Chronic Treatment of AI 119 Pheochromocytoma 149
Acute Adrenal Crisis 120 Subclinical Cushing’s
Conditions That May Syndrome 150
Require an Adjustment Primary Aldosteronism 150
in HC Dosing 120 Differentiating Benign
Patient Education and and Malignant Adrenal
“Sick Day Management” 120 Masses 151
Critical Illness-Related Natural History and
Corticosteroid Insufficiency Follow-Up of Patients with
(“Relative AI”) 121 Adrenal Incidentalomas 153
21 Cushing’s Syndrome 123 26 Adrenocortical
Background 123 Carcinoma 155
Diagnostic Strategy 124 Epidemiology and
Standard Diagnostic Tests Pathophysiology 155
for Cushing’s Syndrome 125 Clinical Presentation 155
Differential Diagnosis Initial Therapy and Surgical
of Cushing’s Syndrome 126 Approach 157
Basics of Management Pathological Evaluation 157
of Major Causes of Adjuvant Mitotane or
Cushing’s Syndrome 127 Radiotherapy and
References 129 Follow-Up 157
Advanced Disease 158
22 Primary Aldosteronism 131 Mitotane Effect on Endocrine
Clinical Presentation 131 Function 158
Screening: Plasma References 159
Aldosterone/Renin
Ratio (ARR) Testing 131
Confirmatory Testing Options 132 SECTION IV: CALCIUM AND BONE 161
Subtype Differentiation 133 27 Calcium Metabolism
Management 134 Essentials 163
References 134 Maintenance of Overall
23 Pheochromocytoma 135 Calcium Balance 163
Pathophysiology 135 PTH 164
Clinical Presentation 136 Vitamin D 165
Diagnostic Evaluation 137 Calcitonin 167
Management 140 References 167
Malignant 28 Hypercalcemia 169
Pheochromocytomas 141 Incidence 169
Follow-Up 141 Pathophysiology 169
Acknowledgments 141 Clinical Presentation 170
References 142 Diagnostic Evaluation 170
24 Congenital Adrenal Management 172
Hyperplasia 143 References 173
Pathophysiology 143 29 Hyperparathyroidism 175
Types of CAH 144 Pathophysiology 175
Clinical Presentation 144 Clinical Presentation 176
Diagnostic Evaluation 145 Diagnostic Evaluation 176
Management 145 Management 178
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x Contents
30 Hypocalcemia 181 36 Testosterone
Pathophysiology 181 Defi ciency in Men 209
Specific Causes 181 Prevalence 209
Clinical Presentation 182 Pathophysiology 209
Laboratory Testing 182 Etiology 210
Management 183 History 211
References 184 Physical Exam 211
Chronic Conditions with
31 Vitamin D Defi ciency 185 High Prevalence of
Pathophysiology 185 Hypogonadism 211
Prevalence of Vitamin D Assays/Tests 212
Deficiency 185 Diagnosis 212
Risk Factors for Vitamin D Potential Risks of Androgen
Deficiency 185 Replacement 213
Clinical Presentation 186 References 216
Diagnosis 186
Management 186 37 Male Infertility 217
References 187 Definition of Infertility 217
32 Osteoporosis 189 Pathophysiology of Male
Epidemiology 189 Infertility 217
Definition 189 Clinical Presentation 218
Bone Metabolism 190 Diagnostic Evaluation 218
Risk Factors 191 Diagnostic Imaging 219
Screening 191 Treatment of Male
Treatment 191 Infertility 219
33 Paget’s Disease of Bone 38 Female Reproduction
(Osteitis Deformans) 195 Essentials 221
Etiology 195 Development of the Female
Pathophysiology 195 Reproductive Tract
Clinical Presentation 195 in the Embryo 221
Physical Examination 196 Puberty 221
Diagnostic Evaluation 196 Hormones of the Menstrual
Management 197 Cycle 221
Assessment of Therapeutic Normal Menstrual Cycle 224
Response 198 Menopause 224
39 Polycystic Ovary
SECTION V: REPRODUCTION 199 Syndrome (PCOS) 227
34 Male Reproduction Background 227
Essentials 201 Definitions 227
Testes 201 Symptoms 227
Reproductive Outflow Signs 228
Tract 202 Investigations 228
Sexual Differentiation 202 Imaging 229
Neuroendocrine General Management
Regulation 203 of PCOS 229
References 204 Approach to Hirsutism
in PCOS 230
35 Gynecomastia 205 Approach to Menstrual
Clinical Presentation 206 Irregularity in PCOS 231
Diagnostic Evaluation 206 Approach to Infertility
Management 207 in PCOS 231
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Contents xi
40 Hirsutism 233 Glycemic Management in
Pathophysiology 233 Type 1 Diabetes:
Clinical Presentation 233 Initiating Outpatient
Diagnostic Evaluation 235 Regimens 264
Management 236 Glycemic Management
References 238 in Type 2 Diabetes:
ADA Guidelines 265
41 Adult-Onset Primary References 266
Ovarian Insuffi ciency
(POI) 239 45 Maturity Onset Diabetes
Definition 239 of the Young 267
Pathophysiology 239 Pathophysiology 267
Clinical Presentation 239 Clinical Presentation 267
Diagnostic Evaluation 240 Diagnostic Evaluation 267
Management 241 Management 268
Acknowledgments 243 References 270
References 244 46 Hyperglycemic Emergencies:
42 Female Infertility 245 Diabetic Ketoacidosis (DKA)
Pathophysiology 245 and the Hyperosmolar
Clinical Presentation 246 Hyperglycemic State
Diagnostic Evaluation 246 (HHS) 271
Management 247 Pathophysiology 271
References 249 Typical Precipitating Factors 272
Evaluation 272
SECTION VI: DIABETES, Commonly Seen Laboratory
METABOLISM, AND OBESITY 251 Abnormalities 273
Management 273
43 Endocrine Pancreas Complications of
and Fuel Metabolism Management 274
Essentials 253 Resolution of the
References 256 Hyperglycemic Crisis 275
44 Diabetes Mellitus 257 Transition from IV Insulin
Background 257 Infusion 275
Pathophysiology References 276
of Type 1 DM 257 47 Hypoglycemia in Patients
Clinical Presentation with Diabetes 277
of Type 1 DM 257 Definition 277
Pathophysiology Symptoms of Hypoglycemia 277
of Type 2 DM 257 Classification of
Clinical Presentation Hypoglycemia in
of Type 2 DM 258 Patients with Diabetes 277
Pathophysiology and Etiologies of Hypoglycemia
Clinical Presentation in Diabetes 277
of Other Forms of DM 258 Hypoglycemia-Associated
American Diabetes Autonomic Failure (HAAF) 278
Association (ADA) Criteria Acute Treatment of
for DM Screening in Adults 259 Hypoglycemia in
ADA Criteria for the Diabetes 279
Diagnosis of DM 259 Prevention of Hypoglycemia
Additional Laboratory in Diabetes 279
Testing for the Diagnosis References 280
and Management of
Glycemia in DM 260 48 Diabetic Retinopathy 281
Pharmaceutical Options for Pathophysiology 281
Diabetes Management 261 Clinical Presentation 281
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xii Contents
Diagnostic Evaluation 281 For Patients in ICUs 309
Management 282 References 310
References 283 54 Prediabetes and Diabetes
49 Diabetic Nephropathy 285 Prevention 311
Epidemiology 285 Pathophysiology 311
Risk Factors 285 Clinical Presentation 311
Pathophysiology 285 Associated Conditions 311
Clinical Presentation 286 Recommendations for
Diagnostic Evaluation 286 Delay of DM Type 2 312
Management 287 Management of CVD
References 288 in Prediabetes 312
Treatment Goals with
50 Distal Symmetric Pharmacologic Therapy 312
Polyneuropathy 289 References 313
Pathophysiology 289
Clinical Presentation 289 55 Diabetic Foot Disease 315
Screening and Monitoring Diabetic Foot Ulceration
of Distal Symmetric and Infection 315
Polyneuropathy (DSPN) 289 Charcot
Management of DSPN 290 Neuroosteoarthropathy
References 290 (CN; the Charcot Foot) 317
References 319
51 Cardiovascular Disease
in Type 2 Diabetes 293 56 Hypoglycemia Disorders 321
Diabetes and Cardiovascular Defined by Whipple’s Triad 321
Risk: Overview 293 Symptoms 321
Pathophysiology 293 Classification of
Glycemic Control 294 Hypoglycemias in Adults 321
Hypertension Management 297 Diagnosis 322
Dyslipidemia 298 Imaging (Localizing Studies) 323
Lipid Guidelines 298 Treatment 323
Antiplatelet Therapy 299 References 324
Coronary Heart Disease 57 Lipid Essentials 325
(CHD) Screening 300 Lipid Profile Reflects the
Management of DM in Acute Lipoproteins Carrying
Coronary Syndrome 300 Cholesterol and Triglyceride 325
References 301 Plasma Lipoproteins Are
Determined by 3 Interrelated
52 Diabetes in Pregnancy 303 Pathways 326
Classification 303 References 329
Risk Factors for GDM 303
Diagnosis of GDM 303 58 Lipid Disorders 331
Preconception Care of Women Lipid Components 331
with Preexisting Diabetes 304 Classification of Total
Management of Diabetes Cholesterol and LDL
in Pregnancy 304 Cholesterol 331
Special Prenatal Common Pharmacologic
Considerations for Therapies 335
Diabetic Patients 305 References 338
Postnatal Care 305 59 Essentials of Adipose
References 306 Tissue Endocrinology 339
53 Glycemic Issues in Types of Adipose Tissue 339
Hospitalized Patients 307 Endocrine Regulation of
For Hospitalized Patients Lipid Storage and Release
Outside the ICU 307 in Adipocytes 339
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Contents xiii
Adipose Tissue Derived Treatment of Symptoms
Efferent Signals 340 of Hormonal
Leptin 340 Hypersecretion by
Adiponectin 340 Tumor Type 358
Obesity 341 Treatment of Patients with
Adipose Tissue Endocrinology Hepatic-Predominant
in Obesity 341 Metastatic Disease 359
Lipodystrophies 342 Systemic Treatment Options
References 342 for Tumor Control 359
References 360
60 Obesity Management 343
Pathophysiology 343 63 Autoimmune
Diagnosis 343 Polyglandular Syndromes
Clinical Presentation 344 and Multiple Endocrine
Treatment 345 Neoplasias 361
References 347 Autoimmune Polyglandular
61 Metabolic Syndrome 349 Syndromes (APS) 361
Introduction 349 Autoimmune Polyglandular
Prevalence 349 Syndromes Type 2
Diagnosis 350 (APS2) 361
Clinical Presentation 350 Autoimmune Polyglandular
Laboratory Testing 350 Syndromes Type 1
Treatment 350 (APS1) 364
References 351 Multiple Endocrine
Neoplasias (MEN) 365
SECTION VII: MISCELLANEOUS 353 Clinical Presentation
of MEN-1 365
62 Pancreatic Neuroendocrine Clinical Presentation
Tumors and Carcinoid of MEN-2 366
Syndrome 355 Diagnosis of MEN-1 367
Pathophysiology 355 Diagnosis of MEN-2 367
Clinical Presentation 356 Management of MEN 368
Diagnosis 357 References 368
General Management
Approach 358 Index 369
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xiv Abbreviations in Text
ABBREVIATIONS IN TEXT
5-HIAA 5-hydroxyindole acetic acid
11OHD 11-hydroxylase deficiency
17-OHP 17-hydroxyprogesterone
17OHD 17-hydroxylase/17, 20-lyase deficiency
18FDG 18-fluorodeoxyglucose
21OHD 21-hydroxylase deficiency
25-OHD 25-hydroxy Vitamin D
3betaHSDD 3beta-hydroxysteroid dehydrogenase deficiency
4d CT four-dimensional computed tomography
ABCA1 ATP-binding cassette transport A1
ABG arterial blood gas
ACC adrenocortical carcinoma
ACCF American College of Cardiology Foundation
ACEI angiontensin-converting enzyme inhibitor
ACOG American College of Obstetrics & Gynecology
ACTH adrenocorticotropic hormone
ADA American Diabetes Association
ADH antidiuretic hormone
AFC antral follicle counts
AGE advanced glycation end products
AGHD adult-onset growth hormone deficiency
AHA American Heart Association
AI adrenal insufficiency
AIRE “autoimmune regulator” gene
AIT amiodarone-induced hyperthyroidism
AITD autoimmune thyroid disease
AMH antimullerian hormone
APECED autoimmunepolyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome
APS-1 autoimmune polyendocrine syndrome, type 1
APS(1/2) autoimmune polyglandular syndrome (type 1/2)
AR androgen receptor
ARB angiotensin (II) receptor blocker
ARR aldosterone/renin ratio
ASA aspirin
ATC anaplastic thyroid cancer
ATD antithyroid drugs
IPSS International Prognostic Scoring System
AUS atypia of undetermined significance
AVP arginine vasopressin
AVPR arginine vasopressin receptor
AZF azoospermic factor [AZFa/b/c]
BMD bone mineral density
BMI body mass index
BP blood pressure
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Abbreviations in Text xv
BPH benign prostatic hyperplasia
BUN blood urea nitrogen
BWL behavioral weight loss
C-peptide connecting peptide
Ca calcium
CAD coronary artery disease
CAH congenital adrenal hyperplasia
cAMP cyclic AMP
CaSR calcium-sensing receptor
CBC complete blood cell count
CBG corticosteroid-binding globulin
CBT cognitive behavioral therapy
CCH C-cell hyperplasia
CDC US Centers for Disease Control and Prevention
CE cholesterol ester
CEA carcinoembryonic antigen
CETP cholesterol ester transport protein
CFRD cystic fibrosis-related diabetes
CGA chromagranin A
CGRP calcitonin gene-related peptide
CHD coronary heart disease
CHF congestive heart failure
Cl- chloride
CM chylomicron
CMC chronic mucocutaneous candidiasis
CN Charcot neuroosteoarthropathy
CNS central nervous system
COPD chronic obstructive pulmonary disease
CPA cyproterone acetate
Cr creatinine
CRH corticotrophin-releasing hormone
CST cosyntropin stimulation test
CT computed tomography
CTR calcitonin receptor
CTx C-terminal telopeptide
CVA cerebrovascular accident
CVD cardiovascular disease
D1/D2/D3 Type 1/2/3 deiodinase
DA dopamine
dDAVP desmopressin
DEXA dual-energy X-ray absorptiometry
DHEA-s DHEA-sulphate
DHEA dehydroepiandrosterone
DHT dihydrotestosterone
DHT dihydrotestosterone
DIT diiodotyrosine
DKA diabetic ketoacidosis
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xvi Abbreviations in Text
DM diabetes mellitus
DOR diminished ovarian reserve
DPP-4 dipeptidyl peptidase-4
DRE digital rectal exam
DSD disorders of sex development
DSP diastolic blood pressure
DSPN distal symmetric polyneuropathy
DST dexamethasone suppression test
DTC differentiated thyroid cancer
EBRT external beam radiation therapy
ECF extracellular fluid
ECG electrocardiogram
EDP etoposide, doxorubicin, and cisplatin
Epi epinephrine
ESRD end-stage renal disease
FA fludrocortisone acetate
FAI free androgen index
FAP familial adenomatous polyposis
FC free cholesterol
FDA U.S. Food and Drug Administration
FDG fluorodeoxyglucose
FFA free fatty acid
FGF fibroblast growth factor
FHH familial hypercalciuric hypercalcemia
FLUS follicular lesion of undertermined significance
FNA fine needle aspiration
FRAX WHO Fracture Risk Assessment Tool
FSH follicular stimulating hormone
FT4 free thyroxine
FTC follicular thyroid carcinoma
FTI free thyroxine index
FTO fat mass and obesity
FXPOI fragile X-associated primary ovarian insufficiency
GCK glucokinase
GD Graves’ disease
GDM gestational diabetes mellitus
GFR glomerular filtration rate
GH growth hormone
GHD growth hormone deficiency
GHRH growth hormone−releasing hormone
GIP gastric inhibitory peptide
GLP-1 glucagon-like peptide 1
GnRH gonadotropin-releasing hormone
GO Graves’ ophthalmolophathy
Gs/Gq 7-transmembrane G-protein-coupled receptor
HAAF hypoglycemia-associated autonomic failure
HAART highly active antiretroviral therapy
48565_FM_i-xx.indd xvi 5/3/13 8:19 PM

Abbreviations in Text xvii
HC hydrocortisone
hCG human chorionic gonadotropin
HCO3 bicarbonate
HCTZ hydrochlorothiazide
HDDST high-dose dexamethasone suppression test
HDL-/LDL-C high-/low-density lipoprotein cholesterol
HDL high-density lipoprotein
HIV human immunodeficiency virus
HL hepatic lipase
HLA human leukocyte antigen
HNF-1alpha hepatocyte nuclear factor 1alpha
HPA hypothalamic-pituitary-adrenal
HPT hypothalamic-pituitary thyroid
HSG hysterosalpingogram
HSL hormone-sensitive lipase
HT Hashimoto’s thyroiditis
HU Hounsfield units
IADSPG International Association of Diabetes
in Pregnancy Study Groups
iCa2+ ionized calcium concentration
ICSI intracytoplasmic sperm injection
ICU intensive care unit
IDL intermediate density lipoprotein
IFG impaired fasting glucose
IGF-1 insulin like growth factor 1
IgG immunoglobulin G
IGT impaired glucose tolerance
IL-1 interleukin 1
IL-6 interleukin 6
IM intramuscularly
IMRT intesnsity-modulated radiation therapy
INSL3 insulin-like factor 3
IPF-1 insulin promoter factor-1
IPSS inferior petrosal sinus sampling
ITT insulin tolerance test
IUI intrauterine unsemination
IV intravenously
IVF in vitro fertilization
JNC Joint National Committee
LADA latent autoimmune diabetes of the adult
LAR long-acting release
LCAH lipoid congenital adrenal hyperplasia
LCAT lecithin cholesterol acyltransferase
LDL low-density lipoprotein
LDLR LDL receptor
LFT liver function test
LH luteinizing hormone
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xviii Abbreviations in Text
LOH loss of heterozygosity
LPL lipoprotein lipase
LT4 levothyroxine
M-CSF Macrophage-Colony Stimulatin Factor
MAPK mitogen-activated protein kinase pathway
MC4R melanocortin 4 receptor
MCT8 monocarboxylate transporter
MEN-1 multiple endocrine neoplasia type 1
[MEN/MEN1/MEN2/MEN-1/MEN-2]
METS Metabolic Equivalent of Tasks
MI myocardial infarction
MIBG mateiodobenzylguanidine
MIT monoiodotyrosine
Mg2+ magnesium concentration
MMI methimazole
MN metanephrine
MNT medical nutrition therapy
MODY maturity-onset diabetes of the young
MRI magnetic resonance imaging
MTC medullary thyroid cancer
NCCAH nonclassic congenital adrenal hyperplasia
NCEP National Cholesterol Education Program
NE norepinephrine
NET neuroendocrine tumor
Nf1 neurofibromatosis type 1
NGSP National Glycohemoglobin Standardization Program
nHDL nascent HDL
NIH National Institutes of Health
NIPHS noninsulinoma pancreatogenous hypoglycemia syndrome
NIS sodium/iodide symporter
NPO nil per os (nothing by mouth)
NSAIDs nonsteroidal anti-inflammatory drugs
NSTEMI non-ST elevation myocardial infarction
NTIS nonthyroidal illness syndrome
NTx N-terminal telopeptide
OCP oral contraceptive pill
ODS osmotic demyelination syndrome
OGTT oral glucose tolerance test
OPG osteoprotegrin
PAD peripheral arterial disease
PCOS polycystic ovary syndrome
PDTC poorly differentiated thyroid cancer
PET positron emission tomography
PG plasma glucose
PGB postgastric bypass
PHPT primary hyperparathyroidism
PI pituitary incidentaloma
48565_FM_i-xx.indd xviii 5/3/13 8:19 PM

Abbreviations in Text xix
PKA protein kinase A
PMCA plasma membrane calcium ATPase
POCT point-of-care testing
POI primary ovarian insufficiency
POMC proopiomelanocortin
POMC proopiomelanocortin
PORD P450-oxioreductase deficiency
PPARgamma peroxisome proliferator-activated receptor gamma
PPI proton pump inhibitors
PPN peripheral parenteral nutrition
PPNAD primary pigmented nodular adrenocortical disease
PRA plasma renin activity
PRL prolactin
PSA prostate specific antigen
PTC papillary thyroid carcinoma
PTH parathyroid hormone
PTHrP PTH related peptide
PTH-1R parathyroid hormone 1 receptor
PTU propylthiouracil
RAI radioactive iodine
RAIU radioactive iodine uptake
RANKL receptor activator of nuclear factor kappa-B ligand
RBC red blood cell count
RET rearranged during transfection
RET rearranged during transfection
rhTSH recombinant-human TSH
RIA radioimmunoassay
RMR resting metabolic rate
RT radiation therapy
SBP systolic blood pressure
SCA-POI steroidogenic cell autoimmune primary ovarian insufficiency
SCS subclinical Cushing’s syndrome
SDHB/D succinate dehydrogenase subunits B and D
SDS standard deviations
SHG saline sonohysterogram
SIADH syndrome of inappropriate antidiuretic hormone secretion
SLE systemic lupus erythematosus
SPEP serum protein electrophoresis
SQ subcutaneous
SR-B1 scavenger receptor B-1
SRS stereotactic radiosurgery
SRY sex-determining region of the Y chromosome
SSKI supersaturated potassium iodide
STD sexually transmitted diseases
STEMI ST elevation myocardial infarction
STI soft tissue infection
SUV Standard Uptake Value
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xx Abbreviations in Text
T3 triiodothyronine
T4 thyroxine
TART testicular adrenal rest tissue
TB tuberculosis
TBG thyroid binding golobulin
TBG thyroid hormone binding globulin
TC total cholesterol
TDD total daily dose
TESA testicular extraction sperm aspiration
TFT thyroid function test
TG triglycerides
Tg thyroglobulin
TgAb thyroglobulin antibodies
TGF transforming growth factor
THRbeta thyroid hormone receptor beta
THRT thyroid hormone replacement therapy
TKI tyrosine-kinase inhibitor
TNF tumor necrosis factor
TNM tumor node metastasis
TPN total parenteral nutrition
TPO thyroid peroxidase
TRAb TSH-receptor antibodies
TRBII thyroid receptor binding inhibitor immunoglobulin
TRH thyrotrophin-releasing hormone
TSH thyroid stimulating hormone
TSI thyroid-stimulating immunoglobulin
TTF1 thyroid transcription factor-1
TVUS transvaginal ultrasound
UA unstable angina
UAE urinary albumin excretion
UPEP urine protein electrophoresis
USDA US Department of Agriculture
USP United States Pharmacopeia
UTI urinary tract infection
UVB photolysis
VDBP vitamin D–binding protein
VDR vitamin D receptor
VEGF vascular endothelial growth factor
VHL Von Hippel-Lindau syndrome
VIP vasoactive intestinal peptide
VIPoma neoplasm secreting vasoactive intestinal peptide
VLDL very low-density lipoprotein
VTE venous thromboembolism
WC waist circumference
WHO World Health Organization
Yq long arm of the Y chromosome
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SECTION I: PITUITARY
48565_ST01_001-046.indd 1 5/1/13 9:35 PM

1 ■ PITUITARY ESSENTIALS
Anthony Heaney, MD
BASIC FACTS
• Comprises an anterior lobe (2/3), the posterior lobe (1/3), and vestigial
intermediate lobe
• Situated within the sella turcica that forms the bony roof of the
sphenoid sinus
• Above is the dural diaphragma sella through which the pituitary stalk
connects to the median eminence of the hypothalamus
• Laterally are bone (lower portion) and dura (upper portion) separating
it from the cavernous sinuses through which the 3rd, 4th, and 6th
cranial nerves and internal carotid arteries run
• Development
° The anterior pituitary (adenohypophysis) forms from Rathke’s
pouch, an ectodermal invagination anterior to the roof of the oral
cavity formed by the 4th to 5th week of gestation
° The posterior pituitary (neurohypophysis) arises from neural
ectoderm associated with third ventricle development
° The posterior pituitary consists of axons from cells in the supra-
optic and paraventricular nuclei of the hypothalamus
• Gland volume enlarges during menstrual cycle and pregnancy
• Blood supply
° Systemic arterial blood supply is provided from the inferior
hypophyseal arteries that are branches from the cavernous internal
carotid and posterior communicating arteries
° Hypophyseal portal vessels, originating from infundibular plexuses
and within the pituitary stalk, together with contractile internal capil-
laries (“gomitoli”) provide both antegrade and retrograde blood flow
■ Ensures bidirectional flow of hypothalamic-pituitary hormonal signals
° Venous drainage: inferior petrosal sinuses

PITUITARY CONTROL
• Control of anterior and pituitary hormone release is depicted in Figure 1-1
• Three tiers of complex intracellular signals control pulsatile release
of the two posterior and six anterior pituitary hormones
° Osmoreceptors and thirst areas of the brain (posterior pituitary)
and specific hypothalamic-derived releasing hormones (corticotrophin-
releasing hormone [CRH], growth hormone–releasing hormone
[GHRH], gonadotrophin-releasing hormone [GnRH], thyrotrophin-
releasing hormone [TRH]) arrive via the portal system to act
48565_ST01_001-046.indd 3 5/1/13 9:35 PM

4
48565_ST01_001-046.indd 4
HYPOTHALAMUS Thirst center
Osmoreceptor +
CRH TRH G
GnRH GHRH
+ S
SMS SMS Dopamine
+ + + + +
Pituitary Essentials
Pituitary
Corticotroph
p
ph Thyrotroph
ph Gonadotroph
Gooonad
G dootttro
d Somatotroph Lactotroph Oxytocin ADH
Trophic
ACTH
ACT
A T
TH FS
FSH
SH & LH GH
Hormone + + FSH +
+ Prolactin +
Tissue Target
+
BP
Target Teste
TTestes
eess Ovaries + Vomiting
hormone Cortisol
Co
Cortisoll T4 & T3 Testosterone
Testo
T oosstte Estrogen LGF-1
IInhibin
nhib
bin
b Progesterone
Action Stress rresponse

esspon nsse
ns Protein
P i synthesis
y h i Spermatogenesis
Sperrmatttog
S gge Ovulation Cell proliferation Lactation Paturition Water balance
Homeostasis
stasis
iss Thermogenesis
Th i Linear growth Lactation
FIGURE 1.1 General control of anterior and posterior pituitary function. CRH, corticotrophin releasing hormone; ACTH, adrenocorticotrophin;
TRH, thyrotrophin releasing hormone; SMS, somatostatin; TSH, thyroid stimulating hormone; GnRH, gonadotrophin releasing hormone; FSH,
follicle stimulating hormone; LH, luteinizing hormone; GHRH, growth hormone releasing hormone; GH, growth hormone; IGF-1, insulin-like
growth factor-1; ADH, antidiuretic hormone.
5/1/13 9:35 PM
Pituitary Function 5
directly on G-protein coupled surface receptors on anterior pituitary

cells (anterior pituitary)
° Pituitary-derived growth factors (fibroblast growth factor [FGF],
vascular endothelial growth factor [VEGF], transforming growth
factors [TGFs]) and cytokines (tumor necrosis factor [TNF],
interleukin-6 [IL-6]) act in paracrine and autocrine fashion to
regulate pituitary cell growth and hormone secretion
° End-organ derived hormones act primarily in negative feedback
manner to regulate anterior pituitary hormone release (e.g., cortisol
on adrenocorticotropic hormone [ACTH]-producing corticotroph,
insulin-like growth factor-1 [IGF-1] on growth hormone [GH]-
producing somatotroph)
PITUITARY FUNCTION
• Posterior pituitary hormones
° Oxytocin
■ Role: regulates parturition, lactation, reproductive behavior
■ Control of release: nipple stimulation, birth canal distension
■ Miscellaneous: oxytocin receptor widely expressed in central nervous
system (CNS) and influences reproductive behavior in some species

° Vasopressin
■ Role: regulation of water balance, potent pressor, ACTH secreta-
gogue, coagulation regulator

■ Control of release: osmotic status, blood pressure (BP)/
circulatory volume, nausea and emesis

■ Miscellaneous: osmoreceptors within the brain but in direct
contact with the circulation via local gaps in blood-brain barrier

interact with vasculature baroreceptors and central thirst
mechanisms to regulate water balance
• Anterior pituitary cells and hormones
° ■ Hormone: GH
Somatotrophs
■ Role: linear and organ growth
■ Control of release
• Stimulatory: GHRH and ghrelin

• Inhibitory: somatostatin
■ Miscellaneous
• Somatotrophs make up ~50% of anterior pituitary cells

• Acidophilic cells, mostly located in lateral wings of anterior lobe
° Lactotrophs
■ Hormone: prolactin (PRL)
■ Role: lactation
• Inhibitory: dopamine (DA)

■ Miscellaneous: only pituitary cell under negative tonic control
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6 Pituitary Essentials
° Mammosomatotrophs
■ Hormone: both PRL and GH
■ Role: linear and organ growth and lactation
• Stimulatory: GHRH
• Inhibitory: somatostatin, DA
■ Miscellaneous
• Indistinguishable from somatotrophs by conventional histology

• Ultrastructural immunocytology demonstrates both GH
(usually intense) and PRL (less prominent) in the same cell,
frequently in same secretory granule
° Corticotrophs
■ Hormone: ACTH; also other derivatives of proopiomelanocortin
(POMC) including melanocyte-stimulating hormone, lipotrophic

hormone, and endorphins
■ Role: cell metabolism and homeostasis
• Stimulatory: CRH
• Inhibitory: cortisol
■ Miscellaneous: basophilic staining
° Thyrotrophs
■ Hormone: thyroid-stimulating hormone (TSH)
■ Role: thermogenesis
• Stimulatory: TRH
• Inhibitory: T4 and T3
° Gonadotrophs
■ Hormone: FSH and LH
■ Role: regulate sex steroid synthesis and ovulation/
spermatogenesis
• Stimulatory: GnRH
• Inhibitory: sex steroids
■ Miscellaneous: follicular stimulating hormone (FSH)/luteinizing
hormone (LH)-expressing gonadotrophs equal in female fetus, LH

gonadotrophs predominate in male fetus
REFERENCES
Anderson E, Haymaker W. Breakthroughs in hypothalamic and pituitary
research. Prog Brain Res, 1974;41:1–60.
Melmed S, ed. The Pituitary. 2nd ed. Malden, MA: Wiley-Blackwell; 2002.
Wass J, Shalet S, eds. The Oxford Textbook of Endocrinology & Diabetes.
New York, NY: Oxford University Press; 2002.
48565_ST01_001-046.indd 6 5/1/13 9:35 PM

2 ■ HYPOPITUITARISM
Theingi Aung, MD and Niki Karavitaki, PhD, FRCP
BACKGROUND
• Clinical syndrome of partial or complete deficiency of anterior and/or
posterior pituitary hormones due to pituitary or hypothalamic disorders
• Incidence 4.2 per 100,000 per year; prevalence 45.5 cases per 100,000
people
PATHOPHYSIOLOGY
Causes of hypopituitarism
• Pituitary/parapituitary tumors
° Pituitary adenoma, craniopharyngioma, meningioma, glioma,
Rathke’s cleft cyst, chordoma, metastasis (e.g., breast, lung)
• Surgery in the area of the pituitary gland
• Radiotherapy (pituitary, cranial, nasopharyngeal)
• Pituitary infarction/hemorrhage (apoplexy)
• Sheehan’s syndrome (postpartum pituitary necrosis)
• Subarachnoid hemorrhage
• Head trauma/traumatic brain injury
• Empty sella syndrome
• Infiltrative lesions
° Sarcoidosis,
histiocytosis
lymphocytic hypophysitis, hemochromatosis,
• Infection
° Tuberculosis (TB), pituitary abscess, meningitis, encephalitis
• Isolated hypothalamic-releasing hormone deficits
° Kallman’s syndrome
• Genetic causes
° Mutations of genes including HESX-1, LHX3, LHX4, PROP-1, POU1F1
CLINICAL PRESENTATION
• The clinical manifestations of hypopituitarism depend mainly on the
underlying disease, as well as the type and degree of the hormonal
deficits
• Tumors in the sellar region with suprasellar or lateral extension may be
associated with visual deterioration, headaches, and ophthalmoplegia
due to damage to cranial nerves (III, IV, or VI) within the cavernous
sinus
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8 Hypopituitarism
• Presentation of hypopituitarism varies from subclinical (diagnosed

only following hormonal investigations) to acute onset requiring hospi-
tal admission; ACTH, TSH, and antidiuretic hormone (ADH) deficiency
are potentially life-threatening, whereas FSH/LH and GH deficiencies
are associated with chronic morbidity
• In most etiologies, the development of hormone deficiencies follows a
particular pattern with GH and LH/FSH being affected first followed by
TSH and ACTH secretion
TABLE 2.1 Manifestations of Defi cient Hormones
Defi cient Hormone Manifestations

ACTH • Weakness, tiredness, weight loss, anorexia, dizziness,
postural hypotension, syncope, nausea, vomiting,
diarrhea
• In contrast to primary adrenal insufficiency, no
hyperpigmentation
• Hypoglycemia, anemia
TSH • Fatigue, lethargy, constipation, menstrual irregularities,
dry skin, hair loss, coarsening of voice, cold intolerance,
weight gain, inability to concentrate, periorbital edema,
prolonged relaxation of deep tendon reflexes, coarse
facial appearance, hypothermia, bradycardia, pallor
LH/FSH • Reduced libido, infertility, menstrual irregularities,
erectile dysfunction, dyspareunia, testicular atrophy
• Decreased muscle mass
• Osteoporosis
GH • Failure to thrive and short stature in children
• In adults, fatigue, reduced exercise capacity, impaired
psychological well-being, reduced lean body mass,
dyslipidaemia, premature atherosclerosis
PRL • Failure of lactation
ADH • Polyuria, nocturia, polydipsia
• Hypernatraemia
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Hormone Replacement 9
DIAGNOSTIC EVALUATION
TABLE 2.2 Hormonal Assessment for Pituitary Hypofunction
Hormone
Defi ciency Basal Hormone Tests* Dynamic Testing*
ACTH 8 AM serum cortisol and plasma Cosyntropin stimulation test, insulin
ACTH tolerance test, glucagon test, or
metyrapone test
TSH Serum TSH, FT4, FT3
LH/FSH Serum LH and FSH with 8 AM
testosterone in males or
estradiol in females
GH Serum IGF-1 Insulin tolerance test, glucagon
test, or GHRH + Arginine test
ADH Paired urine and plasma Water deprivation test
osmolality, blood urea, and
electrolytes
* Results should be interpreted according to the cutoff values of each laboratory.
• Other investigations
° Hormonal investigations to exclude functioning pituitary adenomas
(e.g., prolactinoma)
° Pituitary MRI or CT to detect anatomical abnormalities
(e.g., tumors)
■ Biopsy of lesion sometimes needed for definitive diagnosis
HORMONE REPLACEMENT
• See also chapters on individual hormone deficiency syndromes
• For ACTH deficiency
° In any acute medical emergency, immediate hydrocortisone
(HC; 100 mg intramuscularly [IM] or intravenously [IV])
° Replacement with HC 20 mg daily in divided doses or prednisone
5 mg daily: recommendation includes replacement with the small-
est possible dose of HC that is acceptable to patient and compat-
ible with normal vitality to avoid overreplacement
° Dose adjustment (two- to threefold) during moderate illness
(e.g., fever >37.5°C)
° Patients shouldsystematically
HC injections if major stress (e.g., major surgery)
° identification cardhave a medical alert bracelet and medical
° Adequacy of replacement assessed by checking for manifestations

of steroid deficiency or excess
48565_ST01_001-046.indd 9 5/1/13 9:35 PM

10 Hypopituitarism
• For TSH deficiency

° Replacement
body weight)
with levothyroxine (LT4; mean dose 1.6 mcg/Kg of
° thyroxine (T4) replacement

Exclude and treat concomitant ACTH deficiency before starting
to avoid adrenal crisis
° Target free T4 (FT4) levels in the upper half of the reference range;
TSH levels not useful marker of replacement
• For FSH/LH deficiency
° Males: testosterone replacement
■ Multiple forms: targets for serum testosterone depend on the
preparation
■ Main contraindication = prostate cancer
■ Do not start therapy in patients with palpable prostate nodule
or induration, haematocrit >50%, untreated severe obstructive

sleep apnea, severe lower urinary tract symptoms, or uncon-
trolled heart failure, or in those desiring fertility
■ Monitor hematocrit, prostate specifi c antigen (PSA), and digital
rectal exam
■ Alternatively, gonadotropin therapy is required for fertility
° ■ Multiplehormonal
Females:
options
replacement therapy in premenopausal women
■ Absolute contraindications: vaginal bleeding of unclear etiology,
active thromboembolism, active endometrial cancer, breast

cancer
■ Relative contraindications: history of endometrial cancer, family
or past history of thromboembolism, ischemic heart disease,

cerebrovascular disease, active liver disease, dyslipidemia
■ Alternatively, gonadotropin therapy is required for fertility
• For GH deficiency
° Adults: start with low dose of 150−300 mcg/day and titrate according
to clinical response; side effects and IGF-I levels: maximum dose
1 mg daily
° Contraindications: active malignancy, benign intracranial
hypertension, preproliferative/proliferative retinopathy
° Adverse effects: headaches, benign intracranial hypertension,
carpal tunnel syndrome, arthralgia, myalgia, insulin resistance,
hyperglycemia
• For ADH deficiency (diabetes insipidus)
° Desmopressin oral (0.3−1.2 mg/day) or intranasal (10−40 mcg/day)
divided in 1−4 doses
° plasma osmolalities
Monitor for polyuria/polydipsia and serum sodium, urine and
48565_ST01_001-046.indd 10 5/1/13 9:35 PM

References 11
REFERENCES
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with
androgen deficiency syndromes: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab, 2010;95(6):2536−59.
Grossman AB. Clinical review: the diagnosis and management of central
hypoadrenalism. J Clin Endocrinol Metab 2010;95(11):4855−63.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine
Society. Evaluation and treatment of adult growth hormone deficiency:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(6):1587−609.
Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E.
Hypopituitarism. Lancet, 2007;369(9571):1461−70.
48565_ST01_001-046.indd 11 5/1/13 9:35 PM

48565_ST01_001-046.indd 12 5/1/13 9:35 PM
3 ■ PROLACTINEMIA AND PROLACTINOMA
Mark E. Molitch, MD
PATHOPHYSIOLOGY OF HYPERPROLACTINEMIA AND PROLACTINOMAS

• Inhibition of PRL secretion by DA predominates over hypothalamic stimu-
lation; PRL levels rise when there is interference with this inhibition
° Blockade of DA receptors by drugs (neuroleptics, atypical antipsy-
chotics, metoclopramide, verapamil, methyldopa)
° Lesions interrupting hypothalamic or portal vessel DA pathways
• Stimulation of afferent pathways from breast to hypothalamus result
in increased PRL
° Nipple stimulation (sexual, nipple rings)
° Chest wall irritation (burns, trauma, cancer)
• Other causes: hypothyroidism (due to TRH stimulation of PRL release),
renal insufficiency
• Prolactinomas: benign neoplasms (very rarely malignant) of pituitary
lactotrophs
° Usually sporadic and rarely familial
° Microadenomas: <10 mm; PRL levels usually <100 ng/ml, rarely
cause hypopituitarism
° Macroadenomas: ≥10 mm; can be very large with very high PRL levels
■ Can cause mass effects
■ Can be locally invasive of surrounding bone, brain
• Other pituitary adenomas co-secreting PRL: GH- and ACTH-secreting

adenomas
• Idiopathic
• Pathophysiology: hyperprolactinemia suppresses hypothalamic GnRH
pulsatile secretion, causing hypogonadotropic hypogonadism
TABLE 3.1 Symptoms Due to Hyperprolactinemia

Women Men
Amenorrhea Erectile dysfunction
Galactorrhea Galactorrhea (rare)
Infertility Infertility
Decreased libido Decreased libido
Osteopenia Osteopenia
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14 Prolactinemia and Prolactinoma
• Symptoms due to mass effects

° Visual field defects if tumor compresses optic chiasm
° Ophthalmoplegias if tumor invades cavernous sinus
° Headaches
Hypopituitarism if tumor compresses other pituitary cells or stalk
°
• Physical examination
° Visual fields defects by confrontation
° Galactorrhea
° Testicularhypogonadism
Signs of (decreased hair, muscle bulk)
° Other evidence
atrophy
° of hypopituitarism (see Chapter 2, Hypopituitarism)
• PRL levels
° If<150
caused by drugs and other nonprolactinoma causes, usually
ng/mL
° Microprolactinomas: levels usually <200 ng/mL
° >20,000 ng/mL
Macroprolactinomas: levels usually >200 ng/mL; can be
■ PRL level generally proportional to tumor size
■ Special caution: in some two-site PRL assays, patients with
very large prolactinomas and very high PRL levels may appear to
have PRL levels that are normal or only modestly elevated, thus
mimicking a large, nonfunctioning adenoma due to saturation of
the assay antibodies
• PRL levels should always be remeasured at 1:100 dilution
° high mild
PRL elevations may be due to macroprolactin, which is a
molecular weight PRL aggregate with immunoglobulins with
diminished biologic potency
■ Macroprolactinemia usually found in patients with equivocal
symptoms
■ Detect by precipitating complex with polyethylene glycol
• If PRL levels in supernatant >70% of the upper limit of normal

for assay, patient can be assumed to have true hyperprolac-
tinemia and not an elevation due simply to macroprolactin
■ When PRL elevation due to macroprolactin alone, no treatment
necessary
• Imaging
° contrast
If no obvious cause by history and exam, then image with MRI with
° CT with direct coronal cuts gives less detail

• Visual fields
° If tumor abuts optic chiasm, do formal visual field testing
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Treatment 15
TREATMENT
• Observation
° Ifandpatient has microadenoma or idiopathic hyperprolactinemia
presents with nonbothersome galactorrhea and has normal
estrogen/testosterone levels, he/she can simply be followed with
periodic PRL levels
° Similar patients with amenorrhea but not interested in fertility may
be treated with estrogen replacement
• DA agonists
° DA agonists normalize PRL levels, correct amenorrhea-galactorrhea,
and decrease tumor size by more than 50% in 80−90% of patients
° bromocriptinemore efficacious and better tolerated than
Cabergoline
° Can use cabergoline even if visual field defects, as long as visual

acuity is not threatened by rapid progression or recent tumor
hemorrhage
° 40−50% of patients whose PRL levels normalize and tumors
shrink can eventually be tapered off cabergoline without tumor
reexpansion
° About 50% of patients resistant to bromocriptine will respond to
cabergoline
° About 15−20% of prolactinomas are resistant to cabergoline
■ Important to ensure compliance and to be certain that the
underlying lesion is a prolactinoma and not some other cause

of hyperprolactinemia
■ Most patients resistant to standard doses of cabergoline
respond to larger doses

• Doses >3 mg/day may be associated with cardiac valvular
abnormalities
• Echocardiographic monitoring should be used in patients
taking >2 mg/week
• Transsphenoidal surgery
° 25−40%
Initial remission rates 70−80% for microprolactinomas and
for macroadenomas
° Long-term recurrence rates of 20%
° minimal, but increase
Complications of hypopituitarism, infections, and bleeding are
proportionately with tumor size
° Craniotomy for large tumors rarely curative and much higher
complication rates
• Radiation therapy (RT), usually stereotactic, reserved for patients with
macroadenomas not responding to either medical or surgical treatment
° Irradiation
over years
often causes hypopituitarism, developing gradually
48565_ST01_001-046.indd 15 5/1/13 9:35 PM

16 Prolactinemia and Prolactinoma
FOLLOW-UP
• Goals of treatment
° Normalize PRL levels or at least bring them to levels at which
gonadal/reproductive/sexual function is normalized
° Decrease tumor size
• Once PRL levels reach normal or near-normal, levels can be monitored
every 3−6 months for first year and then every 6−12 months thereafter
• Tumor size monitored by MRI
° Macroadenomas: once maximal size reduction documented, further
scans may not be necessary as long as PRL levels are being monitored
° Microadenomas: necessity of second MRI scan is debatable if PRL
levels are monitored
° significant increasea tumor
Extremely rare for to increase in size without there being a
in PRL levels
° Visual field abnormalities should be repeated until normal or stable
and then do not need to be repeated
PREGNANCY
• DA agonists needed for ovulation and stopped once pregnancy is
diagnosed
° With such fetal exposure, there are no risks for fetal malformations
or other adverse pregnancy outcomes
■ Safety database for bromocriptine is eightfold larger than that
for cabergoline
° DA agonists are then reinstituted when breastfeeding is completed
• Symptomatic growth occurs in 23% of macroprolactinomas and 3%
of microprolactinomas in second or third trimester due to stimulatory
effect of high estrogen levels of pregnancy and withdrawal of the DA
agonist
° Visual field testing each trimester with macroadenomas but only if
symptomatic with microadenomas
° Magnetic resonance imaging (MRI) scans (without gadolinium)
if visual field defects or severe headaches when a therapeutic
intervention is contemplated
° When evidence of significant symptoms and tumor growth, patient
should be restarted on a DA agonist
■ Transsphenoidal surgical decompression can be done if there is
an unsatisfactory response to the DA agonist

■ Delivery of the baby can be done if the pregnancy is suffi ciently
advanced
° PRL levels may rise during pregnancy when there is no tumor size
change and some tumors enlarge without an associated rise in
PRL; therefore, measurement of PRL during pregnancy should not
be carried out
48565_ST01_001-046.indd 16 5/1/13 9:35 PM

References 17
REFERENCES
Casanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the Pituitary
Society for the diagnosis and management of prolactinomas. Clin
Endocrinol (Oxf), 2006;65(2):265−73.
Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of
hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab, 2011;96(2):273−88.
Storgaard H, Jensen CB, Vaag AA, Vølund A, Madsbad S. Insulin secre-
tion after short- and long-term low-grade free fatty acid infusion in
men with increased risk of developing type 2 diabetes. Metabolism,
2003;52(7):885−94.
48565_ST01_001-046.indd 17 5/1/13 9:35 PM

48565_ST01_001-046.indd 18 5/1/13 9:35 PM
4 ■ ACROMEGALY
Laurence Katznelson, MD
PATHOPHYSIOLOGY
• Normal
° GH is secreted in pulses by the pituitary gland, mostly during night
° GHRH stimulates and somatostatin inhibits GH secretion
° GH stimulates hepatic production of IGF-1
° Both GH and IGF-1 have metabolic and growth properties
• In acromegaly
° GH producing somatotroph pituitary tumor is the cause in most cases
° Usually a macroadenoma (greater than 1 cm)
° Rare
tumors
cases of ectopic GHRH or GH production by neuroendocrine
° Pituitary tumors usually sporadic with rare familial cases, such as

multiple endocrine neoplasia type 1 (MEN-1)
° Excess GH causes liver to overproduce IGF-1
° Excess
growth
GH and IGF-1 cause metabolic disturbances and somatic
• History and examination
° Clinical features are due to high serum levels of GH and IGF-1
° Metabolic effects of GH and IGF-1 include insulin antagonism
and lipolysis
° Macroadenomas can cause local mass effects including loss of
peripheral vision through optic chiasmal compression, ophthal-
moplegia through cavernous sinus involvement, and hypopituita-
rism through compression of the normal pituitary gland
° Disease usually present for 6−12 years prior to diagnosis
■ The disease is insidious, and patients rarely present with
complaint of somatic overgrowth

■ In women, the disease is often considered during an evaluation
for oligo/amenorrhea
■ In men, the disease is often considered during evaluation of
headache
48565_ST01_001-046.indd 19 5/1/13 9:35 PM

20 Acromegaly
° Signs and symptoms

■ Headache, excess sweating, joint aches (diffuse), fatigue
■ Somatic overgrowth: large hands (history of rings that need to be
cut), enlarged feet (increasing shoe size), carpal tunnel syndrome

■ Sleep apnea syndrome
■ Glucose intolerance, frank diabetes mellitus type 2
■ Hypertension
■ Hypertrophic cardiomyopathy
• Diastolic and systolic dysfunction in early disease

• Congestive, dilated cardiomyopathy with advanced disease
■ Hypopituitarism: hypothyroidism, adrenal insuffi ciency (AI),
hypogonadism (oligo/amenorrhea in premenopausal women,

sexual dysfunction with testosterone deficiency in men)
° Physical exam
■ Vital signs reveal hypertension
■ Deep “acromegalic” voice
■ Thickening of skin
■ Enlargement of hands and feet (thickening of hand volume and
heel pad)
■ Head with frontal bossing (protruding frontal bones), coarse
features (thickened facial skin), furrowing of brow skin

■ Prognathism (enlarged and widened jaw), jaw malocclusion and
overbite, macroglossia
■ Nodular thyroid goiter
■ Skin tags, especially about neck
■ Gynecomastia in men, galactorrhea in women
■ Testicular atrophy
■ Neurologic exam: ophthalmopathy, visual field defects (temporal),
Tinel’s sign for carpal tunnel syndrome, radiculopathy
• Laboratory testing performed in a patient with clinical suspicion of
disease
• Biochemical testing to determine GH and IGF-1 hypersecretion
• Specific testing
° IGF-1 levels
■ Random IGF-1 level is single best test: elevated in acromegaly
■ IGF-1 is an integrated marker of GH secretion
■ IGF-1 levels do not vary with food intake, time of day, or exercise
■ IGF-1 levels are normalized for age and gender
° GH levels
■ Measurement of GH useful in situations with equivocal serum
IGF-1 levels
■ GH secretion affected by food, exercise, stress, and sleep, and
may be elevated with uncontrolled diabetes mellitus and liver

disease
48565_ST01_001-046.indd 20 5/1/13 9:35 PM

Management 21
■ Random GH levels are not generally useful for diagnosis, unless
very high, and are usually not relied upon for biochemical
confirmation
■ Oral glucose tolerance test (OGTT): normal GH less than 1 ng/ml
■ For OGTT, 75 g of glucose, then GH measured q 30 min for
2 hours, but other protocols include measurements at 1 and

2 hours only
° Additional laboratory testing
■ PRL (commonly co-secreted)
■ Assessment of hypopituitarism (FT4 for hypothyroidism, cortisol
evaluation for AI, serum testosterone in men for gonadal

function)
° Imaging
■ Imaging used to determine source of GH hypersecretion
■ MRI scan is the most sensitive test for identifying a pituitary
adenoma
■ The tumor is a macroadenoma (>1 cm) in at least 75% of cases
■ Imaging can determine tumor extension, including presence of
extrasellar involvement, such as in the cavernous sinus

■ If there is suprasellar extension and tumor touches or com-
presses the optic chiasm, then visual field testing should be

performed
■ If the MRI scan is normal, there may still be a microadenoma
(<1 cm) in the pituitary gland, but need to consider ectopic

secretion of GHRH or GH by a neuroendocrine tumor
• Perform abdominal and chest imaging
• Consider octreoscan to search for ectopic neuroendocrine
tumor
MANAGEMENT
• Goals: normalize biochemical GH and IGF-1 levels, improve medical
comorbidities, improve signs and symptoms, reduce tumor burden,
prevent premature mortality
• Surgery is primary mode of therapy and can rapidly normalize GH
levels, reduce tumor bulk, and reverse local mass effects
• Medical and RT used in an adjuvant role for patients with residual
disease following surgery
• Primary medical therapy in lieu of surgery may be used in a patient
with a tumor that may not be cured with surgery (i.e., cavernous sinus
involvement) and without chiasmal effects
• Surgery
° Transsphenoidal approach most common
■ Surgery with endoscopy frequently performed
■ Craniotomy indicated in patients with tumors that have extensive
extrasellar involvement that cannot be resected via the trans-

sphenoidal approach
48565_ST01_001-046.indd 21 5/1/13 9:35 PM

22 Acromegaly
° Rapidity to perform surgery depends on degree of clinical signs and

symptoms, and presence of local mass effects
° Itimprove
is unclear whether preoperative medical therapy may be useful to
surgical outcome for macroadenomas
° comorbidities,medical
Preoperative therapy may be indicated to improve medical
such as sleep apnea syndrome, prior to surgery
° Following
GH level
surgery, measure day 1 postoperative fasting serum
■ If less than 1 ng/ml postop in a patient with elevated level
preop, then surgery may have been successful

■ Repeat IGF-1 level 8−12 weeks following surgery to gauge
success
■ Repeat OGTT may be useful at 8−12 weeks if the IGF-1 is
borderline
• Medical therapy
° Three types
Usually used in an adjuvant role following incomplete surgery
° GH receptor ofantagonist
medications: Somatostatin analogues, DA agonists,
■ Somatostatin analogues most commonly used given excellent
response in majority of subjects

■ GH receptor antagonist usually recommended in patients with
incomplete response to somatostatin analogue

■ DA agonists may be used in patients with modest disease and in
situations in which cost is a limiting factor

■ Can be used alone or in combination
° Somatostatin analogues
■ Octreotide LAR (long-acting release) and lanreotide autogel:
similar efficacy and side effect profiles

■ Normalizes IGF-1 in approximately 55% of patients
■ Doses based on serum IGF-1 levels drawn after 60−90 days
■ Octreotide LAR (10, 20, 30 mg) administered as monthly IM
injections, usually starting at 20 mg monthly

• A two-week trial of short acting SQ octreotide at 50−100 mcg
TID is recommended to assess tolerance, but most clinicians
offer 1−2 doses only of short-acting octreotide prior to LAR dose
■ Lanreotide autogel (60, 90, and 120 mg) administered as
monthly deep SQ injection at doses usually starting at 90 mg

■ Side effects: GI upset with diarrhea, gallstones, bradycardia,
fatigue, hair loss, hyperglycemia

° ■ Oral
DA agonists (bromocriptine, cabergoline)
administration, and less expensive than other medical
therapies
■ Cabergoline better tolerated and better effi cacy than bromocrip-
tine with normal IGF-1 achieved in up to 40%

■ Dose titrated to normalize IGF-1 levels
■ Side effects: GI upset, dizziness, stuffy nose, headache
48565_ST01_001-046.indd 22 5/1/13 9:35 PM

Management 23
° GH receptor antagonist (pegvisomant)

■ Blocks GH at its receptor without effect at the primary tumor
■ Normalizes IGF-1 value in >90% of cases
■ GH should not be measured on pegvisomant as level will
increase
■ Administered as daily (10, 15, 20 mg) or weekly SQ injections
and titrated to normalize IGF-1 levels

■ Side effects: abnormal liver function tests (LFTs), flulike
syndrome, local skin reactions, local lipohypertrophy

■ Tumor growth uncommon
° Combination therapy
■ Addition of DA agonist or pegvisomant to somatostatin analogue
can be considered in patients with incomplete response (i.e.,

elevated IGF-1 levels, tumor growth)
• RT
°Adjuvant role after incomplete surgery and/or incomplete medical
therapy response
° Conventional fractionated versus stereotactic radiosurgery (SRS)
gamma knife, CyberKnife, or proton beam radiation; SRS indicated
if there is minimum distance between tumor and optic chiasm
° May take up to 5−10 years for efficacy
° Medical therapy indicated until IGF-1 normalizes
° May normalize IGF-1 in approximately half of patients without need
for medical therapy
° Side effects include hypopituitarism, risk of secondary neoplasm,
cerebrovascular atherosclerosis
• Management of medical comorbidities
° Aggressive surveillance and management of type 2 diabetes
mellitus (type 2 DM), hypertension, hyperlipidemia
° Colonoscopy to assess for colon polyps and malignancy
° Sleep study to detect sleep apnea syndrome
° Consider corrective jaw surgery once GH/IGF-1 levels normalized
TABLE 4.1 Testing for Acromegaly

Test Comments
IGF-1 Elevated level consistent with disease
OGTT (75 g) Trough GH >1 ng/ml is abnormal
MRI scan to evaluate for pituitary
adenoma
Visual field testing if adenoma
compresses optic chiasm
48565_ST01_001-046.indd 23 5/1/13 9:35 PM

24 Acromegaly
TABLE 4.2 Medical Therapy Options
Class Name Route Effi cacy Side Effects
Somatostatin Octreotide LAR Intramuscular 55% GI upset/diarrhea,
analogs gallstones,
hyperglycemia,
bradycardia,
hair loss
Lanreotide Deep 55%
autogel subcutaneous
Dopamine Cabergoline Oral 39% GI upset,
agonists headache,
dizziness, nasal
stuffiness
Bromocriptine Oral 8%
GH receptor Pegvisomant Subcutaneous >90% Abnormal
antagonist LFTs, flulike
symptoms,
local skin
reactions, and
lipohypertrophy
REFERENCES
Bevan JS. Clinical review: The antitumoral effects of somatostatin analog
therapy in acromegaly. J Clin Endocrinol Metab, 2005;90(3):1856–63.
Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure
of acromegaly. J Clin Endocrinol Metab, 2010;95(7):3141−8.
Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical
Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis
and Treatment of Acromegaly—2011 update: executive summary. Endocr
Pract, 2011;17(4):636−46.
Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management:
an update. J Clin Endocrinol Metab, 2009;94(5):1509−17.
48565_ST01_001-046.indd 24 5/1/13 9:35 PM

5 ■ GROWTH HORMONE DEFICIENCY IN ADULTS
Kevin C.J. Yuen, MD
PATHOPHYSIOLOGY
• Growth hormone deficiency (GHD) in adults affects 1−3/10,000 people
annually
• As GH levels decline with aging, important to distinguish between
age-related physiological decline in GH levels and pathological GH
deficiency that usually has an identifiable cause
• Causes of GHD in adults
° Mass lesions in the pituitary and hypothalamus: benign (e.g.,
pituitary adenomas, craniopharyngiomas, cysts) and malignant
(e.g., metastases from breast, lung) tumors
° Treatment of hypothalamic and pituitary lesions (e.g., surgery and/
or irradiation)
° Infi ltrative diseases (e.g., lymphocytic hypophysitis, sarcoidosis,
histiocytosis)
° Sheehan
Head trauma/vascular injury (e.g., subarachnoid hemorrhage,
syndrome)
° Apoplexy (e.g., hemorrhage into the pituitary gland)
° Genetic
mutations)
diseases (e.g., PIT-1, PROP-1, LHX3/4, HESX-1, PITX-2
° Infections (meningitis, encephalitis, tuberculous meningitis)

° Idiopathic (e.g., childhood-onset GHD that persists in adulthood
without structural pituitary lesion and no other pituitary hormone
deficiencies)
• History: inquire about history of hypothalamic-pituitary disease,
cranial irradiation, childhood-onset GHD, head trauma, CNS infections,
underlying autoimmune endocrine disease that may affect the pituitary
gland, and unexplained osteopenia
48565_ST01_001-046.indd 25 5/1/13 9:35 PM

26 Growth Hormone Defi ciency in Adults
• Physical exam: as the symptoms of GHD are nonspecific, physical

examination is usually unrevealing
TABLE 5.1 Signs, Symptoms, and Clinical Features of AGHD
Symptoms Signs Clinical Features
• Increased body fat • Overweight, with • Peak GH response to
• Reduced muscle bulk, predominantly central hypoglycemia <3 μg/L
muscle strength, and obesity • Low or low normal (<0
physical fitness • Poor muscular IGF-I SDS) serum IGF-I
• Impaired psychological development levels
well-being • Reduced exercise • Hyperlipidemia (↑ LDL
° Depressed mood,
reduced energy,
performance
• Thin, dry skin
cholesterol and ↓ HDL
cholesterol)
reduced vitality, • Depressed affect • Reduced lean body
reduced physical mass/increased fat
stamina, poor mass
motivation, and • Increased fasting insulin
increased social levels
isolation • Reduced bone mineral
density
LABORATORY EVALUATION
• Serum IGF-I levels ≤2 standard deviations (SDS) is suggestive of GHD,
and a provocative test is required to confirm the diagnosis
48565_ST01_001-046.indd 26 5/1/13 9:35 PM

Laboratory Evaluation 27
TABLE 5.2 Diagnosis of AGHD Based on Recommendations From Various
Consensus Guidelines
American Association
GH Research of Clinical Endocri- Endocrine Society
Society 2007 nologists 2009 2011
Number of • None if ≥3 • None if ≥3 • None if ≥3
Tests to pituitary pituitary hormone pituitary hormone
Establish hormone deficiencies and deficiencies and
Diagnosis deficiencies and low IGF-I low IGF-I
low IGF-I • 1 test in adults with • 1 test in adults
• 1 test in hypothalamic- with hypothalamic-
adults with pituitary disease pituitary disease
hypothalamic- • 1 test in and ≥1 pituitary
pituitary disease reconfirmation of hormone deficiency
and ≥1 pituitary COGHD ≥1 month • 2 tests in adults
hormone after stopping GH with idiopathic
deficiency GHD
• 2 tests in adults • 1 test in
with idiopathic reconfirmation of
GHD COGHD ≥1 month
• 1 test in after stopping GH
reconfirmation of
COGHD
Test of Choice ITT ITT ITT
Alternative • GHRH and • GHRH and arginine • GHRH and arginine
Test (in arginine • Glucagon • Glucagon
order of • Glucagon • Arginine
preference)
GH Cutoff • ITT <5 ng/ml • ITT <5 ng/ml • ITT <5 ng/ml
Levels • GHRH and • GHRH and arginine • GHRH and arginine
arginine – BMI <25, – BMI <25,
– BMI <25, <11 ng/ml <11 ng/ml
<11 ng/ml – BMI 25–30, – BMI 25–30,
– BMI 25–30, <8 ng/ml <8 ng/ml
<8 ng/ml – BMI ≥25, – BMI ≥25,
– BMI ≥25, <4 ng/ml <4 ng/ml
<4 ng/ml • Glucagon <3 ng/ml • Glucagon <3 ng/ml
• Glucagon • Arginine <0.4 ng/ml
<3 ng/ml
• The insulin tolerance test (ITT) is the gold standard test but contrain-
dicated in elderly patients and in patients with a history of coronary
artery disease (CAD), cerebrovascular disease, or seizure disorders
• Alternative tests include GHRH and arginine (currently GHRH analogue
is unavailable in the United States), glucagon, or arginine alone
48565_ST01_001-046.indd 27 5/1/13 9:35 PM

TABLE 5.3 Provocative Dynamic Tests for GH Secretion in Adults
Timing of
samples
Test Administration (min) Advantages Disadvantages
ITT 0.05−0.15 U/ 0, 15, 30, 60, Gold standard Caution in patients
kg IV; glucose 75, 90, 120; test, able with previous head
levels must fall alternatively to test HPA injury, patients aged
<40 mg/dl at 0, 30, 45, axis in >60 yr, patients
60, 90 addition to with hypoglycemic
GH secretion symptoms, and
patient discomfort;
contraindicated
in patients with a
history of coronary
artery disease,
cerebrovascular
disease, or seizure
disorders
GHRH and GHRH 1 μg/ 0, 15, 30, 60 Safer than GHRH not widely
arginine kg IV at time (up to 90); the ITT with available, may
0 followed by alternatively validated cause facial
arginine at 0, 30, 60, cutpoints flushing or metallic
0.5 mg/kg IV 90, 120 based taste; arginine
over 30 mins on BMI, contraindicated in
(max 30 g) applicable liver or renal disease
to wider
patient
population
Glucagon 1 mg IV for 0, 30, 60, Safer than Less effective GH
body weight 90, 120, ITT with stimulant, less
<90 kg and 150, 180; validated discriminatory than
1.5 mg IV for alternatively cutpoints, the ITT, high rate of
body weight at 0, 90, applicable to nausea and vomiting
≥90 kg 120, 150, wider patient
180, 210, population
240
Arginine 0.5 mg/kg IV 0, 15, 30, Safer Least established test,
>30 mins 45, 60; than ITT, less discriminatory
(max 30 g) alternatively applicable than the ITT,
at 0, 30, 60, to wider contraindicated in
90, 120 patient liver or renal disease
population
48565_ST01_001-046.indd 28 5/1/13 9:35 PM

Management 29
IMAGING
• MRI of the hypothalamic-pituitary area is recommended for all
patients once biochemical evidence of GHD is confirmed
MANAGEMENT
• Goals of GH replacement therapy
° Replace GH to restore serum IGF-I levels in the upper half of the
reference range
° Correct abnormalities associated with GHD
■ Improve body composition (↓ fat mass, ↑ lean body mass)
■ Improve metabolism (lipid profile, insulin sensitivity)
■ Improve muscle function and exercise tolerance
■ Improve bone mineral density (BMD)
■ Improve quality of life
• Contraindications to GH replacement therapy: active malignancy,

benign intracranial hypertension, proliferative diabetic retinopathy
TABLE 5.4 Recommendations for GH Replacement Therapy in AGHD
Starting dose:
• Age <30 yrs: 0.4−0.5 mg/day (may be higher for pediatric transition patients)
• Age 30−60 years: 0.2−0.3 mg/day
• Age >60 years: 0.1−0.2 mg/day
Use lower GH doses (0.1−0.2 mg/day) in patients with glucose intolerance
Dose titration: At one- to two-month intervals, increase dose in increments of
0.1−0.2 mg/day based on clinical response, serum IGF-I levels, side effects, and
individual considerations such as glucose intolerance; aim for serum IGF-I levels
≥0 to +2 SDS unless side effects are significant
Monitoring: At six-month intervals once maintenance doses are achieved. Monitoring
should include clinical evaluation, anthropometric measurements, assessment of
side effects, and measurement of serum IGF-I and fasting glucose levels. Lipid profile
should be measured every 12 months, quality of life measurements every 6−12 months.
If the initial bone DEXA scan is abnormal, repeat at two-year intervals. If pituitary
microadenomas or postsurgery residual pituitary tumor is still present, periodic
MRIs should be undertaken. Higher GH doses are required in women on oral, but not
transdermal, estrogens. Patients on concurrent cortisol and thyroid hormone replacement
may need dose adjustments after starting GH replacement therapy.
Length of GH therapy: The appropriate length of GH therapy is unclear; if benefits are
achieved, treatment should continue; if no apparent or objective benefi ts of treatment
are achieved after at least 2 years, discontinuing GH therapy may be considered
48565_ST01_001-046.indd 29 5/1/13 9:35 PM

• Adverse effects tend to be dose-dependent and transient

° Common adverse effects are fluid retention and arthralgia
° Dose reductions are usually required
° the dose upwards
Initiating GH replacement therapy at low doses and slowly titrating
may prevent these events
Transition from pediatric to adult care
• Patients with childhood structural hypothalamic-pituitary damage
(e.g., craniopharyngioma), three or more pituitary hormone deficien-
cies, or genetic defects do not require additional GH stimulation
testing as they enter into adulthood
° In these patients, GH replacement can be continued but lower adult
GH doses should be employed titrated based on serum IGF-I levels
• Patients with isolated idiopathic GHD should be retested with two
tests (e.g., ITT and glucagon test)
° Important to retest patients ≥1 month after stopping GH at the time
of linear growth completion
° ered for resumption
Patients who remain GH-deficient in adulthood should be consid-
of GH replacement therapy
■ Initiation and maintenance GH doses in these patients are
usually greater than those used in typical GHD in adults, and

should not be based on weight or body surface area but on
serum IGF-I levels
REFERENCES
Cook DM, Yuen KC, Biller BM, Kemp SF, Vance ML; American Association
of Clinical Endocrinologists. American Association of Clinical
Endocrinologists medical guidelines for clinical practice for growth
hormone use in growth hormone-deficient adults and transition patients–
2009 update. Endocr Pract, 2009;15(Suppl 2):1−29.
Ho KK; 2007 GH Deficiency Consensus Workshop Participants. Consensus
guidelines for the diagnosis and treatment of adults with GH deficiency II:
a statement of the GH Research Society in association with the European
Society for Pediatric Endocrinology, Lawson Wilkins Society, European
Society of Endocrinology, Japan Endocrine Society, and Endocrine Society
of Australia. Eur J Endocrinol, 2007;157(6):695−700.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine
Society. Evaluation and treatment of adult growth hormone deficiency:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(6):1587−609.
48565_ST01_001-046.indd 30 5/1/13 9:35 PM

6 ■ PITUITARY INCIDENTALOMAS,
NONFUNCTIONING PITUITARY
ADENOMAS, AND CRANIOPHARYNGIOMAS
Geetha Bhat, MD and Marc J. Laufgraben, MD
PITUITARY INCIDENTALOMAS
Background
• Definition
° Athat
pituitary incidentaloma (PI) is a lesion in the pituitary gland
is discovered on an imaging study performed for an unrelated
indication, in a patient without overt signs and symptoms of
pituitary disease
° Microincidentalomas are <1 cm
° Macroincidentalomas are ≥1 cm
• Prevalence
° Prevalence of PI at autopsy is ~10%
° Prevalence of PI on MRI varies but is likely similar to autopsy
° Nearly all PI are <1 cm
■ Lesions ≥1 cm typically present clinically rather than incidentally
• Differential diagnosis
° ~90% are pituitary adenomas
■ Vast majority are nonfunctional
■ Of functional tumors, prolactinomas and GH-secreting adenomas
are most common

° ~9% are craniopharyngioma or Rathke’s cleft cysts
° ~1%: various disorders including aneurysm, metastatases, inflam-
matory or infiltrative diseases, pituitary hyperplasia, germ cell
tumors, meningioma
Evaluation
• Although PIs are by definition discovered during an imaging study for
an unrelated indication, all patients with PI should undergo a careful
history and physical exam with attention to signs and symptoms
of pituitary hyperfunction, pituitary hypofunction, and neurologic
symptoms related to mass effect
• All patients with PI diagnosed by CT should undergo gadolinium-
enhanced MRI with fine cuts of the sella unless contraindicated
48565_ST01_001-046.indd 31 5/1/13 9:35 PM

32 Pituitary Incidentalomas, Nonfunctioning Pituitary Adenomas
• Visual field testing is recommended for all patients with PI that

compress, abut, or approach the optic chiasm
• Screening for hyperfunction
° PRL level should be measured in all patients
■ In patients with macroincidentalomas, PRL <200 may be due to
stalk compression rather than a PRL-secreting tumor

■ For large (>3 cm) macroadenomas, perform 1:100 dilution of
sample to exclude “hook effect”

° IGF-1 should be measured in all patients
■ Acromegaly may be clinically subtle and early diagnosis and
treatment may improve patient outcomes

° Screening for Cushing’s syndrome or other pituitary hyperfunction
if clinically indicated
• Screening for hypopituitarism
° Recommended routinely for all patients with macroincidentalomas
■ Some experts also recommend routine testing for large
(6−9 mm) microincidentalomas
■ Microincidentalomas ≤5 mm are very unlikely to cause
hypopituitarism, though testing is indicated if there is clinical

suspicion
° Testosterone
Typical testing includes AM cortisol, TSH and FT4, and IGF-1
° symptoms may be measured in men, especially those with sexual
° In premenopausal women, an abnormal menstrual history provides
evidence of gonadal dysfunction; in postmenopausal woman, low LH
and FSH indicate gonadotroph dysfunction, though this information
is not likely to alter management
Management
• For patients with hormonal hypersecretion
° Prolactinomas:
and Prolactinoma)
DA agonist therapy (see Chapter 3, Prolactinemia
° For other hormone-secreting tumors: neurosurgical resection

• For patients with hormonally inactive tumors
° Nonfunctioning pituitary adenomas: see next section
° Craniopharyngioma: see Craniopharyngiomas section, page 34
NONFUNCTIONING PITUITARY ADENOMAS

Presentation and natural history
• Nonfunctioning microadenomas (<1 cm)
° Most present as PI
° Significant growth over time is unusual
48565_ST01_001-046.indd 32 5/1/13 9:35 PM

Nonfunctioning Pituitary Adenomas 33
• Nonfunctioning macroadenomas (≥1 cm)

° Most present clinically with
■ Signs or symptoms of mass effect
• Headache
• Visual field deficits from optic chiasm compression
• Ophthalmoplegia from invasion of cavernous sinus causing
compression of cranial nerves
■ Signs or symptoms of hormonal dysfunction
• Hyperprolactinemia (PRL above normal but <200) from stalk

compression
• Hypopituitarism
° long-term follow-up
~20−25% of nonfunctioning macroadenomas will grow over
Management
• Nonfunctioning microadenoma
° Usual approach is surveillance without intervention
■ Repeat MRI in one year, then again in 1−2 years, and then at
increasing intervals (or consider stop testing)

° Can consider surgery if patient has unremitting headache,
but response is variable and improvement cannot be
guaranteed
• Nonfunctioning macroadenomas
° Surgery is recommended for
■ Patients with tumors compressing or abutting the optic chiasm
or optic nerves
■ Patients with tumors causing opthalmoplegia or other neurologic
problems
■ Patients with worsening headache
■ Patients with tumors that grow signifi cantly during follow-up or
approach the optic chiasm

° Surgery can be considered for
■ Patients with hypopituitarism
• Hypopituitarism may improve after resection but cannot be

guaranteed
■ Women who are planning pregnancy who have tumors close to
the optic chiasm

• Increased levels of estrogen in pregnancy may induce tumor
growth resulting in chiasmal compression
° External beam RT is usually reserved for patients with significant or
enlarging tumor remnant after surgery
° ■ Can be considered to lower PRL in patients with symptomatic
DA agonists
hyperprolactinemia from stalk effect who would otherwise not

need surgery
48565_ST01_001-046.indd 33 5/1/13 9:35 PM

■ Have shown some efficacy in reducing tumor volume in uncon-
trolled studies
• Can be considered for patients with nonfunctioning macro-
adenomas for whom surgery would be recommended but who
cannot or will not have surgery
• Can be considered as an alternative to external beam radia-
tion therapy in patients with significant or enlarging tumor
remnant after surgery
° Somatostatin analogues are less effective than DA agonists for
reducing the size of nonfunctioning macroadenomas, but can be
considered in patients who are not surgical candidates and who do
not respond to DA agonist therapy
° For patients who do not require surgical intervention, surveillance
is recommended
■ Repeat MRI in 6 months, then yearly for 3 years, then at increas-
ing intervals
■ Consider repeat evaluation for hypopituitarism at appropri-
ate follow-up intervals, particularly if tumor grows or patient

develops new signs or symptoms
■ Repeat VF testing if tumor grows toward the chiasm
■ Patients should be educated on the symptoms of pituitary
apoplexy and should seek medical attention immediately if such

symptoms occur
CRANIOPHARYNGIOMAS
Background
• Rare benign epithelial tumors arising along the path of the craniopha-
ryngeal duct from remnants of Rathke’s pouch
• Occurs in a bimodal age distribution: peaks at 5−15 years old in
children and 50−74 years old in adults
• Located mainly in the sellar and parasellar region
° 95% are suprasellar or both suprasellar and intrasellar
° The majority of tumors are cystic or mixed cystic-solid
° Majoritycraniopharyngiomas
Half of contain calcifications
° Can exertarepressure
2−4 cm at diagnosis
° pathways, brain parenchyma,
effects on multiple structures including visual
ventricular system, blood vessels,
and hypothalamus and pituitary
48565_ST01_001-046.indd 34 5/1/13 9:35 PM

Craniopharyngiomas 35
Presentation and evaluation

• Signs and symptoms
° Presentation differs depending on pattern of growth (i.e., what
structures are effected)
° ■ Headaches presenting symptoms are
Most common
■ Nausea/vomiting
■ Visual problems
■ Growth failure in children
■ Hypogonadism in adults
• Radiologic evaluation
° Computed
MRI: best study to define relationship of tumor to other structures
° and cystic tomography
components
(CT): useful for indentifying calcifications
° Differential diagnosis includes other cystic lesions of the sellar/

parasellar area including Rathke’s cleft cyst and cystic pituitary
adenoma
• Laboratory evaluation
° The majority of patients have some aspect of compromised pituitary
function
° diabetes insipidus
All patients should have evaluation for hypopituitarism (including
if suggested by symptoms) with deficits treated
as appropriate
Management
• Surgery is the primary treatment modality
• Lifelong radiologic surveillance is necessary for patients with gross
total resection, as recurrence is common
• Adjuvant radiotherapy is recommended for patients with residual tis-
sue on postoperative imaging or who recur during surveillance
° May also be considered as primary therapy for small biopsy-proven
craniopharyngiomas that are not causing compressive symptoms
• Repeat surgery can be considered for acute pressure effects or
life-threatening growth of solid components, but rarely achieves total
removal and is associated with increased perioperative morbidity and
mortality
• Multiple modalities have been employed to control cystic components,
included repeated aspiration, brachytherapy, or intracystic bleomycin
• New problems may occur as a result of tumor growth or recurrence,
surgery, RT, or the use of other treatment modalities
° Patients should be monitored for the development of new pituitary
deficits, new visual compromise, and hypothalamic disorders
including hyperphagia and obesity (“hypothalamic obesity”),
behavioral problems, and loss of control of body temperature
48565_ST01_001-046.indd 35 5/1/13 9:35 PM

REFERENCES
Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G, Savastano S.
Medical therapy for clinically non-functioning pituitary adenomas. Endocr
Relat Cancer, 2008;15(4):905−15.
Fernández-Balsells MM, Murad MH, Barwise A, et al. Natural history of non-
functioning pituitary adenomas and incidentalomas: a systematic review
and metaanalysis. J Clin Endocrinol Metab, 2011;96(4):905−12.
Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(4):894−904.
Jane JA Jr, Laws ER Jr. The management of non-functioning pituitary adeno-
mas. Neurol India, 2003;51(4):461−5.
Karavitaki N, Cudlip S, Adams CB, Wass JA. Craniopharyngiomas. Endocr
Rev, 2006;27(4):371−97.
Karavitaki N, Wass JA. Craniopharyngiomas. Endocrinol Metab Clin North Am,
2008;37(1):173−93.
Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas.
Endocrinol Metab Clin North Am, 2008;37(1):151−71.
Orija IB, Weil RJ, Hamrahian AH. Pituitary incidentaloma. Best Pract Res Clin
48565_ST01_001-046.indd 36 5/1/13 9:35 PM

7 ■ HYPOOSMOLALITY AND THE SYNDROME
OF INAPPROPRIATE ANTIDIURETIC HORMONE
SECRETION
Joseph G. Verbalis, MD
PATHOPHYSIOLOGY
• Hypoosmolality indicates an excess of total body water relative to total
body solute
• Imbalances between body water and solute can be generated either by
depletion of body solute more than body water, or by dilution of body
solute from increases in body water more than body solute
• Most hypoosmolar states include components of both solute depletion
and water retention, but this general concept provides a framework for
understanding hypoosmolar disorders
• Clinical manifestations of hyponatremia are largely neurological, and
primarily reflect brain edema resulting from osmotic water shifts into
the brain
• Symptoms range from nonspecific such as headache and confusion,
to more severe manifestations such as decreased sensorium, coma,
seizures, and death
• Significant CNS symptoms generally do not occur until the serum [Na+]
falls below 125 mmol/L, and the severity of symptoms can be roughly
correlated with the degree of hypoosmolality
• Individual variability is marked, and for any patient the level of
serum [Na+] at which symptoms will appear cannot be accurately
predicted
° Factors other than the severity of the hypoosmolality also affect the
degree of neurological dysfunction, the most important is the time
course over which hypoosmolality develops: rapid development of
severe hypoosmolality frequently causes marked neurological symp-
toms, whereas gradual development over several days or weeks
is often associated with relatively mild symptomatology despite
profound degrees of hypoosmolality
• Underlying neurological and metabolic disorders (hypoxia, hypercapnia,
acidosis, hypercalcemia, etc.) also affect the level of hypoosmolality at
which symptoms appear
48565_ST01_001-046.indd 37 5/1/13 9:35 PM

38 Hypoosmolality and the Syndrome
• Careful history (especially concerning medications)
• Physical examination with emphasis on clinical assessment of the
extracellular fluid (ECF) volume status and thorough neurologic
evaluation
• Laboratory analysis
° Measurement of serum or plasma electrolytes, glucose, blood urea
nitrogen (BUN), creatinine and uric acid
° Determination of simultaneous
Calculated and/or directly measured plasma osmolality
° urine electrolytes and osmolality
CLASSIFICATION OF HYPOOSMOLALITY BY ECF VOLUME STATUS

• Decreased ECF volume (hypovolemia)
° Clinically detectable hypovolemia indicates solute depletion
° Even isotonic or hypotonic fluid losses can cause hypoosmolality if
water or hypotonic fluids are subsequently ingested or infused
° Aoflow urine sodium concentration (UNa) suggests a nonrenal cause
solute depletion, whereas a high UNa suggests renal causes of
solute depletion
° Diuretic use is the most common cause of hypovolemic hypoosmolality
• Normal ECF volume (euvolemia)
° Any disorder causing hypoosmolality can present with a volume sta-
tus that appears normal by standard methods of clinical evaluation
° The presence of normal or low BUN and uric acid concentrations are
helpful laboratory correlates of relatively normal ECF volume
° ary toUNaECF(<30
Low mmol/L) suggests depletional hypoosmolality second-
losses with subsequent volume replacement by water or
other hypotonic fluids
° lality
High UNa (>30 mmol/L) generally indicates a dilutional hypoosmo-
such as the syndrome of inappropriate antidiuretic hormone
secretion
• Increased ECF volume (hypervolemia)
° Clinically
excess
detectable hypervolemia indicates whole body sodium
° intravascular volume
Hypoosmolality in these patients suggests a relatively decreased
and/or pressure leading to water retention as
a result of elevated plasma arginine vasopressin (AVP) levels and
decreased distal delivery of glomerular filtrate to the kidneys
° Patients usually have a low UNa because of secondary hyperaldoste-
ronism, but under certain conditions the UNa may be elevated (e.g.,
diuretic therapy)
° Heart failure and cirrhosis are the most common causes of hyper-
volemic hypoosmolality
48565_ST01_001-046.indd 38 5/1/13 9:35 PM

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 39
SYNDROME OF INAPPROPRIATE ANTIDIURETIC

HORMONE SECRETION (SIADH)
• The clinical criteria necessary to diagnose SIADH remain as initially
defined by Bartter and Schwartz in 1967
° The presence of hyponatremia with a correspondingly low plasma
osmolality (i.e., hypotonic hyponatremia)
° An inappropriately elevated urine osmolality (>100 mOsm/kg H2O)
° Clinical
retention)
euvolemia (i.e., absence of signs of volume depletion or
° UNormal
Na+ >30 mEq/L
° renal, adrenal, and thyroid function
• Many different disorders are associated with SIADH, which can be
divided into four major groups: tumors, CNS disorders, drug effects,
and pulmonary diseases
Treatment
• Current therapies for managing SIADH in hospitalized patients
° Isotonic saline
■ Treatment of choice for hypovolemic hyponatremia (patients
who either have clinical signs of hypovolemia, or in whom a spot

UNa+ is <30 mmol/L)
■ Ineffective for dilutional hyponatremias such as SIADH; admin-
istration of isotonic saline to a euvolemic patient may worsen

hyponatremia and/or cause fluid overload
° ■ Patients saline
Hypertonic
with severe neurological symptoms should be treated
promptly with hypertonic solutions, typically 3% NaCl ([Na+] =
513 mmol/L)
■ The infusion rate of 3% NaCl (mL/h) can be estimated by
multiplying the patient’s weight (kg) by desired correction rate

(mmol/L/h)
• An alternative option is administration of a 100-mL bolus of
3% NaCl, repeated once if no clinical improvement
° Fluid restriction
■ Most widely accepted treatment for patients with chronic
hyponatremia
■ Restrict all fluids to 500 ml less than the 24-hour urine output
■ Serum [Na+] increases slowly (1–2 mmol/L/day) even with
severe fluid restriction

■ Often poorly tolerated because of associated increased thirst
■ Should not be used with hypovolemic patients
■ Difficult in patients with high urine osmolalities secondary
to high AVP levels; if the sum of urine Na+ and K + exceeds

the serum [Na+], most patients will not respond to a fluid
restriction since electrolyte-free water clearance will be
difficult to achieve
48565_ST01_001-046.indd 39 5/1/13 9:35 PM

° Demeclocycline
■ Can be used when patients find fluid restriction unacceptable
■ Initial dose is 300 mg twice a day (BID); titrate upward to
1200 mg/day as needed
■ Can cause nephrotoxicity in patients with heart failure or
cirrhosis
° Urea
■ Induces osmotic diuresis and augments free water excretion
■ Effective doses for treatment of hyponatremia are 30–60 g daily
in divided doses
■ Use limited because there is no United States Pharmacopeia
(USP) formulation and it is associated with poor palatability

■ Mild azotemia can be seen but rarely reaches clinically signifi -
cant levels
° Arginine vasopressin receptor (AVPR) antagonists
■ Antagonists of the AVP V2 (antidiuretic) receptor (“vaptans”) are
approved by the U.S. Food and Drug Administration (FDA) for the
treatment of euvolemic and hypervolemic hyponatremia
■ AVPR antagonists produce electrolyte-free water excretion
(“aquaresis”) without affecting renal sodium and potassium

excretion
■ Serum [Na+] is signifi cantly increased within 24–48 hours,
which is considerably faster than the effects of fluid restriction

(which can take many days)
■ Increased renal fluid excretion can cause or worsen hypotension
in patients with hypovolemic hyponatremia so vaptans are

contraindicated in these patients
■ Conivaptan is available only as an intravenous preparation and
is given as a 20-mg loading dose over 30 min, followed by a

continuous infusion of 20 or 40 mg
• The 20-mg continuous infusion is used for the first 24 h to
gauge the initial response; if the correction of serum [Na+] is
felt to be inadequate (e.g., <5 mmol/L), then the infusion rate
can be increased to 40 mg/day
• Therapy is limited to a maximum duration of 4 days because
of drug-interaction effects with other agents metabolized by
CYP3A4 isoenzymes
• Most common adverse effects include injection-site reactions,
which are generally mild and usually do not lead to treatment
discontinuation, headache, thirst, and hypokalemia
■ Tolvaptan is available as an oral preparation that can be used for
both short- and long-term treatment of hyponatremia

• Similar to conivaptan, tolvaptan must be initiated in the
hospital so that the rate of correction can be monitored
carefully
48565_ST01_001-046.indd 40 5/1/13 9:35 PM

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 41
• Patients with a serum [Na+] <125 mmol/L are eligible for

therapy with tolvaptan as primary therapy; if the serum [Na+]
is ≥125 mmol/L, tolvaptan therapy is only indicated if the
patient has symptoms that could be attributed to the hypona-
tremia and the patient is resistant to fluid restriction
• Starting dose is 15 mg on the first day, and can be titrated
to 30 mg and 60 mg at 24-hour intervals if the serum [Na+]
remains <135 mmol/L or the increase in serum [Na+] has
been ≤5 mmol/L in the previous 24 hours
• Patients should not be on a fluid restriction when tolvaptan
is initiated
• Reported side effects include dry mouth, thirst, increased
urinary frequency, dizziness, nausea, orthostatic hypotension,
and liver injury
■ Hyponatremia treatment guidelines for hospitalized patients
with SIADH are based on their presenting symptoms summarized

as in Figure 7-1
• Monitoring serum [Na+] in hospitalized patients with SIADH
° The frequency of serum [Na+] monitoring is dependent on both the
severity of the hyponatremia and the therapy chosen
° Overly rapid correction of serum [Na+] can cause damage to the
myelin sheath of nerve cells, resulting in central pontine myelinoly-
sis, also called the osmotic demyelination syndrome (ODS)
FIGURE 7.1 Hyponatremia treatment algorithm
48565_ST01_001-046.indd 41 5/1/13 9:35 PM

° Maximal recommended rates of correction are 12 mmol/L within

24 hours or 18 mmol/L within 48 hours; this should be reduced to
8 mmol/L for any 24-hour period in patients with risk factors for
development of osmotic demyelination (severely low serum [Na+],
malnutrition, alcoholism, or hypokalemia)
° Patients undergoing active treatment with hypertonic saline for
level 1 or 2 symptomatic hyponatremia should have frequent
monitoring of serum [Na+] and ECF volume status (every 2−4 hours)
to ensure that the serum [Na+] does not exceeded the recommended
levels during the active phase of correction
° Patients treated with vaptans for level 2 or 3 symptoms should have
serum [Na+] monitored every 6−8 hours during the active phase of
correction, which will generally be the first 24−48 hours of therapy
° In patients with a stable level of serum [Na+] treated with fluid
restriction or therapies other than hypertonic saline, measure-
ment of serum [Na+] daily is generally sufficient, since levels will
not change that quickly in the absence of active therapy or large
changes in fluid intake or administration
° If the correction exceeds recommended limits, administer sufficient
water, either orally or as IV D5W, to bring the overall correction
below desired limits
REFERENCES
Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiure-
sis. N Engl J Med, 2007;356(20):2064−72.
Schrier RW, ed. Diseases of the Kidney and Urinary Tract. 7th ed. Philadelphia,
PA: Lippincott Williams & Wilkins, 2001.
Verbalis JG. Control of brain volume during hypoosmolality and hyperosmo-
lality. Adv Exp Med Biol. 2006;576:113−29.
Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia
treatment guidelines 2007: expert panel recommendations. Am J Med, 2007;
120(11 Suppl 1):S1−21.
48565_ST01_001-046.indd 42 5/1/13 9:35 PM

8 ■ DIABETES INSIPIDUS
Vicky Cheng, MD and Geetha Gopalakrishnan, MD
DEFINITION
• Characterized by the excretion of large volumes of dilute urine
(>2.5−3.0 mL/kg body weight per hour, specific gravity <1.005, urine
osmolality <200 mOsm/kg H2O)
• Types of DI
° Central diabetes insipidus: inadequate secretion of AVP from the
hypothalamus/posterior pituitary
° to AVP
Nephrogenic diabetes insipidus: impaired response of the kidney
° Primary polydipsia: excess intake of water leads to suppression of

AVP; it is typically psychogenic in nature
ETIOLOGIES
TABLE 8.1 Etiologies of Diabetes Insipidus
Central DI Nephrogenic DI
• Congenital (congenital malformations; • Congenital (X-linked recessive AVP V2
autosomal dominant AVP-neurophysin receptor gene mutations; autosomal
gene mutation) dominant/recessive aquaporin-2 water
• Autoimmune (lymphocytic hypophysitis) channel gene mutations)
• Drugs (alcohol, diphenylhydantoin) • Drugs (lithium, demeclocyline,
• Granulomatous disease (sarcoidosis, cisplatin, methoxyflurane)
histiocytosis) • Electrolyte disorders (hypercalcemia,
• Infectious (meningitis, encephalitis) hypokalemia)
• Tumors (craniopharyngioma, metastatic • Infiltrative (sarcoidosis, amyloidosis)
pituitary tumors) • Renal disease (chronic renal failure,
• Trauma (neurosurgery, head injury) obstructive uropathy)
• Vascular (cerebral hemorrhage, • Vascular (sickle cell disease or trait)
infarction)
CLINICAL MANIFESTATIONS
• Polyuria, polydipsia
• Craving for cold water
• Signs and symptoms of dehydration, depending on whether the patient
has intact thirst mechanism and is able to drink fluids
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44 Diabetes Insipidus
DIAGNOSIS
• Rule out osmotic diuresis from hyperglycemia or fluid overload
• Polyuria (urine volume >3L in 24 hours)
• Dilute urine (specific gravity <1.005, urine osmolality <200 mOsm/
kg H2O)
• Serum osmolality and sodium
° Most patients with DI present with normal serum sodium and
osmolality if they are able to maintain oral intake of fluids, elevated
serum osmolality and sodium are only noted in patients who are
unable to drink to thirst
° Typically, patients with diabetes insipidus (DI) have high or high-
normal serum sodium and osmolality; in primary polydipsia, serum
sodium and osmolality are typically in the low end of normal range
• Water deprivation test
° Provocative testing to differentiate central DI from nephrogenic DI
in patients with intact thirst mechanism
■ Fluids are withheld to promote dehydration which is a potent
stimulus for maximal AVP secretion

■ Measure urine volume and osmolality every 1 hour and serum
sodium and osmolality every 2 hours until any of the following

occur
• Serum Na is ≥146 mEq/L
• Urine osmolality reaches a plateau (3 consecutive urines with
<10% differences)
• Body weight decreases by 3%
• Patient develops cardiovascular instability (i.e., low BP or
tachycardia)
■ After one of the above criteria is reached, blood is drawn for
AVP level and the patient is given AVP (5 U) or dDAVP (1 μg) SQ;
measure urine osmolality and urine volume every 30 minutes for
the next 2 hours
° ■ Patients withof central
Interpretation test results
DI will have low or “inappropriately normal”
AVP levels whereas those with nephrogenic DI will have elevated
levels
■ Patients with central DI will have a ≥50% increase in urine
osmolality after dDAVP administration

■ Patients with nephrogenic DI will have a <10% increase in urine
osmolality after dDAVP administration

■ Patients with primary polydipsia are usually eunatremic
and have <10% increases in urine osmolality after dDAVP

administration; plasma AVP levels are appropriate to the plasma
osmolality
48565_ST01_001-046.indd 44 5/1/13 9:35 PM

References 45
Treatment
• Central DI
° Correction of any preexisting water deficits
° Accurate recording of fluid intake and output
° the drug of choice;
Desmospressin acetate (dDAVP): synthetic analogue of AVP, it is
available in parenteral (1−2 μg), oral (0.1 or
0.2 mg), and nasal (10 μg) formulations
° deficit (i.e., some circulating
Other agents that can be considered in DI especially if partial
AVP present)
■ Thiazide diuretics: by causing modest hypovolemia, thiazide
diuretics increase the absorption of salt and water in the

proximal tubule
■ Chlorpropamide: an oral hypoglycemic agent; potentiates the
action of AVP in the kidney

■ Carbamazepine: enhances renal sensitivity to AVP
■ Clofibrate: increases secretion of AVP
■ Nonsteroidal anti-inflammatory drugs (NSAIDs): inhibit the renal
synthesis of prostaglandins, which are AVP antagonists

• Nephrogenic DI
° Correction of
Correction any preexisting fluid deficits
° hypokalemia) of electrolyte disturbances (e.g., hypercalcemia,
° Discontinuation of any drugs that may be causing nephrogenic DI

° Thiazide diuretics: most effective therapy
° propamide, carbamazepine,
Other agents that can be considered include NSAIDs, chlor-
and clofibrate
• Primary polydipsia
° Behavior modifi cation
REFERENCES
Loh JA, Verbalis JG. Disorders of water and salt metabolism associated with
pituitary disease. Endocrinol Metab Clin North Am, 2008;37(1):213−34.
Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a
complex disease. Cleve Clin J Med, 2006;73(1):65−71.
Verbalis JG. Diabetes insipidus. Rev Endocr Metab Disord, 2003;4(2):177–85.
48565_ST01_001-046.indd 45 5/1/13 9:35 PM

48565_ST01_001-046.indd 46 5/1/13 9:35 PM
SECTION II: THYROID
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48565_ST02_047-110.indd 48 5/1/13 9:34 PM
9 ■ THYROID ESSENTIALS AND THYROID
FUNCTION TESTS
Shabina R. Ahmed, MD and David S. Cooper, MD
ANATOMY
• Butterfly-shaped organ that lies under the sternothyroid and sterno-
hyoid muscles
• Composed of left and right lobes joined by an isthmus; occasionally
a pyramidal lobe sits on top of the isthmus, can be palpable in Graves’
disease
• Surrounded by a thin, fibrous capsule attached to the cricoid cartilage
and superior tracheal rings
• The recurrent laryngeal nerves run posteriorly to the gland and the
parathyroid glands sit behind the superior and middle portions of
each lobe
• Highly vascular, supplied by the superior and inferior thyroid arteries
HISTOLOGY
• The thyroid gland is made up of individually functioning units called
follicles
° Lined by simple cuboidal epithelium
° Filled
colloid
with a glycoprotein complex called thyroglobulin (Tg), or
• Epithelium produces thyroid hormone (T4 and T3) within the colloid,
where it is also stored
• The basement membrane of the follicles contain neuroendocrine
secretory cells called C cells, which have a pale granular cytoplasm
and secrete calcitonin
PHYSIOLOGY
• Thyroid hormone is comprised of two iodinated thyronine residues
bonded by an ether linkage
• Thyroid hormone synthesis requires several steps that are dependent
upon iodine (a key structural component of thyroid hormone), the
sodium/iodide symporter (NIS), thyroid peroxidase (TPO), pendrin,
and Tg
48565_ST02_047-110.indd 49 5/1/13 9:34 PM

50 Thyroid Essentials and Thyroid Function Tests
• Trapping and iodide transport: iodide from the circulation is transported

into the follicular cell via NIS at the basal membrane of the thyroid
° Normally NIS is regulated by TSH; iodide also regulates NIS; when
iodine ↑, NIS expression and activity ↓
■ In Graves’ disease, NIS is stimulated by TSH receptor-stimulating
antibodies
° Pendrin is an iodide/chloride transporter at the apical membrane
and positions iodide to act as a substrate for hormonogenesis
■ Patients with mutations in the pendrin gene develop Pendred’s
syndrome, with congenital deafness, goiter, and defective iodide

organification
• Organification: iodide is oxidized at the apical-colloid membrane by
endogenously generated hydrogen peroxide in a reaction catalyzed by
TPO. Oxidized iodide is then bound to tyrosine residues within Tg, a
large glycoprotein with multiple tyrosyl sites.
• Coupling: TPO also catalyzes the coupling of two iodotyrosyl residues
within Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT); two
DITs couple to form T4 and one MIT and one DIT couple to form T3
° The antithyroid drugs (ATDs) methimazole (MMI) and propothio-
uracil (PTU) are competitive inhibitors of TPO and work to block
synthesis of T4 and T3
• Storage of hormone: iodinated Tg containing T4 and T3 is secreted into
the follicular lumen and makes up the bulk of colloid
• Proteolysis and secretion of thyroid hormone
° Thyroglobulin
droplets
reenters the thyrocyte via micropinocytosis of colloid
° Colloid droplets fuse with lysosomes, causing the release of T4 and

T3, and deiodination of MIT and DIT
° recycledthe
Most of Tg is proteolyzed; some is released in the serum or
into the follicular lumen
• Intrathyroidal deiodination of T4: 5’-deiodinase is present in the
peripheral tissues to convert T4 to the biologically active T3, but it also
is present within the thyroid itself
• The thyroid is controlled by the hypothalamus and pituitary. TRH
produced by the hypothalamus stimulates the pituitary to release TSH
or thyrotropin. In turn, TSH acts on thyroid follicular cells to promote
all the steps in thyroid hormone synthesis and release. T4 and T3
inhibit TRH and TSH secretion, so that serum TSH levels increase in
hypothyroidism and decrease in hyperthyroidism.
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Physiology 51
TABLE 9.1 Use and Interpretation of Thyroid Function Tests
Thyroid Function Tests
Test Use Interpretation
TSH • Anterior pituitary • ↑ suggests primary hypothyroidism;
hormone; stimulates rarely pituitary TSHoma or thyroid
release of thyroid hormone hormone resistance
and growth of gland • ↓ suggests hyperthyroidism; rarely
• Very sensitive test; can central hypothyroidism
effectively diagnose hypo- • May be difficult to interpret in
or hyperthyroidism in most nonthyroidal illness, pregnancy,
cases patients on high-dose
glucocorticoids or dopamine
Total thyroxine • Measures bound and free • ↑ suggests hyperthyroidism
(T4) T4 and T3 concentrations • ↓ suggests hypothyroidism
• >99% of thyroid hormone • May not accurately assess thyroid
is bound to thyroid hormone status: many medications
hormone binding globulin and clinical conditions may alter
TBG and affect total T4 levels
FT4 • Measures bioactive T4 • ↑ indicates hyperthyroidism
levels • ↓ indicates hypothyroidism
• Preferrable over free thyroxine index
Total T3 • Measures bound and free • Useful in patients with
T3 levels hyperthyroidism
Free T3 • Measures bioactive T3 • Useful in patients with
levels hyperthyroidism
Thyroid • Binds T4 and T3 • Causes of ↑ TBG
hormone ○ Drugs (estrogen, oral
binding contraceptives, tamoxifen,
globulin heroin, methadone,
(TBG) 5-fluorouracil)
○ Pregnancy
○ Acute hepatitis
○ Congenital
○ Acute intermittent porphyria
• Causes of ↓ TBG
○ Drugs (androgens,
glucocorticoids, slow-release
nicotinic acid)
○ Severe illness or malnutrition
○ Chronic liver disease
○ Protein-losing states (e.g.,
nephritic syndrome)
○ Congenital
(continues)
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52 Thyroid Essentials and Thyroid Function Tests
TABLE 9.1 (continued )

Thyroid Function Tests
Test Use Interpretation
T3 resin • An indirect measure of • ↑ T3RU: hyperthyroidism, low TBG
uptake the binding capacity of states
(T3RU) patient’s serum proteins • ↓ T3RU: hypothyroidism, high TBG
(measures unoccupied states
T4-binding sites)
• Used in conjunction with
serum T4
Free thyroxine • Product of serum T4 and • Highly correlated with free T4
index (FTI) T3RU
• Corrects for changes
in binding protein
concentration
REFERENCES
Bizhanova A, Kopp P. Minireview: The sodium-iodide symporter NIS
and pendrin in iodide homeostasis of the thyroid. Endocrinology,
2009;150(3):1084−90.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology. 8th ed.
New York, NY: McGraw Hill; 2007.
Hall JE, Nieman LK, eds. Handbook of Diagnostic Endocrinology. Totowa, NJ:
Humana Press; 2003.
Moore KL, Dalley AF. Clinically Oriented Anatomy. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 1999.
Pesce L, Bizhanova A, Caraballo JC, et al. TSH regulates pendrin membrane
abundance and enhances iodide efflux in thyroid cells. Endocrinology,
2012;153(1):512−21.
Young B, Heath JW. Wheater’s Functional Histology: A Text and Colour Atlas.
4th ed. Philadelphia, PA: Churchill Livingstone; 2000.
48565_ST02_047-110.indd 52 5/1/13 9:34 PM

10 ■ THYROTOXICOSIS AND
HYPERTHYROIDISM
Anna Milanesi, MD, PhD and Gregory A. Brent, MD
ETIOLOGY AND PATHOPHYSIOLOGY

• Thyrotoxicosis is the clinical condition resulting from an excess of
circulating thyroid hormones from any of a number of etiologies
• Some endocrinologists use the term hyperthyroidism only when there
is increased synthesis of thyroid hormones by the thyroid gland, but
most use the term hyperthyroidism to refer to any condition with
excess thyroid hormone
TABLE 10.1 Causes of Thyrotoxicosis

Etiology Pathophysiology
Graves’ disease Stimulating antibody that recognizes the TSH
receptor
Toxic adenoma or toxic goiter Autonomous thyroid hormone production (often due
to somatic activating mutation of TSH-receptor
gene)
Silent subacute thyroiditis Thyroid inflammation and release of preformed
hormone with positive thyroid autoantibodies (anti-
TPO), most common in the postpartum period
Painful subacute thyroiditis Thyroid inflammation and release of preformed
(De Quervain’s or subacute hormone following a viral infection
granulomatous thyroiditis)
TSH-secreting pituitary TSH-stimulated thyroid growth and thyroid hormone
adenoma production and secretion
Iodine “Jod-Basedow,” excess thyroid hormone secretion,
usually in the setting of multinodular goiter
Medications (e.g., amiodarone, Varied
interferon)
Trophoblastic disease High levels of hCG bind and stimulate TSH-receptor
to stimulate thyroid hormone production
Struma ovarii Ectopic thyroid hormone production from ovarian
teratom
Factitious thyrotoxicosis Ingestion of exogenous thyroxine (T4), triiodothyronine
(T3), or products containing T4 and/or T3
Thyroid hormone resistance Mutation of the thyroid hormone receptor-beta gene
48565_ST02_047-110.indd 53 5/1/13 9:34 PM

54 Thyrotoxicosis and Hyperthyroidism
• The clinical features of hyperthyroidism can be dramatic with manifes-
tations across many organ systems; however, a proportion of patients,
especially the elderly or those with more mild disease, may present
with few symptoms
° Cardiovascular: palpitations, increased heart rate, increased
cardiac output, increased contractility, atrial fibrillation, congestive
heart failure (CHF), cardiovascular collapse and death
° Skeletal muscle: proximal muscle weakness, generalized fatigue,
muscular atrophy
° Neurological: tremor, irritability, nervousness, insomnia, psychosis,
altered mental status, lethargy, and coma
° circulating sex hormone-binding
Gonadal: irregular menstrual cycles, reduced libido, increased
globulin and reduced levels of
free sex hormones
° fracture
Bone: increased bone turnover, ostopenia/osteoporosis, and
° Metabolic: weight loss, sweating

° Gastrointestinal: vomiting, diarrhea
• Disease-associated symptoms and signs
° Graves’disease: thyroid enlargement, thyroid bruit in anterior neck
with auscultation, thyroid-associated orbitopathy (soft-tissue
swelling and inflammation, exophthalmos, proptosis, lid lag),
dermopathy and acropachy
° Toxic multinodular goiter: thyroid enlargement, venous compression
syndrome if the goiter is retrosternal
° Painful subacute thyroiditis: thyroid gland tenderness
DIAGNOSIS
TABLE 10.2 Conditions of TSH

A. CONDITIONS WITH SUPPRESSED SERUM TSH
24-hr Radioio-
dine Uptake and
Disease T4 T3 Scan Other Studies
Graves’ disease ↑ ↑ (T3 > ↑ with TSI/TRBII positive
T4) homogenous
distribution*
Toxic multinodular ↑, normal, ↓ ↑ Inappropriately TSI/TRBII/TPO
goiter in the “normal negative
range” to ↑
with patchy
distribution
(continues)
48565_ST02_047-110.indd 54 5/1/13 9:34 PM

Diagnosis 55

24-hr Radioio-
dine Uptake and
Disease T4 T3 Scan Other Studies
Toxic adenoma ↑/=/↓ ↑ Inappropriately TSI/TRBII/TPO
in the “normal negative
range” to
↑ focal
uptake with
suppression
of the normal
gland
Subacute ↑ ↑ Below normal TSI/TRBII/TPO
thyroiditis negative
Painless thyroiditis ↑ ↑ Below normal TPO positive
Iodine-induced ↑, normal, ↓ ↑ Variable
hyperthyroidism
Factitious ↑ (if T4 is ↑ (if T3 is Below normal Low Tg
hyperthyroidism ingested) ingested)
Struma ovarii ↑ ↑ ↓ uptake in the Whole body iodine
neck scan: pelvic
uptake
Trophoblastic ↑ ↑ ↑ Serum hCG
disease elevated
and uterine
ultrasound
B. CONDITIONS WITH NORMAL OR ELEVATED TSH

24-hr Radioiodine
Disease T4 T3 Uptake and Scan Other Studies
Pituitary adenoma ↑ ↑ Inappropriately Pituitary MRI
normal or ↑
Thyroid hormone ↑ ↑ Inappropriately Sequencing of THRβ
resistance normal or ↑ gene
(THRβ)
TSH: thyroid stimulating antibodies, T3: triiodothyronine, T4: thyroxine, TSI: thyroid-stimulating immu-
noglobulin, TRAb: TSH-receptor antibodies, TRBII: Thyroid Receptor Binding Inhibitory Immunoglobulin,
TPO: thyroid peroxidase antibodies; Tg: thyroglobulin; hCG: human chorionic gonadotropin; THRβ: thyroid
hormone receptor beta.
*24-hr radioiodine uptake does not have to be performed for diagnosis if the clinical presentation is typi-
cal for Graves’ disease (symptoms of hyperthyroidism for weeks to months, symmetrically enlarged thyroid,
thyroid-associated orbitopathy).
48565_ST02_047-110.indd 55 5/1/13 9:34 PM

TABLE 10.3 Laboratory Studies for Diagnosis and Follow-Up
Test Description Utility
TSH Highly sensitive direct serum Required for diagnosis;
measurement standard for monitoring
although will remain
suppressed for up to several
months, even after thyroid
hormone levels are normalized
T4 Free T4 index: total thyroxine Effective for monitoring
measurement and estimate of thyroid response to therapy
binding globulin.
Free T4 by analogue method: indirect
method used in the automated
platform instrument
Free T4 by dialysis: direct measure,
usually sent to reference laboratory
T3 Total T3: direct measure of total Important in the early disease
serum level assessment and response
Free T3 by analogous methods: indirect to therapy
method used in the automated
platform instrument
Free T3 by dialysis: direct measure,
more expensive
TRBII Assay for serum immunoglobulin Support for diagnosis of GD;
interacting with TSH-receptor does persistent elevation correlates
not distinguish between blocking and with disease activity; not
stimulating antibodies necessary for monitoring
TSI Assay measuring cyclic AMP production
after incubation of the patient’s serum
with thyroid follicular cells; specific for
Graves’ disease
TPO Measures antibody to thyroid peroxidase Detected in patients with HT, but
enzyme can also be positive in GD
TRBII: thyroid receptor binding inhibitor immunoglobulin; GD: Graves’ disease; TSI: thyroid-stimulating
immunoglobulin; TPO: thyroid peroxidase antibodies; HT: Hashimoto’s thyroiditis.
• Other diagnostic tests

° Thyroid ultrasound: to assess thyroid enlargement, nodules, and
thyroid vascularity (generally increased in Graves’ disease)
° Radioactive Iodide Uptake (RAIU) and scan: useful for initial
diagnosis and to quantify uptake for radioiodine treatment
° fibrillation
Electrocardiogram (ECG): to assess for irregular rhythm and atrial
48565_ST02_047-110.indd 56 5/1/13 9:34 PM

Management Options 57
° Bone density scan: to assess osteopenia or osteoporosis

° CT of the neck: to assess possible tracheal narrowing (in case
of retrosternal goiter or evidence of tracheal deviation or venous
congestion)
MANAGEMENT OPTIONS
• Pharmacological therapy
° β-adrenergic
symptom control)
receptor blocker (short-term adjunctive therapy for
■ Should be given to patients with signs of adrenergic activation
including tremor, tachycardia, and sweating while ATDs are

begun and titrated to normalize circulating thyroid hormone
levels
■ Typical dose is metoprolol 50−200 mg daily, atenolol 25−100 mg
daily, or propanolol 10−40 mg TID; esmolol IV can be used in a

monitored setting for severe thyrotoxicosis or thyroid storm
■ Caution should be taken in patients with asthma, obstructive
lung disease, or CHF

° ATDs (thionamides: MMI and PTU)
■ Block thyroid hormone synthesis and reduce thyroid hormone
levels
■ Can be used as initial treatment of Graves’ disease,
amiodarone-induced thyrotoxicosis (AIT) type 1, and iodine-

induced hyperthyroidism; ATDs are first-line treatment in
children, lactating women, patients with mild hyperthyroidism,
and older patients
■ MMI (10−40 mg daily) is the preferred medication
■ PTU (50−100 mg TID) has a “black box” warning from the FDA
for liver toxicity and should only be considered for use in two
situations, pregnant women who are in the first trimester
(due to the embryopathy associated with MMI use) and in
those with thyroid storm (because PTU also blocks peripheral
T4 to T3 conversion)
■ A complete blood cell count (CBC) and liver profile are recom-
mended before starting treatment for a baseline, although there

is no established interval for prospective monitoring
■ Patient should have thyroid function tests (TFTs) monitored every
4−6 weeks until serum T4 and T3 concentrations are normalized,

then at longer intervals, as appropriate for clinical course
■ ATDs are usually continued for 6−18 months in patients with
Graves’ disease, and tapered or discontinued when a patient has

a persistently normal range (or elevated) serum TSH. Remission,
defined as a normal range serum TSH off of ATDs, is achieved in
about 40% of patients. Most agree that the remission rate does
not increase when treatment is extended longer than 18 months,
48565_ST02_047-110.indd 57 5/1/13 9:34 PM

although there is no limit to the duration of medical treatment if

the patient is not experiencing side effects
■ Major side effects include polyarthritis and agranulocytosis (it
is recommended to discontinue the medication and check the
white blood cell count in case of fever, sore throat, or signs of
infection), hepatitis, cholestasis, urticaria, vasculitis
■ PTU is associated with fulminant hepatic necrosis
■ MMI is associated in pregnancy with rare complications such as
aplasia cutis and embryopathy (choanal and esophageal atre-

sia); some clinicians, therefore, use PTU in the first trimester,
then switch to MMI
° ■ Used in severe(prednisone
Corticosteroids or dexamethasone)
hyperthyroidism (thyroid storm) or in preparation
for surgery to rapidly reduce T4 to T3 conversion
■ Used in AIT type 2, or subacute thyroiditis with moderate-to
severe symptoms that fails to respond to β-adrenergic blocker

and NSAIDs
° Supersaturated potassium iodide (SSKI)
■ Acute inhibition of thyroid hormone synthesis and release
(referred to as “Wolff-Chaikoff” effect)

■ In preparation for surgery or in patients with thyroid storm
• Radioactive iodine therapy (131Iodine in capsule or liquid)

° Can be used as first-line therapy or after treatment with ATD
° Suggested as preferred treatment in patients with toxic multinodu-
lar goiter and toxic adenoma
° 5−7.5 mCI to the gland
Suffi cient radiation should be given in a single dose to deliver
based on 24-hour uptake measurement
(e.g., 15 mCI given to a patient with a 50% 24-hour uptake would
deliver 7.5 mCi to the thyroid). More active disease and larger
glands may need higher doses. Although some still attempt to
titrate the radioiodine dose to achieve euthyroidism, most target a
sufficient radioiodine dose to achieve hypothyroidism.
° Toxic multinodular goiter and toxic adenoma usually require higher
doses of 131I therapy to achieve euthyroidism and have a lower
incidence of posttreatment hypothyroidism
° Itand,
is recommended to discontinue ATD 3−7 days before treatment
if necessary for significant hyperthyroidism, restart 3−7 days
after treatment with a taper over 4−6 weeks as radioiodine has its
full effect
° Contraindicated in pregnant and lactating women (pregnancy test
should be obtained before treatment) and it is recommended that
conception should not be attempted for at least 6 months after
treatment, to limit any residual radiation effects on the developing
embryo and fetus and to ensure normal thyroid hormone levels
° In patients with active Graves’ ophthalmophathy (GO), prednisone
(40−80 mg) for 3 months should be considered to prevent the
worsening of GO that can be seen after radioactive iodine (RAI)
48565_ST02_047-110.indd 58 5/1/13 9:34 PM

Management Options 59
Smoking significantly worsens GO and patients should be strongly

encouraged to quit. Patients with moderate−severe active GO may
consider ATD or surgery to avoid the worsening seen with RAI
° Acute side effects: mild neck tenderness and transient increase of
serum thyroid hormone levels, rarely symptomatic
° Patients with Graves’ disease achieve hypothyroidism about 80% of
the time at 2−6 months and lifelong thyroid hormone replacement
is required; if hyperthyroidism persists at 6 months, retreatment
with 131I should be considered
• Surgery
° Recommended in case of large goiter with compressive symptoms;
nodule present with abnormal or suspicious cytology; pregnant
patients in the second trimester when rapid control of hyperthy-
roidism is required; female planning a pregnancy in <6 months;
patients intolerant or refractory to ATD; or relapse after antithyroid
therapy in patients refusing 131I therapy
° Preoperative treatment with SSKI for approximately 1 week is
recommended; this treatment is used to reduce thyroid vascularity
and reduce the thyroidal release of thyroid hormone
° Near total or total thyroidectomy is the procedure of choice for
Graves’ disease or toxic multinodular goiter, lobectomy is preferred
for toxic adenoma
° Following surgery for Graves’ disease or toxic multinodular goiter,
thyroid hormone replacement should be started at a dose appropri-
ate for the patient’s weight (1.6 μg/kg/day) and can be started
when free thyroxine (FT4) levels are in the mid−normal range;
serum T4 levels should fall about 50% every 7−10 days
• Overall approach to hyperthyroid patients
° Patients with typical clinical features of Graves’ disease, especially
with GO, do not need imaging unless there are abnormalities on
physical exam and are typically started on ATDs
° Immediate RAI or surgery may be indicated in patients based on the
clinical setting, such as desiring rapid euthyroidism due to desire
for fertility, compressive symptoms, or difficult-to-manage cardiac
disease
° An RAI uptake and scan are appropriate for patients with suspected
thyroiditis or to plan RAI therapy
° Ultrasound can provide additional structural information as well as
assess vascularity
° Patients with toxic multinodular
Mild hyperthyroidism is usually managed with ATDs
° or surgery, although assessmentgoiter are often treated with RAI
of nonfunctioning nodules with
fine needle aspiration (FNA) as well as assessment for tracheal
compression should be entertained. Patients with hyperthyroidism
and nodules suspicious for thyroid cancer should be treated
surgically
48565_ST02_047-110.indd 59 5/1/13 9:34 PM

THYROID STORM: DIAGNOSIS AND MANAGEMENT

• Thyroid storm is thyrotoxicosis with additional findings, and is associ-
ated with a mortality of approximately 10%; appropriate diagnosis and
aggressive treatment are important
• Examples of these additional manifestations include
° Fever
° CNS: delirium, psychosis, altered consciousness, seizures
° Cardiac: CHF, atrial fibrillation
° hyperbilirubinemia
Gastrointestinal/hepatic: nausea, vomiting, diarrhea,
• Fever and CNS manifestations are hallmarks of the thyroid storm,

although the clinical presentation can vary
• There is often a trigger, such as irregular use or discontinuation of
ATDs, infection, surgery, or other stress
• Thyroid storm treatment
TABLE 10.4 Treatment of Thyroid Storm

Drug Drug/Dose Comment
β-blockers Propanolol 60−80 mg every At high doses, may reduce
4 hours T4-to-T3 conversion
Esmolol IV pump 50−100 μg/ Needs to be administered in a
kg/min monitored setting
Antithyroid drugs Propylthiouracil 500−1000-mg Blocks T4-to-T3 conversion
load, 250 mg every 4 hours
MMI 60−80 mg day
Iodine (SSKI) 5 drops (250 mg) every 4 hours Start at least one hour after
antithyroid drug is started
Hydrocortisone 100 mg IV every 8 hours Blocks T4 to T3 conversion;
treats potential adrenal
insufficiency
SUBCLINICAL HYPERTHYROIDISM
• Pattern of suppressed serum TSH and normal range T4 and T3 levels
• Despite the term “subclinical,” it can be associated with symptoms,
bone loss, and cardiac manifestations, such as atrial arrhythmias
• Younger patients with mild TSH suppression (0.1−0.4 mU/L) and
no clinical manifestations can usually be observed with serum TSH
measured at intervals of 6−12 months
• In contrast, older patients and all patients with TSH <0.1 mU/L should
be evaluated with measurement of T4 and T3 and etiology of sup-
pressed TSH (e.g., RAIU, TRBII, TSI), as well as assessments of cardiac
status and bone density
48565_ST02_047-110.indd 60 5/1/13 9:34 PM

References 61
• Persistent TSH suppression is typical of a nodular goiter with areas

of autonomous function, while mild Graves’ disease can resolve
spontaneously
• The decision to treat depends on the magnitude of TSH suppression,
age, and manifestations
° If■ serum TSH <0.1 mU/L, treatment should be considered if
≥65 years old
■ Hyperthyroid symptoms
■ Evidence of cardiac risk factors or cardiac disease
■ Osteoporosis
■ Postmenopausal woman not being treated with bisphosphonates
■ Treatment can also be considered in patients who are <65 years
old and asymptomatic with no comorbidity

° If■ serum TSH 0.1−0.4 mU/L, treatment should be considered if
≥65 years old
■ Hyperthyroid symptoms
■ Evidence of cardiac disease
■ Patient <65, asymptomatic with or without osteoporosis, can be
observed with monitor of thyroid function every 6−12 months
REFERENCES
Akamizu T, Satoh T, Isozaki O, et al. Diagnostic criteria, clinical features,
and incidence of thyroid storm based on nationwide surveys. Thyroid,
2012;22(7):661−79.
Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes
of thyrotoxicosis: management guidelines of the American Thyroid
Association and American Association of Clinical Endocrinologists.
Thyroid, 2011;21(6):593−646.
Brent GA. Clinical practice. Graves’ disease. N Engl J Med,
2008;358(24):2594−605.
Cooper DS, Biondi B. Subclinical thyroid disease. Lancet,
2012;379(9821):1142−54.
Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med,
2011;364(6):542−50.
48565_ST02_047-110.indd 61 5/1/13 9:34 PM

48565_ST02_047-110.indd 62 5/1/13 9:34 PM
11 ■ HYPOTHYROIDISM
Jaya Kothapally, MD and Marc J. Laufgraben, MD
BACKGROUND
• Hypothyroidism: insufficient thyroid hormone levels
° Primary hypothyroidism
■ Usually due to disorders affecting the thyroid gland itself
■ Represents the overwhelming majority (~99%) of hypothyroidism
° Central hypothyroidism
■ Due to disorders causing insuffi cient TSH
■ Includes both secondary hypothyroidism, where defect is in the
pituitary; and tertiary hypothyroidism, where the defect is in the

hypothalamus
■ Usually seen in conjunction with other aspects of hypopituitarism
• 10x more common in women compared to men

• Increased prevalence with aging
Causes of primary hypothyroidism
• Chronic autoimmune thyroiditis (also known as Hashimoto’s
thyroiditis [HT])
° Most common cause in the developed world
° Can occur as part of autoimmune polyglandular syndromes
• Other forms of thyroiditis (subacute, silent, postpartum)
• Iodine deficiency
° Very common cause worldwide
• Thyroid surgery, radioiodine therapy, and ATDs
• External radiation (e.g., as part of cancer therapy)
• Medications, e.g., lithium, amiodarone, interferon-α, tyrosine-kinase
inhibitors (TKIs)
• Congenital hypothyroidism including thyroid gland agenesis and
defects in thyroid hormone synthesis
• Miscellaneous: infiltrative or infectious disorders, iodine excess,
thyroid hormone consumption from tumors expressing deiodinase
Causes of central hypothyroidism
• Essentially any disorder disrupting pituitary or hypothalamic function
(see Chapter 2, Hypopituitarism)
• Other causes: congenital abnormalities, defects in TRH or TSH
synthesis, medications (e.g., bexarotene)
48565_ST02_047-110.indd 63 5/1/13 9:34 PM

64 Hypothyroidism
TABLE 11.1 Clinical Presentation* of Hypothyroidism

Symptoms Fatigue, low energy, weakness, arthralgias, myalgias,
cold intolerance, weight gain, depression, constipation,
sexual dysfunction, menorrhagia, dry skin, coarse brittle
hair and nails, decreased concentration, memory
impairment, slow speech, periorbital puffiness, headaches,
hoarseness
Signs Bradycardia, hypertension, periorbital edema, reflex
delay, ⫹/⫺ goiter, lateral thinning of eyebrows (Queen
Anne’s sign), pericardial effusions, pleural effusion,
ascites
Laboratory findings Macrocytic anemia, elevated creatine kinase,
hypercholesterolemia, hyponatremia
*Clinical presentation is highly variable, and individual findings have low sensitivity and low specificity.
DIAGNOSIS
• Testing should be entertained based on the presence of symptoms of
hypothyroidism
° Screening of general population is controversial
° Screening of women who are pregnant or planning pregnancy is
controversial
• TSH is best initial screening test (unless there is a suspicion for
central hypothyroidism)
° Normal TSH will exclude primary hypothyroidism
° Check FT4 in patients with elevated TSH
■ Low FT4 and elevated TSH is overt hypothyroidism
■ Normal FT4 and elevated TSH is subclinical hypothyroidism
(See Subclinical Hypothyroidism section on page 66)

° Testing of TPO antibody can confirm clinical suspicion of chronic
autoimmune thyroiditis as the etiology, but is not usually necessary
in clinical practice
■ Exception: may have management implications in patients with
subclinical hypothyroidism
• If central hypothyroidism is suspected, check TSH and FT4
° Check
FT4 will be low and TSH will be low or “inappropriately normal”
° with confi pituitary MRI and other tests of pituitary function in patients
rmed central hypothyroidism
48565_ST02_047-110.indd 64 5/1/13 9:34 PM

Treatment 65
TREATMENT
• Synthetic LT4 is treatment of choice
° Combination therapy with LT4 and T3 not demonstrated to be
advantageous in most studies
° ized and contains excess
Dessicated porcine thyroid should be avoided as it is not standard-
T3
° Both generic and branded LT4 formulations are available
■ Formulations differ in composition and absorption
■ Patients prescribed generic LT4 may receive different formula-
tions each month that may result in fluctuations in thyroid

hormone levels with clinical consequences; for this reason, many
experts recommend use of branded LT4
• To avoid interference with absorption, LT4 should be taken on an empty
stomach (in the morning at least 30 minutes before breakfast or at
bedtime at least 2 hours after the evening meal) and separate from all
medications, vitamins, and supplements
• Can start with full replacement dose of 1.6 mcg/kg/day in young
healthy patients with overt hypothyroidism
° TSH should be rechecked 6 weeks after initiation and the dose
adjusted if necessary, with further TSH assessment in another
6 weeks
° Goal TSH for most patients with primary hypothyroidism is within
the normal lab reference range
■ Though controversial, there is no evidence to support that a
TSH goal in the lower part of the reference range improves

patient outcomes
■ TSH goal 0.5−2.5 reasonable in women who may become
pregnant as upper limit of normal range in first trimester

of pregnancy is 2.5 (see Chapter 18, Thyroid Disorders in
Pregnancy)
• In patients >60 years old or with documented heart disease, treatment
should be initiated with 25 mcg daily and increased incrementally
every 2−4 weeks until a normal TSH is achieved
• For patients with central hypothyroidism, treatment goal is a FT4 level
in the upper half of the normal reference range
° Ifbefore
patient also has central AI, initiate glucocorticoid replacement
thyroid replacement (thyroid hormone can accelerate cortisol
metabolism and initiate adrenal crisis)
• Women with hypothyroidism who become pregnant require LT4 dose
adjustment and frequent monitoring, and should be referred to an
endocrinologist or obstetrician with expertise in the management
of thyroid disease in pregnancy (see Chapter 18, Thyroid Disorders
in Pregnancy)
48565_ST02_047-110.indd 65 5/1/13 9:34 PM

66 Hypothyroidism
• AI should be considered in any patient with hypothyroidism who

appears to worsen after initiation of LT4
• If patient’s TFTs do not improve with anticipated doses of LT4, consider
malabsorption (including celiac disease), nonadherence with therapy,
and effect of coadministered medications
° Once weekly therapy may be an option for poorly adherent patients
who are young and healthy
SUBCLINICAL HYPOTHYROIDISM
• Elevated (usually mildly) TSH with normal FT4 in a patient who is typi-
cally asymptomatic or minimally symptomatic
° Testing including TPO antibody should be repeated in 3 months to
confirm the diagnosis
• Increased risk of progression to overt hypothyroidism in patients with
positive TPO antibodies and/or TSH >10
• Associated with dyslipidemia and other markers of enhanced cardio-
vascular risk
° Treatment with LT4 to normalize thyroid parameters improves these
markers, but no evidence for improved patient outcomes
• Consider LT4 treatment in
° Patients with positive TPO antibodies
° Patients with TSH >10
° Patients witharesevere
Women who pregnant or planning a pregnancy
° Patients who are symptomatic
dyslipidemia
° continue if patient reports improvement)
(3−6 month treatment trial; only
• If patient to be monitored without treatment, check TSH and FT4

annually
MYXEDEMA COMA
• A state of severe decompensated hypothyroidism
° Typically seen in elderly women with longstanding hypothyroidism
° May be initiated by illness or exposure to cold
° Presentation often includes change in mental status (ranging from
confusion to coma), hypothermia, bradycardia, and hypoventilation
which can progress to hypercarbic respiratory failure
° Patients may have features of severe hypothyroidism: very dry skin,
nonpitting edema, macroglossia, hoarse voice, delayed reflexes,
pericardial effusion, ileus
° In addition to TFTs consistent with hypothyroidism, labwork may
also show hyponatremia, hypoglycemia, hypercalcemia, macrocytic
anemia, elevated creatinine kinase; arterial blood gas (ABG) may
show hypoxia, hypercarbia, and acidosis
48565_ST02_047-110.indd 66 5/1/13 9:34 PM

References 67
• The diagnosis of myxedema coma is based on typical clinical presenta-

tion in a patient with elevated TSH and low FT4
° The severity of the clinical presentation may be disproportionate
to the TFTs
° Treatment
• Management
should not be delayed while awaiting TFT results
° Admission to intensive care unit (ICU)

° Ventilatory support if required
° Passive rewarming and pressors if required
Fluid resuscitation
° Correct metabolic disturbances (hyponatremia, hypoglycemia)
° IV HC 100 mg q 8 hours for 24−48 hours
° ■ Rationale
• Cortisol production is low in severe hypothyroidism and
initiation of thyroid replacement can accelerate cortisol
metabolism resulting in a transient AI
• Patients with hypothyroidism may rarely have undiagnosed
primary AI as well
■ Consider definitive testing if signs of AI are evident as HC is
tapered
° Thyroid hormone therapy
■ If clinical suspicion of myxedema coma is high, treatment should
not be delayed while awaiting TFT results

■ Should be initiated IV due to risk of poor oral absorption from
bowel edema and poor intestinal motility

■ Typical treatment is IV LT4 200−400 mcg daily for 2 days, fol-
lowed by 50−100 mcg IV daily

• Patient can be changed to typical oral replacement dose as
condition improves
■ Use of IV T3 as an adjunct to IV LT4 in acute management of
myxedema coma is controversial but can be considered (typical

regimen is 10−20 mcg IV q 4 hours for the first 24−48 hours)
° infarction)
Seek out and treat potential precipitating illness (e.g., infection,
° Despite advances in management, mortality from myxedema coma

remains 25−50%
REFERENCES
Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and manage-
ment. Med Clin North Am, 2012;96(2):203−21.
Devdhar M, Ousman YH, Burman KD. Hypothyroidism. Endocrinol Metab Clin
North Am, 2007;36(3):595−615.
Jones DD, May KE, Geraci SA. Subclinical thyroid disease. Am J Med,
2010;123(6):502−4.
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68 Hypothyroidism
McDermott MT. In the clinic. Hypothyroidism. Ann Intern Med,

2009;151(11):ITC6-1–ITC6–16.
Thyroid Disease Manager. Thyroidmanager.org. Accessed July 26, 2012.
Vaidya B, Pearce SH. Management of hypothyroidism in adults. BMJ,
2008;337:a801.
Yamada M, Mori M. Mechanisms related to the pathophysiology and
management of central hypothyroidism. Nat Clin Pract Endocrinol Metab,
2008;4(12):683−94.
48565_ST02_047-110.indd 68 5/1/13 9:34 PM

12 ■ NONTHYROIDAL ILLNESS SYNDROME
Maryam Khan, MD and Marc J. Laufgraben, MD, MBA
BACKGROUND
• Nonthyroidal illness syndrome (NTIS) refers to the complex
alterations in thyroid hormone metabolism occurring in acute and
chronic illness that affect the entire hypothalamic-pituitary-thyroid
(HPT) axis
° Leads to considerable difficulty in recognizing preexisting thyroid
dysfunction in hospitalized patients
• NTIS is associated with increased mortality
° Low triiodothyronine (T3) is an independent predictor of
survival
° Low T3/rT3<3ratio
FT4 index is associated with increased mortality
° ICU are also associated
and high reverse T3 (rT3) on the first day in the
with increased mortality
PATHOPHYSIOLOGY
• Endocrine systems including the HPT axis are affected by inflamma-
tion, altered tissue perfusion, and other changes seen in systemic
illness
• Changes at all the levels of the HPT axis including neuroendocrine
regulation, peripheral transport, thyroid hormone metabolism and
receptor binding have been proposed to contribute to altered thyroid
hormone economy in NTIS
° Cytokines such as interleukin-1 (IL-1), IL-6, Interferon-alpha and
TNF-α are hypothesized as mediators of NTIS
° ■ Type 1 deiodinase
Changes in deiodinase activity are felt to be a major component
(D1) catalyses the conversion of T4 to T3
and rT3 to T2; activity of D1 is decreased in patients with NTIS
resulting in reduced T3 levels
■ Type 2 deiodinase (D2) catalyses the conversion of T4 to T3 and
is present in the brain, anterior pituitary, thyroid gland, and

skeletal muscle; D2 is responsible for local T3 production in
these organs
■ Type 3 deiodinase (D3) catalyses the conversion of T4 to rT3 and
T3 to T2, also called inactivating enzyme; activation of D3 is

demonstrated in patients with critical illness
48565_ST02_047-110.indd 69 5/1/13 9:34 PM

70 Nonthyroidal Illness Syndrome
° Other alterations
■ Reduced TRH gene expression due to elevated rT3 levels in
hypothalamus
■ Reduced levels of binding proteins leading to low total T4 levels
■ Increased monocarboxylate transporter 8 (MCT8) transport
proteins in skeletal muscle, which could increase uptake of T3

even at low tissue levels
■ Reduced uptake of T4 by the liver; inhibitors of thyroid hormone
binding (e.g., bilirubin and nonesterified fatty acids) may reduce

thyroid hormone uptake in the cells
■ Reduced T3 concentrations in tissues of patients with chronic
illness
■ Increased expression of active form of thyroid hormone receptor
to increase sensitivity to T3
• The changes in the HPT axis vary over the time course of the illness
° normalillness:
Acute changes similar to those seen in starvation (low T3,
to low T4, and low FT3) are felt to represent an adaptive
response to illness with “conservation of resources”
° Chronic illness: continued reduced activity of HPT axis;
debated as to whether this is adaptive or a form of central
hypothyroidism
° Recovery: improvement in thyroid hormone parameters seen during
recovery phase of illness are marked by normal T4 and T3 and
slightly increased TSH levels
• Measurement of thyroid hormone levels during systemic illness is
confounded by multiple factors: altered binding proteins, presence
of fatty acids that inhibit binding of thyroid hormones to proteins,
effects of concurrent medications (see Table 12.1), altered tissue
perfusion, etc.
• Most hospitalized patients with abnormal TFTs will have normal TFTs
on outpatient follow-up
° TFTs in hospitalized patients should only be checked if there is a
strong clinical suspicion of underlying thyroid dysfunction
• Evaluation of thyroid status in hospitalized patients should include
measurement of both serum TSH and FT4; if either is abnormal, T3
should be also measured
• T3: low T3 is the most common alteration identified in NTIS
• TSH: TSH levels are highly variable in hospitalized patients
° TSH
NTIS
levels of 0.05−20 mIU/L are commonly seen in patients with
° TSH levels >20

TSH levels mIU/L are suggestive of primary hypothyroidism
° if FT4 is elevated)
<0.05 mIU/L are suggestive of thyrotoxicosis (confirmed
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References 71
TABLE 12.1 Effect of Drugs on Thyroid Hormone Economy

Mechanism Drugs
Suppress TSH Glucocorticoids, dopamine, opiates
Inhibit peripheral conversion Glucocorticoids, propranol,
benzodiazepines, amiodarone
Displace T4 from binding proteins Furosemide, salicylates
Increase T4 clearance Barbiturates, antiepileptics
Alter thyroid hormone release Iodine (IV contrast, dressings)
• FT4: FT4 levels are generally in the normal range during NTIS but may
be low in prolonged severe illness
° Note: FT4 generally is measured by analogue methods, which may
be affected by binding protein abnormalities
• TT4: low TT4 is also a common finding in ICU patients due to reduced
levels of thyroid hormone binding proteins
• rT3: levels are commonly elevated in NTIS, but measurements of rT3
are not clinically useful as the results are not readily available
MANAGEMENT
• Treatment of NTIS with thyroid hormone replacement has not been
shown to improve outcome and may potentially be harmful
° beReduced thyroid hormone economy in critical illness might
an adaptive mechanism to conserve energy and reduce
catabolism
• Thyroid hormone replacement should only be considered in situations
in which there is strong clinical suspicion and evidence of preexisting
thyroid dysfunction.
• TRH infusions are currently being investigated as an intervention in
patients with NTIS
REFERENCES
Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab
Clin North Am, 2007;36(3):657−72.
Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid
hormone metabolism during inflammation and infection. Endocr Rev,
2011;32(5):670−93.
48565_ST02_047-110.indd 71 5/1/13 9:34 PM

72 Nonthyroidal Illness Syndrome
Farwell, AP. Thyroid hormone therapy is not indicated in majority of

patients with the Sick Euthyroid Syndrome. Endocrine Practice,
2008;14:(9):1180−87
Hassan-Smith Z, Cooper MS. Overview of the endocrine response to criti-
cal illness: how to measure it and when to treat. Best Pract Res Clin
Mebis L, Van-den Burghe, G. The hypothalamus Pituitary Thyroid axis in
critical illness. Neth J Med, 2009;67(10);331−40.
48565_ST02_047-110.indd 72 5/1/13 9:34 PM

13 ■ DRUGS AFFECTING THYROID FUNCTION
AND THYROID HORMONE REPLACEMENT
Guiseppe Barbesino, MD
GENERAL COMMENTS
• Drugs that affect TH absorption will affect patients relying on a fixed
amount of TH provided by thyroid hormone replacement therapy (THRT)
• Drugs that affect TH metabolism will generally only affect patients
relying on THRT, since most patients with a normally functioning
thyroid axis will be able to increase TH production to compensate for
increased TH metabolism
• Drugs that affect TH production by the thyroid will mostly affect
“normal” patients who rely on typical endogenous production of TH
DRUGS AFFECTING THYROID ABSORPTION

• Normal T4 absorption
° 60−80% of an ingested dose of T4 is absorbed
° Absorption
and ileus
is enhanced by gastric acid and occurs in the jejunum
• Proton pump inhibitors (PPI) and H2 receptor antagonists

° Mechanism: reduction of gastric acidity reduces T4 absorption
° Effects: increased T4 requirement to meet TSH target in patients on
THRT; effect is variable and not confirmed in all studies
° Management:
education
increase T4 dose, more frequent TFTs, patient
• Sevelamer hydrochloride, lanthanum carbonate, and calcium carbon-

ate (phosphate binders)
° Mechanism: binding and insolubilization of thyroid hormone
° Effect: marked decreased absorption of T4, increased T4 require-
ment to meet TSH target in patients on THRT
° Management:
education
• Iron and calcium supplements, including those contained in

multivitamins
° Mechanism: binding and precipitation of thyroid hormone
° Effect: decreased absorption of T4, increased T4 requirement to
meet TSH target in patients on THRT
° Management: interval of 3−4 hours between T4 intake and supple-
ment intake, patient education
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74 Drugs Affecting Thyroid Function and Thyroid Hormone Replacement
• Bile acid sequestrants: cholestyramine and colsevelam

° Effect: marked decreased absorption of T4, increased T4 require-
ment to meet TSH target in patients on THRT
° Management: increase T4 dose, more frequent TFTs, and patient
education; since these medications are often given in several daily
doses, spacing has uncertain efficacy
° Note: cholestyramine has been used to treat endogenous and
exogenous thyrotoxicosis
• Sucralfate and aluminum-based antacids
° Management: interval of 3−4 hours between T4 intake and supple-
ment intake, patient education
• Raloxifene
° Mechanism: unknown
° Management:
education
° Note: only case reports available
DRUGS AFFECTING THYROID HORMONE METABOLISM

• Main pathways regulating thyroid hormone metabolism
° Deiodinases:
Function Tests
see Chapter 9, Thyroid Essentials and Thyroid
° and urinary excretion

Liver enzymes for glucuronidation and sulfation leading to biliary
• Rifampicin, barbiturates, phenytoin, carbamazepine

° Mechanism: increased liver glucuronidation of TH, other?
° Effect: shorter half-life of absorbed TH
° TFTs, patient education
Management: increase T4 dose (often up to 100%), more frequent
• Imatinib
° Mechanism: unknown, likely increased liver metabolism of TH
° Effect:
on THRT
increased T4 requirement to meet TSH target in patients
° Management: increase T4 dose (often up to 100%), more frequent

TFTs, patient education
48565_ST02_047-110.indd 74 5/1/13 9:34 PM

Drugs Directly Affecting Thyroid Function 75
DRUGS DIRECTLY AFFECTING THYROID FUNCTION

• Amiodarone
° Pharmacology
■ A 300-mg pill of amiodarone contains 111 mg of iodine
■ The rate of iodine release from amiodarone is estimated at 10% per day
■ Lipophilic drug with large distribution volume, half life is
40−60 days
° ■ Early, transient variant
Hypothyroidism
• Mechanism: iodine causing Wolff-Chaikoff effect

• Effect: mild, transient elevation of TSH at the initiation of
amiodarone therapy
• Management: if mild, monitor
■ Late, persistent variant
• Mechanism: precipitation of thyroid autoimmunity in predis-

posed subjects; cytotoxic effect of amiodarone
• Effect: overt, persistent hypothyroidism
• Management: start LT4, can continue amiodarone
° Amiodarone-induced
■ Classifi cation
Thyrotoxicosis
• Type I AIT
– Unremitting, severe, resistant hyperthyroidism; uncommon
– Mechanism: effect of large iodine load in patient with preexist-
ing thyroid autonomy (mild Graves’ disease or nodular goiter)
• Type II AIT
– Moderate, self-limited thyrotoxicosis; more common than
type I AIT, especially in iodine-replete areas
– Mechanism: cytotoxic effect of drug resulting in destructive
thyroiditis
■ Differential diagnosis
• Type I AIT
– Suggestive: thyroid nodules on ultrasound, increased
thyroidal color flow-doppler
– Definitive: RAIU >3%, positive thyroid-receptor antibody
(TRAb)
• Type II AIT
– Suggestive: normal thyroid appearance on ultrasound, RAIU
<3%, increased serum IL-6 levels
■ Management
• Type I AIT
– MMI 40 to 60 mg daily
– Sodium perchlorate up to 500 mg BID (not available in
the US)
– Thyroidectomy in extreme situations
– Discontinuation of amiodarone should be considered
48565_ST02_047-110.indd 75 5/1/13 9:34 PM

• Type II AIT
– Prednisone 40 mg daily, tapered by 10 mg q 2 weeks, upon
favorable response
– Discontinuation of amiodarone may decrease risk of
relapses and speed response, but must be weighed against
benefits of amiodarone
• Note: when the distinction between types I and II cannot be
made with confidence (a frequent scenario), both MMI and
prednisone should be administered
• Lithium
° Mechanisms: increased intrathyroidal half-life of iodine, leading to
decreased release of thyroid hormone; direct toxic effect on thyroid
follicular cells (both hypothetical)
° Effects
■ Goiter
• Proposed mechanism: increased intrathyroidal half-life of

iodine, leading to decreased release of thyroid hormone
• Incidence is variable across studies; simple, nontoxic, diffuse
goiter is most common
• Management: TSH suppression with LT4 may be considered
in otherwise healthy young subjects, but efficacy not well
documented
■ Hypothyroidism
• Proposed mechanism: increased intrathyroidal half-life of

iodine, leading to decreased release of thyroid hormone
• Incidence is variable across studies; more frequent in TPO
antibody-positive patients
• Management: THRT
■ Painless thyroiditis
• Proposed mechanism: direct toxic effect on thyroid follicular cells

• Clinical presentation: transient-mild to-moderate thyrotoxicosis
with low RAIU; thyroid antibody is negative in >50% of cases
• Management: symptom control with β-blockers if necessary
• Alemtuzumab
° Mechanism:
sclerosis
unknown; humanized anti-CD-52 used in multiple
° oped Graves’ disease;

When used in multiple sclerosis, 20−30% of patients devel-
smaller number developed autoimmune
hypothyroidism
° Management:
• Interferon-α
usual Graves’ disease or hypothyroidism treatment
° Mechanism: induction of thyroid autoimmunity

° Effects are variable
■ Development of thyroid antibodies
• Incidence: 10−40%
• Management: monitor TFTs
48565_ST02_047-110.indd 76 5/1/13 9:34 PM

Drugs Causing Central Hypothyroidism 77
■ Clinical thyroid dysfunction
• Incidence: 5−15%
• Destructive thyroiditis
– Incidence: 50% of thyroid dysfunctions
– Thyroid antibody often negative
– Management: β-blockers in the hyperthyroid phase, prompt
correction of hypothyroidism
• Classical HT with or without hypothyroidism
– Incidence: unknown, but more likely in patients with
preexisting thyroid autoantibody
– Management: treatment of hypothyroidism
• Graves’ disease
– Incidence: uncommon
– Management: usual management of Graves’ disease
• Interleukin-2
° with the development
Mechanism: induction of autoimmunity? (Most cases are associated
of anti-TPO antibody)
° Incidence: 20−40%
° May be preceded by transient thyrotoxicosis
° Management: treatment of hypothyroidism
• Sunitinib and sorafenib (TKI)
° Mechanism: damage to thyroid microvasculature
° Associated with hypothyroidism in 30−50% of cases
° Management: frequent
Mild thyrotoxicosis seen early on in a minority of cases
° hypothyroidism TSH checks, usual management of
DRUGS CAUSING CENTRAL HYPOTHYROIDISM

• Bexarotene
° Mechanism: direct suppression of the b-TSH gene transcription
° Results
of cases
in profound symptomatic central hypothyroidism in 70%
° Management: FT4 monitoring and THRT

• Glucocorticoid
° Mechanism: transient TSH suppression
° Because of the transient nature of the phenomenon, this does not
cause hypothyroid symptoms
• Dopamine
° Mechanism: TSH suppression
° Since DA is only used short-term, it mostly causes problems in the
interpretation of TFTs
48565_ST02_047-110.indd 77 5/1/13 9:34 PM

REFERENCES
Barbesino G. Drugs affecting thyroid function. Thyroid, 2010;20(7):763−70.
Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate
reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern
Med, 1992;117(12):1010−3.
Eskes SA, Wiersinga WM. Amiodarone and thyroid. Best Pract Res Clin
Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab,
2009;23(6):723−33.
Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine
absorption. Best Pract Res Clin Endocrinol Metab, 2009;23(6):781−92.
Roti E, Minelli R, Giuberti T, et al. Multiple changes in thyroid function in
patients with chronic active HCV hepatitis treated with recombinant
interferon-alpha. Am J Med, 1996;101(5):482−7.
Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in
advanced cancer patients and may inhibit thyroid peroxidase activity.
Thyroid, 2007;17(4):351−5.
48565_ST02_047-110.indd 78 5/1/13 9:34 PM

14 ■ THYROID NODULE EVALUATION
Ole-Petter R. Hamnvik, MBBCh, BAO and Erik K. Alexander, MD
EPIDEMIOLOGY AND PATHOPHYSIOLOGY

• Palpable nodules are present in 5−10% of women and 1% of men;
prevalence by ultrasound is 19−67%
• Most nodules are benign (85−90%), asymptomatic, and nonfunctional
(i.e., do not produce thyroid hormone)
• Multiple nodules are frequently present; the risk of malignancy in
a given patient is the same whether there is one nodule or multiple
nodules
• Over 50,000 new cases of thyroid cancer are diagnosed annually in
the US
• If cancerous, ~95% are well-differentiated malignancies (papillary
carcinoma or follicular carcinoma) which arise from the thyroid fol-
licular cell; <5% are medullary carcinoma arising from C-cells, and
<1% are anaplastic carcinoma
• History
° Most thyroid nodules (90%) are incidental and asymptomatic, often
detected upon separate imaging (such as CT or MRI) or on physical
examination
° 10% present with symptoms, most commonly a sensation of a
throat mass; other rare symptoms include voice change (hoarse-
ness), neck pain, or difficulty swallowing
° Initial evaluation should focus on identifying factors that impart a
higher risk of thyroid cancer. These include a history of childhood
head or neck radiation (before age 16), a family history of thyroid
cancer (or familial syndromes associated with thyroid cancer such
as MEN2, familial adenomatous polyposis, or Cowden’s syndrome),
and high-risk signs or symptoms including hoarseness, dysphagia,
dysphonia, cough, enlarged cervical lymph nodes, large nodules
>4 cm, and rapidly growing nodules
° The patient should be asked about symptoms of thyrotoxicosis such
as sweating, tremors, heat intolerance, or weight loss, as these may
signal a functional (or “hot”) nodule
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80 Thyroid Nodule Evaluation
° The thyroid isthmus is palpable just below the thyroid and cricoid
cartilage, with a right and left lobe extending laterally and posteri-
orly along the trachea
° The examination should always be performed with a glass of water,
with instructions to swallow at the time of examination; observation
and palpation may detect asymmetry, nodules, or tenderness
° The thyroid gland is best palpated with the patient sitting upright,
head facing straight forward or slightly downward (to relax the
strap muscles)
° Examination of the thyroid should assess the size and location of
the gland, as well as any nodules
■ Nodules should be assessed for size, texture, tenderness, and
fixation to surrounding structures

■ Tracheal deviation should be assessed
■ Voice quality should also be analyzed for hoarseness.
° In a nodule that is functional, evidence of thyroid hormone excess

may also be found
• Laboratory testing
° Ifconcentration
a nodule is suspected or detected upon examination, a serum TSH
should be measured
• Imaging
° Ifruled
the TSH is suppressed, a functional (or “hot” nodule) should be
out via a thyroid scan
■ If a hot nodule is identifi ed, the risk of malignancy is nearly
zero, and cytologic evaluation is not necessary; hyperthyroidism,

however, must be treated (see Chapter 10, Thyrotoxicosis and
Hyperthyroidism)
° hyperfunctioning
Ultrasound imaging should be performed on all nodules that are not
(i.e., in patients with normal or elevated TSH, or
patients with “cold” nodules detected on thyroid scan irrespective
of serum TSH)
■ Ultrasound is optimal imaging modality for the thyroid, as it can
obtain high-resolution images of the thyroid gland and confirm

the presence and location of nodules
■ Sonographic features can predict cancer risk; those associated
with increased cancer risk include

• Microcalcifications
• Hypoechogenicity
• Irregular borders
• Presence of lymphadenopathy (especially unilateral)
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Management 81
■ Sonographic features associated with a decreased risk of
cancer include
• >75% cystic fluid
• Spongiform appearance
■ If two or more high-risk sonographic features are present, the
risk of malignancy is >90%; if one or more low-risk sonographic
features are present, the risk of malignancy is <2%; most
cancers, however, are sonographically unremarkable
MANAGEMENT
• In most circumstances, FNA should be performed on nodules larger
than 1.0−1.5 cm; however, the decision to perform FNA should be
guided by the nodule size as well as other clinical factors (Table 14-1)
° The goal of FNA is to obtain a sample of cells for cytologic examination
• Whenever possible, ultrasound guidance should be used to guide all
FNAs. Under direct visualization, a 24−27 gauge needle is inserted
into the solid component of the nodule. Ultrasound guidance minimizes
nondiagnostic samples and improves sampling accuracy
• Following insertion, the needle is rapidly moved back and forth within
the nodule for about 5 seconds. Cellular material enters the needle tip by
capillary action whether suction is applied or not. Most often 3−4 sepa-
rate needle samples constitute a complete FNA from a thyroid nodule
• There are few absolute contraindications to thyroid nodule FNA, though
anticoagulation is a relative contraindication because of increased
risk for bleeding
• FNA can also be used to drain >75% cystic nodules, providing symp-
tom relief and decompression
• FNA cytology should be read by an experienced cytopathologist, and
classified using the Bethesda classification system (Table 14-2)
TABLE 14.1 Decision-Making for Thyroid FNA
Clinical/Imaging Features Size Threshold to Consider FNA
If high-risk clinical history* >0.5 cm
If high-risk features on imaging† >0.5–1.0 cm
If a solid nodule >1.0 cm
If >75% cystic or spongiform nodule >1.5–2.0 cm
If 100% cystic No FNA (unless for symptom relief)
If abnormal lymph nodes are detected >0.5–1.0cm
* High-risk history includes childhood radiation exposure, a family history of thyroid cancer, and known
RET protooncogene mutations.
† High-risk features on imaging include ultrasound findings of microcalcifications, hypoechogenicity,
irregular borders, the presence of lymphadenopathy, or 18FDG avidity on positron emission tomography
(PET) scanning.
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82 Thyroid Nodule Evaluation
TABLE 14.2 Thyroid Nodule Malignancy Risk by Cytologic Diagnosis
Cytology Category Cancer Risk
Nondiagnostic or unsatisfactory 1–4%
Benign 0–3%
Atypia of undetermined significance (AUS) or follicular lesion of
undetermined significance (FLUS) 5–15%
Follicular neoplasm or suspicious for a follicular neoplasm 20–30%
Suspicious for papillary carcinoma 60–75%
Malignant 97–99%
• Nondiagnostic samples occur when there is insufficient cellular mate-

rial for diagnosis (<6 follicular groups, each with 10−15 cells); the
FNA should be repeated to obtain a sufficient sample, as a diagnostic
specimen is subsequently obtained in >50% of cases
• If cytology is malignant (most often papillary thyroid cancer), the
patient should be referred for thyroid surgery
• If cytology is indeterminate (AUS/FLUS, suspicious for a follicular or
Hürthle cell neoplasm, or suspicious for papillary carcinoma)
° Consider referral for surgery (hemithyroidectomy or thyroidectomy):
this is performed for diagnostic as well as therapeutic purposes;
>50% of indeterminate nodules prove benign upon histopathology
° Consider molecular testing of the nodule. Molecular markers such
as BRAF, RAS, RET/PTC and PAX8/PPARG have a high positive
predictive value. A separate gene expression classifier test called
Afirma has a high negative predictive value (>95%).
° Consider conservative follow-up without intervention if malignancy
risk is low or outweighed by the estimated morbidity or risk from
any intervention
• If cytology is benign, a repeat ultrasound in 12−24 months, and then
every 3−5 years thereafter; a repeat FNA should be performed if the
nodule has increased in size by ≥20% in two or more dimensions
• Surgical removal should be considered for benign nodules if they cause
compressive symptoms, or grow >4 cm in diameter
REFERENCES
American Thyroid Association Guidelines Taskforce on Thyroid Nodules
and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al.
Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid,
2009;19(11):1167−214.
48565_ST02_047-110.indd 82 5/1/13 9:34 PM

References 83
Cibas ES, Ali SZ. The Bethesda System for reporting thyroid cytopathology.
Am J Clin Pathol, 2009;132(5):658−65.
Hegedüs L. Clinical practice. The thyroid nodule. N Engl J Med,
2004;351(17):1764−71.
Moon WJ, Jung SL, Lee JH, et al. Benign and malignant thyroid nodules:
US differentiation—multicenter retrospective study. Radiology,
2008;247(3):762−70.
Sherman SI. Thyroid carcinoma. Lancet, 2003;361(9356):501−11.
48565_ST02_047-110.indd 83 5/1/13 9:34 PM

48565_ST02_047-110.indd 84 5/1/13 9:34 PM
15 ■ PAPILLARY AND FOLLICULAR
THYROID CARCINOMA
Hilary Whitlatch, MD
DEFINITION
• Differentiated thyroid cancer (DTC) includes papillary thyroid carci-
noma (PTC) and follicular thyroid carcinoma (FTC) and accounts for
>90% of all thyroid cancer
EPIDEMIOLOGY
• DTC is the most common endocrine malignancy, although it represents
<1% of all human tumors
° 85% PTC, 10% FTC, 3% Hurthle cell (aggressive FTC subtype)
• PTC affects women more often than men (2.5:1), has a higher
incidence among Caucasians than African Americans, and is typically
diagnosed at age 30−50 years
• FTC affects older patients (>40 years of age) and incidence does not
vary substantially by race
• Yearly incidence of DTC has increased from 3.6 per 100,000 in 1973 to
8.7 per 100,000 in 2002 (2.4-fold increase)
° Almost the entire change is attributable to an increase in the
incidence of PTC
° 89% of the rise is attributable to cancers measuring ≤2 cm
■ Suggests that earlier diagnosis of small DTC is occurring through
widespread use of neck ultrasonography and FNA cytology

• Despite increasing incidence, the mortality from DTC has declined over
the last 3 decades
° Unclear
disease
if this is due to earlier diagnosis or improved treatment in
RISK FACTORS
• Head and neck external beam radiation therapy (EBRT), particularly
during childhood
° Previously
lesions)
used to treat benign childhood conditions (acne, skin
° Treatment of malignancies
• Exposure to a nuclear explosion or fallout
• History of thyroid cancer in a first-degree relative
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86 Papillary and Follicular Thyroid Carcinoma
• Family history of a syndrome associated with thyroid cancer

° Carney complex: developmental delay, pigmented nodular adreno-
cortical disease, myxomas, breast adenomas, PTC and FTC
° coma, soft
Werner syndrome: connective tissue disease, progeria, osteosar-
tissue sarcoma, PTC and FTC
° Cowden’s syndrome: harmartomas and DTC
° Familial polyposis: gastrointestinal adenomatous polyps and PTC
• In areas of iodine deficiency, there is a higher prevalence of follicular
cancer (mechanism unclear)
PATHOGENESIS
• Mutations in the mitogen-activated protein kinase pathway (MAPK)
are often responsible for malignant transformation of thyroid follicular
cells
° This is a complex sequential phosphorylation cascade pathway
involving serine/thyronine kinases that ultimately acts in the cell
nucleus to promote cell division
° Tumorigenesis occurs when this pathway is constitutively activated
by mutations in associated genes (RET, TRK, RAS, or BRAF)
■ Activating mutations have been found in up to 70% of DTC
■ Tumors with a BRAF mutation are more aggressive, with higher
rates of extrathyroidal extension, lymph node metastases, and

recurrence
• Inactivating mutations of tumor suppressor genes, such as p53, can
be seen in FTC
• The gene fusion product of thyroid-specific transcription factor (PAX8)
and the nuclear receptor peroxisome proliferator-activated receptor
gamma (PPARγ) results in loss of growth inhibition; associated with
10% of follicular adenomas and 41% of follicular cancers
• VEGF plays a significant role in the process of neovascularization
associated with malignancy; VEGF and its receptors are overexpressed
in thyroid cancer, promoting blood supply and playing an important
role in tumorigenesis and progression
PATHOLOGICAL FEATURES
• PTC is characterized by layers of tumor cells surrounding a fibrovascu-
lar core to form papillae
° The nuclei are oval, large, and overlapping, and may contain
hypodense chromatin, pseudoinclusions, and nuclear grooves
° tions of calcium
Psamomma bodies are seen in 50% of PTC; these are round collec-
that form when papillae infarct
° Often, PTC is multifocal, either due to intrathyroidal metastasis or
due to multiple cancerous clones
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Prognosis 87
° Up to 80% of patients with PTC have lymph node metastasis at the

time of diagnosis
■ 1/3 are clinically evident on exam or preoperative ultrasound,
2/3 are microscopic

° 2−10% of patients with PTC have metastases beyond the neck at
the time of diagnosis
■ Most commonly pulmonary (60%) and skeletal (25%)
• FTC histology ranges from well-differentiated epithelium with clearly

identifiable follicles and colloid to poorly differentiated solid tumors
with marked nuclear atypia and absence of follicles
° Hurthle cell cancer, a variant of FTC, contains eosinophilic oxyphilic
cells with abundant cytoplasm, closely packed mitochondria, and
round oval nuclei with prominent nucleoli
° Distinguishing FTC from a benign follicular adenoma requires
identification of vascular invasion or tumor extension through the
tumor capsule
° Tumors are usually uninodular
° Lymph node spread is present in 8−13% of cases
° Distant metastases occur in 10−15% of cases
CLINICAL PRESENTATION AND DIAGNOSIS
• DTC is generally detected by palpation or neck ultrasound
• Nodule features on ultrasound associated with malignancy include
hypoechogenicity, microcalcifications, absence of peripheral halo,
irregular borders, solid aspect, increased vascularity, and being taller
than wide
• The gold standard for diagnosis of malignancy is FNA cytology
° PTC diagnosis can reliably be made by FNA cytology
° FNA cytology cannot distinguish benign follicular adenoma/
neoplasm from FTC
° and identifi
FTC can only be diagnosed by histologic examination of the nodule
cation of vascular or capsular invasion
° Ifrecommended
FNA cytology is suggestive of a follicular neoplasm, surgery is
to determine whether the tumor is FTC (20−30% risk)
PROGNOSIS
• Both PTC and FTC have a generally good prognosis with overall
mortality <10%
• Certain clinical/pathologic features are associated with worse
prognosis
° Older age at diagnosis: involvement of lymph nodes does not affect
survival of patients <45 years old, but increases risk of death by
46% in those ≥45 years old
48565_ST02_047-110.indd 87 5/1/13 9:34 PM

° Larger tumors
° Soft tissue invasions increases the risk of death fivefold
° Distant metastases
° Certain histologic subtypes
■ PTC: tall cell variant, columnar cell variant, diffuse sclerosing
variant
■ FTC: Hurthle cell, insular thyroid cancer
° Certain gene mutations, including BRAF mutation
TUMOR NODE METASTASIS (TNM) CLASSIFICATION

• Useful in determining overall risk of mortality from DTC
• Primary tumor (T)
° T0: no evidence of primary tumor
° T1a: ≤1 cm, limited to thyroid
° T2: >2>1cm
T1b: cm but ≤2 cm, limited to thyroid
° T3: >4 cm,but ≤4 cm, limited to thyroid
° (sternothyroid
limited to thyroid or minimal extrathyroidal extension
muscle or perithyroid soft tissues)
° T4a: tumor extends beyond thyroid capsule and invades subcutane-
ous (SQ) soft tissues, larynx, trachea, esophagus, or recurrent
laryngeal nerve
° T4b: tumor invades prevertebral fascia or encases carotid artery or
mediastinal vessels
• Regional lymph nodes (N)
° N0: no metastatic nodes
° N1a: metastases to level VI (pretracheal, paratracheal, prelaryn-
geal) lymph nodes
° N1b: metastases to cervical or superior mediastinal nodes
• Distant metastases (M)
° M0: no distant metastases
° M1: distant metastases
TABLE 15.1 TNM Staging
<45 years of age ≥45 years of age
Stage I Any T, any N, M0 T1, N0, M0
Stage II Any T, any N, M1 T2, N0, M0
Stage III T3, N0, M0
T1−3, N1a, M0
Stage IVA T4a, N0−1a, M0
Any T, N1b, M0
T4a, N1b, M0
Stage IVB T4b, any N, M0
Stage IVC Any T, any N, M1
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Initial Treatment of DTC 89
INITIAL TREATMENT OF DTC

• Surgery is the primary therapy for DTC
° Total thyroidectomy if >1 cm, extrathyroidal extension, or lymph
node metastases
° <1 cm andlobectomy
Unilateral and isthmusectomy can be considered if tumor
confined to one lobe
° Ifforunifocal DTC is incidentally diagnosed on pathology after surgery
presumed benign thyroid disease, a completion thyroidectomy
should be performed unless tumor <1 cm, intrathyroidal, and of
favorable histologic type (papillary, follicular variant papillary,
minimally invasive follicular)
° Regional neck dissection if evidence of nodal involvement on exam
or preoperative ultrasound
° The American Thyroid Association also recommends prophylac-
tic central neck dissection in patients with advanced papillary
cancer (T3 or T4) even in the absence of clinical evidence of nodal
involvement
• RAI ablation of the thyroid tissue remnant not removed during initial
surgery has several potential benefits
° Facilitates initial staging by identifying previously undiagnosed
regional or distant metastatic disease on posttreatment whole
body scan
° Facilitates long-term follow-up in enabling early detection of recur-
rence based on serum Tg measurement or RAI whole body scan
° cells, thereby reducing
Serves as adjuvant therapy by destroying persistent thyroid cancer
risk for recurrence or DTC-specific mortality
in certain subsets of patients
■ Proven to decrease risk of death and risk of recurrence in patients
≥45 years of age with tumors >4 cm and in those patients with
gross extrathyroidal extension and distant metastases
° Recommended for those with known distant metastases, gross
extrathyroidal extension, or primary tumor >4 cm
° thyroid who havein documented
Recommended select patients with tumor 1−4 cm confined to
lymph node metastases or other
high-risk features (vascular invasion, aggressive histologic
subtypes)
° drawal
RAI ablation (30−100 mCi131I) is performed following LT4 with-
(to achieve a TSH >30) or recombinant-human TSH (rhTSH)
stimulation after 2 weeks of a low-iodine diet to maximize 131I
uptake by remnant thyroid tissue
• LT4 therapy minimizes potential TSH stimulation of tumor growth
° Initial TSH suppression <0.1 mU/L is recommended for high-risk
and intermediate risk DTC patients
° patients suppression 0.1−0.5 mU/L is appropriate for low-risk
Initial TSH
48565_ST02_047-110.indd 89 5/1/13 9:34 PM

Assessing Risk of Recurrence

• While useful in predicting disease-specific mortality, TNM staging is
less useful in assessing risk of recurrence
° Young patients have a low risk of DTC-related death, but may have
significant risk of recurrence
• The American Thyroid Association has proposed a system to stage risk
of recurrence based on tumor-related parameters and other clinical
features
TABLE 15.2 Features Indicating Risk of Recurrence of DTC
Low Risk Intermediate Risk High Risk
• No local or distant • Microscopic invasion • Macroscopic tumor
metastases into perithyroidal soft invasion
• All macroscopic tumor tissues • Incomplete tumor
has been resected • Cervical lymph node resection
• No invasion of local metastases • Distant metastasis
tissues • 131I uptake outside • Thyroglobulin levels
• No aggressive histology thyroid bed on higher than would be
or vascular invasion posttreatment whole expected for 131I uptake
• No 131I uptake outside body scan on posttreatment whole
thyroid bed on • Aggressive histology or body scan
posttreatment whole vascular invasion
body scan
LONG-TERM MANAGEMENT
• Changes in serum Tg over time are useful in monitoring patients for
recurrence, provided thyroglobulin antibodies (TgAb), which interfere
with Tg assays, are not present
° Ashould
rise in Tg or conversion from negative to positive TgAb status
prompt imaging studies to evaluate for recurrence
• Patients who have undergone total thyroidectomy and RAI remnant
ablation should be assessed for remission 6−12 months after initial
treatment
° Tg on thyroid hormone suppression should be undetectable in the
absence of TgAb
° Thyroid bed and neck ultrasound to evaluate for abnormal lymph-
adenopathy or new/persistent tissue in thyroid bed, which would
warrant biopsy
° IfrhTSH
TgAb negative, measurement of serum Tg after T4 withdrawal or
stimulation
■ A stimulated Tg <1 ng/ml with negative antibodies suggests
disease remission
° withdrawal
If TgAb positive, whole-body 123I uptake scans after thyroid hormone
or rhTSH stimulation
■ Uptake would suggest persistent/recurrent disease
48565_ST02_047-110.indd 90 5/1/13 9:34 PM

Management of Persistent/Recurrent Disease 91
° Provided ultrasound is negative for recurrent disease and

stimulated Tg <1 ng/ml or stimulated whole-body uptake scan is
negative, low-risk patients can subsequently be followed up with a
yearly clinical exam and Tg/TgAb measurement on thyroid hormone;
neck ultrasounds may also be done periodically
• In patients who have undergone less than a total thyroidectomy
and those who have had a total thyroidectomy but not RAI ablation,
periodic serum Tg/TgAb measurements (every 6−12 months) are
recommended, along with neck ultrasounds
° While specific Tg cutoff levels during TSH suppression distinguish-
ing normal residual thyroid tissue from persistent DTC are unknown
in this group of patients, rising Tg value over time is suspicious for
persistent/recurrent disease
• TSH suppression
° In patients with persistent disease, TSH should be maintained
<0.1 mU/L in the absence of specific contraindications (significant
thyrotoxic symptoms, history of heart disease/cardiac arrhythmias,
osteoporosis)
° In patients clinically and biochemically free of disease but who
presented with high-risk disease, TSH should be maintained at
0.1−0.5 mU/L for 5−10 years
° In patients free of disease and at low risk for recurrence, TSH may
be kept in low−normal range (0.3−2.0)
MANAGEMENT OF PERSISTENT/RECURRENT DISEASE

• Detected by clinical examination, rising serum Tg concentration, or
neck ultrasound
° Ifmodalities
neck ultrasound does not reveal disease location, other imaging
include MRI, CT, skeletal X-rays, RAI whole body scans,
and PET (PET is particularly useful if tumor does not concentrate
RAI)
• Surgery is useful to remove clinically significant lymph nodes or
solitary distant metastases
° Risk of surgical complications must be weighed against overall
disease prognosis
• RAI therapy: rhTSH-stimulated or LT4 withdrawal 131I therapy is useful,
provided there is persistent radioidine uptake
° Tumors may fail to concentrate iodine due to dedifferentiation
• External radiotherapy is useful in patients with aggressive local
disease and bone metastases
• Ethanol injection of cervical nodal metastases
• Radiofrequency ablation of cervical, bone, or pulmonary metastases is
an alternative in poor surgical candidates with RAI-resistant tumors
• Combination cytotoxic chemotherapy has been shown to be minimally
effective in treating progressive thyroid cancer
48565_ST02_047-110.indd 91 5/1/13 9:34 PM

• Novel therapies that target the distal steps in the MAPK pathway and
inhibit the action of VEGF are currently under investigation for the
treatment of advanced/resistant DTC
° TKIs include axitinib, lenvatinib, motesanib, pazopanib, sorafenib,
sunitinib, and vandetanib
REFERENCES
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid
Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM,
et al. Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid,
2009;19(11):1167−214.
Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer
incidence patterns in the United States by histologic type, 1992–2006.
Thyroid, 2011;21(2):125−34.
Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: diagnos-
tic and clinical implications. Best Pract Res Clin Endocrinol Metab,
2008;22(6):955−69.
Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with
differentiated thyroid carcinoma following initial therapy. Thyroid,
2006;16(12):1229−42.
Kojic KL, Kojic SL, Wiseman SM. Differentiated thyroid cancers: a compre-
hensive review of novel targeted therapies. Expert Rev Anticancer Ther,
2012;12(3):345−57.
Pacini F, Castagna MG. Approach to and treatment of differentiated thyroid
carcinoma. Med Clin North Am, 2012;96(2):369−83.
48565_ST02_047-110.indd 92 5/1/13 9:34 PM

16 ■ MEDULLARY THYROID CANCER
Jennifer Sipos, MD
PATHOPHYSIOLOGY
• Malignancy of calcitonin-secreting parafollicular C cells of the thyroid
gland, derived from the neural crest
° May start as C-cell hyperplasia (CCH), which progresses to
invasive MTC
° CCH may be seen as a secondary condition not associated with MTC
° Autosomal-dominant inherited disease in ~25%; caused by a
germline mutation in the rearranged during transfection (RET )
proto-oncogene; typically multifocal or bilateral
° Sporadic in ~75%, typically unifocal
• The inherited form of medullary thyroid cancer (MTC) may be associ-
ated with other endocrine tumors, termed MEN
° MEN2A-hyperparathyroidism, pheochromocytoma, MTC
° MEN2B-pheochromocytoma, mucosal neuromas of the lips and
tongue, ganglioneuromatosis of the GI tract, Marfanoid body
habitus, MTC
° Familial medullary thyroid cancer (FMTC)-inherited MTC is the only
manifestation; at least four family members with no other signs or
symptoms of pheochromocytoma or hyperparathyroidism
TABLE 16.1 Features of Familial Syndromes Associated with Medullary

Thyroid Cancer
Syndrome MTC Hyperparathyroidism Pheochromocytoma
MEN2A Yes Yes Yes
MEN2B Yes No Yes
FMTC Yes No No
Epidemiology
• 3% of all thyroid cancers are MTC
° Affects 1 in 30,000 people.
° 1000 to 2000 new cases of MTC in US annually
° (21 years)
Age at diagnosis is older for sporadic cases (51 years) than genetic
° 83% 5-year survival for MTC, compared to 94% in patients with

PTC; survival is affected by tumor size (stage) at diagnosis, younger
age at diagnosis, and diagnosis by screening (familial form)
48565_ST02_047-110.indd 93 5/1/13 9:34 PM

94 Medullary Thyroid Cancer
• Nodule/mass: mass effect from local tumor compression; hoarseness,
dysphagia, lymphadenopathy
• Flushing, diarrhea: unclear etiology, possibly from humoral secretions
by the tumor
• Pheochromocytoma: tumor of the catecholamine-producing chromaffin
cells of the adrenal medulla; presents with refractory hypertension;
may also present with abdominal pain, flushing, and headaches;
poses a risk to health and life if left untreated
• Hyperparathyroidism: may present with kidney stones or fractures
DIAGNOSIS
• Imaging is typical method of initial detection
° Ultrasound of the neck reveals thyroid nodule and possibly meta-
static lymph nodes
° CT of the chest may reveal lymph node involvement in mediastinum
or pulmonary nodules
° CT of the abdomen may reveal hepatic metastases
• FNA under ultrasound guidance into thyroid nodule or suspicious lymph
node
° Immunohistochemical staining for calcitonin
° Amyloid deposits seen on pathology
• Genetic testing: RET gene testing should be performed in all patients
with MTC; if positive, all first-degree family members should also be
tested
° Those family members who have a RET mutation should have
a prophylactic thyroidectomy; penetrance of disease in carriers
is very high
• Elevated serum calcitonin
° Basal calcitonin >10 pg/ml is elevated
■ May be elevated in males and smokers and those with renal
failure, nodular thyroid disease, or Hashimoto’s thyroiditis

° Stimulated calcitonin after pentagastrin infusion (not available in
US) or calcium injection (not standardized); stimulated values are
more sensitive than basal, but not specific
• Primary hyperparathyroidism (PHPT)
° Elevated serum parathyroid hormone (PTH)
° Elevated serum calcium
• Pheochromocytoma
° Fractionated plasma metanephrines (MNs) or 24-hour urine
catecholamines and MNs
° metaiodobenzylguanidine
If biochemical testing is positive, then localizing study with MRI or
(MIBG) can be considered
48565_ST02_047-110.indd 94 5/1/13 9:34 PM

Therapy 95
CLINICAL FEATURES
• Locoregional metastases: cervical lymph node metastases occur early
in the disease course and can be seen even with tumors measuring
several millimeters
• Distant metastases: tumors over 1.5 cm are more likely to metastasize
to distant sites (i.e., lung, liver, and bone)
• Cushing’s syndrome: tumor may secrete ACTH
STAGING
• When lymph node metastases are identified or when preoperative cal-
citonin is >400 pg/mL, CT scanning for distant metastases is advised
with focus on the neck, chest, and liver
• PET scanning is not advised in MTC for initial screening for
metastases
• Testing for parathyroid tumors and pheochromocytoma is advised prior
to thyroidectomy
• Staging is based on the American Joint Committee on Cancer pTNM
staging
° Stage I: <2 cm with no evidence of disease outside of the thyroid
° Stage II: any tumor 2−4 cm with no evidence of extrathyroidal
disease
° microscopic
Stage III: any tumor >4 cm, central neck nodal metastases, or
extrathyroidal invasion regardless of tumor size
° Stage IV: any distant metastases or lymph node involvement
outside of the central neck, or gross soft tissue extension
THERAPY
• Surgery: this is the only possible method for curing patients with MTC
° Total thyroidectomy: removal of all thyroid tissue is the preferred
initial treatment for MTC as many patients with sporadic disease
and nearly all with inherited disease will have bilateral tumors
° Lymph node dissection: lymph nodes may be present in up to 50%
of patients at initial presentation. Central neck dissection is recom-
mended for most patients with a preoperative diagnosis of MTC
to remove involved nodes. Identification of abnormal nodes in the
lateral neck or mediastinum by ultrasound or CT should prompt a
more extensive neck dissection to remove the disease
° Distant disease: removal of all involved nodes or radical neck
dissection is not indicated in patients with distant disease as it
does not improve survival; instead, debulking of the tumor and
removing nodes that threaten to extend into vital structures may
be performed
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96 Medullary Thyroid Cancer
• LT4 replacement: unlike DTCs (papillary and follicular), there are no

TSH receptors on the C cell; TSH suppression therapy is not necessary;
replacement target is to set TSH in the normal range
• EBRT: may be used in nonoperable disease to control the threat of local
extension into vital structures
• Vandetanib TKI: FDA-approved for use in patients with nonoperable
progressive disease
• Cabozantinib TKI: FDA-approved for use in patients with metastatic
disease
• Management in MEN2 (see Chapter 63, Polyglandular Syndrome
(Autoimmune and MEN))
° Adrenalectomy: patients with pheochromocytoma require surgical
removal of involved glands. There is an increased prevalence of
bilateral tumors. Patients should be administered α blockers prior
to surgery to control hypertension and prevent release of catechol-
amines intraoperatively
° Parathyroidectomy: most patients will have multigland involvement;
removal of 3.5 glands with reimplantation into the sternocleido-
mastoid or forearm is the typical approach
FOLLOW-UP
• Calcitonin: should be measured at the same lab each time; the amount
of time it takes for the calcitonin to double (doubling time) is used to
determine the interval between follow-up visits
• Carcinoembryonic antigen (CEA): a small minority of tumors preferen-
tially secrete this marker rather than calcitonin
• Imaging: CT or ultrasound may be used to follow for progression of
known metastases or for development of new lesions
• Freedom from disease: undetectable basal and stimulated calcitonin
with no evidence of tumor by imaging
° Recurrence rates ~3% if patients are rendered free of disease
based on above criteria; lifelong follow up is recommended
REFERENCES
American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al.
Medullary thyroid cancer: management guidelines of the American Thyroid
Association. Thyroid, 2009;19(6):565−612.
Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet
Med, 2011;13(9):755−64.
Tuttle RM, Ball DW, Byrd D, et al. Medullary carcinoma. J Natl Compr Canc
Netw, 2010;8(5):512−30.
Wu LS, Roman SA, Sosa JA. Medullary thyroid cancer: an update of new
guidelines and recent developments. Curr Opin Oncol, 2011;23(1):22−7.
48565_ST02_047-110.indd 96 5/1/13 9:34 PM

17 ■ ANAPLASTIC THYROID CANCER AND
POORLY DIFFERENTIATED THYROID CANCER
Rebecca Leboeuf, MD
PATHOPHYSIOLOGY
• Anaplastic thyroid cancers (ATCs) are highly aggressive undifferenti-
ated tumors originating from thyroid follicular epithelium
• Accounts for about 1.7% of all thyroid cancers
• There is good evidence suggesting that ATC develops from more
differentiated tumors as a result of dedifferentiation events
° ~20% of patients with ATC have a history of DTC and ~20−30%
have coexisting DTC
• ATCs have complete loss of expression of thyroid specific proteins
such as Tg, NIS, TSH receptor, and thyroid transcription factor-1
(TTF1)
• Poorly differentiated thyroid cancer (PDTC), an intermediate
between DTC and ATC, can sometime mimic ATC but is usually less
aggressive
• A rapidly enlarging neck mass is the most common symptom, occurring
in about 85% of patients
• The vast majority of patients have regional (≥90%) or distant
metastases (up to 50%) at the time of presentation
° Regional involvement includes perithyroidal fat and muscle, lymph
nodes, tonsils, larynx, trachea, esophagus, and the great vessels of
the neck and mediastinum
° Distant metastases often involve the lung, bones and brain, and
less frequently, the skin, liver, kidneys, and adrenal glands
• The most frequent symptoms and signs are listed in the following
table
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98 Anaplastic Thyroid Cancer and Poorly Differentiated Thyroid Cancer
TABLE 17.1 Signs and Symptoms of Anaplastic Thyroid Cancer
Symptoms Signs
Rapidly enlarging neck mass Thyroid enlargement, often asymetric,
hard, fi xed
Neck pain and tenderness Dominant thyroid nodule often present,
often >5 cm
Dyspnea Enlarged cervical lymph nodes
Dysphagia Stridor
Hoarseness Tracheal deviation
Cough Vocal cord paralysis
Hemoptysis Venous dilatation, superior vena cava
syndrome
Pains from metastases (bone pain, Focal neurological signs if brain
headache, confusion, chest pain, metastases
abdominal pain)
Constitutional symptoms, like weight
loss, fatigue, anorexia, fever of unknown
origin
• The diagnosis of ATC is usually established by core biopsy or open
surgical biopsy. In some case, a diagnosis can be made by FNA, though
caution is required with FNA because other disorders may resemble
ATC cytologically (see Table 17.2).
• Cytological or histological examination of ATC tumor will reveal
° Spindle cells pattern
° Pleomorphic giant cells pattern
° Squamoid cells pattern
TABLE 17.2 Differential Diagnosis of Anaplastic Thyroid Carcinoma on FNAB

Differential Diagnosis of Anaplastic Thyroid Carcinoma on FNAB
Benign cells misinterpreted as ATC
• Fibroblast (granulation tissue, stroma, granuloma)
• Histiocytes
• Atypical follicular cells secondary to 131I therapy
• Degenerating follicular cells
Malignant neoplasms misinterpreted as ATC
• MTC
• Poorly differentiated cancer metastatic to the thyroid
• Lymphoma
48565_ST02_047-110.indd 98 5/1/13 9:34 PM

TABLE 17.3 Summary of Differences Between PDTC and ATC
PDTC ATC
Mutational status
RET/PTC rearrangement + –
BRAF + +
RAS + +
Immunohistochemical Markers
TTF1 + –
PAX8 + –
Thyroglobulin + –
NIS + but can be ↓ –
p53 Rare + +
B cadherin + –
Clinical Presentation Often aggressive Fulminant course

Pathology • Architectural growth • Pleomorphic cells
pattern of large, and nuclei, giant
well-defined solid nests, multinucleated
mimicking neuroendocrine cells, spindle cells,
tumor (insular) or squamoid cells
trabecular growth • Extensive necrosis
• Tumor cells are uniform • High mitotic activity
• Small foci of necrosis
• Some mitotic activity
RAI uptake May retain some RAI uptake No RAI uptake
• Most patients have normal serum TSH, except for those with tumor-
induced thyroiditis
• Imaging studies are useful to define the extent of disease and
plan therapy, but should be scheduled urgently so as not to delay
management
° CT of the neck and mediastinum can accurately identify the extent
of the tumor and its invasion to local structures
° extension and nodal
Ultrasonography can be informative to the extent of extrathyroidal
involvement
° PET/CT will demonstrate hypermetabolic lesions where present
° Chest X-ray will often detect pulmonary metastases
• TNM staging definition: all ATC are Stage IV disease
° T4a: intrathyroidal ATC
° T4b: ATC with gross extrathyroidal extension
48565_ST02_047-110.indd 99 5/1/13 9:34 PM

TABLE 17.4 TNM Stage Defi nition
Stage T N M
IVA T4a Any N M0
IVB T4b Any N M0
IVC Any T Any N M1
MANAGEMENT
• ATC does not respond to RAI and treatment or scan with RAI should not
be part of management
• Prognostic factors
° ATC is almost universally fatal, with median survival ranging from
3−7 months and 20% one-year survival
° Patients with disease either confined to the thyroid (Stage IVA)
or with local and regional metastases (Stage IVB) have a longer
survival than those with distant metastases (Stage IVC)
° Patients with tumor <6 cm have a better 2-year survival than those
with larger tumors (25% versus 3−15%)
° worse prognosis
Older age, male sex or dyspnea as presenting symptom confers
SURGERY
• If the tumor appears to be localized to the thyroid, complete resection
should be attempted with total thyroidectomy and therapeutic lymph
node dissection
• En bloc resection should be considered for patient with extrathyroidal
extension if gross negative margin can be achieved
• Surgery is not indicated when patients present in a more advanced
stage
EXTERNAL RADIATION THERAPY

• Postoperative RT with or without chemotherapy is recommended
for patients with good performance status with complete resection
of gross disease based on uncontrolled data suggesting improved
survival
• Intensity-modulated radiation therapy (IMRT) is preferable for optimal
dose delivery to target tissue while minimizing dose to uninvolved
organs if the planning can be done quickly and not delay primary
therapy
48565_ST02_047-110.indd 100 5/1/13 9:34 PM

External Radiation Therapy 101
• Hyperfractionated RT (multiple small radiation doses allowing >1

radiation treatment per day) of 60 Gy should be considered because
treatment can be accelerated and given over a shorter course of time
than with conventional EBRT
• Adjuvant radiosensitizing chemotherapy may improve ATC outcome and
may be offered to patients with good performance status along with
RT (e.g., taxanes [paclitaxel, docetaxel], anthracyclines [doxorubicin],
or platins [cisplatin, carboplatin])
• If unresectable tumor is present or gross residual disease is present
after surgical attempt, RT with or without chemotherapy should be
offered to patients with good performance status as it may achieve
long-term local control
° Surgery can be reconsidered after RT as it may render the tumor
resectable
Chemotherapy
• For Stage IVC patients, there are no randomized data suggesting that
systemic therapy may improve survival or improve quality of life, but
transient and occasional more durable tumor regression/control can
be achieved
• Combination or monotherapy including a taxane (paclitaxel, docetaxel)
and/or an anthracycline (doxorubicin) may be considered with the
current data available
• Antimicrotubule disrupting agents (fosbretabulin, combretastatin A4
phosphate, crolibulin) and TKIs (sorafenib, imatinib) are also being
evaluated
• Patients with advanced/metastatic ATC who wish to follow a more
aggressive approach should be offered participation in a clinical trial
when available
TABLE 17.5 Summary of Treatment Options and Suggestions According

to ATC Stage
Stage IVA Stage IVB Stage IVC
Surgery En bloc resection if Palliative measures
feasible
IMRT/hyperfractionated RT IMRT/hyperfractionated IMRT/hyperfractionated
RT and reconsider RT*
surgery if now tumor
resectable*
Chemotherapy Chemotherapy* Chemotherapy*
Consider clinical trial Consider clinical trial Consider clinical trial
*If good performance status along with the patient’s desire.
48565_ST02_047-110.indd 101 5/1/13 9:34 PM

REFERENCES
Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma
with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative
Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group.
Thyroid, 2000;10(7):587−94.
Brierley JD. Update on external beam radiation therapy in thyroid cancer.
J Clin Endocrinol Metab, 2011;96(8):2289−95.
Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregion-
ally confined anaplastic thyroid carcinoma: a single-institution experience
using aggressive multimodal therapy. Thyroid, 2011;21(1):25−30.
Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic
thyroid carcinoma. Treatment outcome and prognostic factors. Cancer,
2005;103(7):1330−5.
Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced
primary and metastatic radioactive iodine-refractory thyroid cancers
reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer
Res, 2009;69(11):4885−93.
Smallridge RC, Ain KB, Asa SL. American Thyroid Association Guidelines
for Management of Patients with Anaplastic Thyroid Cancer. Thyroid,
2012;22(11):1104−39.
Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer:
molecular pathogenesis and emerging therapies. Endocr Relat Cancer,
2009;16(1):17−44.
48565_ST02_047-110.indd 102 5/1/13 9:34 PM

18 ■ THYROID DISORDERS IN PREGNANCY
Ivana Lukacova-Zib, MD and Geetha Gopalakrishnan, MD
HYPOTHYROIDISM IN PREGNANCY

• Autoimmune (Hashimoto’s) thyroiditis is the most common etiology;
other causes include pituitary and hypothalamic disorders (see
Chapter 11, Hypothroidism)
• Certain factors in pregnancy exacerbate or precipitate hypothyroidism
in pregnancy. These factors result in higher requirements of thyroid
hormone replacement and iodine intake during pregnancy.
° Pregnancy increases production of thyroid binding globulin
(TBG) and decreases TBG clearance; as a result both T4 and T3
requirements increase in pregnancy
° Requirements of iodine increase in pregnancy due to an increase
in maternal T4 production and an increase in renal clearance
of iodine
• General signs and symptoms of hypothyroidism are discussed in
Chapter 11. Hypothyroidism
• Pregnancy-related complications of hypothyroidism include premature
birth, miscarriage, placental abruption, gestational hypertension, low
birth weight, fetal death, reduction of infant IQ, motor delay, and a
delay in language and attention
• TPO antibody titers in euthyroid women are associated with fetal loss,
perinatal mortality, and large-for-gestation-age infant
SCREENING FOR HYPOTHYROIDISM IN PREGNANCY

• Universal screening of asymptomatic pregnant women is controversial
• Screening is recommended for high-risk women: family or personal
history of thyroid disease, signs or symptoms suggestive of thyroid
disease, history of head or neck irradiation, presence of other autoim-
mune condition like type 1 diabetes, infertility, preterm delivery or
miscarriage
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104 Thyroid Disorders in Pregnancy
• TRAb
° Screen women with history of Graves’ at 20−24 weeks gestation
• TPO antibody
° Screening can be considered in women at high risk for
hypothyroidism
• TSH
° Screening in high-risk women
° Monitoring therapy in primary hypothyroidism
° Abnormal if >2.5mU/L in the first trimester and >3mU/L in the
second/third trimester
• FT4
° Monitoring therapy in secondary hypothyroidism
DIAGNOSIS
• See Chapter 11, Hypothyroidism
• Primary hypothyroidism
° Overt hypothyroid: elevated TSH and low FT4
° Subclinical hypothyroid: elevated TSH and normal FT4
• Central hypothyroid: low FT4 with low or normal TSH
• Euthyroid with positive antibody: TPO positive and TSH normal
MANAGEMENT
• Primary hypothyroidism
° Preconception TSH goal in normal range but <2.5 mU/L
° Once pregnant, increase LT4 by 30%
° least once between4 26
Monitor TSH every weeks in the first half of pregnancy and at
and 32 weeks gestation
° Target TSH within trimester-specific reference ranges (first
trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third
trimester, 0.3–3.0 mIU/L)
° Postpartum, LT4 should be reduced to prepregnancy levels and TSH
measured after 6 weeks
• Central hypothyroidism
° LT4 replacement preconception and during pregnancy to target
mid−upper reference range of FT4
° Monitor FT4 every 4 weeks for dose titration during the first half of
pregnancy and at least once between 26 and 32 weeks gestation
after target is reached
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Etiology and Pathophysiology 105
• Euthyroid with positive TPO

° Insuffi cient evidence to support LT4 treatment in this population
if TSH is abnormal; however, several experts consider starting low
dose LT4 in high-risk women (i.e., those who have had multiple
miscarriages)
° Since these women are at risk for hypothyroidism, monitor TSH
every 4 weeks during the first half of pregnancy and at least once
between 26 and 32 weeks gestation; if abnormal for pregnancy,
start treatment with LT4
• Iodine supplementation for all pregnant and lactating woman
° Ingest a minimum of 250 mcg (but not exceeding 500−1100 mcg)
of iodine daily to prevent fetal hypothyroidism
° potassium iodide
Many prenatal vitamins will contain this amount; if not, additional
supplements are preferred to kelp or seaweed
which do not contain a consistent quantity of iodine
• Hypothyroid after treatment of Graves’
° TRAb at 20−24 weeks gestation
° Ifultrasound
elevated (3 times upper limit of normal), perform serial fetal
to evaluate for fetal goiter, growth, heart rate, and
amniotic fluid volume
HYPERTHYROIDISM IN PREGNANCY

• Graves’ is the most common etiology in reproductive age women
• Other causes include toxic multinodular goiter, toxic adenoma,
factitious hyperthyroidism, hyperthyroid phase of thyroiditis,
struma ovarii, metastatic thyroid cancer, and TSH-secreting
pituitary tumor
• Factors to consider in pregnancy
° Elevation of HCG (normal pregnancy, multiple gestations,
hydatidiform mole, choriocarcinoma) could stimulate TSH receptor
and cause gestational hyperthyroidism; typically, the normal
physiologic response to HCG is transient and resolves by the
second trimester
° TRAb elevation in Graves’ disease in third trimester crosses pla-
centa and can cause fetal goiter or neonatal hypo- or hyperthyroid-
ism (fetal tachycardia, intrauterine growth restriction, accelerated
bone maturation, CHF, and fetal hydrops)
48565_ST02_047-110.indd 105 5/1/13 9:34 PM

• General signs and symptoms of hyperthyroidism and Graves’ disease
(see Chapter 10, Thyrotoxicosis and Hyperthyroidism)
• Pregnancy related: miscarriages, pregnancy-induced hyperten-
sion, prematurity, low birth weight, intrauterine growth restriction,
stillbirth, thyroid storm, and maternal CHF
• Gestational hyperthyroidism (i.e., HCG-mediated thyrotoxicosis) is
often associated with hyperemesis gravidarum during the first trimes-
ter of pregnancy and resolves by the second trimester; these patients
have a normal thyroid gland on exam
• TSH
°
• FT4
Not used to follow therapy

° Monitoring therapy with a goal in high−normal range
• TRAb
° Check during second trimester for high-risk women
■ Graves’ disease (past or current with or without thyroidectomy
or radioiodine ablation)
■ History delivering an infant with hyperthyroidism
° Ifultrasound
elevated (3 times upper limit of normal), perform diagnostic fetal
to evaluate for fetal goiter, amniotic fluid volume, fetal
growth, and heart rate; in high risk cases, cordocentesis can be
considered to evaluate the functional status of the fetal thyroid
DIAGNOSIS
• See Chapter 10, Thyrotoxicosis and Hyperthyroidism
• Gestational hyperthyroid
° Low TSH (⫹/⫺ mild elevations in FT4 and T3) identified in the first
trimester
° Resolves by 14−18 weeks gestation
• Primary hyperthyroidism
° Overt hyperthyroid: low TSH and elevated FT4/T3
° Subclinical hyperthyroid: low TSH and normal FT4 (persistent
abnormality in second and third trimesters)
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Etiology and Pathophysiology 107
MANAGEMENT
• Gestational hyperthyroidism with or without hyperemesis gravidarum
° Supportive treatment may be sufficient to prevent dehydration
° ATDs can be considered if maternal weight loss or fetal growth
retardation
• Thyrotoxicosis related to Graves’ disease, multinodular goiter, thyroid
nodule during pregnancy
° Radioactive iodine is absolutely contraindicated in pregnancy women
° β-adrenergic blocking agents
■ Propranolol 20−40 mg every 6−8 hours can be considered to
address symptoms (i.e,. tachycardia and tremors); typically

can be tapered off after symptoms resolve
■ Potential side effects include fetal bradycardia, intrauterine
growth restriction, and neonatal hypoglycemia; monitor and

titrate off medication when appropriate
° breastfeeding
ATDs: PTU and MMI can be considered in pregnancy and with
■ PTU is recommended for the first trimester of pregnancy
• Starting dose can range from 50−300 mg daily divided

three times per day; monitor FT4 levels every 2−4 weeks
and maintain levels at or slightly above the upper normal
reference range
• Associated with liver toxicity (see Chapter 10, Thyrotoxicosis
and Hyperthyroidism) and therefore, many experts recommend
switching to MMI in the second trimester
■ MMI is recommended second and third trimester
• MMI teratogenicity: choanal and esophageal atresia,

dysmorphic features, and aplasia cutis; avoid in first
trimester
• Starting dose 5−15 mg daily; may decrease the dose or dis-
continue MMI as the pregnancy progresses; monitor FT4 levels
every 2−4 weeks and maintain levels at or slightly above the
upper normal reference range
■ Warning: fetal goiter and hypothyroidism a complication of
overtreatment with MMI and PTU

° Thyroidectomy
■ Can be consider in the second trimester of pregnancy for non-
compliant patients or if antithyroid drugs are contraindicated
THYROID NODULES AND THYROID CANCER

• Thyroid nodules can increase with pregnancy and parity
• Pregnancy does not affect course or prognosis of DTC
48565_ST02_047-110.indd 107 5/1/13 9:34 PM

• See Chapter 14, Thyroid Nodule Evaluation; Chapter 15, Papillar and
Follicular Thyroid Cancer; Chapter 16, Medullary Thyroid Cancer; and
Chapter 17, Anaplastic and Other Poorly Differentiated Thyroid Cancer
DIAGNOSIS AND MANAGEMENT

• See Figure 18.1
TSH and Ultrasound
Nodule Nodule >1cm

<1cm and Compressive
Or US Surgery
symptoms
>1cm and suspicious for
benign US malignancy
features
Immediate
FNA Anaplastic
surgery
Follow Suspicious Immediate

Benign Malignant Medullary
postpartum for surgery for
malignancy large tumor
Papillary or
Surgery in follicular
second
trimester or
postpartum Local or
distant
Yes No
2nd US and TG
trimester each trimester
surgery LT4 suppressive therapy
TSH goal 0.1–1.5
Nodule growth
or metastasis
Yes No
2nd trimester surgery Surgery postpartum
FIGURE 18.1 Thyroid Cancer Diagnosis and Management

Source: Adapted from Stagnaro-Green, Alex et al. Guidelines of the American Thyroid Association ...
Thyroid. 21: 10. 2011. © Mary Ann Liebert, Inc.
48565_ST02_047-110.indd 108 5/1/13 9:34 PM

HISTORY OF THYROID CANCER

• LT4 suppressive therapy recommended during pregnancy; monitor TSH,
targets are:
° Persistent thyroid cancer: TSH goal <0.1 mU/L
° Disease-free, high-risk tumor: TSH goal 0.1−0.5
° Disease-free, low-risk tumor: TSH 0.3−1.5
• Thyroid ultrasound
° Low-risk tumor or no evidence of persistence: no need for ultra-
sound during pregnancy
° High levels of Tg or evidence of persistence before pregnancy:
ultrasound every trimester
• Note: RAI administration is contraindicated during pregnancy and at
least 6 months prior to pregnancy
POSTPARTUM THYROIDITIS

• Autoimmune condition within one year postpartum associated with
elevated TPO and Tg antibody, complement activation, elevated immu-
noglobulin G (IgG), increased natural killer activity, specific human
leukocyte antigen (HLA) haplotype
• Starts as mild thyroid hormone elevation or isolated hypothyroidism
possibly followed by temporary or permanent hypothyroidism
• Risk increase with multiparty, advanced age, miscarriage, TPO
antibody titer
• Predisposition include: type 1 diabetes, chronic viral hepatitis,
systemic lupus, Graves’ disease, prior episode of postpartum
hyroiditis, HT
• Signs and symptoms of hyper- or hypothyroidism can be present
depending on timing of presentation
• TSH and FT4
° Screen 3–6 months postpartum if history positive of type 1
diabetes, positive TPO antibody, postpartum depression, prior
postpartum thyroiditis
° Assess in all symptomatic patients
48565_ST02_047-110.indd 109 5/1/13 9:34 PM

TREATMENT AND MONITORING

• Hyperthyroid phase
° β-blockers: propranolol 10−20 mg four times a day (QID)
• Hypothyroid phase
° Repeat TSH every 8 weeks for at least 1 year postpartum
° LT4 can be considered in women who are symptomatic, breastfeed-
ing, or pregnant or attempting pregnancy
° Dose can be titrated off after 6−12 months in most women except if
■ Breastfeeding
■ Pregnant or attempting pregnancy
■ Permanent hypothyroidism
• 20−40% will eventually develop permanent hypothyroidism

• Yearly TFT recommended for women with history of
postpartum thyroiditis
REFERENCES
Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction
during pregnancy and postpartum: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2007;92(Suppl 8):S1−47.
Committee on Patient Safety and Quality Improvement; Committee on
Professional Liability. ACOG Committee Opinion No. 381: Subclinical
hypothyroidism in pregnancy. Obstet Gynecol, 2007;110(4):959−60.
Stagnaro-Green A. Approach to the patient with postpartum thyroiditis.
Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of
the American Thyroid Association for the diagnosis and manage-
ment of thyroid disease during pregnancy and postpartum. Thyroid,
2011;21(10):1081−125.
48565_ST02_047-110.indd 110 5/1/13 9:34 PM

SECTION III: ADRENAL
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48565_ST03_111-160.indd 112 5/1/13 9:34 PM
19 ■ ADRENAL ESSENTIALS
Jane V. Mayrin, MD
ANATOMY
• Pyramidal shape; located above the upper poles of kidneys in
retroperitoneum
• Cortex makes up 90% of adrenal weight, medulla makes up 10%
• Blood supply
° Arteries: superior (from inferior phrenic arteries), middle (from
aorta), and inferior adrenal arteries (from renal arteries)
Veins: right adrenal vein → inferior vena cava; left adrenal vein →
° left renal vein
HISTOLOGY
• Adrenal cortex: divided into three histological and functional zones
(mnemonics: G-F-R or salt-stress-sex)
° Zona glomerulosa (outer): secretes aldosterone (mineralocorticoids)
■ 15% of cortical volume
■ Lacks 17α-hydroxylase and cannot produce cortisol or
androgens
° Zona fasciculata (intermediate): secretes cortisol (glucocorticoids)
and androgens
■ 75% of cortex, (cortisol >> androgens)
° Zona reticularis (inner): secretes androgens and cortisol

■ Androgens > cortisol and estrogens
• Adrenal medulla: neuroendocrine origin, secretes catecholamines
HORMONE SYNTHESIS
• Steroidogenesis (see Figure 19-1)
• Catecholamines synthesis: tyrosine → dehydroxyphenylalanine → DA
(acts primarily as neurotransmitter in CNS) → norepinephrine (NE;
found in adrenal medulla, CNS, and peripheral sympathetic nerves) →
epinephrine (Epi; synthesized only in the adrenal medulla)
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114 Adrenal Essentials
Cholesterol
17α hydroxylase 17,20–lyase
Pregnenolone 17OH-Pregnenelone DHEA Androstenediol
3β HSD
Progesterone 17OH-Progesterone Androstenedione Testosterone
21α-hydroxylase
11- 11-deoxycortisol
deoxycorticosterone
11β hydroxylase
Corticosterone Estrone Estradiol
Aldosterone 18-OH corticosterone
synthase
Aldosterone Cortisol
Zona Glomerulosa Zona Fasciculata and Zona Reticularis
3β HSD- 3-hydroxysteroid dehydrogenase.
FIGURE 19.1 Adrenal Steroidgenesis
REGULATION OF ADRENAL FUNCTION

• Glucocorticoids
° Cortisol circulates mostly bound to cortisol-binding globulin
(~75%) and albumin (~15 %); ~10% is free
° Hypothalamic-Pituitary-Adrenal
• Mineralocorticoids
axis (see Figure 19-2).
° Primarily controlled by renin-angiotensin-aldosterone system

■ Renin release is stimulated by low Na+ and Cl – load, low renal
perfusion, sympathetic nervous system, K +, angiotensin II, and

atrial natriuretic peptide
Renin release ACE
■ Angiotensinogen Angiotensin
Angiotensin II Aldosterone release
■ System is very sensitive to dietary sodium intake
° Hyperkalemia and high concentrations of ACTH also directly stimu-

late aldosterone release
° extent, cortisol-bindingprimarily
Aldosterone circulates bound to albumin and, to a lesser
globulin; 30−50% is free
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Function of Adrenal Hormones 115
Hypothalamus
CRH
Pituitary
ACTH
Cortisol Adrenal
Cortex
CRH - corticotropin-releasing hormone

ACTH - adrenocorticotropic hormone
FIGURE 19.2 Regulation of Glucocorticoid Synthesis and Release: Hypothalamic-

Pituitary-Adrenal Axis (Adopted and modified from Greenspan’s Basic and Clinical
Endocrinology)
FUNCTION OF ADRENAL HORMONES

• Glucocorticoids
° Bind to glucocorticoid receptor inside the cytoplasm → steroid-receptor
complex enters nucleus → binds to glucocorticoid regulatory elements
→ influences transcription of glucocorticoid-responsive genes
• Normal functions include maintaining vascular tone, permitting lipoly-
sis, increasing plasma glucose during fasting, maintaining emotional
balance, and limiting inflammation
• Adrenal androgens
° Function mostly as precursors for peripheral conversion to the
active androgens (testosterone and dihydrotestosterone [DHT])
■ In adult males with normal gonadal function, the effect of
adrenal androgen is negligible

■ In females, adrenal androgens contribute ~50% of total
androgens
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116 Adrenal Essentials
• Mineralocorticoids
° Main functions: regulation of extracellular volume (via Na resorp-
tion) and control of K + homeostasis
■ Bind to cytoplasmic mineralocorticoid receptor → steroid-
receptor complex enters nucleus → binds to mineralocorticoid

regulatory elements → influences transcription of mineralocor-
ticoid-responsive genes, particularly regulation of Na channels
(Na reabsorption) and the Na+ -K + ATPase pump (Na reabsorption
with K + and H + excretion)
• Catecholamines
° Work through adrenergic receptors (α∙∙ , β, DA)
° α-1: vascular and smooth muscle contraction → vasoconstriction
and increased BP
° α-2: inhibit NE release → decreased BP
° β-1: positive inotropic and chronotropic effect on heart (responsive
to isoproterenol) → increased heart rate, increased renin secretion
in kidneys
° β-2: bronchial, vascular, and uterine smooth muscle relaxation →
bronchodilatation, vasodilatation in skeletal muscle; glycogenolysis
β-3:
° DA-1:regulates energy expenditure and lipolysis
° vascular vasodilatation in cerebral, renal, mesenteric, and coronary
beds
° DA-2: inhibit release of NE and PRL, and ganglionic transmissions
REFERENCES
Carey RM. Overview of endocrine systems in primary hypertension.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology, 8th ed.
New York, NY: McGraw Hill; 2007.
McNicol AM. Lesions of the adrenal cortex. Arch Pathol Lab Med,
2008;132(8):1263−71.
McNicol AM. Update on tumours of the adrenal cortex, phaeochromocytoma
and extra-adrenal paraganglioma. Histopathology, 2011;58(2):155−68.
Miller WL. Disorders of androgen synthesis—from cholesterol to dehydroepi-
androsterone. Med Princ Pract, 2005;14(Suppl 1):58−68.
Williams GH. Aldosterone biosynthesis, regulation, and classical mechanism
of action. Heart Fail Rev, 2005;10(1):7−13.
48565_ST03_111-160.indd 116 5/1/13 9:34 PM

20 ■ ADRENAL INSUFFICIENCY
Farah Morgan, MD and Marc J. Laufgraben, MD
CAUSES OF ADRENAL INSUFFICIENCY

• Primary AI
° Caused by lack of hormone production at the level of the adrenal
gland resulting in both low cortisol and low aldosterone
° bacterial),include
Etiologies autoimmune adrenalitis, infection (TB, fungal,
inherited disorders (adrenoleukodystrophy, congenital
adrenal hyperplasia [CAH]), drugs (ketoconazole, etomidate),
infiltration, hemorrhage, infarction, metastatic disease
■ Autoimmune adrenalitis is the most common cause in developed
countries, though TB is the most common cause worldwide

■ Autoimmune adrenalitis often seen with other endocrine and non-
endocrine autoimmune disorders (see Chapter 63, Autoimmune

Polyglandular Syndroms and Multiple Endocrine Neoplasias)
• Secondary AI
° Caused by lack of production of CRH from the hypothalamus and/or
ACTH from the pituitary gland, resulting in low cortisol (with normal
aldosterone)
° Etiologies include exogenous glucocorticoids (or megestrol) causing
suppression of hypothalamic-pituitary-adrenal (HPA) axis, pituitary
disorders (tumor, infiltration, hemorrhage, infarction), traumatic
brain injury, congenital isolated adrenocorticotrophic deficiency,
Prader-Willi Syndrome, POMC deficiency
■ Patients with pituitary disorders resulting in AI will often have other
deficits in pituitary function (see Chapter 2, Hypopituitarism)

TABLE 20.1 Typical Symptoms and Finding in AI
Symptoms Laboratory Values Physical Exam Findings
Malaise Hypoglycemia Orthostatic hypotension
Decreased appetite Hyponatremia* Low blood pressure
Weight loss Hyperkalemia† Hyperpigmentation‡
Dizziness
Nausea/vomiting
Myalgias
Abdominal pain
* Hyponatremia due to impaired excretion of free water mimicking SIADH.
† Hyperkalemia in primary AI only due to mineralocorticoid deficiency; in secondary AI, mineralocorticoid
function is intact.
‡ Hyperpigmentation in primary AI only caused by simulation of melanocytes by elevated ACTH levels; in
secondary AI, ACTH not elevated.
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118 Adrenal Insuffi ciency
DIAGNOSIS OF AI
• Suspect based on laboratory values and symptoms
• Random or 8 AM cortisol >18 mcg/dL rules out AI
• 8 AM cortisol <5 mcg/dL is highly suspicious for AI in patients not
taking exogenous glucocorticoids
• 250-mcg cosyntropin stimulation test (CST) with measurement of
0-minute (baseline), 30-minute, and 60-minute cortisol
° If■ stimulated cortisol is <18, patient has AI
Check ACTH: high = primary AI, low/normal = secondary AI
° Stimulated cortisol >18 rules out primary or long-term secondary AI
■ Doesn’t rule out early or partial secondary AI as adrenal atrophy
is not present
■ If CST is normal but partial or early secondary AI is suspected,
perform one of the following

• Overnight metyrapone test: give metyrapone 30 mg/kg (maxi-
mum: 3000 mg) at midnight and draw blood for cortisol and
11-deoxycortisol at 8 AM. Normal response is cortisol <5 and
11-deoxycortisol >7. Generally considered safe to perform in
outpatient setting, though very small risk of causing adrenal
crisis. Metyrapone is available directly from HRA Pharma at
www.metopirone.us
• ITT: give regular insulin 0.1 units/kg IV (0.15 units/kg if obese)
and draw blood for cortisol when glucose <40 mg/dL. Normal
response is cortisol >18 mcg/dL. Though often considered the
“gold standard” test for AI, it is infrequently performed as it
requires close medical supervision, is unpleasant for patients,
and is contraindicated in patients >60 yo, patients with
seizure disorder, or patient with CAD.
■ 1-mcg CST has been proposed as a more sensitive investigation
for secondary AI, but concerns about specificity have limited

enthusiasm for its use
• Dexamethasone will not interfere with cortisol assay, but will suppress
ACTH
° Dexamethasone can be given for emergent treatment of suspected
AI but testing must be performed expediently to avoid altered
results from ACTH suppression
• If primary AI is diagnosed
° Check antiadrenal antibodies
° Inquire about other autoimmune diseases in patient or family
° drugs withpossibility
Consider of infections, especially TB, or exposure to
antiadrenal effects
° Ifchain
antibody testing is negative in a young man, measure very−long-
fatty acids to exclude adrenoleukodystrophy
° antibody testing negative, check adrenal CT scan
If
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Chronic Treatment of AI 119
• If secondary AI is diagnosed
° Inquire about possible exposure to exogenous glucocorticoids (from
any source: oral, IV, intra-articular, topical, inhaled, etc.) or megestrol
° ■ Check pituitary MRI
If no exposure
■ Check other tests of pituitary function
CHRONIC TREATMENT OF AI
• Glucocorticoid replacement
° Typically HC 20 mg (+/– 5 mg) daily in divided doses
■ e.g., 15 mg in the morning and 5 mg in the afternoon; or 10 mg
at breakfast, 5 mg at lunch, and 5 at mg supper

° Longer-acting steroids (prednisone 5 mg daily or dexamethasone
0.5 mg daily) can be used in patients who cannot or will not take
multiple daily doses of HC
° Monitor by clinical response to therapy: signs/symptoms of gluco-
corticoid deficiency or glucocorticoid excess?
■ There are no appropriate lab parameters for monitoring
• Monitoring ACTH leads invariably to overtreatment

• Mineralocorticoid replacement
° Indicated in primary AI but not secondary AI
■ In secondary AI, the renin-angiotensin-aldosterone system is
intact
° Fludrocortisone:
daily
start 100 mcg daily, typical dose 50−250 mcg
° ■ Plasma potassium should be normal

Monitoring
■ Plasma renin activity (PRA) should be normal
■ Postural hypotension indicates inadequate treatment
■ Edema may indicate overtreatment
• Adrenal androgen replacement

° Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA
sulfate (DHEA-S) constitute a major source of androgens in women,
less important in men
■ Levels are decreased in AI
° Some data support use of DHEA supplements though long-term

efficacy and safety data are lacking
° ■ FemaleDHEA
Consider 25−50 mg daily in
AI patients with low libido or other symptoms of androgen
deficiency
■ Male or female AI patients with impaired sense of well-being on
otherwise appropriate therapy
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120 Adrenal Insuffi ciency
TABLE 20.2 Equivalency Chart for Glucocorticoids (GCs)
Drug Name Equivalent dose (mg) GC potency ½ life (hours)
Dexamethasone 0.5 25−50 36−54
Methylprednisolone 4 5 18−36
Prednisone 5 4 18−36
Hydrocortisone 20 1 8−12
ACUTE ADRENAL CRISIS

• Typically a patient with known AI who presents in extremis (volume
depletion and shock) precipitated by infection or other stress, but also
may be initial presentation of AI
• Management
° IV saline for volume resuscitation
° HC 100 mg IV, followed by 50 mg IV q 8 h or 150−200 mg/24 hours
as a continuous infusion, tapered as patient improves
° Fludrocortisone
<50 mg/24 hours
not required (even in primary AI) unless HC dose
° Diagnose and treat precipitating illness
CONDITIONS THAT MAY REQUIRE AN ADJUSTMENT IN HC DOSING

• Intercurrent illness → double dose
• Vomiting → hospital admission for IV HC
• Serious medical illness → 50 mg IV HC every 8 hours
• Surgery → double dose day of surgery for minor surgery or invasive
diagnostic procedure; IV steroids for major surgery
• Labor and delivery → double dose
• Physical exercise → increase dose by 5 mg, only for strenuous
exercise
PATIENT EDUCATION AND “SICK DAY MANAGEMENT”

• All patients with AI should have medical alert identification (bracelet,
necklace)
• Patients should understand the need to increase steroid dose by
2−3 times for illness
• If vomiting, patients should understand the need to go to hospital for
IV treatment
• Consider prescribing HC kit (100 mg to be given IM) for emergent home
use, particularly if patient lives far away from an acute care center
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References 121
CRITICAL ILLNESS-RELATED CORTICOSTEROID

INSUFFICIENCY (“RELATIVE AI”)
• Remains a highly controversial concept, with debates over its actual
existence, diagnostic criteria, and treatment
• 2012 Surviving Sepsis Guidelines suggest the following
° Corticosteroid treatment only for patients with septic shock who are
hemodynamically unstable despite adequate fluid resuscitation and
vasopressor therapy
° In such situations, treat with IV HC 200 mg daily given as a
continuous infusion
■ Continuous infusion reduces glucose fluctuations seen with
bolus steroids
■ Fludrocortisone is not needed
° Cortrosyn stimulation testing is not necessary

° Corticosteroid
longer needed
therapy should be tapered when vasopressors are no
REFERENCES
Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency.
Batzofin BM, Sprung CL, Weiss YG. The use of steroids in the treatment of
severe sepsis and septic shock. Best Pract Res Clin Endocrinol Metab,
2011;25(5):735−43.
Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med,
2009;360(22):2328−39.
Chakera AJ, Vaidya B. Addison disease in adults: diagnosis and manage-
ment. Am J Med, 2010;123(5):409−13.
Dellinger RP, Mitchell ML, Rhodes A, et al. Surviving Sepsis Campaign:
International Guidelines for Management of Severe Sepsis and Septic
Shock: 2012. Crit Care Med, 2013;41(2):580−637.
Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment.
Curr Opin Endocrinol Diabetes Obes, 2010;17(3):217−23.
Quinkler M, Hahner S. What is the best long-term management strategy
for patients with primary adrenal insufficiency? Clin Endocrinol (Oxf),
2012;76(1):21−5.
Salvatori R. Adrenal insufficiency. JAMA, 2005;294(19):2481−8.
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48565_ST03_111-160.indd 122 5/1/13 9:34 PM
21 ■ CUSHING’S SYNDROME
Guari Dhir, MD and Marc J. Laufgraben, MD, MBA
BACKGROUND
• Results from prolonged exposure to excess glucocorticoids
° Most common cause is iatrogenic (exogenous) from use of high-
dose glucocorticoids to treat other illnesses
° This chapter will focus on endogenous Cushing’s syndrome and will
use the term Cushing’s syndrome to refer to endogenous causes
• Cushing’s syndrome is a rare disorder (1−2 per million) with female
preponderance
• Uncontrolled Cushing’s syndrome results in 5× increased mortality
• Clinical features of Cushing’s syndrome
° Presentation extremely variable as individual features may or may
not present, or may differ depending on age and sex of patient and
severity of hypercortisolism
° Features of Cushing’s syndrome overlap greatly with signs and
symptoms seen in the general population
° proximal muscle
Relatively specific features: facial plethora, wide purple striae,
weakness, thin skin/easy bruising, truncal obesity
with thin extremities
■ In children: weight gain with decreased linear growth
° Features that are less specific though common in Cushing’s syn-

drome: weight gain or obesity, hypertension, glucose intolerance,
psychiatric symptoms, osteoporosis, menstrual irregularity and
hirsutism in women, hypogonadism in men
• Etiologies of Cushing’s syndrome
° Typically divided into ACTH-dependent and ACTH-independent cause
■ ACTH-dependent causes make up 80% of Cushing’s syndrome
• Of these, 80% due to an ACTH-secreting pituitary adenoma

(also known as Cushing’s disease)
• The remainder due to ACTH-secreting nonpituitary neoplasms
(especially small-cell lung cancer and bronchial carcinoid
tumors) as well as rare CRH-secreting neoplasms
■ ACTH-independent causes are of adrenal origin and make up
20% of Cushing’s syndrome

• Of these, nearly all are unilateral adrenal neoplasms
■ 60% adrenal adenoma, 40% adrenal carcinoma
• Rare adrenal causes include ACTH-independent macronodular
adrenal hyperplasia, primary pigmented nodular adrenal
disease (PPNAD), and McCune-Albright syndrome
48565_ST03_111-160.indd 123 5/1/13 9:34 PM

124 Cushing’s Syndrome
• Cushing’s syndrome must also be distinguished from Psuedo-

Cushing’s syndrome
° Psuedo-Cushing’s syndrome: other conditions causing hypercor-
tisolism that may be associated with clinical features similar to
■ Examples: psychiatric illnesses (especially depression), alcohol-
ism, pregnancy, morbid obesity, poorly controlled diabetes
DIAGNOSTIC STRATEGY
• Before proceeding with diagnostic studies, exclude (by detailed
history) exposure to exogenous glucocorticoids
• Any testing strategy for Cushing’s syndrome needs to acknowledge
that the available diagnostic tests have limitations in sensitivity,
specificity, and accuracy; therefore use of multiple tests is often
needed to be certain of the diagnosis
• Diagnostic testing is recommended for
° Patients with multiple and progressive features of Cushing’s
syndrome, particularly those patients with relatively specific
features
° Patients with unusual features for their age (e.g., younger people
with hypertension or osteoporosis)
° Children with adrenal
Patients with incidentaloma
° weight gain but decreased linear growth
• Diagnostic testing may also be considered for obese patients with
poorly controlled diabetes
° Prevalence of Cushing’s syndrome may be 2−5% in this population
• For initial testing, any of the following tests may be performed
depending on patient characteristics (see Standard Diagnostic Tests for
Cushing’s Syndrome)
° 124-hour
mg overnight dexamethasone suppression test (DST)
° Late-night urine collection for free cortisol (done two times)
° 2-day low-dose salivary cortisol (done two times)
DST (0.5 mg q 6 hours × 48 hours)
°
• In patients with a normal test result, further testing may be
performed if there is a very high pretest probability of Cushing’s
syndrome (e.g., a patient with many specific features), if features
progress over 6 months of follow-up, or if cyclic Cushing’s syndrome
is suspected
• Patients with an abnormal test result should be referred to an endocri-
nologist for further testing
° Patients with an abnormal test result should undergo another
recommended screening test
° to have Cushing’s
Patients who have positive results on two different tests are likely
syndrome (assuming Pseudo-Cushing’s syndrome
and use of exogenous glucocorticoids has been considered)
48565_ST03_111-160.indd 124 5/1/13 9:34 PM

Standard Diagnostic Tests for Cushing’s Syndrome 125
° Patients with normal results on two different tests are very unlikely
to have Cushing’s syndrome except in the rare case of cyclic
Cushing’s
° Patients with discordant results should be followed and reevaluated
as appropriate, especially if there are progressive features of
Cushing’s syndrome over time
STANDARD DIAGNOSTIC TESTS FOR CUSHING’S SYNDROME

• 1 mg overnight DST
° Patient takes 1 mg dexamethasone at 11 PM and reports to lab for
cortisol level at 8 AM
■ Using a postdexamethasone cortisol <1.8 mcg/dL as a normal
response is recommended
• A cutoff of 1.8 rather than 5 increases sensitivity, though at
the loss of specificity
° False positives: use of estrogen-containing compounds including
oral contraceptive pills (OCPs) (increase corticosteroid-binding
globulin [CBG] and cause a 50% false positive rate); use of drugs
that increase dexamethasone metabolism (especially CYP3A4
inducers such as antiepileptics and barbiturates); Pseudo-
° False negatives: reduced dexamethasone clearance in renal failure
and hepatic failure; use of drugs that decrease dexamethasone
metabolism (especially CYP3A4 inhibitors such as fluoxetine,
cimetidine, and diltiazem)
• 24-hour urine collection for free cortisol
° Patients should receive careful instructions for performing the
collection, and creatinine should be measured to ensure a complete
collection
° False positives: overcollection of urine, fluid intake >5 liters/day,
any stressful condition that increases cortisol production, Pseudo-
° False negatives: undercollection of urine, creatinine clearance
<60 ml/min, mild Cushing’s syndrome, collection during an inactive
period in cyclic Cushing’s
° Urine-free cortisol >4 times the upper limit of normal is highly
specific for Cushing’s syndrome
• Late-night salivary cortisol
° The loss of the nomal cortisol nadir at midnight is a consistent
finding in Cushing’s syndrome
° Cortisol in saliva is in equilibrium with free cortisol in blood
■ Patients collect saliva at bedtime by drooling or chewing on
cotton salivette
48565_ST03_111-160.indd 125 5/1/13 9:34 PM

°False positives: conditions that may alter normal circadian rhythms

(shift work, depression, changing time zones, illness), cigarette smok-
ing or use of licorice or chewing tobacco, contamination with blood,
stress before sample is collected, Pseudo-Cushing’s syndrome
° False negatives: poor sample collection
• 2-day low-dose DST
° Patient takes 0.5 mg dexamethasone every 6 hours for 48 hours
beginning at 9 AM on day 1 with last dose at 3 AM on day 3; serum
cortisol is drawn 6 hours later at 9 AM on day 3
■ A normal response is considered a postdexamethasone cortisol
<1.8 mcg/dL
° syndrome
Recommended test for patients who may have Pseudo-Cushing’s
° Same potential for false-postives and false-negatives as 1 mg

overnight DST
° CRH injection) is occasionally
Dexamethasone-CRH testing (a 2-day low-dose DST followed by
recommended in equivocal cases and
is reported to have high diagnostic accuracy
DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME

• Testing to differentiate the cause of Cushing’s syndrome should only
be pursued in patients confirmed to have the disorder based on careful
endocrinologic evaluation
• Check ACTH level to distinguish ACTH-dependent from ACTH-
independent causes
° ACTH <5 pg/ml consistent with ACTH-independent causes
° ACTH >15 pg/ml consistent with ACTH-dependent causes
° ACTH 5−15 pg/ml is equivocal
■ Perform CRH stimulation test
• Patients with ACTH-independent Cushing’s will not respond

to CRH
• Evaluation of patients with ACTH-independent Cushing’s syndrome
° ■ Adrenal
Check adrenal CT or MRI
imaging is abnormal in virtually all cases of ACTH-
independent Cushing’s syndrome
• Exception: some patients with PPNAD may have normal-
appearing adrenal glands on CT
• Evaluation of ACTH-dependent Cushing’s syndrome is VERY
CHALLENGING
° Multiple tests often performed to attempt to distinguish ACTH-
secreting pituitary adenoma (Cushing’s disease) from ectopic
ACTH-secreting tumors, including
■ High-dose dexamethasone test (HDDST)
• Problems: most (but not all) patients with Cushing’s disease

will suppress, but some patients with carcinoid tumors will
suppress, too
48565_ST03_111-160.indd 126 5/1/13 9:34 PM

Basics of Management of Major Causes of Cushing’s Syndrome 127
■ CRH testing
• Problems: most (but not all) patients with Cushing’s disease
will stimulate, but some patients with carcinoid tumors will
stimulate, too
■ Pituitary MRI
• Problems: only 50% of patients with Cushing’s disease will

have visible tumor on MRI, while 10% of normal population
has a pituitary incidentaloma
■ If patient has pituitary tumor >6 mm on MRI, and has both CRH
and HDDST consistent with Cushing’s disease, then the diag-

nosis of Cushing’s is highly likely; otherwise, bilateral inferior
petrosal sinus sampling (IPSS) is necessary
° Bilateral IPSS
■ Considered “gold standard” for establishing source of ACTH
secretion, but the procedure is invasive and technically

challenging
■ Test consists of simultaneous sampling of bilateral inferior
petrosal sinuses (venous drainage of pituitary) and peripheral

blood, usually following CRH infusion, to establish whether or
not a gradient exists between petrosal ACTH and peripheral
ACTH
• Petrosal: peripheral ACTH ratio of 2 in basal state, or petrosal:
peripheral ACTH ratio of 3 following CRH, is consistent with
pituitary source of ACTH (Cushing’s disease)
• Patients without an elevated ratio are likely to have ectopic
ACTH production
■ Check CT or MRI of neck/chest
– If negative, image abdomen/pelvis as well
■ Consider other imaging modalities (octreotide scan or PET)
if CT/MRI negative
■ Localization of these tumors can be extremely difficult and
1/3 may remain occult for extended periods of time
BASICS OF MANAGEMENT OF MAJOR CAUSES OF CUSHING’S SYNDROME

• Adrenal adenoma
° Unilateral adrenalectomy is curative
• Adrenocortical carcinoma
° See Chapter 26, Adrenocortical Carcinoma
• Cushing’s disease (ACTH-secreting pituitary adenoma)
° Optimal
adenoma
initial treatment is selective neurosurgical resection of the
■ If tumor not identifi ed during sellar exploration, total or partial
hypophysectomy may be considered
48565_ST03_111-160.indd 127 5/1/13 9:34 PM

■Remission is indicated by AM cortisol <2 during the first
postoperative week (assuming glucocorticoids have not been
given)
■ Patients in remission require temporary provision of replace-
ment glucocorticoids until HPA axis recovered from prolonged

suppression
• Occasionally, supraphysiologic doses are needed on a
temporary basis for patients who experience symptoms from
“glucocorticoid withdrawal”
■ Patients in remission require lifelong surveillance for recurrence
° For patients who have persistent or recurrent disease after initial

neurosurgery, treatment options may include
■ Reoperation
• Can be considered as soon as it is apparent that disease

persists or has recurred after initial surgery
• Accompanied by an increased risk of hypopituitarism
■ Radiotherapy
• Options include fractionated EBRT or SRS

■ Successful control of hypercortisolism in ~1/2 of patients
over 3−5 years
■ Long-term risk of hypopituitarism
■ Bilateral adrenalectomy
• Provides definitive, immediate control of hypercortisolism

• Results in permanent AI
• Risk of development of Nelson’s syndrome (unrestrained
growth of the adenoma)
■ Antiadrenal medical therapy
• Typically used in patients with persistent disease who are

waiting for RT to become effective
■ Occasionally used to prepare very ill patients for surgery
• Antiadrenal agents include ketoconazole (inhibits several
steroidogenic enzymes), metyrapone (inhibits 11β-hydroylase),
and mifepristone (glucocorticoid receptor antagonist)
• Pasireotide: somatostatin analog which directly inhibits ACTH
release from corticotroph tumors
• Ectopic ACTH syndrome
° neoplasm
When possible, surgical resection and cure of the underlying
effectively resolves the hypercortisolism
■ In the case of metastatic disease or occult tumors, this is not
possible
° Other therapies may be directed at the underlying tumor depending
on its origin, including chemotherapy, radiotherapy, somatostatin
analogues, etc.
° Patients often require antiadrenal medical therapy (see previous
section) or bilateral adrenalectomy to control hypercortisolism
48565_ST03_111-160.indd 128 5/1/13 9:34 PM

References 129
REFERENCES
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of
Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab,
2003;88(12):5593−602.
Biller BM, Grossman AB, Stewart PM, et al. Treatment of
adrenocorticotropin-dependent Cushing’s syndrome: a consensus
statement. J Clin Endocrinol Metab, 2008;93(7):2454−62.
Boscaro M, Arnaldi G. Approach to the patient with possible Cushing’s
syndrome. J Clin Endocrinol Metab, 2009;94(9):3121−31.
Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome.
Lancet, 2006;367(9522):1605−17.
Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syn-
drome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab, 2008;93(5):1526−40.
Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing’s
syndrome. Endocrinol Metab Clin North Am, 2008;37(1):135−49.
Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev
Endocrinol, 2011;7(5):279−89.
48565_ST03_111-160.indd 129 5/1/13 9:34 PM

48565_ST03_111-160.indd 130 5/1/13 9:34 PM
22 ■ PRIMARY ALDOSTERONISM
Michael Stowasser, MD
TABLE 22.1 Subtypes of Primary Aldosteronism

Unilateral Forms Bilateral Forms
• Aldosterone-producing adenoma • Bilateral adrenal hyperplasia, diffuse or
(+/– associated diffuse or nodular nodular
cortical hyperplasia); 40% of tumors • Glucocorticoid-remediable
associated with somatic mutations in aldosteronism caused by hybrid
KCNJ5 CYP11B1/CYP11B2 mutation, leading
• Unilateral adrenal hyperplasia to ACTH-regulated aldosterone
• Aldosterone-producing carcinoma overproduction
• Hypertension: primary aldosteronism is thought to account for 5−15%
of patients with hypertension
• Hypokalemia: present in <25% of patients with primary aldosteron-
ism, and <50% with aldosterone-producing adenoma; associated
symptoms include nocturia, polyuria, muscle weakness, cramps,
parasthesias, and palpitations
• May be familial
° Glucocorticoid-remediable aldosteronism (familial hyperaldosteron-
ism type I) inherited in an autosomal dominant pattern and may be
associated with severe, early-onset hypertension
° Familial hyperaldosteronism type II is nonglucocorticoid-
remediable, is not associated with the hybrid gene mutation, and
affected family members may demonstrate either unilateral or
bilateral primary aldosteronism
SCREENING: PLASMA ALDOSTERONE/RENIN RATIO (ARR) TESTING

• Prior to testing
° Correct hypokalemia
° Encourage patient to liberalize sodium intake
° the ratio
Where possible, withdraw medications that significantly affect
■ At least 4 weeks for diuretics including spironolactone, eplere-
none, and amiloride
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132 Primary Aldosteronism
■ At least 2 weeks before testing for β-blockers, clonidine,
methyldopa, NSAIDs, angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin II receptor blockers (ARBs), dihydropyridine
calcium blockers
TABLE 22.2 Effect of Medication on Ratio

Medications That Lower the Ratio Medications That Raise the Ratio
(Could Cause False Negatives) (Could Cause False Positives)
Diuretics (including spironolactone, β-blockers
eplerenone, and amiloride)
Angiotensin-converting enzyme inhibitors Clonidine
Angiotensin receptor blockers Methyldopa
Dihydropyridine calcium blockers Nonsteroidal anti-inflammatory drugs
° Substitute other antihypertensives that have lesser effects on

the ratio (verapamil slow-release ± hydralazine, and prazosin or
doxazosin)
° FYI: estrogen-containing oral contraceptives may lower direct renin
concentration and cause false positive ratios; testing for PRA is
recommended
• Collect blood midmorning, when the patient has been ambulatory for
at least 2 h, seated for 5−15 min
• Ratio of >20 (plasma aldosterone in ng/dL, PRA in ng/mL/h) or >70
(plasma aldosterone in pmol/L, plasma active renin concentration in
mU/L) suggestive of primary aldosteronism; repeat before considering
confirmatory testing
• When the absolute plasma aldosterone level is <166 pmol/L (<6 ng/dL),
primary aldosteronism is unlikely, even in the presence of an elevated
ARR
CONFIRMATORY TESTING OPTIONS

• Oral salt loading: 24-hour urinary aldosterone level of >12 μg/day on
the third day of oral salt loading (sufficient to achieve a urine sodium
excretion of >200 mmol/day [which requires a dietary intake of at
least 12 g per day] with enough KCl supplementation to maintain
normokalaemia) is regarded as diagnostic
• IV saline infusion testing: at the conclusion of an IV infusion of 0.9%
saline (2 L over 4 hours), diagnosis is unlikely if plasma aldosterone
level <5 ng/dL (<140 pmol/L), probable if >10 ng/dL (>280 pmol/L),
and indeterminate if 5−10 ng/dL (140–280 pmol/L)
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Subtype Differentiation 133
• Fludrocortisone suppression testing: positive if plasma aldosterone

>6 ng/dL (>165 pmol/L) after 4 days of fludrocortisone (0.1 mg every
6 hours), slow release NaCl (30 mmol three times daily with meals) and
sufficient dietary salt to maintain urinary excretion rate of ≥3 mmol
sodium/kg/day, provided that on day 4:
° Upright renin is suppressed (<1 ng/mL/h or <8 mU/L)
° Plasma cortisol levels are lower at 1000 h than at 0700 h (excludes
an acute ACTH rise)
° Plasma potassium is in the normal range, achieved by giving
sufficient slow-release KCl 6 times hourly
SUBTYPE DIFFERENTIATION
• Differentiating unilateral from bilateral primary aldosteronism
° Adrenal CT detects all aldosterone-producing carcinomas but
only 50% of aldosterone-producing adenomas and can be frankly
misleading as detected nodules may be nonfunctioning
° Adrenal venous sampling is the only way to reliably distinguish
unilateral from bilateral primary aldosteronism
■ Requires admission to a center with high expertise
■ Patient kept recumbent overnight and throughout procedure
■ Samples (at least 2) collected from each adrenal vein in turn and
simultaneously from a peripheral vein

■ Adrenal/peripheral venous cortisol ratios of ≥3 indicate success-
ful sampling
■ If the aldosterone/cortisol ratio on one side is >2 times higher
than simultaneous peripheral ratios, and if the aldosterone/

cortisol ratio on the other side is no higher than peripheral, the
study shows lateralization
• Glucocorticoid-remediable aldosteronism (GRA)
° family history
Consider especially in patients with early-onset hypertension, a
of hypertension, or a personal or family history of
stroke
° Hybrid gene mutation detected by genetic blood testing
° Ifaldosterone
genetic testing not available, perform DST (0.5 mg q 6 h: plasma
falls to <4 ng/dL [110 pmol/L] within 1−2 days and
remains suppressed up to day 4)
° Elevated 24-hour urinary levels of “hybrid steroids” (18-hydroxy-
and 18-oxo-cortisol) occur in patients with GRA, but also in some
patients with aldosterone-producing adenoma
48565_ST03_111-160.indd 133 5/1/13 9:34 PM

134 Primary Aldosteronism
MANAGEMENT
• Unilateral primary aldosteronism
° Laparoscopic unilateral adrenalectomy results in cure of hyperten-
sion in 60−80% and improvement in remaining patients
° aldosteronism or contraindicated, treat as for bilateral primary
If surgery declined
• Bilateral primary aldosteronism

° Spironolactone (12.5–50 mg daily): side effects (e.g., gynecomastia
or menstrual irregularities) are dose-dependent
° Amiloride (2.5–20 mg daily) or, where available, eplerenone
(25–100 mg daily) are useful alternatives (these drugs avoid the
side effects associated with spironolactone)
° Use caution with potassium supplements; carefully monitor renal
function and electrolytes especially if renal function impaired or on
other agents that retain K + (e.g., nonsteroidal anti-inflammatory
drugs, drugs blocking the renin-angiotensin system)
• Glucocorticoid-remediable aldosteronism
° Dexamethasone
daily)
(0.25–0.5 mg daily) or prednisolone (2.5–5 mg
° Alternatively, treat as for bilateral primary aldosteronism
REFERENCES
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treat-
ment of patients with primary aldosteronism: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab, 2008;93(9):3266–81.
Gordon RD. Primary aldosteronism. J Endocrinol Invest, 1995;18(7):495–511.
Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary
aldosteronism, including surgically correctable forms, in centers from five
continents. J Clin Endocrinol Metab, 2004;89(3):1045–50.
Stowasser M, Gordon RD. The aldosterone-renin ratio for screening for
primary aldosteronism. Endocrinologist, 2004;14:267–76.
Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ.
Diagnosis and management of primary aldosteronism. J Renin Angiotensin
Aldosterone Syst, 2001;2(3):156–69.
Young WF, Stanson AW. What are the keys to successful adrenal venous
sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol
(Oxf), 2009;70(1):14–7.
48565_ST03_111-160.indd 134 5/1/13 9:34 PM

23 ■ PHEOCHROMOCYTOMA
Urvi Shah, MD and Karel Pacak, MD, PhD, DSc
PATHOPHYSIOLOGY
• Prevalence: 0.05–0.6% of all hypertensive patients
• Catecholamine-producing tumors of chromaffin cells
° 80% adrenal origin (also known as pheochromocytoma)
° 20% extra adrenal origin (also known as paraganglioma)
■ Sympathetic: paravertebral and paraaortic (neck to pelvis)
■ Parasympathetic: head and neck (glomus, carotid body)
• May be sporadic or hereditary

° Hereditary/genetic:
usually <40 years
about 35% of patients, younger age group
■ Major susceptibility genes (85–90% of hereditary tumors)
• RET → MEN-2
• VHL → Von Hippel-Lindau syndrome (VHL)
• SDHB/D (Succinate Dehydrogenase subunits B and
D) → familial paraganglioma syndrome
• NF1 → neurofibromatosis type 1
■ Minor susceptibility genes (10–15% of hereditary tumors)
• Include SDHA/C, SDHAF2, MAX, TMEM127, HIF2α

° Sporadic: about 60% of patients, older age group >40–50 years
• Most produce Epi and/or NE
° Some produce DA
° 15–20% are biochemically silent (do not release catecholamines)
• Effects mediated via catecholamine receptors
° Stimulation of α1 receptors: vasoconstriction and hypertension
° Stimulation of α2 receptors: vasodilatation (except coronary
vasoconstriction)
■ α1 effect causing vasoconstriction predominates
° Stimulation of β1 receptors: positive ionotropic and chronotropic

effects (palpitations)
° Stimulation β2 receptors: vasodilatation and hypotension
Epi stimulates α1, α2, β1, and β2 but NE stimulates only α1, α2,
° and β1, not β2
■ Predominantly NE-producing tumors present with hypertension
■ Predominantly Epi-producing tumors may present with palpita-
tions and normotension (or even hypotension)
48565_ST03_111-160.indd 135 5/1/13 9:34 PM

136 Pheochromocytoma
• Classic triad: episodic headache + diaphoresis + palpitations
° 90% of pheochromocytoma patients will have at least one symptom
of the classic triad
° Full triad present in 20–30% of pheochromocytoma patients
• General presentation: history of paroxysmal spells lasting several
minutes to an hour
° Predominant
pallor
symptoms: palpitations, anxiety/panic attacks,
° Other potential symptoms: dyspnea, headaches, blurry vision,

tremors, constipation, polyuria, nausea, vomiting, sweating,
weakness, polydipsia, flushing, pallor
• Family history of similar symptoms, associated genetic disorders, or
Pheo?
• Look for clinical manifestations of
° MEN2A: MTC, hyperparathyroidism
° MEN2B: MTC, marfanoid habitus, mucosal ganglioneuromas
° VHL: retinal angiomas, CNS hemangioblastomas, renal cysts
° NF1: skin and mucosal neurofibromas, café-au lait-spots
° Zhuang
HIF2α: polycythemia, multiple duodenal somatostatinomas (Pacak-
syndrome)
° SDHB/D/C: renal cell carcinoma, pulmonary chondroma, gastro-
intestinal stromal tumor (Carney-Stratakis syndrome), pituitary
adenoma
• Assess for exposure to foods/medications/substances that can cause
symptoms that mimic pheochromocytoma: tricyclic antidepressants,
metoclopramide, glucagon, tyramine-containing foods, amphetamines,
nicotine, and caffeine
• DA-producing tumor may present with symptoms of tumor mass effect
without other typical symptoms
• Physical examination/signs
° BP
■ Paroxysmal hypertension: 50%
■ Sustained hypertension: 35−45%
■ Normotensive: 5−15%
■ Hypotension: in predominantly DA- or Epi-producing tumors
■ Orthostatic hypotension: due to chronic vasoconstriction and
volume contraction
° Tachycardia
° edemapotential
Other signs: fever, cervical/abdominal lymphadenopathy,
(especially if cardiomyopathy), arrhythmias, palpable tumor
in neck or abdomen, tremors
• Adrenal incidentaloma: ~5% of adrenal incidentaloma are pheo-
chromocytomas; all patients with adrenal incidentaloma should be
screened for Pheo even if asymptomatic; ~25% of pheos are diagnosed
based on evaluation of incidentaloma
48565_ST03_111-160.indd 136 5/1/13 9:34 PM

• Screening test strategy
° Begin with plasma-free MNs or 24-hour urinary fractionated MNs
■ MNs (metabolites of Epi and NE) are secreted in a constant
fashion from Pheo

■ Both tests are highly sensitive
■ Plasma-free MNs usually favored over urinary fractionated MNs
since easier to obtain and greater specificity

• Draw blood after patient resting supine for at least
15−20 minutes prior to a blood draw
° Interpretation of MN testing
■ > 4 times the upper limit of normal: almost 100% probability
of Pheo (exceptions may be in patients taking certain

antidepressants)
■ Normal result: high negative predictive value, pheochromocy-
toma is very unlikely

■ 1−4 times the upper limit of normal: pheochromocytoma
possible
• Rule out false positives from drugs and food
■ Common culprits: antidepressants, cold medication,
chocolate, wine, stress
• Consider clonidine suppression test
■ Measure plasma catecholamines and MNs before and
3 hours after a 0.3 mg/70 kg−oral dose of clonidine
■ Suppression of plasma normetanephrine to <40% of
baseline (or into the normal range) has a high negative
predictive value (i.e. pheochromocytoma is unlikely)
° ■ Plasma or urine tests
Other biochemical
catecholamines (NE, Epi, DA)
• Not recommended for initial diagnosis, but biochemical profile
may give guidance for anatomic localization and genetic
testing
■ Plasma methoxytyramine (DA metabolite)
• Useful to assess for metastases in patients with familial

paraganglioma
■ Plasma chromogranin A
• Nonspecific marker of neuroendocrine tumors

• Elevation supports diagnosis of pheochromocytoma
• Can be monitored for follow-up after initial treatment
48565_ST03_111-160.indd 137 5/1/13 9:34 PM

• Anatomical imaging: CT or MRI for initial tumor localization

° CT and MRI are sensitive but not specific
° Abdominal
tumors
CT scan used for adrenal and abdominal extraadrenal
■ No adrenergic blockade required
° Abdominal MRI (T2-weighted with gadolinium enhancement)

preferred for pregnant women, children, extraadrenal tumors, or
allergies to contrast
■ No adrenergic blockade required
■ Pheochromocytomas appear hyperintense and other adrenal
tumors appear isointense as compared to liver

• Functional imaging
° ■ More specifi
123
I-labeled MIBG scintigraphy
c than CT or MRI
■ Used for patients with extraadrenal or large (>5 cm)
adrenal tumors with increased risk of malignant disease or

patients with high suspicion of the presence of multifocal
disease
■ Also used in patients with a high suspicion of pheochromocy-
toma due to clinical and biochemical evidence but who have had
a negative CT/MRI
° PET scanning: for use in specialized situations usually involving
metastatic disease
• Genetic testing (see Figure 23-1)
° Usually indicated in patients <50 years, patients with multiple
tumors or extraadrenal tumors, a family history of pheochromocy-
toma or associated disorders, metastatic tumors, or increased DA
secretion
° Decision for sequence in which to test for mutations is based
on clinical presentation, family history, biochemistry, and
imaging
° Some general guidance
■ NF1 gene too large to be tested and diagnosis always made
clinically
■ If elevated MN and no clinical features of neurofibromatosis,
start with RET

■ In patients with metastatic disease but no family history of
pheochromocytoma, start with SDHB

■ If adrenal tumor secretes normetanephrine/NE but not MN/Epi,
start with VHL

■ If head or neck paraganglioma, or multiple abdominal paragan-
glioma, start with SDHD
48565_ST03_111-160.indd 138 5/1/13 9:34 PM

48565_ST03_111-160.indd 139
Diagnostic Evaluation
FIGURE 23.1 Clinical Algorithm for Sequential Gene Testing for Functional Pheo/PGL Based on
139
Clinical and Biochemical Predictors. Courtesy of Karel Pacak and the NIH.
5/1/13 9:34 PM
MANAGEMENT
Preoperative management
• α blockade
° Pretreatment with an α-blocker beginning about 10−14 days prior
to surgery
° Phenoxybenzamine: noncompetitive α blockers
■ Advantage: cannot be displaced from receptors by an over-
whelming surge of catecholamines during surgery

■ Disadvantage: risk of postoperative hypotension
■ Side effects: orthostasis, nasal stuffiness, marked fatigue
■ Dose: 10 mg twice a day; can be increased by 10−20 mg every
2−3 days; max dose 1 mg/kg/day

° Doxazosin or other competitive α-blockers can be used instead
■ Advantage: less risk of postoperative hypotension
• β blockade
° In patients with tachyarrhythmia, β-blockers (propranolol 40 mg
three times daily, atenolol 25−50 mg once daily) can be added
several days after initiation of α blockade
° αα-mediated
blockade should always precede β blockade to avoid unopposed
vasoconstriction resulting in hypertensive crisis
• In phenoxybenzemine-intolerant patients, labetalol or nicardipine can
be used
• Metyrosine (inhibitor of catecholamine synthesis) is sometimes used pre-
operatively and is an excellent option for patients with metastatic disease
• Liberal salt and fluid intake are encouraged to promote intravascular
expansion
• Adequate preoperative preparation indicated by
° BP <160/90 for at least 24 hours
° Presence of orthostatic hypotension (though BP in upright position
should not fall below 80/45 mm Hg)
° <1 ventricular extrasystole every 5 min
° No new ST-segment changes or T-wave inversions on ECG
Operative management
• Elective surgery preferred as adequate preoperative preparation
improves survival
• Laparoscopic removal preferred as reduces postoperative morbidity,
hospital stay, and expense compared to conventional laparotomy
° Laparotomy
tumors >10 cm
is preferred for patients with recurrent disease or
• In patients with bilateral disease adrenal cortical−sparing surgery

(partial adrenalectomy) is preferred, as this would avoid morbidity
associated with medical adrenal replacement
• Intraoperative hypertensive crisis
° Caused by manipulation of the tumor during surgery leading to
release of catecholamines
48565_ST03_111-160.indd 140 5/1/13 9:34 PM

Acknowledgments 141
°Treatment
■ IV infusion of sodium nitroprusside 0.5−5 μg/kg/min
■ Other drugs used: phentolamine, nicardipine
Postoperative management
• Close BP monitoring required
° Hypotension: due to acute withdrawal of catecholamines
■ Volume replacement is the treatment of choice
■ Volume of fluid required is often large, can be 0.5−1.5 times the
patient’s total blood volume during the first 24−48 hours after
surgery
° ity, essential hypertension,
Hypertension: related to pain, volume overload, autonomic instabil-
or residual tumor
• Risk of hypoglycemia
MALIGNANT PHEOCHROMOCYTOMAS
• If disease is limited at the time of diagnosis, surgery may be
curative
• Debulking surgery may facilitate subsequent chemotherapy and
131
I-MIBG in patients with more widespread disease
• 131I-MIBG therapy: option for patients who are 123I-MIBG scintigraphy
positive
° More effective for soft tissue than bony metastasis
• Chemotherapy: cyclophosphamide, vincristine and dacarbazine
indicated in patients with negative 123I-MIBG scintigraphy or with
rapidly growing tumors
• EBRT can be used for solitary bone lesions
FOLLOW-UP
• Patients with sporadic tumors: to check for recurrence of tumor,
biochemical testing is done yearly for at least 10 years after
surgery
• Patients with familial or extraadrenal tumors: annual biochemical
testing is done indefinitely
• Patients with malignant pheochromocytoma: the 10-year survival
is ~40%
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program of the Eunice
Kennedy Shriver National Institute of Child Health and Human Development,
National Institutes of Health (NIH), Bethesda, Maryland.
48565_ST03_111-160.indd 141 5/1/13 9:34 PM

REFERENCES
Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine
Tumor Society consensus guideline for the diagnosis and management of
neuroendocrine tumors: pheochromocytoma, paraganglioma, and medul-
lary thyroid cancer. Pancreas, 2010;39(6):775−83.
Kantorovich V, Pacak K. Pheochromocytoma and paraganglioma. Prog Brain
Res, 2010;182:343−73.
K. Pacak. Phaeochromocytoma: a catecholamine and oxidative stress
disorder. Endo Reg, 2011;45(2):23:65−90.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet,
2005;366(9486):665−75.
Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma: advances
in genetics, diagnosis, localization, and treatment. Hematol Oncol Clin
North Am, 2007;21(3):509−25.
Zhuang Z, Chunzhang Y, Felipe L, et al. Somatic HIF2A Gain-of-Function
Mutations in Paraganglioma with Polycythemia. N Engl J M, 2012;367(10):
922–30.
48565_ST03_111-160.indd 142 5/1/13 9:34 PM

Cholesterol
48565_ST03_111-160.indd 143
17α 17,20
Pregnenolone 17-hydroxypregnenolone DHEA
3β 3β
Richard Auchus, MD, PhD
17α 17,20 3β
Progesterone 17-hydroxypregesterone Androstenedione Estrone below block (see Figure 24-1)
• Autosomal recessive disorders
21 21
Deoxycorticosterone Deoxycortisol Testosterone Estradiol
11β 11β
PATHOPHYSIOLOGY
Coritcosterone Cortisol Dihydrostestosterone
Aldosterone
FIGURE 24.1 Steroid Biosynthesis Pathway

24 ■ CONGENITAL ADRENAL HYPERPLASIA
• Deficiencies in various adrenal enzymes result in hormone deficiencies
5/1/13 9:34 PM
144 Congenital Adrenal Hyperplasia
• Block in cortisol production increases ACTH and production of

precursors above blocks
• Hormone excess from precursors above enzyme block are shunted to
other pathways
• Fetal exposure to high or low androgens causes disorders of sex devel-
opment (DSD) and results in hyperplasia of the adrenal cortex
TYPES OF CAH
• 21-hydroxylase deficiency (21OHD): most common >95% including
nonclassical
° Classical: presents at birth
■ Block in cortisol and aldosterone production, androgen excess
• “Salt-wasting” (no enzyme activity)

• “Simple virilizing (trace enzyme activity)
° ■ Androgen excess
Nonclassical: normal at birth
but no cortisol or aldosterone deficiency
• 11-hydroxylase deficiency (11OHD)
° Block in cortisol
• Lipoid CAH (LCAH)
production; mineralocorticoid and androgen excess
° Defect in cholesterol transport resulting in adrenal hormone

deficiencies
° Nonclassical
Classical form: no steroids formed (often lethal)
° form: manifests primarily cortisol deficiency
• 17-hydroxylase/17,20-lyase deficiency (17OHD)
° Block
excess
in cortisol and androgen production, mineralocorticoid
° only 17,20-lyase deficiency is not CAH, androgen deficiency

Isolated
• 3β-hydroxysteroid dehydrogenase deficiency (3βHSDD)

° Block in all steroid hormones, moderate androgen excess in
females
• P450-oxidoreductase deficiency (PORD)
° Block
21OHD)
in all steroids past progesterone (similar presentation to
° Paradoxical virilization of girls and mother
• History
° Birth: maternal virilization, DSD (genital ambiguity), hypotension,
poor feeding
° Adult: menses,
Childhood: timing of pubic hair and puberty, growth rate
° muscle weakness, fatigue, androgenization
48565_ST03_111-160.indd 144 5/1/13 9:34 PM

Management 145
• Physical exam
° Genitalia:
isosexual
labioscrotal fusion and phallic length, contra—or
° Skin pigmentation,weight,
BP, orthostatics, body proportions
° Males: testis size, consistency,
thinning (on treatment)
° Females: hirsutism, acne, virilization
masses
°
• Laboratory testing: precursor/product ratio after cosyntropin high
across block
TABLE 24.1 Laboratory Testing and Diagnostic Evaluation

21OHD 11OHD LCAH 17OHD 3␤HSDD PORD
Gene(s) CYP21A2 CYP11B1 STAR* CYP17A1 HSD3B2 POR
High 17OHP, C19 DOC, S None DOC, B 17Preg Prog
Low F, Aldo F All F, C19 Δ4 Varies
Nonclassic Common Rare Yes No Rare No†
* Rarely CYP11A1.
† All cases are partial but highly variable phenotypes.
17OHP = 17-hydroxyprogesterone, C19 = 19-carbon steroids, DOC = 11-deoxycorticosterone,
S = 11-deoxycortisol, B = corticosterone, 17Preg = 17-hydroxypregnenolone, Prog = progesterone,
F = cortisol, Aldo = aldosterone, Δ 4 = all Δ 4-steroids.
• Imaging
° Adrenal CT or MRI: hyperplasia, usually not necessary
° Massive myelolipomas: low-density CT and loss of signal MRI
out-of-phase
° Ovarian ultrasoundhypoechoic testicular adrenal rest tissue (TART)
Testis ultrasound:
° ■ Polycystic if androgen excess
■ Hypoplasia if androgen block
° Plain films: bone age in childhood (see Management section,

following)
MANAGEMENT
• 21OHD
° Principles of treatment
■ Maintain euvolemia and BP
■ Treat AI plus stress dosing
■ Normalize androgens not precursors
48565_ST03_111-160.indd 145 5/1/13 9:34 PM

■ Minimal glucocorticoids dose to minimize androgen excess

consequences
• Hydrocortisone (HC) best if given in 3 divided doses
• Consider longer acting dexamethasone, prednisone,
prednisolone
• Combination therapies: HC during day, prednisolone at night
° Newborn (classical): HC + fludrocortisone acetate (FA) + salt
■ Higher dose HC (20−30 mg/m2 /day) initially until controlled
■ Maintenance HC <17 mg/m2 /day in 3 divided doses
■ Consider genital reconstruction surgery in females
■ Monitor electrolytes, PRA, 17-hydroxyprogesterone (17-OHP)
■ Nearly all identifi ed via newborn screening in the US
° Child/adolescent
■ Classic: similar to newborn
■ Also monitor growth rate, bone age
■ If true precocious puberty occurs, suppress with GnRH agonist
■ Nonclassic: Rx indications—advancing bone age, hirsutism,
irregular menses
• Replacement HC an option
• Dexamethasone minimal dose (0.25 mg 3 times a week)
• Monitor testosterone, menses, growth and bone age,
hirsutism
° Adult
■ Male: replacement HC + FA normally suffi cient if compliant
• Screen for TART with physical exam, sonography

• LH, FSH, androstenedione to determine source of testosterone
• Semen analysis if fertility desired
• TART
■ Dexamethasone 1−2 mg at night
■ Dexamethasone 0.1−0.25 mg at night + HC in AM
■ Female: replacement HC + FA if compliant
• Prednisone sometimes controls with 5−7.5 mg/AM

• Prednisolone: active drug, more reliable 5 mg/AM
• Combo Rx
■ Daytime HC + prednisolone 1−2 mg
■ Daytime HC + dexamethasone 0.1−0.2 mg night
■ Nonclassic males rarely ascertained or require Rx unless severe
■ Nonclassic females glucocorticoids sparingly if symptoms,
infertility
• Other treatments (spironolactone, OCP, mechanical) for
hirsutism
• Genetic counseling: ~70% carriers of classic 21OHD allele
■ Pregnancy
• Continue HC in pregnancy
• Dexamethasone to prevent DSD in female fetus of carrier
parents is not recommended at this time and is considered
experimental
48565_ST03_111-160.indd 146 5/1/13 9:34 PM

Management 147
■ Monitor androstenedione, testosterone, 17-OHP, DHEA-S with
goal of lowering serum concentrations to slightly above upper
normal range
• 11OHD
° Mineralocorticoid
Glucocorticoid replacement similar to 21OHD
° for BP, K antagonist (spironolactone or eplerenone)
■ Spironolactone also treats androgen excess, ideal in females
■ Goal: normalize PRA, K, BP
■ Alternatives to mineralocorticoid antagonist: triamterene,
amiloride
• LCAH
° replacement
Classical: raise as females, provide complete steroid hormone
° Nonclassical: glucocorticoid replacement only although variable
•
°17OHD
Monitor for replacement only
° All raised as females

° No AI due to high corticosterone, mineralocorticoid excess
° Monitor BP
Control and potassium (K) with spironolactone or eplerenone
° ConsiderK,10−20
BP, PRA (want PRA detectable, low−normal)
° hyperplasia mg/day HC if difficult to control or adrenal
° Monitor 11-deoxycorticosterone with goal slightly above upper
normal range
•
°3βHSDD
Estrogen replacement at puberty and adult, add progestin if 46,XX
° Require glucocorticoids and sometimes mineralocorticoid

replacement
° Males generally infertile, require testosterone replacement
° Females often mild androgen excess controlled with HC
° Males and females
Nonclassic form very rare
° surgery have DSD and some require reconstruction
• PORD
° Highly variable phenotypes
° Requires glucocorticoids and mineralocorticoid replacement
° Accumulating precursors poorly metabolized to active steroids
° Requires gonadal steroid replacement: estrogen for girls, testos-
terone for boys
° Males
surgery
and females have mild DSD, some require reconstruction
48565_ST03_111-160.indd 147 5/1/13 9:34 PM

REFERENCES
Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital
adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol
Metab, 2010;95(11):5110−21.
Auchus RJ. Congenital adrenal hyperplasia in adults. Curr Opin Endocrinol
Diabetes Obes, 2010;17(3):210−6.
Casteràs A, De Silva P, Rumsby G, Conway GS. Reassessing fecundity
in women with classical congenital adrenal hyperplasia (CAH):
normal pregnancy rate but reduced fertility rate. Clin Endocrinol (Oxf),
2009;70(6):833−7.
Claahsen-van der Grinten HL, Otten BJ, Hermus AR, Sweep FC, Hulsbergen-
van de Kaa CA. Testicular adrenal rest tumors in patients with congenital
adrenal hyperplasia can cause severe testicular damage. Fertil Steril,
2008;89(3):597−601.
Merke DP. Approach to the adult with congenital adrenal hyperplasia due to
21-hydroxylase deficiency. J Clin Endocrinol Metab, 2008;93(3):653−60.
Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of
human steroidogenesis and its disorders. Endocr Rev, 2011;32(1):81−151.
Reisch N, Flade L, Scherr M, et al. High prevalence of reduced fecundity
in men with congenital adrenal hyperplasia. J Clin Endocrinol Metab,
2009;94(5):1665−70.
Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to
steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice
48565_ST03_111-160.indd 148 5/1/13 9:34 PM

25 ■ ADRENAL INCIDENTALOMA
Kevin M. Pantalone, MD and Amir H. Hamrahian, MD
INTRODUCTION
• The development and widespread use of modern imaging techniques
has led to the detection of adrenal masses in patients with increasing
frequency
• Adrenal masses incidentally discovered by these techniques in the
absence of clinical signs and symptoms of adrenal disease have been
termed adrenal incidentalomas (this definition excludes patients who
are undergoing evaluation for a known malignancy)
• Adrenal masses are found in approximately 4% of patients undergoing
high-resolution imaging studies, and their prevalence increases
with age
• When an adrenal mass is discovered, one must determine whether the
mass is functional and/or malignant, both of which usually necessitate
surgical resection of the mass
ASSESSMENT FOR HORMONE HYPERSECRETION

• All patients with an adrenal incidentaloma should be evaluated
for autonomous cortisol secretion referred to as subclinical
Cushing’s syndrome (SCS), pheochromocytoma, and if hypertensive,
hyperaldosteronism
• Additional hormonal evaluation may be considered based on a detailed
history and physical exam
PHEOCHROMOCYTOMA
• An increasing number of pheochromocytomas are diagnosed as
adrenal incidentalomas, and up to 1/2 of such patients are without
hypertension at the time of diagnosis
• Both fractionated plasma MNs and 24-hour urinary MNs are reason-
able initial screening tests; however, measurement of plasma MNs
is more convenient for the patient and a normal result makes the
diagnosis of a pheochromocytoma extremely unlikely
• Using the reference range currently utilized by most commercial
laboratories, the measurement of plasma MNs is associated with a
false-positive result in 15−20% of patients
48565_ST03_111-160.indd 149 5/1/13 9:34 PM

150 Adrenal Incidentaloma
• An elevation of plasma MNs > four times the upper limit of normal is
usually diagnostic for a pheochromocytoma, and further evaluation
may include additional imaging
• Most patients with elevated plasma MNs < three to four times the
upper limit of normal do not have a pheochromocytoma; such patients
need to proceed with measurement of 24-hour urine MNs, and in
selected cases, undergo further confirmatory tests such as a clonidine
suppression test before proceeding with imaging studies
SUBCLINICAL CUSHING’S SYNDROME

• Subtle elevations in serum cortisol insufficient to result in the typical
clinical manifestations of overt Cushing’s syndrome, but enough to
suppress ACTH secretion from the anterior pituitary is commonly
referred to as SCS
• Identification of patients with SCS is important because associated
comorbidities such as hypertension and/or diabetes may abate or even
disappear with surgical resection of the tumor
• The 1-mg overnight DST is the best test to evaluate for SCS
• Although a variety of different cut-off values for cortisol during
the 1-mg DST have been proposed, in the setting of an adrenal
incidentaloma, a serum cortisol >5 μg/dL is used for the diagnosis
of SCS in the presence of an early-morning low or undetectable
ACTH level
PRIMARY ALDOSTERONISM
• An adrenal incidentaloma in a hypertensive patient requires investiga-
tion for primary aldosteronism, with a prevalence <2%
• Most patients with an aldosterone-producing adenoma are normoka-
lemic and therefore lack of hypokalemia should not preclude further
evaluation
• Measurement of plasma aldosterone and PRA to calculate the ARR is
the best initial test for evaluation of primary aldosteronism
° Aofratio >20 with a serum aldosterone level >9 ng/dL is suggestive
primary aldosteronism; in such patients the PRA is usually sup-
pressed (<1 ng/mL/hour).
• Aldosterone antagonists (spironolactone or eplerenone) should be
discontinued for at least 4 weeks prior to screening
• Patients with an elevated ARR should proceed with a confirmatory test
such as the salt loading test or saline suppression test
48565_ST03_111-160.indd 150 5/1/13 9:34 PM

Differentiating Benign and Malignant Adrenal Masses 151
DIFFERENTIATING BENIGN AND MALIGNANT ADRENAL MASSES

• The preferred imaging modality for the evaluation of an adrenal mass
is CT
• A variety of techniques have been used to estimate the probability
of malignancy in an adrenal mass, including the size of the mass,
the imaging characteristics such as noncontrast CT Hounsfi eld
units [HU] and washout percentage, and the growth rate on
serial imaging
• The lack of a primary cancer site in a patient with a true adrenal
incidentaloma would make the diagnosis of a metastatic lesion
unlikely
• All adrenal incidentalomas >4 cm that lack characteristic benign
radiological features should be surgically removed, regardless of
whether or not they are functional
• The noncontrast CT HU is a measure of density; a HU ≤10 is observed
in lipid-rich adrenal adenomas and is always consistent with a benign
pathology
• A HU >10 can be observed in both lipid-poor adrenal adenomas
(benign) as well as in nonadenomas (pheochromocytoma, metastases,
or primary adrenal malignancy such as lymphoma or adrenal cortical
carcinoma)
• Adrenal tumors ≥4 cm in size with a HU >10 are concerning for
malignancy and should be referred for surgery
• If the adrenal mass is <4 cm and has a HU >10, one can obtain the
absolute washout percentage 15 minutes after the administration of
IV contrast to further assist in characterizing the mass; an absolute
washout percentage of more than 60% supports the diagnosis of a
benign adenoma
• Lipid-poor adrenal tumors with lower washout percentages should be
surgically removed
• A pheochromocytoma may occasionally manifest with washout charac-
teristics similar to that of an adrenal adenoma
• Adrenal mass growth has also been shown to be a modest predictor
of malignancy; an absolute growth of ≥0.8 cm within 3−12 months is
suggestive of malignancy, and surgical resection in the appropriate
clinical and radiological setting may be considered
• Figure 25-1 illustrates the algorithm for approach to patients with
adrenal incidentaloma
• The role of FNA in the evaluation and management of an adrenal
incidentaloma is limited and is not generally recommended
• FNA of an adrenal mass may be warranted in patients with a known
malignancy without any other evidence of metastasis
• A pheochromocytoma should always be excluded prior to FNA to avoid
a potential hypertensive crisis
48565_ST03_111-160.indd 151 5/1/13 9:34 PM

Incidentally Discovered
Adrenal Mass
Surgically
Functional remove
Noncontrast CT attenuation Noncontrast CT attenuation

value ≤ 10 HU value > 10 HU
< 4 cm ≥ 4 cm
Calculate the absolute

Yearly hormonal
washout percentage
evaluation for up
at 15 min
to 5 years and then
intermittently as
clinically indicated
Surgically
≥ 60% < 60%
remove
No change in size ≥ 0.8 cm increase in

in 3–12 months size in 3–12 months
Follow up CT Concerning
image for up to radiological
two years features
FIGURE 25.1 Evaluation and Management of Patients with Adrenal Incidentaloma

Adapted from J Clin Endocrinol Metab. 2011 Jul;96(7):2004–15. 2011 Jun 1
48565_ST03_111-160.indd 152 5/1/13 9:34 PM

References 153
NATURAL HISTORY AND FOLLOW-UP OF PATIENTS

WITH ADRENAL INCIDENTALOMAS
• Excess hormone secretion may develop in up to 20% of patients with
previously nonfunctional adrenal tumors during follow-up
• Annual biochemical evaluation for hormone hypersecretion for up to
5 years is recommended for adrenal incidentalomas that do not
undergo resection, especially if the tumor size is >3 cm
• A routine follow-up imaging study for adrenal incidentalomas with a
noncontrast CT attenuation value ≤10 HU is not required, although a
one-time follow-up scan in 6−12 months may be reassuring
• Patients with adrenal masses <4 cm in size and a noncontrast attenu-
ation value >10 HU should have a repeat CT study in 3−6 months
and then yearly for two years; there is no good evidence supporting
continued radiological surveillance in such patients
REFERENCES
Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions:
principles, techniques, and algorithms for imaging characterization.
Radiology, 2008;249(3):756−75.
Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma
in a contemporary computerized tomography series. J Endocrinol Invest,
2006;29(4):298−302.
Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of noncon-
trast computed tomography attenuation value (hounsfield units) to dif-
ferentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland
Clinic experience. J Clin Endocrinol Metab, 2005;90(2):871−7.
Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison
of CT findings in symptomatic and incidentally discovered pheochromocy-
tomas. AJR Am J Roentgenol, 2005;185(3):684−8.
Nunes ML, Vattaut S, Corcuff JB, et al. Late-night salivary cortisol
for diagnosis of overt and subclinical Cushing’s syndrome in
hospitalized and ambulatory patients. J Clin Endocrinol Metab,
2009;94(2):456−62.
Pantalone KM, Gopan T, Remer EM, et al. Change in adrenal mass size as a
predictor of a malignant tumor. Endocr Pract, 2010;16(4):577−87.
Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of bio-
chemical tests for pheochromocytoma: measurement of fractionated
plasma metanephrines compared with the combination of 24-hour
urinary metanephrines and catecholamines. J Clin Endocrinol Metab,
2003;88(2):553−8.
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Vanderveen KA, Thompson SM, Callstrom MR, et al. Biopsy of pheo-

chromocytomas and paragangliomas: potential for disaster. Surgery,
2009;146(6):1158−66.
Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evalua-
tion and treatment of adrenal incidentalomas. J Clin Endocrinol Metab,
2011;96(7):2004−15.
Zeiger MA, Thompson GB, Duh QY, et al. American Association of
Clinical Endocrinologists and American Association of Endocrine
Surgeons Medical Guidelines for the Management of Adrenal
Incidentalomas: executive summary of recommendations. Endocr Pract,
2009;15(5):450−3.
48565_ST03_111-160.indd 154 5/1/13 9:34 PM

26 ■ ADRENOCORTICAL CARCINOMA
André Lacroix, MD
EPIDEMIOLOGY AND PATHOPHYSIOLOGY

• Rare disease: incidence is about 2 people out of every 1 million in the
population, mostly sporadic
• Bimodal age distribution, with peaks before five years and between
fourth to fifth decades
• Women are more often affected than men (1.5:1)
• Adrenocortical carcinoma (ACC) in adrenal incidentaloma: 2% if
<4 cm, 6% if 4.1–6 cm, 25% if >6 cm
• Incidence is 10-fold higher in children in southern Brazil where specific
TP53 germline mutation (R337H) occurs
• Many genetic alterations in sporadic ACC with loss of heterozygosity
(LOH) or allelic imbalance at chromosomes 11q13 (≥90%), 17p13
(≥85%) and 2p16 (92%) and overexpression of IGF-2
• Hereditary forms: Li-Fraumeni syndrome (TP53 mutations),
Beckwith-Wiedemann syndrome (IGF-2 overexpression), rarely
MEN-1
• Hormone-secreting ACC (~60%): Cushing’s syndrome (45%);
Cushing’s syndrome with hyperandrogenemia/virilization (25%);
hyperandrogenemia/virilization alone (10%); estrogen excess (gyneco-
mastia in men, uterine bleeding in women) or mineralocorticoid excess
(hypertension, edema) in <10%
• Nonsecreting tumors (~40%): abdominal pain or incidental
adrenal mass
• Fever and leucocytosis may occur from tumor necrosis
48565_ST03_111-160.indd 155 5/1/13 9:34 PM

156 Adrenocortical Carcinoma
TABLE 26.1 Hormonal Evaluation
Cortisol excess – DST (1 mg, 23:00 h)
(minimum 3 out of 4 tests) – Urinary free cortisol (24-hour urine)
– Basal cortisol (serum)
– Basal ACTH (plasma)
Sexual steroids and steroid – DHEA-S (serum)
precursors – Androstenedione (serum)
– Testosterone (serum)
– 17-OH-progesterone (serum)
– 17β-estradiol (serum, in men and
postmenopausal women)
Mineralocorticoid excess – Potassium (serum)
– ARR (only in patients with arterial hypertension
and/or hypokalemia)
Exclusion of pheochromocytoma – Catecholamine excretion (24-hour urine)
(minimum 1 out of 3 tests) – MN excretion (24-hour urine)
– Meta- and normetanephrines (plasma)
Based on recommendations of the European Network for the Study of Adrenal Tumors (ENS@T) www.ensat.
org/acc.htm in 2005.
Imaging investigation
• Unenhanced CT scan attenuation >10 HU: review with radiologist for
features suggesting ACC: size >6 cm, irregular borders, heterogeneous
density, calcifications, local invasion, adjacent adenopathies
TABLE 26.2 Staging for Adult ACC

Stage UICC/WHO 2004 ENSAT 2008
TNM 5-year Disease- TNM 5-year Disease-
Free Survival Free Survival
I T1, N0, M0 82% T1, N0, M0 82%
II T2, N0, M0 58% T2, N0, M0 61%
III T1–2, N1, M0 55% T1-2, N1, M0 50%
T3, N0, M0 T3–4, N0–1, M0
IV T1–4, N0–1, M1 18% T1–4, N0–1, M1 13%

T3, N1, M0 T4,
N0–1, M0
ENSAT: also venous tumor thrombus in vena cava/renal vein; T1 tumor = <5 cm, T2 tumor = >5 cm, T3
tumor= infiltration in surrounding tissue, T4 tumor = invasion in adjacent organs, N0 = no positive lymph
nodes, N1= positive lymph node(s), M0 = no distant metastases, M1 = presence of distant metastasis
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Adjuvant Mitotane or Radiotherapy and Follow-Up 157
• MRI may better identify vascular invasion

• FDG-PET to better characterize suspicious lesions on CT scan or MRI
with Standard Uptake Value (SUV) > 1.45
• When ACC is likely, look for extent of disease with chest CT and
FDG-PET; bone imaging or brain MRI if symptoms of metastasis at
these sites
INITIAL THERAPY AND SURGICAL APPROACH

• Patient should be followed by multidisciplinary team including endo-
crinologist, expert surgeon, medical oncologist, systematic follow-up
nurse, psychologist, palliative care team
• Noninvading incidentaloma up to 10 cm: laparoscopic or open surgery
according to expert surgeon evaluation; incidentaloma >10 cm, local
invasion or high suspicion of ACC: open radical surgery avoiding tumor
spillage
• Recent limited studies indicate that lymphadenectomy may improve
outcome, but this will require larger studies
• Distant disease: remove primary lesion only if this allows removal of
high proportion of tumor burden and improves excess steroid secretion
PATHOLOGICAL EVALUATION
• Review slides of tumor or biopsy material with expert pathologist and
assess Weiss score
• Five criteria are used in the updated Weiss score: >6 mitoses/50 high
power fields, ≤25% clear tumor cells, abnormal mitoses, necrosis, and
capsular invasion
° Each is scored 0 when absent, or 2 for the first two criteria and
1 for the last three when present; malignancy is a total score ≥3
• Evaluate Ki-67 index, IGF-2, P-53, and SF1 by immunohistochemistry
• Tumor genetic markers of malignancy and prognosis under
development
ADJUVANT MITOTANE OR RADIOTHERAPY AND FOLLOW-UP

• Recommend adjuvant mitotane for tumors with revised Weiss criteria ≥3
• Use 2 g/day initially for Stage I and II tumors during a minimum period
of 2 years
• Increase to 6 g/day rapidly if tolerated for Stage III tumors or Stage I or
II tumors with Ki-67 >10% (5 years duration)
• Monitor serum mitotane levels and adjust dose to reach levels between
14–20 mcg/ml
• Initiate replacement with HC (see section Mitotane Effect on Endocrine
Function)
48565_ST03_111-160.indd 157 5/1/13 9:34 PM

158 Adrenocortical Carcinoma
• Mitotane is a potent inducer of CYP3A4 with potential interactions

with many drugs
• Monitor liver function and cholesterol; treat with statins (pravastatin
or rovustatin as non-CYP3A4 substrates) if needed
• Use effective contraception in female patients during reproductive
age (oral contraceptives not utilized by some experts as mitotane
increases its metabolism and reduces its efficiency)
• Follow with chest CT and abdominal CT/MRI every 3 months for
2 years, every 6 months until 5 years, and yearly x 10 years; FDG-PET
can also be utilized in early follow-up
• Monitor urinary cortisol, ACTH, renin, and marker steroid levels
• Consider adjuvant radiotherapy in patients with Stage III disease, R1
incomplete resection, complete resection with initial tumor >8 cm,
blood vessel invasion, and Ki-67 >10%
ADVANCED DISEASE
• Surgically remove resectable residual tumor or isolated metastatic
lesions if complete resection is possible
• Initiate mitotane as rapidly as possible to 6 g/day split during 3 meals
to reach serum levels of 14–20 mcg/ml; monitor every 2–3 weeks
initially to adjust dose
• Use antinausea drugs as needed (prochloperazine, metoclopramide,
serotonin 5-HT3 receptor antagonist)
• Control steroid excess with mitotane and steroid enzyme inhibitors
such as metyrapone or ketoconazole
• Correct hypokalemia with potassium supplements, spironolactone,
eplerenone, or amiloride
• Frequent monitoring of electrolytes, creatinine, urinary cortisol to
avoid acute hyperkalemia when cortisol excess is controlled
• Treat diabetes and high BP
MITOTANE EFFECT ON ENDOCRINE FUNCTION

• After ACC-induced hypercortisolism (if present) is resolved, begin HC
30 mg/day in three divided doses
° Mitotane progressively increases HC requirements by 2–3 times
■ Adjust doses based on symptoms and levels of plasma ACTH and
urinary-free cortisol
■ Serum cortisol levels are not reliable because mitotane increases
CBG levels
• Add fludrocortisone replacement when renin levels increase; require-
ments may be increased two-to threefold by mitotane and are adjusted
based on BP and renin levels
• Monitor TSH, FT4, and testosterone, which can be effected by mitotane
48565_ST03_111-160.indd 158 5/1/13 9:34 PM

References 159
Systemic Chemotherapy
• In advanced metastatic disease, administer combination of etoposide,
doxorubicin, and cisplatin (EDP) with mitotane as first choice
• Second-line therapy may be steptozotocin and mitotane or other
combination therapies preferably in the context of multicenter
collaborative research protocols
• Consider salvage therapy with new drugs such as IGF-1 receptor
antagonists or TKI within multicenter research protocols
REFERENCES
Berruti A, Fassnacht M, Baudin E, et al. Adjuvant therapy in patients with
adrenocortical carcinoma: A position of an international panel. J Clin
Oncol, 2010;28:e401–e402.
Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of
the 2004 International Union Against Cancer staging classification for
adrenocortical carcinoma: proposal for a Revised TNM Classification.
Cancer, 2009;115(2):243–50.
Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocortical carcinoma: a
clinician’s update. Nat Rev Endocrinol, 2011;7(6):32–35.
Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in
advanced adrenocortical carcinoma. N Engl J Med, 2012;366(23):2189–97.
Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with
mitotane by induction of CYP3A4 metabolism in the clinical management
of adrenocortical carcinoma. Clin Endocrinol (Oxf), 2011;75(5):585–91.
Lacroix A. Approach to the patient with adrenocortical carcinoma. J Clin
Endocrinol Metab, 2010;95(11):4812–22.
Polat B, Fassnacht M, Pfreundner L, et al. Radiotherapy in adrenocortical
carcinoma. Cancer, 2009;115(13):2816–23.
Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with
adrenal cancer: recommendations of an international consensus confer-
ence. Endocr Relat Cancer, 2005;12(3):667–80.
Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations
and the use of mitotane as a chemotherapeutic agent for adrenocortical
carcinoma. J Clin Oncol, 2009;27(27):4619–29.
Zini L, Porpiglia F, Fassnacht M. Contemporary management of adrenocortical
carcinoma. Eur Urol, 2011;60(5):1055–65.
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SECTION IV: CALCIUM AND BONE
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48565_ST04_161-198.indd 162 5/1/13 9:33 PM
27 ■ CALCIUM METABOLISM ESSENTIALS
Chad D. Sagnella, MD and Pam Taxel, MD
MAINTENANCE OF OVERALL CALCIUM BALANCE

• Calcium is an essential dietary element with critical roles in normal
physiology
° Extracellular calcium functions in bone mineralization, blood
coagulation, membrane excitability, enzyme kinetics
° contraction, hormonefunctions
Intracellular calcium
secretion
in neuronal activation, muscle
• Human body contains about 1000 g of calcium, the majority of which

(99%) resides in bone and teeth as calcium hydroxyapatite
• Dietary intake of calcium
° 75% lost in feces
° 25% absorbed in the proximal small intestine
■ By passive diffusion
■ By hormonally regulated active transport (stimulated by vitamin D)
• Renal excretion normally results in 100–250 mg of calcium loss per

day (with adequate intake)
• Plasma calcium divided into three fractions
° 50% ionized calcium
° 40% protein-bound calcium (albumin, globulins)
° 10% complexed to anions (including citrate, phosphate, sulfate,
bicarbonate)
• Calcium-sensing receptor (CaSR)
° Located in the parathyroid glands and kidney
■ Regulates PTH secretion
■ Regulates renal excretion of calcium
° Responds
basis
to fluctuations in ionized calcium on minute-to-minute
• Approximately 1 g of calcium is recommended per day (Table 27.1)

° Dietary sources of calcium (1 dairy serving size = 250–300 mg
calcium)
■ Dairy products including milk, cheeses, yogurts, calcium-
fortified soy milk, and calcium-fortified tofu

■ Canned salmon with bones
■ Green vegetables such as turnips, collard greens, kale, and
broccoli
° Supplemental
supplements)
calcium intake (i.e., multivitamin and calcium
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164 Calcium Metabolism Essentials
TABLE 27.1 Recommended Intakes for Calcium
Estimated Average Recommended Upper Level
Requirement Dietary Allowance* Intake
(mg/day) (mg/day) (mg/day)
9–18 years old 1100 1300 3000
19–50 years old 800 1000 2500
51–70-year-old 800 1000 2000
males
51–70-year-old 1000 1200 2000
females
>70 years old 1000 1200 2000
*RDA includes total dietary + supplemental calcium intake.
PTH
• Parathyroid gland anatomy
° 4lobes
small ovoid glands located on the dorsal aspect of left and right
of the thyroid
■ Inferior parathyroid glands derived from third branchial pouches
■ Superior parathyroid glands derived from fourth branchial pouches
■ Approximately 10–20% of humans have fi fth parathyroid gland,
often located in mediastinum

° ■ cell
2 types
Chief (or principal) cells: predominant epithelial cell type with
clear cytoplasm
■ Oxyphil cells: larger, mitochondria-rich cell type with granular
eosinophilic cytoplasm
• Structure and synthesis of PTH
° 84-amino acid polypeptide synthesized as a pre-prohormone by the
chief cells of the parathyroid
° ing PTH <5 minutes)cleaved by liver and kidney (half-life of circulat-
PTH proteolytically
° Normal range for serum intact PTH is approximately 10–65 pg/mL

• Secretion of PTH
° Regulated by serum ionized calcium (iCa2+)
■ ↑ iCa2+ can activate CaSR and suppress PTH secretion
■ ↓ iCa 2+
stimulates PTH secretion
° Regulated by serum magnesium Mg2+
■ ↓ Mg 2+ can inhibit PTH secretion and action
■ ↑ Mg 2+ can activate CaSR and thus suppress PTH secretion
• PTH 1-receptor (PTH-1R)

° 7-transmembrane G-protein−coupled receptor (Gs/Gq) expressed
on osteoblasts and proximal and distal tubules of the kidney
° PTH-1R binds PTH and PTH-related protein (PTHrP) with equal affinity
48565_ST04_161-198.indd 164 5/1/13 9:33 PM

Vitamin D 165
• Actions of PTH
° Bone
■ ↑ bone resorption of calcium by directly stimulating osteoblasts
and indirectly stimulating osteoclasts via Macrophage-Colony

Stinulatin Factor (M-CSF), receptor activator of nuclear factor
kappa-B ligand (RANKL), Osteoprotegrin (OPG) (decoy receptor
for RANKL)
° ■ ↑ renal reabsorption of calcium by ↑ insertion of apical Ca2+
Kidney
channels in the distal tubule

■ ↑ renal 1α-hydroxylase activity to ↑ 1,25-(OH) vitamin D
2
production in the proximal tubule, to increase both calcium and
phosphate absorption in gut
VITAMIN D
• Structure and synthesis of vitamin D
° Inactive prohormones
■ Vitamin D : ergocalciferol
2
• Produced by photolysis (UVB) from ergosterol (in plants)
■ Vitamin D : cholecalciferol
3
• Produced by UVB from 7-dehydrocholesterol
• Formed in the skin, mainly in the deepest layers of the
epidermis
■ 25-hydroxyvitamin D: calcidiol (or calcifediol)
• Vitamin D2 /D3 rapidly converted in the liver to

25-hydroxyvitamin D by hepatic 25-hydroxylase (constitutively
active)
• >85% of vitamin D metabolites carried in the blood bound to
vitamin D–binding protein (VDBP)
° Regulation of vitamin D
■ Activation to 1,25-(OH) vitamin D (calcitriol) occurs via
2 3
1α-hydroxylase cytochrome P-450 1-alpha (CYP1α) in the
mitochondria of renal proximal tubule
• ↓ [iCa2+] stimulates 1,25-(OH)2 vitamin D via CaSR to ↑
1α-hydroxylase production
• ↑ PTH stimulates 1,25-(OH)2 vitamin D via PTH-1R to ↑
1α-hydroxylase production
• ↑ 1,25-(OH)2 vitamin D causes ↓ 1α-hydroxylase activity
(feedback inhibition)
• ↓ [phosphate] stimulates 1,25-(OH)2 vitamin D generation
48565_ST04_161-198.indd 165 5/1/13 9:33 PM

■ Inactivation to 24,25-(OH)2 or 1,24,25-(OH)2 occurs alternatively
via renal 24-hydroxylase (CYP24) in the proximal tubule
• Vitamin D receptor (VDR)
° 50-kDa nuclear hormone receptor that acts as a transcription fac-
tor by binding to vitamin D-responsive elements in deoxyribonucleic
acid (DNA)
° Regulates gene expression in target tissues of the small intestine,
bone, parathyroid gland, and kidney
• Actions of 1,25 (OH)2 D3
° ↑route
intestinal Ca2+ absorption via the active-transport transcellular
■ ↑ enterocyte expression of luminal epithelial calcium channels
known as transient receptor potential channels –villanoid 5 and

6 (TrpV5 and TrpV6)
■ ↑ intracellular calcium-binding protein, calbindin-D9K, facili-
tator of enterocyte Ca2+ diffusion, and apical-to-basolateral

transport
■ ↑ expression of plasma membrane calcium adenosine triphosphate
(ATPase) (PMCA), basolateral Ca2+ transporter out of enterocyte

° ■ bone
↑ resorption of Ca2+
↑ osteoblast differentiation, indirectly ↑ osteoclast activity,
sensitizes osteoblasts to PTH
■ facilitates osteoid production and proper bone calcifi cation
° ↓ parathyroid
↑ renal Ca2+ reabsorption
° ■ ↓ PTH polypeptide
gland PTH secretion
gene expression
■ ↑ CaSR gene expression
• Recommended vitamin D
° Dietary
egg
source: dairy, fish (e.g., salmon, trout, and tuna), liver,
° Exposure
a day
to UVB: direct sunlight to the skin for 10−15 minutes
TABLE 27.2 Recommended Intakes for Vitamin D

Estimated Average Recommended Upper Level
Requirement Dietary Allowance Intake
(IU/day) (IU/day) (IU/day)
9–18 years old 400 600 4000
19–70 years old 400 600 4000
>70 years old 400 800 4000
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References 167
CALCITONIN
• Structure and synthesis of calcitonin
° 32-amino acid polypeptide hormone synthesized by the para-
follicular C cells of the thyroid
° Normal serum calcitonin levels <19 pg/mL with a half-life <1 hour
• Secretion of calcitonin
° inhibited
↑ serum ionized Ca2+ levels stimulate calcitonin secretion, release
by hypocalcemia
° Secretion under control of serum ionized calcium using the same
CaSR that regulates PTH secretion in the parathyroid gland
° Nonessential physiologic role in human calcium handling or bone
metabolism; decrease in serum levels of calcium (and phosphate)
requires supraphysiologic calcitonin levels
° Causes natriuresis as well as calcium and phosphate excretion in
renal tubules
• Calcitonin receptor (CTR)
° Gs/Gq expressed on osteoclasts in addition to the proximal tubules
of the kidney
• Actions of calcitonin
° Bone
■ ↓ bone resorption of calcium by rapidly deactivating osteoclasts,
causing shrinkage in size of osteoclasts and retraction of their

ruffled border
° ■ ↓ renal reabsorption of phosphorous and ↑ excretion of renal
Kidney
Ca2+
REFERENCES
Costanzo LS. Chapter 9. Endocrine Physiology. In: Costanzo LS, ed. Physiology.
4th ed. Philadelphia, PA: Saunders-Elsevier; 2010.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology. 9th ed.
New York, NY: McGraw-Hill; 2011.
Institute of Medicine of the National Academies. Dietary reference intakes
for calcium and vitamin D. Available at: www.iom.edu/Reports/2010/
Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed
Nov, 2010.
48565_ST04_161-198.indd 167 5/1/13 9:33 PM

Melmed S, Polonsky KS, Larson PR, Kronenberg, HM. Williams Textbook of

Endocrinology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011.
Molina P. Endocrine Physiology. 3rd ed. New York, NY: McGraw-Hill; 2010.
Porterfield SP, White B. Endocrine Physiology. 3rd ed. St. Louis, MO. Mosby-
Elsevier; 2007.
Rose DB, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders.
5th ed. New York, NY: McGraw-Hill; 2001.
Whitehead SA, Nussey SS. Endocrinology: An Integrated Approach. Osford, UK:
BIOS Scientific Publishers; 2001.
48565_ST04_161-198.indd 168 5/1/13 9:33 PM

28 ■ HYPERCALCEMIA
Azeez Farooki, MD
INCIDENCE
• Primary Hyperparathyroidism (PHPT) and malignancy account for 90%
of hypercalcemia cases
PATHOPHYSIOLOGY
• Increase bone resorption
° PHPT
■ Autonomous production of PTH via: an adenoma (85%), 4-gland
hyperplasia (15−20%) or carcinoma (<1%) causes ↑ in bone

resorption, renal calcium reabsorption, and GI calcium absorption
° Malignancy
■ Local osteolysis via osteoclast stimulation (due to release of
cytokines by tumor cells in the bone microenvironment)

• Bone metastases due to breast, prostate, lung, thyroid, and
others
• Multiple myeloma
• Rarely lymphoma and leukemia
■ Without advanced cancer in the bone
• PTHrP production by primary tumor: “humoral hypercalce-

mia of malignancy”; causes increased bone resorption and
decreased renal calcium clearance
■ Solid tumors: head and neck or lung squamous cell carcino-
mas, renal, bladder, breast, or ovarian carcinomas

■ Other tumors: non-Hodgkins lymphoma, blast phase of chronic
myeloid leukemia, and adult T-cell leukemia-lymphoma

• Ectopic PTH production by primary tumor (rare)
° Other causes
■ Immobilization
■ Hypervitaminosis A
■ Thyrotoxicosis
■ Teriparatide therapy
• Increased calcium intake, absorption, and/or decreased renal calcium

excretion
° High calcium intake in the setting of renal insufficiency
° Chronic renal disease
° Vitamin D intoxication
Milk-alkali syndrome
° Thiazide diuretics (decreased renal excretion)
°
48565_ST04_161-198.indd 169 5/1/13 9:33 PM

170 Hypercalcemia
°Extrarenal production of 1,25 dihydroxyvitamin D: accelerated GI

absorption plus increased resorption exceeds renal threshold for
excretion
■ Granulomatous diseases
■ Lymphoma
• Miscellaneous
° Lithium therapy
° Addisonian crisis
° Theophylline
Familial hypocalciuric hypercalcemia
° Pheochromocytoma
toxicity
° Acute renal failure (usually with rhabdomyolysis)
°
• History: symptoms depend on the severity and rapidity of
hypercalcemia
° Acute increase to >12 mg/dL: polyuria, polydipsia, volume deple-
tion, anorexia, nausea, weakness, and change in mental status
° Chronic
TABLE 28.1 Symptoms of Chronic Hypercalcemia

Mild: upper limit of Moderate: 12−14
normal to 12 mg/dL mg/dL Severe: >14 mg/dL
Chronic Asymptomatic Asymptomatic Nausea, weakness,
elevation or nonspecific or nonspecific mental status
symptoms symptoms like symptoms like change, progressive
malaise, depression, malaise, depression, volume depletion,
constipation, constipation, renal failure
musculoskeletal pain musculoskeletal pain
°
Clinical manifestations may include
■ Nephrolithiasis, nephrocalcinosis
■ Cognitive dysfunction
■ Constipation, anorexia, nausea
■ Mild weakness
• Physical exam: findings related to underlying disease
• Laboratory testing and imaging
° Check calcium with albumin and ionized calcium
■ Calculate corrected calcium
• Corrected calcium [Ca] = Measured total [Ca] + (0.8 ×

(4.0 - [albumin]))
48565_ST04_161-198.indd 170 5/1/13 9:33 PM

■ If normal ionized calcium in setting of myeloma, then suspect
paraprotein binding calcium and spuriously elevating total
calcium (pseudohypercalcemia)
° Check PTH
■ Inappropriately high (>20 pg/mL) = parathyroid autonomy
versus familial hypercalciuric hypercalcemia (FHH) versus

lithium use
• Ask medical history (i.e., lithium use or hypercalcemia
duration)
• Ask family history
■ Autosomal dominant family history of hypercalcemia →
suspect FHH
■ Positive family or personal history of endocrine tumors →
suspect MEN syndrome

• Check 24-hour urine calcium (Ca) and creatinine (Cr)
• Calculate Ca/Cr clearance ratio
■ Ca/Cr clearance ratio = [24-hour urine Ca ⫻ serum Cr] ⫼
[serum Ca ⫻ 24-hour urine Cr]

■ If ratio < 0.01, consistent with FHH
■ If ratio > 0.02, consistent with PHPT (see Chapter 29,
Hyperarathyroidism
• Determine if surgical indications (Figure 28-2)
• Parathyroid imaging only required if patient meets surgical
indications
■ Appropriately suppressed (<20) = malignancy versus other
conditions
• Ask medical history
■ Intake of large doses of calcium-based antacids (milk-
alkali syndrome)
■ Vitamin D intoxication (high 25-hydroxyvitamin D (25OHD)
>125 ng/mL)
■ Vitamin A (including analogues used to treat acne)
■ Hydrochlorothiazide (HCTZ), theophylline ,and teriparatide
use
■ Immobilization
• Pursue malignancy and granulomatous disease work up

• Rule out myeloma (Serum and Urine protein electrophoresis)
• Check PTHrP (high PTHrP → scan to locate primary
malignancy)
• Check 1,25 D and 25OHD
■ High 1,25OHD: granulomatous disease versus lymphoma
■ PPD, chest X-ray, other imaging as needed
■ Check TSH and cortisol
• TSH <0.1: likely hyperthyroidism (see Chapter 10,

Thyrotoxicosis and Hyperthyroidism)
• If AM cortisol low and symptoms of AI, ACTH stimulation test
(see Chapter 20, Adrenal Insufficiency)
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172 Hypercalcemia
TABLE 28.2 Indications for Parathyroidectomy in Asymptomatic Primary
Hyperparathyroidism
Serum calcium concentration ≥1.0 mg/dL above the upper limit of normal
Creatinine clearance <60 mL/min
History of fragility fracture or osteoporotic bone density (T score at lumbar spine, hip,
or distal radius <-2.5)
Age <50 years
MANAGEMENT
• Acute treatment
° Calcium
status)
>12 mg/dL with severe symptoms (change in mental
■ Reverse intravascular volume depletion
• IV NS at 200−300 cc/hour (lower rate if heart failure or renal

disease)
• Once volume replete, loop diuretics prn to prevent volume
overload
• If NS not feasible, hemodialysis
■ IV bisphosphonate (zoledronic acid or pamidronate)
• Maximum effect seen in 2−4 days

■ SQ salmon calcitonin at 4 IU/kg every 8 hours
• Consider if calcium >14 mg/dL

• Maximum effect in 4−6 hours
• Efficacy limited by tachyphylaxis in 48−72 hours
• Chronic treatment: directed to underlying cause
° All patients should maintain adequate hydration since hypercalce-
mia predisposes to dehydration
■ PHPT (see Chapter 29, Hyperparathyroidism)
• If poor surgical candidate and calcium ≥1.0 mg/dL above

normal: consider Rx cinacalcet to lower calcium level
• Without a surgical indication → observation
■ Malignancy with bone metastases or myeloma
• Monthly IV bisphosphonates or denosumab to prevent skeletal

events
■ Granulomatous disease or lymphoma
• Prednisone 20−40 mg/day to reduce 1,25 D production

• Do not aggressively replace vitamin D (goal 25OHD:
20−30 ng/mL)
■ Immobilization
• If mobilization not possible, IV or oral bisphosphonate
48565_ST04_161-198.indd 172 5/1/13 9:33 PM

References 173
REFERENCES
Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymp-
tomatic primary hyperparathyroidism: summary statement from the third
international workshop. J Clin Endocrinol Metab, 2009;94(2):335−9.
Deftos LJ. Hypercalcemia in malignant and inflammatory diseases.
Kacprowicz RF, Lloyd JD. Electrolyte complications of malignancy. Hematol
Oncol Clin North Am, 2010;24(3):553−65.
Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res,
1991;6(Suppl 2):S51−9.
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J
Med, 2005;352(4):373−9.
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48565_ST04_161-198.indd 174 5/1/13 9:33 PM
29 ■ HYPERPARATHYROIDISM
Zohair Rahman, MD and Amina Khan, MD, FRCPC, FACP, FACE
PATHOPHYSIOLOGY
• PHPT
° Approximately 90% of cases are caused by sporadic PTH-secreting
solitary adenoma of parathyroid chief cells, multiglandular hyper-
plasia approximately 5%, parathyroid carcinoma <1%
° May be associated with hereditary syndromes such as
■ Multiple endocrine neoplasia type 1
■ Multiple endocrine neoplasia type 2a
■ Familial hyperparathyroidism jaw tumor syndrome
■ Neonatal severe hyperparathyroidism
■ Familial-isolated hyperparathyroidism
° PHPT can be mimicked by FHH

■ FHH is a benign cause of hypercalcemia
■ Inherited as an autosomal dominant condition
■ Caused by an inactivating mutation of the CaSR gene
• FHH: calcium to creatinine clearance ratio usually <0.01

• PHPT: calcium to creatinine clearance ratio >0.01 in ~80%
of cases
° lithiumcan also be mimicked by drugs such as thiazide diuretics or
PHTP
■ Thiazide diuretics ↓ urinary calcium excretion
■ Lithium shifts the set point of calcium PTH curve to the right
° Prior radiation exposure to head and neck or RAI may also contrib-
ute to development of PHPT
• Secondary hyperparathyroidism
° Commonly seen in hypocalcemia, vitamin D insufficiency, or chronic
kidney disease
■ Hypocalcemia simulates PTH
■ Vitamin D insufficiency ↓ intestinal calcium absorption and ↑ PTH
when 25-hydroxyvitamin D levels are <20 ng/mL (50 nmol/L)

■ Chronic kidney disease causes ↑ PTH by ↓ serum calcium,
↑ phosphate, ↓ 1,25 hydroxyvitamin D; PTH ↑ when glomerular

filtration rate (GFR) <60 mls/min
• Tertiary hyperparathyroidism
° Seen in chronic kidney disease
° Chronic stimulation of parathyroid glands by high phosphate levels
results in nodular hyperplasia of the parathyroid glands and high
PTH levels in the presence of hypercalcemia
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176 Hyperparathyroidism
• PHPT
° Symptomatic PHPT
■ Only 15% of patients present at this stage in developed countries,
but symptomatic presentation still common in developing countries

■ Clinical features may include
• Bone pain, fragility fractures or osteitis fibrosa cystica

(parathyroid bone disease)
• Nephrolithiasis, nephrocalcinosis, and renal insufficiency
• Polyuria, polydipsia (↑ calcium decreases renal concentrating
ability)
• Nausea, vomiting, peptic ulcer disease, constipation,
pancreatitis
• Depression, lethargy, cognitive impairment
• Psychosis, coma
• Gout, pseudogout may be associated with PHPT
• Hypercalcemic crisis usually precipitated by intercurrent
illness or volume contraction
° Asymptomatic PHPT
■ 85% of patients currently present at this stage in developed
countries
■ May have fatigue or mild depression
■ May have low bone density with preferential bone loss at cortical
skeletal sites
° Normocalcemic hyperparathyroidism
■ Normal serum calcium and persistently elevated PTH levels with
normal vitamin D levels and normal renal function

■ May progress to symptomatic PHPT
■ No physical findings on examination
■ Typically identifi ed on workup for osteoporosis
• Secondary hyperparathyroidism
° Bowing of the bone
Osteoporosis, pain, fractures
° Proximal muscle tibiae and femora may be seen in children
° Myopathy weakness may occur with vitamin D deficiency
°
• Tertiary hyperparathyroidism
° Fragility fractures, muscle weakness
• History: evaluate for evidence of skeletal fragility or prior renal stones;
exclude other causes of hypercalcemia including thyroid disease, AI,
granulomatous disease, immobility, presence of malignancy; evaluate
medications particularly use of thiazide diuretics, vitamin D, vitamin A,
antacids, or lithium (see Chapter 28, Hypercalcemia)
48565_ST04_161-198.indd 176 5/1/13 9:33 PM

• On examination check
° BP, pulse, volume status
° Neck masses
° Dorsal kyphosis, height loss
• Biochemical evaluation
° Intact PTH
■ PTH ↑ in parathyroid related causes of hypercalcemia
■ PTH ↓ or undetectable in association with other causes of hyper-
calcemia like malignancy related or granulomatous disease

° Calcium (see Chapter 28, Hypercalcemia)
■ Correct total serum calcium for albumin
■ Measure ionized calcium
° Serum phosphorous
■ ↓ or low normal in PHPT
■ ↑ in secondary PHPT due to CKD and tertiary PHPT
° 25 hydroxyvitamin D
■ In PHPT, 25-hydroxyvitamin D is usually low-normal since it is
converted to 1,25-dihydroxyvitamin D. Typically, 1,25-dihydroxy

vitamin D is normal or elevated in PHPT
■ Vitamin D defi ciency (low 25-hydroxy vitamin D) can result in
secondary HPT. Treatment with vitamin D can normalize PTH

levels (see Chapter 31, Vitamin D Deficiency)
° Urinary calcium to creatinine clearance ratio (see Chapter 28,
Hypercalcemia)
■ <0.01 in FHH and >0.01 in PHT in 80% of cases
■ DNA analysis of the CaSR gene if de novo case of FHH
suspected
° Consider
Check creatinine and estimate GFR
° Bone density
ultrasound of kidneys to exclude occult renal stones
° skeletal effectatoflumbar
PHPT
spine, hip, and 1/3 radial site to assess
° minimally invasive unilateral preoperatively

Parathyroid imaging of value to determine if a
surgical approach is possible; imaging
does not confirm diagnosis or exclude PHPT
■ Sestamibi scanning: sensitivity 78% and positive predictive
value 90% (varies from center to center)

■ Ultrasound: can be considered in patients who are not candi-
dates for sestamibi scanning

■ CT scanning (4 Dimensional CT) can be considered in some
patients for localizing adenomas especially individuals with

prior neck surgery
° PHPT in young adults or children consider familial hyperparathy-
roid syndrome and consider DNA analysis to exclude MEN, FHHH,
Hyperparathyroid Jaw tumor syndrome and familial isolated
hyperparathyroidism
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178 Hyperparathyroidism
° If family history of hyperparathyroidism; multiple endocrine tumors

present; or presence of coexisting hypertension, peptic ulcer dis-
ease, symptoms of pheochromocytoma, exclude MEN and consider
DNA analysis of the MEN1 and/or RET gene
MANAGEMENT
• Stop precipitating medications if possible (e.g., HCTZ and lithium)
• Calcium supplements can be discontinued if serum calcium is
elevated
• If hypercalcemic crisis (see Chapter 28, Hypercalcemia)
° Begin saline infusion to correct volume contraction
° Saline increases GFR and filtered calcium load
° Diuretics (i.e., furosemide) following volume replacement esp. in
patients at risk for heart failure
° symptomatic hypercalcemia
IV bisphosphonates and calcitonin can be considered for severe or
• Treatment in primary HPT

° Parathyroidectomy
hyperparathyroid
for symptomatic PHPT and tertiary
° Parathyroidectomy recommended if any of the following:

■ Symptoms including renal stones
■ Serum calcium >1 ng/dL (0.25 mmol/l) above upper limit of
normal
■ Calculated creatinine clearance <60 mls/min
■ BMD T-score ≤ ⫺2.5 at any site or previous fragility fracture
■ Age <50
° Medical management recommended for asymptomatic PHPT and

patients not meeting the guidelines for surgery or unable/unwilling
to have surgery
■ Skeletal protection
• Aminobisphosphonates (antiresorptive agent)

■ BMD increases
■ No change in serum calcium or PTH
• Estrogen (antiresorptive agent)

■ BMD increases
■ No change in serum calcium or PTH
■ For lowering calcium levels in patients who are not candidates
for parathyroid surgery as well as in patients with secondary HPT

due to chronic renal failure
• Cinacalcet (calcimimetic agent)
■ ↓ serum calcium and PTH
48565_ST04_161-198.indd 178 5/1/13 9:33 PM

References 179
REFERENCES
Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the Management of
Asymptomatic Primary Hyperparathyroidism: Summary Statement
from the Third International Workshop. J. Clin Endocrinol Metab,
2009;94(2):335–39.
Khan A, Bilezikian JP, Potts JT Jr. The Diagnosis and Management of
Asymptomatic Primary Hyperparathyroidism Revisited. J. Clin. Endocrinol
Metab, 2009;94(2):333–334.
Pallan S, Rahman O, Khan A. Hyperparathyroidism Diagnosis and
Management A Clinical Review BMJ, 2012;344:e1012.
Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation
of asymptomatic primary hyperparathyroidism: proceedings of the Third
International Workshop. J Clin Endocrinol Metab, 2009;94(2):351–65.
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48565_ST04_161-198.indd 180 5/1/13 9:33 PM
30 ■ HYPOCALCEMIA
Mark Cooper, MD and Neil Gittoes, MD
PATHOPHYSIOLOGY
• Common and potentially life threatening condition caused by
° An imbalance in the absorption of calcium from the GI tract and its
urinary excretion
° An excessive amount of calcium leaving the circulation to be
incorporated into bone matrix
SPECIFIC CAUSES
• Vitamin D deficiency/resistance
° Low exposure to UV light
° Low nutritional intake
° Drugs that accelerate vitamin D metabolism (e.g., anticonvulsants)
Malabsorption
° VDR mutations (very rare)
°
• Reduced vitamin D activation
° Hypoparathyroidism (post–neck surgery or autoimmune)
° Hypomagnesemia (functional hypoparathyroidism)
° Kidney disease
° PTH resistance
• Other etiology
° Autosomal dominant hypocalcemia (calcium-sensing mutation,
usually asymptomatic)
° Sclerotic
bone)
metastases (movement of circulating calcium into
° magnesium after
Hungry bone syndrome (massive skeletal uptake of calcium and
successful surgery for PHPT)
° Massive
products)
blood transfusion (due to calcium chelators in blood
° Post–fi rst dose of IV bisphosphonates (usually only if vitamin D

deficient)
° Pancreatitis
48565_ST04_161-198.indd 181 5/1/13 9:33 PM

182 Hypocalcemia
• Depends on degree of hypocalcemia and its rate of onset
• Risks of symptoms much higher if rapid fall in calcium level
• Acute symptoms due to abnormal neuromuscular function
• Symptoms
° Paraesthesia (tingling in hands or perioral)
° Muscle twitches or spasms
° Seizures
Diffi culty breathing (suggests laryngeal spasm)
° Palpitations (rare)
° Psychiatric manifestations (e.g., depression, psychosis)
° Visual symptoms (secondary to optic atrophy; rare)
°
• Features suggesting underlying diagnosis: frequency of sun exposure,
dietary intake of foods containing vitamin D, previous neck surgery,
symptoms suggesting malabsorption, family history of hypocalcemia
or neck operations
• Drug history with focus on medications that could cause vitamin D
deficiency (e.g., anticonvulsants) or hypomagnesemia (diuretics, PPIs)
° Examine for overt signs of neuromuscular excitability (e.g., muscle
twitches, spasms)
° Chvostek’s sign: muscle twitching of facial muscles following
pressure over facial nerve in the parotid region (positive in ~70%
of patients with hypocalcemia and in ~10% of nonhypocalcemic
individuals)
° Trousseau’s sign: carpal spasm induced by mild tissue hypoxia
induced by inflation of BP cuff for up to 3 minutes (positive in
>90% of patients with hypocalcemia and in ~1% of nonhypocalce-
mic individuals)
° Proximal myopathy (would support vitamin D deficiency)
° Evidence of skeletal dysplasia (Albright’s hereditary
osteodystrophy) – short third and fourth metacarpals
LABORATORY TESTING
• Serum calcium exists either in an ionized form (~50%) or is bound to
albumin or other ions
° While only ionized calcium is biologically important, typical lab
measurement of serum calcium measures “total” (bound and
unbound) calcium and therefore needs to be adjusted for serum
albumin, using the following formula
■ Corrected calcium (mg/dL) = serum calcium + [0.8 × (4-serum
albumin in g/dL)]
■ This is only an approximation
■ Ionized calcium can also be measured directly
48565_ST04_161-198.indd 182 5/1/13 9:33 PM

Management 183
Hypocalcemia (adjusted
for albumin)
LOW OR Serum PTH

NORMAL HIGH
LOW HIGH
Magnesium
Magnesium Urea, Creat Renal failure
deficiency
Hypoparathyroidism
25-hydroxy
Calcium sensing defect
vitamin D
(rare)
LOW NORMAL
Vitamin D Pseudo-
deficiency hypoparathyroidism
Calcium deficiency
(rare)
FIGURE 30.1 Diagnostic Evaluation Scheme for Hypocalcemia
Source: BMJ June 7, 2008 Volume 336 page 1301
• Diagnoses can be made quickly on basis of limited number of tests:

serum PTH, creatinine, alkaline phosphatase, magnesium, phosphorus
and 25-hydroxyvitamin D (Figure 30-1)
• Other tests that might be needed
° Urinary calcium to creatinine excretion ratio (high in autosomal
dominant hypocalcemia)
° Imaging normally not needed
■ Hand X-rays indicated if pseudohypoparathyroidism suspected
■ Skull X-rays or head CT might show basal ganglia calcifi cation
if hypocalcemia long standing
MANAGEMENT
• See Figure 30-2
• In hypomagnesemia, hypocalcemia is unlikely to correct without
replacement of magnesium
• Calcium infusion: 10 ampoules of 10 mL of 10% calcium gluconate
in 1L of 5% dextrose or 0.9% saline; initial infusion rate 50 mL/
hour aiming to maintain serum calcium at lower end of reference
range; infusion of 10 mL/kg of this solution over 4–6 hours is likely to
increase serum calcium ~1.2–2.0 mg/dL
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184 Hypocalcemia
Symptomatic hypocalcemia or calcium
<7.6mg/dL with unknown cause
For control over For control over days
minutes to hours to weeks if indicated
IV calcium gluconate Vitamin D treatment

10 mls of 10%
solution over 10 min
PTH deficient PTH intact
If hypocalcemia
persistent or recurrent,
Vitamin D analogue Colecalciferol or
then start calcium
(calcitriol or α-calcidol) ergocalciferol
gluconate infusion
(see text) and adjust Start dose 0.5-1 μg/day Typical dose 50,000
rate every 4 hours as Can be increased IU per week orally
required every 4-7 days for 8 weeks
FIGURE 30.2 Management Scheme for Hypocalcemia

Source: BMJ, 2008;336:1301
REFERENCES
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ,
2008;336(7656):1298–302.
Pearce SH, Cheetham TD. Diagnosis and management of vitamin D
deficiency. BMJ, 2010;340:b5664.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med,
2008;359(4):391–403.
48565_ST04_161-198.indd 184 5/1/13 9:33 PM

31 ■ VITAMIN D DEFICIENCY
Vin Tangpricha, MD, PhD
PATHOPHYSIOLOGY
• Vitamin D is a steroid hormone important in the maintenance of
calcium homeostasis and optimal skeletal health; vitamin D may have
other effects outside its classic role in calcium and bone
• Metabolism of vitamin D
° Vitamin D is made in skin (vitamin D3) or absorbed in the intestines
(vitamin D2 and vitamin D3)
° Vitamin D enters the circulation and is hydroxylated in the liver to
form 25-hydroxyvitamin D (25(OH)D), which is the best marker for
vitamin D status
° Atosecond hydroxylation step occurs in the kidney and other tissues
form 1,25-dihydroxyvitamin D (1,25(OH)2D), which is the hormon-
ally active form of vitamin D
° 1,25(OH)
900 genes
2D binds to the VDR and then DNA in cells to regulate over
PREVALENCE OF VITAMIN D DEFICIENCY

• Vitamin D insufficiency (25-D <30 ng/mL)
° 75% of the United States population
° 95% of non-Hispanic blacks
° 60% of Hispanic whites
• Vitamin D deficiency (25-D <20 ng/ml)
° 30% of the United States population
° 70% of non-Hispanic blacks
° 22% of Hispanic whites
RISK FACTORS FOR VITAMIN D DEFICIENCY

• Increased age
• Increased adiposity
• Indoor lifestyle
• Malabsorption
• Decreased or little intake of vitamin D−containing foods
• Darker skin tone
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186 Vitamin D Defi ciency
• Medical history
° Most patients with vitamin D deficiency are asymptomatic
° More
pain
moderate-to-severe deficiency may result in muscle and bone
° Severe vitamin D deficiency can result in symptoms of hypocalcemia

° Prolonged vitamin D deficiency can result in rickets in children and
osteomalacia/osteoporosis in adults
• Physical exam
° Rickets: bowing of the legs, enlargement of the costochondral
junction, frontal bossing, widening of wrist, craniotabes (soft skull
bones)
° Osteomalacia: sternal or periostial tenderness
DIAGNOSIS
• Serum 25-hydroxyvitamin D
° Vitamin D insufficiency: <30 ng/mL
° Vitamin D deficiency: <20 ng/mL
• Vitamin D insufficiency/deficiency can be accompanied by
° Elevated serum PTH concentrations (secondary
hyperparathyroidism)
° vitamin D deficiency
Hypocalcemia and/or hypophosphatemia can be seen in severe
• 1,25-dihydroxyvitamin D should not be routinely measured to assess

vitamin D status since its concentrations are much lower than 25(OH)
D and it is much more tightly regulated by PTH in response to serum
calcium concentrations; as a result, it could be high, normal, or low
• Evaluation of malabsorption syndromes (e.g., celiac disease) should be
considered in patients with persistently low 25-hydoxvitamin D levels
despite replacement
MANAGEMENT
• Vitamin D 400−800 IU recommended per day (see Chapter 27, Calcium
Metabolism Essentials)
° Dietary sources of vitamin D include milk, fish (e.g., salmon, tuna),
beef liver
° day (the amount
Exposure to UVB: direct sunlight to the skin for 10−15 minutes a
may vary according to time of day, season, age,
adiposity, skin tone)
• Vitamin D insufficiency/deficiency requires additional supplementa-
tion; cholecalciferol (D3) appears to be superior to ergocalciferol (D2) in
terms of bioavailability and circulating half-life of 25(OH)D
48565_ST04_161-198.indd 186 5/1/13 9:33 PM

References 187
• For patients with vitamin D insufficiency, increasing the daily intake

with a daily vitamin D supplement is one approach; the rule of thumb
is for every 1 ng/mL of 25(OH)D that is desired, you need an additional
100 IU of vitamin D daily
• For patients with vitamin D deficiency, additional daily vitamin D as
above or a short course of weekly bolus vitamin D can be implemented;
an example is cholecalciferol 50,000 IU weekly for 8−12 weeks fol-
lowed by a maintenance amount of vitamin D 1500 – 2000 IU daily in
children and adults >1 year of age
REFERENCES
Ganji V, Zhang X, Tangpricha V. Serum 25-hydroxyvitamin D concentrations
and prevalence estimates of hypovitaminosis D in the U.S. population
based on assay-adjusted data. J Nutr, 2012;142(3):498−507.
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and
prevention of vitamin D deficiency: an Endocrine Society clinical practice
Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference
intakes for calcium and vitamin D from the Institute of Medicine: what
clinicians need to know. J Clin Endocrinol Metab, 2011;96(1):53−8.
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48565_ST04_161-198.indd 188 5/1/13 9:33 PM
32 ■ OSTEOPOROSIS
Ben O’Donnell, MD and Geetha Gopalakrishnan, MD
EPIDEMIOLOGY
• In the US, it is estimated that there are 10 million people with osteopo-
rosis and another 33 million at risk for osteoporosis (i.e., osteopenia)
• Osteoporotic fractures are estimated to occur in
° 11 in
in 2 postmenopausal Caucasian women
° 5 men >50 years
• Osteoporotic fractures typically involve the spine, hip, and forearm
° Vertebral (spine) fractures are usually asymptomatic but can lead
to kyphosis and restrictive lung disease
° mortality are associated with an increase in morbidity and
Hip fractures
■ Mortality rates can be as high as 10−20% after a hip fracture
■ Only 40% return to a prefracture level of independence and 25%
require long-term nursing home care
DEFINITION
• Osteoporosis is diagnosed based on BMD measurements at spine, hip,
or forearm
° Two sites, typically spine and hip, are measured with a dual-energy
X-ray absorptiometry (DEXA)
• The World Health Organization (WHO) has set criteria for diagnosis
based on the T-score, which represents a standard deviation of
the calculated BMD when compared with healthy 20−30 year-old
controls
TABLE 32.1 BMD by DEXA

WHO Classifi cation T-Score
Normal ≥-1
Osteopenia -2.5 to -1
Osteoporosis ≤-2.5
Severe Osteoporosis ≤-2.5 with ≥1 fragility fracture
48565_ST04_161-198.indd 189 5/1/13 9:33 PM

190 Osteoporosis
• The diagnostic criteria can only be applied to postmenopausal women

and men >age 50
• In premenopausal women and men <age 50, the diagnosis of osteopo-
rosis should not be made on the basis of BMD criteria alone
° Age- and race-matched Z-scores define individuals as “below
expected range for age” if Z-score is <-2.0
• Osteoporosis can also be diagnosed based on presence of a fragility
fracture when the T-score is low, but not in the osteoporotic range;
fragility fractures occur as a result of low trauma (i.e., fall from stand-
ing height, fall from one step or less, spontaneous vertebral fracture)
and typically involve the spine, hip and forearm
BONE METABOLISM
• Bone remodeling exists in a state of balance between bone formation
and bone resorption
° Osteoblasts are responsible for new bone formation
° Osteoclasts are responsible for bone resorption
• Prior to age 25−30, this balance favors bone formation. As a person
ages, the balance shifts towards bone resorption. Reductions in sex
hormones, testosterone and estrogen, accelerate the bone loss.
• A person’s peak bone mass will determine the density of bone present
prior to the expected bone loss seen with aging, and is influenced by
a number of factors, including genetics, lifetime calcium and vitamin
D intake, level of physical activity, and exposure to a number of
secondary causes
TABLE 32.2 Secondary Causes of Osteoporosis (Selected)

Hypogonadism or premature menopause (<45 years)
Chronic malnutrition, or malabsorption and chronic liver disease
Rheumatoid arthritis, systemic lupus erythematosus (SLE), or ankylosing spondylitis
Malignancy such as multiple myeloma
Untreated long-standing hyperthyroidism
Type 1 (insulin dependent) diabetes mellitus
Osteogenesis imperfecta in adults
Immobility
Medications (antiepileptics, chemotherapy, glucocorticoids)
Source: FRAX Who Calculation Tool/NOF Clinical Guidelines
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Treatment 191
RISK FACTORS
• Major risk factors associated with fractures in Caucasian women
TABLE 32.3 Risk Factors for Osteoporosis and Fracture

Major Risk Factors Additional Risk Factors
Personal history of fracture as an adult Impaired vision
History of hip fracture in first-degree relative Early menopause (<age 45)
Low body weight Dementia
Current smoking Poor health or frailty
Use of oral glucocorticoid (equivalent of ≥5 mg of Recent falls
prednisone for ≥ 3 months)
Low lifelong calcium intake
Low level of physical activity
>2 alcoholic drinks per day
SCREENING
• Multiple guidelines exist for screening (Table 32-4)
• In general, all women > age 65 should be screened
• Little consensus exists in terms of interval between screening
TABLE 32.4 Screening Guidelines (Men and Women)

US Preventive Services Task Force Women >65 years old; postmenopausal Women;
(2011) <65 with FRAX score >9.3%; Men: no evidence
to screen (www.shef.ac.uk/FRAX/tool.jsp)
National Osteoporosis Foundation Women >65 y/o, men >70 y/o; Postmenopausal
(2010) women <65 and men >50 with risk factor(s)
American Congress of Obstetricians Women >65 years old; postmenopausal women
and Gynecologists (2008) <65 with risk factor(s)
American College of Physicians Periodically screen men for risk and obtain DEXA
(2008) in those with risk and who are candidates
for therapy
TREATMENT
• For a diagnosis of osteopenia or osteoporosis both calcium (1000−
1200 mg daily) and Vitamin D (800−1000 units daily) are recommended;
dietary sources of calcium are preferred (see Chapter 27, Calcium
Metabolism Essentials)
• Weight-bearing and balance exercises can also help to prevent fractures
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192 Osteoporosis
• Pharmacological therapy is recommended for individuals with a

° Vertebral or hip fragility fracture
° BMD diagnosis of osteoporosis (T-score ≤-2.5)
° ■ A risk profile individuals
Other high-risk
can be determined by using Fracture Risk
Assessment (FRAX) WHO Calculation Tool (http://www.shef.
ac.uk/FRAX/tool.jsp)
■ Pharmacological therapy is recommended in patients with
osteopenia (T-score between -1 and -2.5) if the FRAX tool

calculates the
• 10-year probability of a hip fracture to be >3%
• 10-year probability of other major osteoporotic fractures to
be >20%
• Several pharmalogical agents have been approved for the treatment
and prevention of osteoporosis (Table 32-3). Recommendations for
choosing drugs to treat osteoporosis
° First-line agents: alendronate, risedronate, zoledronic acid, denosumab
° Second-line agent: ibandronate, raloxifene
° Third-line agent: calcitonin
° and/or multiplepatients
Treatment for with very high fracture risk (i.e., T-score < -3.5
fragility fractures) or in whom bisphosphonate therapy
has failed: teriparatide
• Although no consensus exists on the frequency of retesting, DEXA
should not be repeated more frequently than every 2 years in post-
menopausal osteoporosis
TABLE 32.5 Medical Therapy for Use in Osteoporosis

Name Action Form Dose
Alendronate (Fosamax) Inhibits osteoclasts PO 70 mg/week
Risedronate (Actonel) Inhibits osteoclasts PO 35 mg/week or
150 mg/month
Ibandronate (Boniva) Inhibits osteoclasts PO/IV 150 mg po/mo or
3 mg IV q 3 mo
Zoledronic acid Inhibits osteoclasts IV 5 mg/year
(Reclast, Zometa)
Teriperatide (Forteo) PTH analog, stimulates Subcutaneous 20 mcg/day
bone formation
Denosumab (Prolia) Monoclonal antibodies Subcutaneous 60 mg q6mo
to RANKL, inhibits
osteoclast
Calcitonin Inhibits osteoclasts Intranasal/SQ/IM 1 spray/day
SERM-Raloxifene Stimulates estrogen PO 60 mg/day
(Evista) receptors in bone
Estrogen HRT Stimulates estrogen PO Variable
receptors in bone
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References 193
REFERENCES
ACOG Committee Opinion No. 407: low bone mass (osteopenia) and fracture
risk. Obstet Gynecol, 2008;111(5):1259−61.
Cummings, SR, MD et al, Risk Factors for Hip Fracture in White Women, The
Study of Osteoporotic Fractures Group, N Engl J Med, 1995;332:767–73.
Khosla, Sundeep MD and Melton, Joseph, MD, MPH. Osteopenia. N Engl J Med,
2007;356:2293–300.
Low bone mass (osteopenia) and fracture risk. ACOG Committee Opionion
No. 407. American College of Obstetricians and Gynecologists. Obstet
Gynecol, 2008;111:1259–61.
National Osteoporosis Foundation. Clinician’s Guide to Prevention and
Treatment of Osteoporosis. Washington, DC: National Osteoporosis
Foundation; 2010.
Qaseem, Amir MD et al; Screening for Osteoporosis in Men: A Clinical Practice
Guideline from the American College of Physicians. Annals of Internal
Medicine. 2008 May;148(9):680–684.
Screening for Osteoporosis: U.S. Preventive Services Task Force
Recommendation Statement. Annals of Internal Medicine. 2011
Mar;154(5):356–364.
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33 ■ PAGET’S DISEASE OF BONE
(OSTEITIS DEFORMANS)
Joseph Tucci, MD
ETIOLOGY
• Genetic: data consistent with important genetic component with
documented mutations in sporadic and familial Paget’s disease
• Viral: possibility of an underlying paramyxoviral infection based
on findings of viral-like inclusions in pagetic osteoclasts and other
extensive but somewhat conflicting laboratory data
PATHOPHYSIOLOGY
• Focal disorder of one or more bones (frequent sites include pelvis,
skull, spine, femur, tibia) characterized by accelerated remodeling,
high bone turnover
• Initially, bone changes characterized by an increase in number and bone
resorbing activity of enlarged osteoclasts with up to 100 nuclei per cell
• Subsequently, there is an associated increase in abnormal activity
of marrow stromal cells and an increase in number and activity of
osteoblasts with abnormal bone formation
• As a result, bone mass tends to increase and normal lamellar bone is
replaced by a chaotic mosaic pattern of woven and lamellar bone that
is structurally inferior to normal bone
• Increased vascularity of pagetic bone and marrow, replacement of
bone marrow by fibrous connective tissue
• A later phase is characterized by diminished bone turnover and scle-
rotic bone consistent with so-called “burned out” Paget’s disease
• Frequently, an asymptomatic patient with an incidental radiologic finding
and/or an increase in serum alkaline phosphatase on blood chemistry profile
• Bone pain related to increased vascularity, advancing lytic lesions in
long bones, deformation, fissure and chalkstick fractures, nonunion of
fractures in up to 10% of cases
• Joint pain due to degeneration of hip and/or knee joints (secondary
osteoarthritis) adjacent to pagetic bone
• Abnormal posture with abnormal tilt of trunk due to enlarged vertebral,
pelvic, and/or long bone deformities
• Bone deformity, long-bone bowing, skull enlargement with and without
frontal bossing, facial bone deformities
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196 Paget’s Disease of Bone (Osteitis Deformans)
• Neurologic symptoms: pagetic changes in skull with headaches,

cranial nerve deficits related to narrowed foramina especially hearing
loss, platybasia, brain stem compression, obstructive hydrocephalus,
myelopathy, spinal cord compression, spinal vascular steal syndrome,
spinal stenosis
• Cardiovascular complications: especially with extensive disease, high-
output CHF, endocardial and aortic valve calcifications, generalized
atherosclerosis
• Neoplastic: osteosarcoma (in <1% of patients), benign giant cell tumors
• Metabolic: hypercalcemia and/or hypercalciuria with immobilization of
patients with extensive disease, secondary hyperparathyroidism in up
to 20% of patients, coincidental PHPT
PHYSICAL EXAMINATION
• Angioid streaks on retinal exam
• Skull enlargement with or without frontal bossing or supraorbital
deformities, corrugation of skull surface, hearing deficits, deformation
of long bones with bowing, facial and clavicular deformities
• Increased warmth over pagetic bone
• Postural changes and gait abnormalities related to severe deformities
of spine, pelvis, and/or long bones
• Biochemical
° Increase in serum alkaline phosphatase and/or bone-specific
alkaline phosphatase, increase in bone resorption markers such as
urine N-telopeptide of collagen cross-links (NTx)/creatinine ratio or
plasma C-telopeptide of collagen cross-links (CTx)
° Degree of biochemical abnormalities related to extent of disease
and skull involvement
• Imaging
° Technetium bone scan most sensitive in delineating pagetic sites
of involvement
° Skeletal
on scan
X-rays provide a definitive assessment of positive sites
• Radiologic findings: bone enlargement, bowing of long bones, osteo-

lytic wedge or “blade of grass” appearance in long bones, lytic and
sclerotic bone changes, cortical and trabecular thickening, skull with
osteoporosis circumscripta, external and/or internal cranial thickening,
“picture frame” vertebrae, pelvic changes with sclerosis, and lytic
lesions with or without protrusion acetabuli
• Histologic: bone biopsy through pagetic bone occasionally performed
to distinguish Paget’s disease from metastatic cancer (e.g., prostate
cancer) or osteosarcoma
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Management 197
MANAGEMENT
• Rationale: to decrease bone turnover through inhibition of osteoclastic
bone resorption with bisphosphonates or calcitonin
• Objectives: to alleviate pagetic-related symptoms, effect sustained
biochemical and clinical remissions, prevent progression of pagetic
disease
• Comments
° Generally, the greater the activity and extent of disease, the higher
the serum alkaline phosphatase level and the greater likelihood of a
diminished response to therapy
° Before therapy, critically important to optimize calcium and vitamin D
intake to avoid hypocalcemia with bisphosphonate therapy
• Indications for therapy
° Extensive disease
° Pagetic pain
° Pagetic deformity
Pagetic fracture
° Neurologic complications
° Area(s) of critical involvement
° High-output CHF
° Preparation for surgery on pagetic bone to prevent excess bleeding
° Sarcoma
°
• Pharmacotherapy
° Aminobisphosphonates
■ Pamidronate (Aredia): 30 mg each day for 3 days given IV (over
4 hours in normal saline or 5% dextrose in water), 60 mg weekly

for 3 weeks, or up to 90 mg weekly for 4 weeks
• Normalization of serum alkaline phosphatase in majority of
patients
• Adverse effects: transient bone pain, acute phase reaction
or flulike syndrome occurring within several days following
the first infusion lasting up to two days or so (alleviated by
acetaminophen therapy), rare cases of uveitis
■ Zoledronic acid (Reclast): a single infusion of 5 mg over a 15-to-
30−minute period
• Efficacy: single most potent therapy with rapid normalization
of serum alkaline phosphatase and more sustained remissions
in 90% of patients
• Adverse effects: similar to therapy with pamidronate
■ Alendronate (Fosamax): 40 mg per day given orally for 6 months
in the fasting state with 8 oz of water and no food for

30−60 minutes, then remain sitting or standing for 30 minutes
• Efficacy: normalization of serum alkaline phosphatase in
60−70% of patients
• Adverse effects: chest and/or abdominal pain, reflux
symptoms, esophagitis
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198 Paget’s Disease of Bone (Osteitis Deformans)
■ Risedronate (Actonel): 30 mg per day given orally for 2 months in
fasting state with 8 oz of water and no food for 30−60 minutes,
then remain sitting or standing for 30 minutes
• Efficacy: normalization of serum alkaline phosphatase in
>70% of patients
• Adverse effects: chest and/or abdominal pain, reflux symp-
toms, esophagitis
° Salmon calcitonin (Miacalcin) second-line therapy: 50−100 units
injected SQ, 3 or 4 times weekly to daily
■ Particularly useful in patients intolerant to bisphosphonates and
in those with renal insufficiency

■ Therapeutic effect
• Generally 50% reduction in serum alkaline phosphatase with

no further reduction despite continued therapy (so-called
plateau response)
• Therefore, probable biochemical normalization in those with
serum alkaline phosphatase levels no higher than 2−3 times
upper limit of normal
• There may be an analgesic effect
■ Adverse effects: nausea, flushing of ears, possible development
of resistance especially with prolonged therapy
ASSESSMENT OF THERAPEUTIC RESPONSE

• Serum alkaline phosphatase and/or urine NTx creatinine ratio or
plasma CTx 1−2 months following initiation of therapy and then at
3-, 4-, or 6-monthly intervals
• Retreatment: 6 months or longer after initial therapy if remission not
effected or evidence of reactivation evidenced by an increase in serum
alkaline phosphatase of 25% above therapeutic peak response
• Other effects of therapy: alleviation of pagetic pain, replacement of
pagetic bone by more normal bone as evidenced by technetium scan-
ning, X-rays, or bone biopsy
REFERENCES
Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget’s
disease of bone. Lancet, 2008;372(9633):155–63.
Reid IR, Lyles K, Su G, et al. A single infusion of zoledronic acid produces
sustained remissions in Paget disease: data to 6.5 years. J Bone Miner
Res, 2011;26(9):2261–70.
Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of
zoledronic acid with risedronate for Paget’s disease. N Engl J Med,
2005;353(9):898–908.
Shankar S, Hosking DJ. Biochemical assessment of Paget’s disease of bone.
J Bone Miner Res, 2006;21(Suppl 2):22–7.
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SECTION V: REPRODUCTION
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48565_ST05_199-250.indd 200 5/1/13 9:32 PM
34 ■ MALE REPRODUCTION ESSENTIALS
Bruce Redmon, MD
TESTES
• Paired organs, each 15–30 ml volume (3.5–5.5 cm length, 2–3 cm
width)
• Endocrine and exocrine functions
° Endocrine function: synthesis and secretion of androgenic and
estrogenic hormones (primarily testosterone) and other hormones
involved in sexual differentiation and spermatogenesis (antimulle-
rian hormone [AMH], inhibin, androgen-binding protein, insulin-like
factor 3 [INSL3])
° Exocrine function: spermatogenesis
• Two compartment model
° Seminiferous tubules (exocrine compartment): 600–1200 per testis
■ Differentiating germ cells (germ cell → spermatogonia →
spermatocytes → spermatid → spermatozoa)

• 40–70 day time span for sperm differentiation/maturation
• ~120 million sperm produced per day
• Key genes regulating spermatogenesis localized to the
azoospermic factor (AZF) region of the long arm of the Y
chromosome (Yq)
■ Three regions (AZFa, AZFb, AZFc) identifi ed
■ Microdeletions of genes in these regions associated with
azoospermia or severe oligospermia

■ Sertoli cells
• “Nurse cells” surrounding differentiating germ cells

• Tight junctions form blood-testis barrier
■ Maintain specialized, immunologically restricted
environment for spermatogenesis

• Receptors for FSH and androgens
• Secretory function: proteins (e.g., androgen-binding protein,
inhibin, AMH) and extracellular matrix constituents
° ■ Leydig cells
Interstitial compartment
• Production and secretion of testosterone and other steroids in

response to LH
■ Three peaks in testosterone production: 12–18 weeks
gestation, 1–2 months of age, second to third decade

• Production of INSL3 (regulator of early testicular descent)
■ Supporting cells: myoid cells, fibroblasts, macrophages,
neurovascular cells
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202 Male Reproduction Essentials
REPRODUCTIVE OUTFLOW TRACT

• Epididymis
° Coiled tubule 3–6 m in length connecting testes to vas deferens
° Site of sperm storage (estimated 155–200 million sperm stored in
each epididymis) and maturation; estimated transit time 2–12 days;
transit associated with acquisition of motility and ability to fertilize egg
° Androgen-dependent (primarily DHT)
• Seminal vesicle/ejaculatory duct
° Seminal vesicle: collagenous tubular structure with outer muscular
layer, secretes up to 80% of seminal plasma (alkaline fluid containing
fructose, prostaglandins, coagulants)
° Ejaculatory duct: tubular continuation of seminal vesicle, extending
from junction of vas deferens and seminal vesicle to prostatic urethra
• Prostate/bulbourethral glands
° Prostate: secretes thin, acidic fluid (~20% of semen volume)
containing citric acid, acid phosphatase, proteolytic enzymes
■ Contributes to seminal plasma for sperm transport, nourishment,
and function
° alkaline fluid containing
Bulbourethral glands: secrete initial part of the ejaculate, a clear
glycoproteins that provides mechanical
lubrication and neutralizes the acidic mileu in the male urethral
and female vaginal tract
SEXUAL DIFFERENTIATION
• Four to six weeks gestation: migration of primordial germ cells from yolk
sac to genital ridge (primitive bipotential gonad) and development of
mesonephric (Wollfian) and paramesonephric (Mullerian) duct systems
• Testicular differentiation occurs in the presence of a Y chromosome via
activation of the transcription factor SRY (sex-determining region of
the Y chromosome) leading to
° Sertoli differentiation (week 7)
° AMH production with Mullerian duct regression (weeks 7–12)
° (weeks 8–9)differentiation with androgen and INSL3 production
Leydig cell
• Wollfian duct differentiation to form epididymis, vas deferens, seminal

vesicles in response to fetal testosterone (weeks 8–15)
• Development of external genitalia (scrotal fusion, development of
penis, prostate) in response to fetal DHT (weeks 8–15)
• Testicular descent
° Transabdominal: weeks 10–23, regulated by testosterone and INSL3
° Inguinal-scrotal: weeks 26–birth, regulated by testosterone
• Early postnatal period: transient activation of hypothalamic-pituitary-
testicular axis at 1–6 months with increased LH, FSH, testosterone
production, Sertoli cell proliferation, formation of early spermatogonia
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Neuroendocrine Regulation 203
• Puberty: sustained reactivation of hypothalamic-pituitary-testicular axis

with increased gonadotropins, testosterone production, development of
secondary sexual characteristics, Sertoli cell stimulation of spermato-
genesis with seminiferous tubule growth and increased testicular size
NEUROENDOCRINE REGULATION
• Pulsatile hypothalamic GnRH release drives pulsatile LH (12–16 pulses/
day) and FSH release (less pulsatility)
° Differential activation of gonadotropins gene expression in
response to pulse frequency
• Regulation of GnRH via central neurotransmitters (stimulatory:
kisspeptin, neurokinin; inhibitory: dynorphin, PRL, opiates, CRH/
glucocorticoids) and peripheral metabolic signals (stimulatory: leptin)
Opiates
Prolactin
--
Glucocorticoids
+ Hypothalmus +/--
Hypothalamic
KNDy neurons
GnRH
Leptin +
Pituitary --
-- Estrogen
LH
Peripheral
fat stores FSH
Testosterone
Inhibin + DHT
Testes
Note: Steroid hormone feedback regulation at the level of the hypothalamus is felt
to be indirect and mediated via hypothalamic KNDy neurons containing kisspeptin
(K), neurokinin (N) and dynorphin (Dy). Kisspeptin and neurokinin promote GnRH
release while dynorpnin is inhibitory.
FIGURE 34.1 Hypothalamic-Pituitary-Testes Axis
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204 Male Reproduction Essentials
• Negative feedback by sex steroids at level of hypothalamus (testicular-

derived testosterone, progesterone, and estradiol derived via aromati-
zation of testosterone by aromatase found in multiple tisses, including
testis, fat, brain, and liver) and pituitary (estradiol primarily), and
Sertoli cell-derived inhibin B (suppression of FSH)
° Sex steroid regulation at the hypothalamus likely indirect, possibly
via neurons co-staining for kisspeptin/neurokinin/dynorphin
• Autocrine/paracrine regulation of FSH secretion via gonadotrope-derived
peptides: activins (stimulatory), inhibin (structurally related to activins
but inhibitory) and follistatin (inhibitory activin-binding protein)
REFERENCES
Bronson R. Biology of the male reproductive tract: its cellular and morpho-
logical considerations. Am J Reprod Immunol, 2011;65(3):212–9.
Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin
B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the
control of gonadotropin-releasing hormone secretion. Endocrinology,
2010;151(8):3479–89.
Matsumoto AM, Bremner WJ. Testicular disorders. In: Melmed S, Polonsky KS,
Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 12th ed.
Philadelphia, PA: Saunders Elsevier; 2011:688–777.
Sam S, Frohman LA. Normal physiology of hypothalamic pituitary regulation.
Endocrinol Metab Clin North Am, 2008;37(1):1–22.
Turek P. Male reproductive physiology. In: Wein A, Kavoussi W, Novick A,
Partin A, Peters C. Urology. 10th ed. Boston, MA: Saunders Elsevier; 2011:
591 Chapter 20:591–625.
48565_ST05_199-250.indd 204 5/1/13 9:32 PM

35 ■ GYNECOMASTIA
Harmeet Narula, MD and Harold Carlson
• Gynecomastia definition
° Benign enlargement of male breast
• Pseudogynecomastia (lipomastia)
° Fatty breasts, common in obese men, no true glandular breast
tissue palpable
• Pathophysiology
° Altered androgen (A) to estrogen (E) ratio
■ ↓ level or action of androgens, and/or
■ ↑ level or action of estrogens
TABLE 35.1 Pathogenesis of Gynecomastia

Decreased Androgens
(↓Total or Bioavailable Testosterone)
Primary hypogonadism Secondary hypogonadism
(↑ LH/FSH) (normal or ↓ LH/FSH )
Klinefelter’s syndrome: only cause of Kallman syndrome and all other causes of
gynecomastia with increased breast secondary hypogonadism
cancer risk
Mumps orchitis and any cause of Elevated prolactin from any cause including
primary hypogonadism drugs (antipsychotics, metoclopramide)
Drugs: cytotoxic chemotherapy, Drugs: GnRH agonists/antagonists, opiates
ketoconazole, spironolactone in high doses in high doses
Increased Estrogens
Exogenous estrogens Endogenous estrogens
Oral, injectable, or percutaneous Testicular
exposure Sertoli or Leydig cell tumors;
stimulation of normal testes by LH/hCG
Anabolic steroids (if aromatized to Adrenal
estrogens) Feminizing adrenocortical tumors
Increased aromatization of androgens
to estrogens: aging, obesity, cirrhosis,
hyperthyroidism, aromatase excess syndrome
Decreased androgen action Altered A to E ratio
Defective androgen receptors (AR) Puberty, aging (physiologic)
AR blockade: marijuana, spironolactone, “Refeeding” gynecomastia: dialysis,
cimetidine, bicalutamide, flutamide cirrhosis, CHF, hyperthyroidism
Kennedy disease (↑ CAG repeats in Drugs (e.g., finasteride)
AR gene)
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206 Gynecomastia
• Often asymptomatic, incidentally found on routine exam, especially at
extremes of age (puberty and aging)
• Breast pain, sensitivity: in men with recent-onset enlargement
• Breast enlargement: usually symmetrical, bilateral
TABLE 35.2 History and Physical Examination in Gynecomastia
History Physical Exam
Duration of gynecomastia General: thyroid, stigmata of liver disease
Breast pain or tenderness Degree of virilization: voice, facial and
body hair, skeletal muscle mass
Underlying systemic disease Genitalia: penile size and development,
testicular size and/or masses
Fertility and sexual function
Use of medications, recreational drugs, Breast exam: rule out fatty breasts
and supplements (specifically anabolic (lipomastia) and malignancy, unilateral
steroids, marijuana, opiates) or bilateral, symmetric or asymmetric
enlargement
Any exposure to estrogenic chemicals
including phytoestrogens
Family history of gynecomastia: suggests Worrisome findings suggestive of breast
androgen insensitivity or aromatase cancer: asymmetry, eccentric location (not
excess syndromes centered beneath the areola), fixation to
the skin or chest wall, nipple retraction,
bleeding or nipple discharge, ulceration, or
associated lymphadenopathy (if present,
refer to expert breast surgeon for excision
and/or biopsy)
• Laboratory testing: serum testosterone (total and/or bioavailable),
estradiol, LH, FSH, PRL, β-hCG, TSH, BUN/creatinine, LFTs
• Imaging: NO need for routine mammograms, ultrasounds, or any other
imaging study in men with gynecomastia unless there are any worri-
some signs of malignancy or the breast enlargement is asymmetric,
unilateral, or recent onset
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References 207
MANAGEMENT
• Observation: in healthy men with longstanding stable gynecomastia,
puberty, aging
• Withdrawal of offending agent (if reversible cause of gynecomastia
found on workup)
° Up to 50% of gynecomastia may be due to drugs; stopping offend-
ing drug may lead to spontaneous resolution of gynecomastia in
6−12 months
• Medical Rx
° In symptomatic men, especially if gynecomastia of recent onset
(<2 years)
° ■ May worsenRx:gynecomastia
Testosterone in men with hypogonadism
(testosterone aromatized to estradiol)
° Tamoxifen (antiestrogen): drug of choice (off-label); 10−20 mg/day
for 3−9 months; raloxifene 60 mg/day may be equally effective
° Anastrazole (aromatase inhibitor): in men with aromatase excess
syndrome or who develop gynecomastia on testosterone therapy
• Breast irradiation: in men with prostate cancer planning androgen
ablation therapy, breast irradiation may prevent gynecomastia
• Surgery
° Ifmastia,
medical therapy ineffective or declined, for longstanding gyneco-
or for cosmesis
° regrowth
Rule out underlying endocrine disorder BEFORE surgery (to prevent
of breast tissue after surgery)
REFERENCES
Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med, 2007;357(12):
1229−37.
Carlson HE. Approach to the patient with gynecomastia. J Clin Endocrinol
Metab, 2011;96(1):15−21.
Narula HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am,
2007;36(2):497−519.
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48565_ST05_199-250.indd 208 5/1/13 9:32 PM
36 ■ TESTOSTERONE DEFICIENCY IN MEN
Diana R. Engineer, MD and Glenn R. Cunningham, MD
PREVALENCE
• Symptomatic androgen deficiency prevalence increases with age:
<70 yrs age 3.1−7%; >70 yrs age 18.4%
• Diagnosis requires presence of signs/symptoms + low testosterone
level
PATHOPHYSIOLOGY
FIGURE 36.1 Hypothalamic-pituitary-testicular axis in a normal male.
• Hypothalamic-pituitary-testicular axis in a normal male. GnRH =

gonadotropin-releasing hormone, LH = luteinizing hormone, FSH =
follicular stimulating hormone, DHT = 5α-dihydrotestosterone
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210 Testosterone Defi ciency in Men
ETIOLOGY
TABLE 36.1 Etiology of Testosterone Defi ciency in Men

Secondary (hypothalamic- Primary (testicu-
pituitary dysfunction) lar dysfunction) Mixed
Congenital Idiopathic GnRH deficiency, Chromosomal
Kallman syndrome, Prader- abnormalities
Willi syndrome, Laurence- (Klinefelter’s,
Moon-Biedl syndrome, XX male gonadal
panhypopituitarism, dysgenesis),
pituitary hypoplasia defects in
androgen
biosynthesis,
myotonia
dystrophica,
cryptorchidism,
varicocele
Inflammatory Orchitis (mumps, Chronic infection
human (HIV, tuberculosis,
immunodeficiency fungal infection)
virus [HIV], viral,
leprosy)
Trauma Postsurgical blunt head Orchiectomy Irradiation
trauma
Tumor Pituitary adenoma,
craniopharyngioma
Vascular Pituitary infarct/apoplexy, Testicular torsion
insult carotid aneurysm
Drugs Sex steroids, drug-induced Cytotoxic drugs, Corticosteroids
hyperprolactinemia, ketoconazole,
opioids cimetidine,
spironolactone
Systemic Anorexia nervosa Malnutrition,
Illness chronic renal
failure, liver
failure, chronic
inflammatory
disease
Autoimmune Autoimmune hypophysitis
Infiltrative Sarcoidosis,
histiocytosis,
hemochromatosis
Toxins Alcohol,
fungicides,
insecticides,
heavy metals
Other Obesity, aging
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Chronic Conditions with High Prevalence of Hypogonadism 211
HISTORY
• Depressed mood, quality of life, confidence
• Developmental history (testicular descent, onset of puberty, body/
facial hair development, age achieved maximal height)
• Detailed medical history (systemic illness, sexually transmitted diseases
[STDs], orchitis, orchiectomy, irradiation, prostate surgery, drugs)
• Detailed sexual history (libido, erectile and ejaculatory function,
coitus, fertility)
• Frequency of shaving, body hair patterns
• Height loss, decreased bone density, fragility fractures
• Hot flashes or sweats
• Mild anemia (normochromic, normocytic)
• Sleep disturbance, increased sleepiness, sleep apnea
PHYSICAL EXAM
• Breast tenderness or gynecomastia
• Eunuchoid proportions (arm span ≥2 inches greater than height; lower
segment [floor to pubis] ≥2 inches greater than upper body segment
[pubis to crown])
• Hair patterns: decreased facial/axillary/chest/pubic hair, female
(triangular) escutcheon
• Increased body and visceral fat
• Acne
• GU exam: penis length, urethra for hypospadia, prostate exam for
small/atrophied prostate (can be obscured by benign prostatic
hyperplasia [BPH])
• Scrotal exam for testicular descent, consistency, and size (<4 × 2 cm
or <20 mL), varicocele
• Musculoskeletal development, strength, muscle atrophy, bone
deformity/fractures
CHRONIC CONDITIONS WITH HIGH PREVALENCE OF HYPOGONADISM

• Consider screening for testosterone deficiency
° Chronic liver disease
° Chronic obstructive pulmonary disease (COPD), moderate−severe
° Glucocorticoid
End-stage renal disease (ESRD) and hemodialysis
° Human immunodefi or opiod use
° Hypertension ciency virus (HIV)-associated weight loss
° Hyperlipidemia
° Infertility
° Obesity
°
48565_ST05_199-250.indd 211 5/1/13 9:33 PM

° Obstructive sleep apnea

° Osteoporosis or fragility fracture
° Rheumatoid arthritis
° Sellar mass, radiation to sella
° Type 2 diabetes
ASSAYS/TESTS
• Total testosterone: liquid chromatography with tandem mass spec-
trometry (preferred), radioimmunoassay (RIA), platform immunoassays
(more variable)
• Direct analogue free testosterone: not valid
• Total testosterone/sex hormone–binding globulin (SHBG) ratio: not
very reliable
• Free testosterone: equilibrium dialysis (gold standard); calculated free
T (need total + SHBG)
• Bioavailable testosterone: NH4SO4 precipitation of T-SHBG; calculated
bioavailable T (need total T, SHBG, albumin)
• SHBG: varies in different conditions; 40−50% of testosterone is bound
to SHBG; changes in SHBG will affect the total testosterone level, but
will not affect the free or bioavailable testosterone level
TABLE 36.2 Variations in SHBG

Increased SHBG Decreased SHBG
Aging Glucocorticoid, progestin, anabolic
steroid use
Anticonvulsant use Hypothyroidism
Cirrhosis Nephrotic syndrome
Estrogen use Obesity, metabolic syndrome
Hyperthyroidism Type 2 diabetes
HIV infection
Malnutrition, malabsorption
DIAGNOSIS
• Requires signs/symptoms + low total testosterone level
° Normal and low testosterone levels should be defined for each
assay. There is an ongoing effort by the US Centers for Disease
Control and Prevention (CDC) to harmonize testosterone assays to
the same standard, which should help to harmonize normal ranges.
The International Society of Andrology defines low testosterone
as levels <231 ng/dL and borderline levels 231–346 ng/dL. The
Endocrine Society uses <300 ng/dL
48565_ST05_199-250.indd 212 5/1/13 9:33 PM

Potential Risks of Androgen Replacement 213
TABLE 36.3 Etiology of Testosterone Defi ciency in Men

Hypogonadism Etiology Further Work-Up Treatment
Hypogonadotropic Prolactin, iron saturation, HCG or T to virilize,
hypogonadism (central) pituitary function testing, gonadotropins or
MRI sella turcica* pulsatile GnRH for fertility
+ virilization
Testicular insufficiency Karyotype T to virilize
(primary)
T = serum testosterone
*MRI pituitary in secondary/central hypogonadism if tumor suspected clinically or if total testosterone
<150 ng/dL.
• Initial labs: fasting 7−10 AM serum total testosterone; if low total

testosterone, repeat and include LH, FSH, PRL
• Measure free or bioavailable testosterone level in men with borderline
low total testosterone or in whom alterations in SHBG are suspected
• Evaluation of androgen deficiency should not be done during any acute
or subacute illness
• DEXA scan recommended for all men with severe testosterone
deficiency or fragility fracture
Avoid Testosterone Therapy if:
• Breast or untreated prostate cancer
• Hematocrit >50%
• Untreated, severe obstructive sleep apnea
• Severe lower urinary tract symptoms (American Urological Associaton
(AUA) International Prostate Sympton Score (IPSS) >19)
• Uncontrolled CHF (New York Heart Association (NYHA) Class III or IV)
• Desire for fertility
POTENTIAL RISKS OF ANDROGEN REPLACEMENT

• Acne/oily skin
• Decreased high-density lipoprotein (HDL) cholesterol
• Erythrocytosis (excessive increase in red blood cell count [RBC])
• Growth of metastatic prostate cancer, breast cancer
• Gynecomastia (via aromatization)
• Increased male pattern balding
• Induce or worsen sleep apnea
• Possible increase in cardiovascular disease (CVD) risk
• Reduced sperm production and fertility
• Worsening of benign prostatic hypertrophy or lower urinary tract
symptoms
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TABLE 36.4 Androgen Replacement
Preparations Dosage Pros Cons/Risks
Injectable/ • Testosterone • Inexpensive • Nonphysiologic
Intramuscular enanthate • Certainty of troughs/peaks
• Testosterone compliance • Pain at injection
cypionate • Testosterone site
• Start 50–100 undecanoate • Check serum T
mg/week or requires less mid-way between
100–200 mg frequent dosing injections (goal
q2weeks 400–700 ng/dL)
• Testosterone
undecanoate*
Transdermal • Gel (Androgel 1% Relatively steady • Transfer by
or 1.6%, Testim serum intimate contact
1%) concentrations (gel)
• Start 5–10 g Ease of application • Skin irritation
of 1% gel/day (patch)
(provides 50–100 • Check level
mg T daily) 4–8 hours after
• Lotion (Axiron): application
60 mg once daily
applied to axilla
(30–120 mg/d)
• Fortesta 2% gel
60 mg/d
• Patch (Andoderm)
• Start 4–8 mg
daily
Buccal • Tablets: 30 mg • Ease of • Variable
applied twice administration absorption
daily • 2x/day dosing
• Alteration in
taste
• Gum irritation
• Check serum
T immediately
before or after
application
(continues)
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Potential Risks of Androgen Replacement 215
Preparations Dosage Pros Cons/Risks
Implants • Pellets: 100–200 • Steady serum • Surgical
mg, 3–6 concentrations insertion
pellets inserted • Less frequent • Infection
subcutaneously dosing • Expulsion of
every 4–6 • Compliance pellet
months • Check T level
1–2 months after
implantation
Oral • Testosterone • Ease of • Variable
undecanoate* administration absorption*
*Only available in Europe.
TABLE 36.5 Monitoring

Every 6−12
Parameter Baseline 2−3 Months 6 Months 12 Months Months
Symptom √ √ √ √
Response
Adverse √ √ √ √
Events
Testosterone √ √ √ √
Level
Hematocrit* √ √ √ √ √
PSA† √ √ √ √ √
DRE† √ √ √ √
BMD‡ √ √
DRE = digital rectal exam
* If Hct >54%, stop therapy until Hct decreases to safe levels, evaluate for hypoxia and OSA, and restart
testosterone therapy with reduced dose.
† After 3 months, continue to follow PSA and DRE per age and race-appropriate guidelines.
‡ For patients with osteoporosis or fragility fracture; recheck at 12−24 months.
• Stop therapy and refer to urology if

° PSA increases >1.4 ng/mL within 12 months
° PSA>4 ng/mL
° levelsvelocity
PSA >0.4 ng/mL per year over >6 months (must have PSA
≥2 years)
° Abnormal Digital Rectal Exam (DRE)
° AUA/IPSS >19
48565_ST05_199-250.indd 215 5/1/13 9:33 PM

REFERENCES
Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen
deficiency in men. J Clin Endocrinol Metab, 2007;92(11):4241–7.
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone Therapy in Men
with Androgen Deficiency Syndromes: Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2010;95:2536–59.
Guay AT, Spark RF, Bansal S, et al. American Association of Clinical
Endocrinologists medical guidelines for clinical practice for the evaluation
and treatment of male sexual dysfunction: a couple’s problem—2003
update. Endocr Pract, 2003;9(1):77–95.
Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and moni-
toring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and
ASA recommendations. Eur J Endocrinol, 2008;159(5):507–14.
Wu FCW, Tajar A, Beynon JM. Identification of Late-Onset Hypogonadism in
Middle-Aged and Elderly Men. N Engl J Med, 2010;363:123–35.
48565_ST05_199-250.indd 216 5/1/13 9:33 PM

37 ■ MALE INFERTILITY
Bradley Anawalt, MD
DEFINITION OF INFERTILITY
• Failure to conceive after 1 year of frequent intercourse without
contraception
PATHOPHYSIOLOGY OF MALE INFERTILITY

• Broad categories (prevalence %)
° Primary testicular defect in sperm production (70−80%)
■ Idiopathic
■ Chemotherapy
■ Pelvic irradiation
■ Orchidectomy (even unilateral)
■ Trauma
■ Klinefelter’s syndrome
■ Testicular cancer
■ Large varicoceles
■ Autoimmune
° Transport of sperm defect (5−10%)

■ Obstruction
• Congenital absence of the vas deferens (usually due to cystic

fibrosis)
■ Ejaculatory dysfunction
• Anejaculation (e.g., spinal cord lesions)

• Retrograde ejaculation
° ■ Hypothalamopituitary
Endocrinopathies (5%)
disease (masses, infiltrative disorders)
■ Hyperprolactinemia
■ Thyroid dysfunction
• Untreated hyperthyroidism
• Untreated hypothyroidism
■ Obesity
■ Cushing’s syndrome
° Sexual disorders (5%)

■ Erectile dysfunction
■ Failure to have intercourse
• Lack of libido
• Relationship dysfunction
■ Anorgasmia (sometimes associated with anejaculation) due
to selective serotonergic reuptake inhibitors
48565_ST05_199-250.indd 217 5/1/13 9:33 PM

218 Male Infertility
• History
° Sexual history
■ Normal libido? Normal erections? Cloudy postcoital urine
(suggesting retrograde ejaculation)? Frequency of vaginal

intercourse (at least 2−3 times weekly)? Ever fathered a child?
° ■ Historyhistory
Medical
of testicular trauma, surgery, pelvic irradiation?
■ Systemic illness (any severe systemic illness can suppress
sperm production)
■ History of chemotherapy
■ Drugs and toxins such as tetrahydracannabinol, opiates, nicotine
° Height, weight, body mass index (BMI)
° Skin examination for evidence of corticosteroid excess (broad
purple striae, ecchymoses)
° Thyroid exam for goiter
° Breast exam for gynecomastia, galactorrhea
° large varicocele,
Genitourinary exam for evidence of hypospadias, penile fibroses,
small testes (<15 cc or <3.5 cm in longest axis),
testicular mass, palpable vas deferens (if not palpable, consider
forme fruste of cystic fibrosis)
° Neurologic
anesthesia
examination for signs of autonomic neuropathy, saddle
• Blood tests
° Serum total and calculated free testosterone, LH, and FSH from a
fasting early morning blood sample
° LH), then patientis has
If testosterone low and LH and FSH are both high (FSH >
primary testicular dysfunction (primary
hypogonadism)
° then patient has hypothalamopituitary
If testosterone is low and LH and FSH are both normal or low,
disease (secondary
hypogonadism)
° Iflikely
testosterone and LH are both normal but FSH is high, then patient
has an isolated defect in testicular sperm production
° Serum TSH
Serum if clinical evidence of thyroid dysfunction
° FSH arePRL and iron saturation if testosterone is low and LH and
both normal or low
° Serum karyotyping if patient has small testes and primary
hypogonadism
° Sperm autoantibodies: consider if history of trauma, torsion, or uni-
lateral orchidectomy, or if clumps of sperm on seminal fluid analysis
48565_ST05_199-250.indd 218 5/1/13 9:33 PM

Treatment of Male Infertility 219
° Gene mutation testing for cystic fibrosis if patient does not have
palpable vas deferens and seminal fluid suggestive of obstruction
° Testing for Y chromosome microdeletion if patient has normal serum
testosterone and LH, but sperm concentration 0−10 million/ml
• Seminal fluid analysis
° At least two seminal fluid analyses obtained after abstention from
ejaculation for at least 48 hours
° ■ If ≤1.5fluid
Seminal volume should exceed 1.5 ml
cc (many experts use ≤2.0 ml), then it is either an incom-
plete collection (spilled) or a sign of obstruction
■ Other signs of obstruction: pH <7.2, absence of fructose
° There should
Sperm concentration should exceed 15 million/ml
° be few white blood cells (<1 million/ml) in seminal fluid
DIAGNOSTIC IMAGING
• Scrotal ultrasound if scrotal or testicular mass or large varicocele
• Transrectal ultrasound if seminal fluid analysis suggests obstruction
or if significant number of white blood cells repeatedly in seminal fluid
• Sellar imaging if patient has biochemical evidence of secondary
hypogonadism
TREATMENT OF MALE INFERTILITY

• Adoption may be considered as an option for any couple
• Therapies for primary testicular failure
° Consider referral to specialist for assisted reproductive technology
■ Sperm retrieval by microsurgery followed by intracytoplasmic
sperm injection (ICSI) into recipient egg

• Expensive
° Consider varicocelectomy for a large varicocele
• Therapies for transport of sperm defects
° Obstruction
■ Referral to specialist for possible surgery or sperm retrieval by
microsurgery
° Ejaculatory dysfunction
■ α agonist for retrograde ejaculation
■ Referral for electrostimulation for anejaculation (e.g., patient
with spinal cord injury)

• Therapies for endocrinopathies
° Hypothalamopituitary disease
■ Gonadotropin therapy with hCG +/– rhFSH generally
recommended
48565_ST05_199-250.indd 219 5/1/13 9:33 PM

220 Male Infertility
° Hyperprolactinemia
■ DA agonists
■ Gonadotropin therapy
° ■ See Section
Thyroid dysfunction
II, Thyroid
° Obesity
■ Weight loss via lifestyle or bariatric surgery
■ Consider gonadotropin therapy
■ Consider an aromatase inhibitor (for <12−18 months)
° Cushing’s syndrome
■ See Chapter 12, Cushing’s Syndrome
• Therapies for sexual disorders

° Erectile dysfunction
■ Oral phosphodiesterase therapy and/or alprostadil administered
via urethral capsule or intracavernosal injection

° Failure to have intercourse
■ Counseling
° Anorgasmia due to selective serotonergic reuptake inhibitors

■ Consider adding or switching to bupropion
REFERENCES
Bhasin S. Approach to the infertile man. J Clin Endocrinol Metab,
2007;92(6):1995−2004.
Jungwirth A, Giwercman A, Tournaye H, et al. European Association
of Urology guidelines on Male Infertility: the 2012 update. Eur Urol,
2012;62(2):324−32.
McLachlan RI, O’Bryan MK. Clinical Review: state of the art for genetic test-
ing of infertile men. J Clin Endocrinol Metab, 2010;95(3):1013−24.
Patel ZP, Niederberger CS. Male factor assessment in infertility. Med Clin
North Am, 2011;95(1):223−34.
48565_ST05_199-250.indd 220 5/1/13 9:33 PM

38 ■ FEMALE REPRODUCTION ESSENTIALS
Natali Franzblau, MD
DEVELOPMENT OF THE FEMALE REPRODUCTIVE TRACT IN THE EMBRYO

• During the sixth week of gestation the undifferentiated gonad begins to
develop into an ovary. This development process continues with mitosis
to increase the number of oogonia and then at approximately 12 weeks,
some of the oogonia begin to undergo meiosis becoming primary oocytes.
Meiosis arrests in prophase I until ovulation begins in the teen years.
• The uterus, cervix, and fallopian tubes develop from the parmeso-
nephric ducts (mullerian ducts). These two ducts remain separate to
form the fallopian tubes and fuse more caudally to form one uterus
and cervix. Abnormalities in this process result in anatomic anomalies
of the uterus and cervix
• The vagina develops from the urogenital sinus in conjunction with
the fused mullerian ducts. The primordial vagina starts out as a solid
structure that then canalizes. Abnormalities in this development will
lead to congenital anomalies of the vagina, primarily horizontal or
transverse vaginal septums
PUBERTY
• Menarche: age of first menses; usually occurs at age 11−15
° It may take up to two years for an adolescent to have regular menses
• Preceded by
° Thelarche: start of breast development, occurs at age 8−13
° Pubarche/adrenarche: start of axillary and pubic hair growth and
sweat gland maturation, begins between the ages of 8 and 10
° Growth spurt begins between 10 and 14 years of age
HORMONES OF THE MENSTRUAL CYCLE

• GnRH
° Deca-peptide released from the arcuate nucleus of the hypothalamus
in a pulsatile fashion
° pituitary glandthe portal circulation, which goes directly to the
Secreted into
° The changes in the amplitude and frequency of the pulsatile

secretion contributes to the hormonal changes in the menstrual
cycle. Estrogen increases the frequency of pulses and progesterone
and testosterone decrease the frequency of pulses. Catecholamine
neurotransmitters also increase the frequency of the pulses
48565_ST05_199-250.indd 221 5/1/13 9:33 PM

222 Female Reproduction Essentials
• FSH
° Glycoprotein secreted from anterior pituitary in pulsatile fashion
° Levels vary by age and time in cycle
° follicular phase of cycle
Secreted in greater amounts when estrogen levels are lower in the
° Stimulates granulosa cells of the ovary to produce estradiol

° Stimulates the development of ovarian follicles
° pituitary to inhibit
As estradiol levels rise, there is negative feedback on the anterior
secretion of FSH
° An elevated FSH in particular clinical settings is highly suggestive
of menopause
• LH
° Glycoprotein secreted from anterior pituitary in pulsatile fashion
° When estradiol reaches the appropriate level, there is a positive
feedback loop that stimulates LH secretion
° This LH surge triggers oocyte maturation and ovulation
° After ovulation, LH promotes the development and maintenance
of the corpus luteum
• Estradiol
° Produced primarily by the ovary and by the corpus luteum
° 1−3% free in blood with 40% bound to SHBG; remaining is bound
to albumin
■ Estrogens have a negative feedback effect on the secretion of
FSH. Estrogen can have either positive or negative feedback

effects on LH at different times and in different hormonal milieus
° Levels can be checked to monitor follicular development in women
undergoing infertility evaluation and treatment
° of menstrualoverlap
Signifi cant in estradiol levels in women of different stages
cycle; perimenopause and early menopause make it
less reliable for determining if a woman is in menopause
• Progesterone
° Produced
ovulation)
by the corpus luteum (formed from the follicle after
° Prepares
tion occurs
the uterine lining for implantation of an embryo if concep-
° 80% boundbetoused
Levels can to assess if ovulation has occurred
° other binding globulins
albumin, 2% free; remainder bound to SHBG and
° Levels can vary greatly in the luteal phase because it is secreted in

a pulsatile fashion
° conception occurs,
Progesterone is crucial to the maintenance of a pregnancy. If
hCG (produced by the placenta starting 10 days
postovulation) maintains the integrity of the corpus luteum’s hormone
production in early pregnancy. Later, the placenta itself produces
progesterone
48565_ST05_199-250.indd 222 5/1/13 9:33 PM

Hormones of the Menstrual Cycle 223
• Androgens
° Androgens (androstenedione, DHEA and testosterone) are produced
in varying amounts by the ovary in response to LH and FSH by the
theca cells
° The granulosa cells of the ovary aromatize androgens to produce
estradiol
° Androgens are also produced by the adrenal gland
TABLE 38.1 The Menstrual Cycle
Menses/Follicular
Phase Ovulation Luteal Phase
Pituitary Hormones FSH stimulates LH surge at day Low levels of FSH
follicular 14 in response and LH due to
development to increasing suppression by
and estrogen estrogen levels progesterone
production;
positive feedback
of estrogen
stimulates LH
production
Ovarian Estrogen slowly Estrogen is at Progesterone
Hormones increases and its peak and starts to peak
progesterone progesterone 4 days after
remains low during begins to rise ovulation; if there
the follicular is no fertilization,
phase progesterone
levels begin to
recede, resulting
in beginning of
the next cycle;
estrogen levels
slowly return to
baseline
Ovary Follicle development Mature oocyte is Follicle converts
begins with a rise released from to corpus luteum
in FSH. By the follicle in response and produces
fourth day of cycle, to the LH surge progesterone
estrogen levels
increase. Follicles
continue to mature
until one is singled
out to be the
dominant follicle
and others become
atretic.
(continues)
48565_ST05_199-250.indd 223 5/1/13 9:33 PM

Menses/Follicular
Phase Ovulation Luteal Phase
Endometrium Menses start and Endometrium Progesterone
the endometrium reaches a maximal stimulates
sloughs down to thickness by the stroma to
its base levels ovulation become loose
within 4−6 days. and edematous;
Then it begins to the blood vessels
regenerate again thicken and the
in response to glands become
rising estrogen tortuous
levels. In this
proliferative
phase,
endometrial
glands elongate
and stroma
thickens.
NORMAL MENSTRUAL CYCLE

• Cycle length: 21−35 days
• Period length: 2−7 days
• Amount of blood loss: average is 30 ml, >80 ml is abnormal
• Pattern: no bleeding between the periods
• Conventional terminology: first day of cycle is the day the menstrual
bleeding starts
MENOPAUSE
• Menopause: average age of occurrence is 51; defined as 1 year without
menses
• Perimenopause usually begins sometime between ages 39 and 51, a
time during which menstrual cycles may be less predictable
° During this time, gynecological evaluation is recommended if
periods last >7 days in length, if periods are more frequent than
every 21 days, if there is bleeding between periods, or if the
bleeding becomes significantly heavier
48565_ST05_199-250.indd 224 5/1/13 9:33 PM

Menopause 225
(continues)
FIGURE 38.1 Menstrual Cycle diagram
48565_ST05_199-250.indd 225 5/1/13 9:33 PM

(continued )
Source: © Grei/ShutterStock, Inc.
REFERENCES
American College of Obstetricians & Gynecologists, Precis. Precis: An Update in
Obstetrics and Gynecology: Reproductive Endocrinology. 3rd ed. Washington,
DC: American College of Obstetricians; 2007.
Droegmueller W; Herbst A; Mishell D; Stenchever M., Comprehensive
Gynecology, 1st edition. Philadelphia, PA: Mosby; 1987: 3–242.
Emans SJ, Goldstein D, Laufer M. Pediatric and Adolescent Gynecology. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 120–155.
Fritz MA, Speroff L. Clinical Gynecology Endocrinology and Infertility. 8th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2011:105–120;199–242.

48565_ST05_199-250.indd 226 5/1/13 9:33 PM

39 ■ POLYCYSTIC OVARY SYNDROME (PCOS)
Thozhukat Sathyapalan, MD, FRCP and Stephen L. Atkin, FRCP, PhD
BACKGROUND
• Heterogeneous syndrome involving ovarian abnormality, disturbance
to the menstrual cycle, infrequent or absent ovulation, hyperandrogen-
ism, and metabolic disturbances
• Most common endocrine disorder of women in reproductive age group
• Affects 6−8% of Caucasian women; more prevalent in Asian
population
DEFINITIONS
• There are two different but overlapping criteria for PCOS (the NIH and
the Rotterdam criteria) in wide use
• NIH criteria
° Menstrual irregularity due to oligo- or anovulation
° Evidence of hyperandrogenism, whether clinical (hirsutism, acne,
or male-pattern balding) or biochemical (high-serum androgen
concentrations)
° Exclusion of other causes of hyperandrogenism and menstrual
irregularity, such as CAH, androgen-secreting tumors, and
hyperprolactinemia
• Revised Rotterdam 2003 criteria
° Two of the following three criteria must be fulfilled for a diagnosis
of PCOS
■ A clinical diagnosis of oligomenorrhoea or amenorrhoea:
menstrual cycles >35 days or <10 periods a year

■ Clinical (hirsutism, acne, or androgen alopecia) or biochemical
(raised free-androgen index) evidence of hyperandrogenism

■ Polycystic ovaries on ultrasound examination
° syndrome must
Late-onset CAH, androgen-secreting tumors, and Cushing’s
be excluded in women with raised androgens;
thyroid disorders and raised PRL should be excluded in women with
menstrual disturbances
SYMPTOMS
• Age of onset usually around the time of menarche
• Variable progression: many will later have normal ovulatory cycle,
whereas others will develop menstrual cycle irregularities and hyper-
androgenism in adulthood
48565_ST05_199-250.indd 227 5/1/13 9:33 PM

228 Polycystic Ovary Syndrome (PCOS)
• Hyperandrogenism
° Acne, oily skin, hirsutism, male pattern alopecia
• Menstrual abnormalities
° Irregular, scant, or infrequent periods, often starting at menarche
° Amenorrhea
° Up to 25% of patients with PCOS (by Rotterdam criteria) have
regular periods
• Infertility or subfertility
• Obesity is common, but many women with PCOS are of normal weight
SIGNS
• Hirsutism: if present assess pattern and severity of hair growth
• Acne or oily skin
• Male pattern alopecia
• Acanthosis nigricans (brown pigmentation on neck, axillae, submam-
mary area, subpanniculus, perineum)
• Signs of virilization (e.g., deep voice, reduced breast size, increased
muscle bulk, clitoral hypertrophy) rarely seen in PCOS; if present,
exclude androgen-producing ovarian or adrenal tumor
INVESTIGATIONS
• Samples should be taken between days 1 and 5 of the menstrual cycle
if woman has a regular cycle; with amenorrhoea, testing will need to
be random
• Recommended for all patients
° Pregnancy test
° Assessment of testosterone status
■ Total testosterone
■ Free testosterone, if available
■ If free testosterone not available, measure SHBG (inversely pro-
portional to insulin resistance) and calculate free androgen index

(FAI; calculated as total testosterone/SHBG x 100; this correlates
with free testosterone and may be raised in PCOS)
° LH and FSH: high levels indicate premature ovarian failure
■ N.B. LH/FSH ratio not within the diagnostic criteria for PCOS
° Prolactinfunction tests
Thyroid
°
• If there is clinical evidence of virilization and total testosterone
≥150 ng/dL (≥5 nmol/L)
° 17-OHP to exclude CAH (especially if a high index of suspicion in
specific groups such as Ashkenazi Jews)
° DHEA-S: may be normal or slightly elevated in PCOS; values
≥800 μg/dL (≥21.7 μmol/L) warrant consideration of an adrenal tumor
° Exclude androgen-secreting tumors
48565_ST05_199-250.indd 228 5/1/13 9:33 PM

General Management of PCOS 229
• If there is clinical suspicion of Cushing’s syndrome: 24-hour urine free

cortisol or 1-mg overnight DST
• For women with confirmed PCOS
° BP, fasting lipid profile
° Glycemic testing
■ Fasting glucose tests in all women with PCOS
■ Performing an OGTT in women who have a BMI >30 kg/m2, a
strong family history of type 2 diabetes, or a fasting glucose

level of 100 mg/dL (5.6 mmol/L) or greater
■ A1c testing for glycemic screening has not been validated in
women with PCOS

■ In women who have impaired glucose tolerance, offer an OGTT
annually to evaluate for progression to diabetes

■ Offer early screening for gestational diabetes mellitus (GDM) if
patient with PCOS becomes pregnant

° Consider obstructive sleep apnea
■ PCOS is associated with sleep apnea
■ Inquire about snoring, daytime fatigue, and/or somnolence

■ Investigate and treat as appropriate
IMAGING
• Ovarian ultrasound not necessary to diagnose PCOS by NIH criteria
• Transvaginal ultrasound of ovaries preferred imaging modality
(when using Rotterdam criteria)
• Characteristics of polycystic ovaries
° A■ polycystic ovary has at least one of the following:
12 or more follicles in each ovary, each follicle measuring
2−9 mm in diameter
■ Ovarian volume >10 ml
° One polycystic ovary is sufficient for the diagnosis

of PCOS
GENERAL MANAGEMENT OF PCOS

• Education
° About the possible long-term risks of the condition, particularly
type 2 diabetes and cardiovascular disease
• Offer psychological support and counseling
• Weight loss
° Advise to keep weight in the normal range and to exercise
regularly
48565_ST05_199-250.indd 229 5/1/13 9:33 PM

230 Polycystic Ovary Syndrome (PCOS)
° Regular exercise and weight loss are reported to

■ Normalize glucose metabolism and decrease risk of developing
type 2 diabetes
■ Lower androgen levels and raise levels of SHBG hormone, which
binds with excess testosterone levels

■ Resume ovulation and improve fertility
° Aim for 30 minutes moderate−intensity exercise daily

■ Nutrition counseling
° Consider Orlistat
° Consider metformin if concomitant diabetes or prediabetes
° Consider bariatric surgery in morbidly obese women with PCOS
APPROACH TO HIRSUTISM IN PCOS

• Laser and photoepilation treatments may lead to temporary short-term
hair removal
• Combined oral contraceptives
° Act as androgen suppressors and are usually the first-line of treat-
ment for PCOS
° testosterone
Increase production of SHBG, which reduces levels of free
° Improves acne and hirsutism (in addition to restoring regular menses)

• Metformin
° Acts as an insulin sensitizer
° Improves hyperandrogenemia
° Modest beneficial effects on hirsutism
• Antiandrogens (may not be available in some countries)
° Often used in addition to the combined OCP; can also be used alone
° Consider adding an antiandrogen if combined OCPs do not improve
acne or hirsutism sufficiently
° adequacy ofantiandrogens
Whenever
contraception
are used, it is essential to consider the
° Antiandrogen
■ Spironolactone
options
■ Cyproterone acetate (a synthetic progestin with antiandrogenic
activity) plus ethinylestradiol can be used for the treatment

of hirsutism; contraindicated in those with high risk of venous
thromboembolism (VTE) (not available in the US)
■ Drospirenone (a spironolactone-like drug) may be considered
if cyproterone acetate−ethinylestradiol or second-generation

combined oral contraceptives are not tolerated (not available
in the US)
■ Flutamide: not recommended for PCOS as it is associated with
fatal liver toxicity

■ Finasteride
• Other options: topical eflornithine cream
48565_ST05_199-250.indd 230 5/1/13 9:33 PM

References 231
APPROACH TO MENSTRUAL IRREGULARITY IN PCOS

• Induction of regular withdrawal bleeding reduces the risk of endo-
metrial hyperplasia and possibly endometrial cancer in women with
infrequent periods (interval between periods of 3 months or longer)
° Combined oral contraceptives restore menstrual regularity
° Intermittent progestin such as medroxyprogesterone 10 mg for
10−12 days every 2−3 months may be used
• Metformin improves menstrual irregularity and may be appropriate for
women who don’t want to take OCP
APPROACH TO INFERTILITY IN PCOS

• Carry out an assessment to identify possible causes of infertility,
which might not be due to PCOS
• Strongly advise the woman to lose weight, if appropriate
• Women with PCOS may be offered clomiphene citrate as first-line
treatment for up to 12 months to induce ovulation; should be used in
women with a BMI of 35 or less
• Women with PCOS who have not responded to clomiphene citrate may
be offered treatment with gonadotrophins or laparoscopic ovarian
drilling
• The role of metformin in fertility treatment is controversial, though it
may still have some merit in obese women with PCOS
REFERENCES
Ledger WL, Atkin SL, Cho LW. Long term consequences of polycystic ovary
syndrome. RCOG, 2007;33:11
Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of
hirsutism in premenopausal women: an endocrine society clinical practice
Mason H, Colao A, Blume-Peytavi U, et al. Polycystic ovary syndrome
(PCOS) trilogy: a translational and clinical review. Clin Endocrinol (Oxf),
2008;69(6):831−44.
Morin-Papunen L, Rantala AS, Unkila-Kallio L, et al. Metformin improves
pregnancy and live-birth rates in women with polycystic ovary syndrome
(PCOS): a multicenter, double-blind, placebo-controlled randomized trial.
Sathyapalan T, Atkin SL. Recent advances in cardiovascular aspects of
polycystic ovary syndrome. Eur J Endocrinol, 2012;166(4):575−83.
48565_ST05_199-250.indd 231 5/1/13 9:33 PM

48565_ST05_199-250.indd 232 5/1/13 9:33 PM
40 ■ HIRSUTISM
Nupur Bahl, MD and Geetha Gopalakrishnan, MD
PATHOPHYSIOLOGY
• Hirsutism: excessive terminal hair in a male-pattern distribution.
• Differential diagnosis for excess androgen production
° CAH (See Chapter 24, Congenital Adrenal Hyperplasia)
° Nonclassic congenital adrenal hyperplasia (NCCAH)
■ Present in <5% of hyperandrogenic women
■ Patients present after puberty with menstrual dysfunction,
infertility, and oligoanovulation

° Androgen-secreting
■ >50% are malignant
tumors (0.2% of hyperandrogenic women)
° dysfunction can be associated

Hyperprolactinemia, Cushing’s syndrome, acromegaly, and thyroid
with hirsutism, though hirsutism is
usually not the presenting problem in these disorders
° danazol, valproic acid)
Androgen or androgenic medications (i.e., anabolic steroids,
° PCOS (See Chapter 39, Polycystic Ovary Syndrome [PCOS])

■ Most common etiology of hirsutism
° ■ Hirsutism
Idiopathic hirsutism
associated with normal ovulation and androgen levels
■ Accounts for 4−7% of all hirsutism cases
° Idiopathic hyperandrogenemia
■ Presents as hirsutism with normal menses, normal ovaries on
ultrasound, but elevated androgen levels

■ Accounts for <20% of cases
• Hirsutism is a clinical diagnosis
• Physical exam
° Hirsutism must be differentiated from hypertrichosis
■ Hypertrichosis is not due to excess androgen; it is characterized
by generalized excessive hair growth in a nonsexual pattern that

may be hereditary, due to a metabolic condition (such as thyroid
dysfunction, anorexia, or porphyria), or a side effect from certain
medications
° Most women with twofold or greater elevation in androgen levels
will have some degree of hirsutism or another pilosebaceous
response such as acne vulgaris, seborrhea, or male-pattern
alopecia
48565_ST05_199-250.indd 233 5/1/13 9:33 PM

234 Hirsutism
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
1 2 3 4
FIGURE 40.1 Ferriman Gallwey Hirsutism Scoring System
48565_ST05_199-250.indd 234 5/1/13 9:33 PM

° Gold standard is the modified Ferriman-Gallwey hirsutism scoring

system (excludes forearm and leg from original 11-area scoring
system)
■ Score of 0−4 given in the following body areas: upper lip, chin/
neck, chest, upper abdomen, lower abdomen, upper back, lower

back, upper arms, thighs
■ Score 8−16 is mild hirsutism, 16−25 is moderate, >25 is severe
• Laboratory testing for elevated androgens in the following patients
° Moderate or severe hirsutism
° Any level of hirsutism associated with
■ Menstrual irregularity or infertility
■ Rapid progression
■ Clitoromegaly
■ Male-pattern balding
■ deepening of voice
■ Acne
■ Central obesity (Cushingoid habitus)
• Basic initial evaluation may include

° Pregnancy test for patients with amenorrhea
° Total testosterone and DHEA-sulfate
■ Mildly elevated in PCOS
■ Androgen-producing tumors should be considered if levels are
2−3 times the upper limit of normal

• Pelvic ultrasound to detect ovarian neoplasm; morning
testosterone level often >200 ng/dL (6.94 nmol/L)
• Adrenal ultrasound to detect adrenal tumors; DHEA-s level
usually >700 mcg/dL (13.6 μmol/L)
° Assessment of Cushing’s syndrome, thyroid dysfunction, hyper-
prolactinemia, or acromegaly if other features of these conditions
are present
° In patients at high risk for CAH (i.e., Ashkenazi Jews, Hispanic and
Slavic people), check an early morning follicular phase level of
17-OHP. Levels >200 ng/dL suggest the diagnosis and patient need
to undergo follow-up testing with ACTH stimulation. (See Chapter 24,
Congenital Adrenal Hyperplasia)
° Iftestosterone
this evaluation is negative, consider PCOS if there is an elevated
level, menstrual irregularity, or polycystic ovaries
48565_ST05_199-250.indd 235 5/1/13 9:33 PM

236 Hirsutism
MANAGEMENT
• Weight reduction
° Obesity increases serum androgen levels in women and therefore over-
weight or obese patients should be strongly encouraged to lose weight
• Pharmacological therapy (recommend 6-month trial so hair follicles can
go through 1 average life cycle prior to changing dose or medication, or
adding medication)
° Oral contraceptives: contain synthetic estrogen in the form of
ethinyl estradiol combined with progestin
■ OCPs reduce hyperandrogenism in several ways
• Suppression of LH secretion leading to decreased ovarian

androgen secretion
• Stimulation of hepatic SHBG production to increase androgen
binding and thus decrease free androgen concentrations
• Reduced secretion of adrenal androgens
• Blockage in the binding of androgens to their receptor
■ Progestins derived from testosterone show mild androgenicity on
laboratory markers. However, progestins not structurally related

to testosterone (i.e., cyproterone acetate [not available in the US]
and drospirenone) function as androgen receptor (AR) antago-
nists. These agents are preferred in the treatment of hirsutism.
° Antiandrogens
■ Can be added if suboptimal response after 6 months of OCP
therapy
■ These agents have teratogenic potential (i.e., fetal male pseudo-
hermaphroditism) and therefore, contraceptive agents are also

prescribed with these agents
■ Spironolactone
• Androgen receptor (AR) antagonist (in addition to aldosterone

receptor antagonism)
■ Competes with DHT for binding to the AR
■ Inhibits enzymes involved in androgen biosynthesis
• Starting dose is 50 mg BID and titrated to 100 mg BID

• May have side effects of hyperkalemia, postural hypotension,
and dizziness
■ Cyproterone acetate (CPA)
• Progestogenic compound with antiandrogen effects

■ Competes with DHT for binding to the AR
■ Reduces serum LH and ovarian androgen concentrations
• Potential risk of hepatotoxicity limits use of this agent

■ OCPs with low dose CPA (2 mg) and monotherapy in higher dose
(12.5−100 mg) are available in Europe but not in the US
48565_ST05_199-250.indd 236 5/1/13 9:33 PM

Management 237
■ Drospirenone acts as a weak antiandrogen and is used in some
OCPs; dose used in OCPs is 3 mg, which is equivalent to 25 mg
of spironolactone
■ Finasteride inhibits type 2 5α-reductase activity, but does not
inhibit type 1 so only a partial effect is noted. Potential harm with

pregnancy (i.e., teratogenic effect on male fetus), so contraception
recommended with treatment
■ Flutamide is a nonsteroidal AR blocker; limited use as a result
of hepatotoxicity that can lead to liver failure and death even at

very low doses
■ Data equivocal regarding topical antiandrogens (such as
canrenone and finasteride)

° Insulin-lowering
abnormalities
medications for patients with PCOS and metabolic
■ Metformin (a biguanide)
• Inhibits hepatic glucose output, leading to lower insulin

concentrations, and thus reducing theca cell production
of androgens
• May also have a small direct effect on ovarian steroidogenesis
° gens in patientscan
Glucocorticoids be used long-term to suppress adrenal andro-
with CAH and NCCAH due to 210HD (CYP21A2)
(see Chapter 24, Congenital Adrenal Hyperplasia)
° GnRH agonists
■ Inhibit LH and FSH leading to decreased ovarian androgen
production
■ Limitations
• Less effective for hirsutism than OCPs and antiandrogens

• Leads to severe estrogen deficiency with menopausal symp-
toms of bone loss and hot flashes
• Requires injections
• Relatively more expensive than other therapies
■ Can be considered in women with severe forms of hyperandro-
genemia (i.e., ovarian hyperthecosis) who have suboptimal

response to OCPs and antiandrogens
• Other pharmacologic treatments
° ■ Inhibits ornithine
Efl ornithine cream
decarboxylase, an enzyme necessary for
hair growth
■ Applied topically to affected area
■ May take several months for results, but should be stopped if no
improvement after 4 months

■ Hair regrows if discontinued
■ Can be considered in mild or localized hirsutism
48565_ST05_199-250.indd 237 5/1/13 9:33 PM

238 Hirsutism
• Cosmetic therapies
° Bleach: usually contains hydrogen peroxide and sulfates; side
effects include irritation, pruritus, and possible skin discoloration
° ■ Depilation:
Direct hair removal techniques
removes hair shaft from skin surface
• Shaving does not affect hair regrowth or diameter, but blunt
tip may cause hair to appear thicker
• Chemical depilation: most contain sulfur and thioglycolates to
disrupt disulfide bonds; may cause irritant dermatitis
■ Epilation: extracts hair to above the bulb
• Plucking/waxing
• Electrolysis: electrical current destroys hair follicle with a
heat or chemical
• Laser/photoepilation: hair is damaged by wavelengths of light
REFERENCES
Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women:
experience with over 1000 consecutive patients. J Clin Endocrinol Metab,
2004;89(2):453−62.
Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician,
2012;85(4):373−80.
Escobar-Morreale HF, Carmina E, Dewailly D, et al. Epidemiology, diagnosis
and management of hirsutism: a consensus statement by the Androgen
Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update,
2012;18(2):146−70.
Franks S. The investigation and management of hirsutism. J Fam Plann
Reprod Health Care, 2012;38(3):182−6.
Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of
hirsutism in premenopausal women: an endocrine society clinical practice
Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med, 2005;353(24):
2578−88.
Unluhizarci K, Kaltsas G, Kelestimur F. Non polycystic ovary syndrome-
related endocrine disorders associated with hirsutism. Eur J Clin Invest,
2012;42(1):86−94.
48565_ST05_199-250.indd 238 5/1/13 9:33 PM

41 ■ ADULT-ONSET PRIMARY OVARIAN
INSUFFICIENCY (POI)
Lawrence M. Nelson, MD
DEFINITION
• Overt POI: FSH levels in the menopausal range on two occasions, at
least one month apart, and in association with 4 months of disordered
menses in a woman under the age of 40
• In fact, this condition is a continuum of impaired ovarian function to
include occult POI. This category includes women who have regular
menses but evidence of impaired ovarian function as determined by:
(1) low response to gonadotropin stimulation as part of infertility
therapy; or (2) elevated menstrual cycle day 3 serum FSH levels
PATHOPHYSIOLOGY
• May be a result of chemotherapy or radiation
• May be due to follicle depletion or follicle dysfunction
• 90% of spontaneous cases are idiopathic
° ~4% due to steroidogenic cell autoimmunity
° ~6% due to a premutation in the FMR1 gene
° ~Rarely
2% are due to an X-chromosomal abnormality
° LH-receptor
due to a single gene defect such as FSH-receptor mutation,
mutation, G-protein mutation
° syndrome, type
Rarely may be part of a syndrome such as autoimmune polyendocrine
1 (APS-1); CAH due to 17-α-hydroxylase deficiency;
galactosemia; aromatase deficiency; Fanconi anemia; and others
° Rarely due to industrial exposure such as to 2-bromopropane
• In spontaneous cases 75% of women have ovarian follicles remaining
in the ovary
• Characteristically, spontaneous cases exhibit intermittent and unpre-
dictable ovarian function that may persist for decades
• History
° What factors might have induced secondary amenorrhea? Is the
patient pregnant? Has there been a decline in general health as a
result of chronic illness? Is there excessive exercise, inadequate
caloric intake, or emotional stress? Has there been prior radiation
or chemotherapy?
■ It is inappropriate to attribute oligo-/amenorrhea to stress
without more in depth evaluation
48565_ST05_199-250.indd 239 5/1/13 9:33 PM

240 Adult-Onset Primary Ovarian Insuffi ciency (POI)
°
The four most common causes of secondary amenorrhea (aside
from pregnancy) are PCOS, hypothalamic amenorrhea, hyperprolac-
tinemia, and POI
° In■ POI
Menses may stop abruptly or fail to resume after a normal
pregnancy or after stopping oral contraceptives; however,
most commonly there is a prodrome of oligomenorrhea,
polymenorrhea, or dysfunctional uterine bleeding
■ Symptoms of estrogen defi ciency such as vasomotor instability
and vaginal dryness are not always present due to residual

ovarian function in many women
■ There is a positive family history in 10−15%
■ Query regarding other autoimmune disorders such as hypothy-
roidism and AI
■ Query regarding family history of fragile X syndrome, intellectual
disability, and tremor ataxia syndrome (related to the FMR1

premutation)
• Physical exam
° Galactorrhea or signs of androgen excess?
° Vaginal exam may suggest normal estrogenization because not all
patients have profound estrogen deficiency
° Look for vitiligo or hyperpigmentation (related to AI)
° Look for thyroid enlargement
° neck,for
Look stigmata of Turner syndrome such as short stature, webbed
and high, arched palate
• Laboratory testing
° Rule out pregnancy
° In the evaluation of secondary amenorrhea, measure serum PRL,
FSH, and TSH levels
° In cases of amenorrhea caused by stress (i.e., hypothalamic amen-
orrhea), the serum FSH is in the low or normal range
° laboratory,
If the FSH is in the menopausal range, as defined by the reporting
the test should be repeated in 1 month along with a
serum estradiol measurement
° Use of the progestin challenge test is not recommended: nearly
50% of women with POI have withdrawal bleeding in response to
the test despite the presence of menopausal-level gonadotropins;
relying on this method delays diagnosis
° Two serum FSH levels in the menopausal range (at least one month
apart) associated with four months of disordered menses confirm
the diagnosis of POI
48565_ST05_199-250.indd 240 5/1/13 9:33 PM

Management 241
° Once the diagnosis is confirmed, further tests to define the mecha-

nism and identify associated disorders
■ Ovarian antibodies lack specifi city, so testing for them is not
warranted
■ Karyotype analysis to detect Turner syndrome
■ Test for an FMR1 premutation to detect fragile X-associated
primary ovarian insufficiency (FXPOI)

■ Test for adrenal antibodies using indirect immunofluorescence
and 21-hydroxlase (CYP21) immunoprecipitation. Positive tests

indicate women with steroidogenic cell autoimmune primary
ovarian insufficiency (SCA-POI). These women are at risk of
developing autoimmune AI, and cosyntropin stimulation testing
should be performed annually
■ Check serum TSH and TPO antibodies
• Imaging
° Pelvic ultrasound is indicated at the time of diagnosis in all women
with overt POI to identify cases involving enlarged, multifollicular
ovaries
■ These may be seen in isolated 17,20-lyase defi ciency or autoim-
mune lymphocytic oophoritis

■ In these cases the ovarian enlargement is not neoplastic and
surgery is not indicated except in the case of torsion

° Measure BMD at the time of diagnosis in all women with overt POI
as hypogonadism is a risk factor for bone loss
MANAGEMENT
• The diagnosis of POI has profound effects on a woman’s sense of
well-being: there are emotional and physical sequelae, and both must
be addressed with vigor
• Many women report severe emotional distress upon hearing the
diagnosis: inform with sensitivity in person, face to face, and in an
unhurried comfortable setting; informing by telephone, voice mail, or
email is inappropriate
• Associated conditions may develop such as generalized anxiety dis-
order, major depression, and posttraumatic stress disorder. Shyness,
social anxiety, impaired self esteem, and perceived low level of social
support are more common than in controls
• Help patients identify sources of emotional support and refer them for
guidance on how to cope with the emotional sequelae
48565_ST05_199-250.indd 241 5/1/13 9:33 PM

• Treat the estradiol deficiency with a full replacement dose of

transdermal or transvaginal estradiol (100 micrograms per day) until
the normal age of menopause (age 50). Avoid use of oral estrogens,
which increase risk of VTE due to the first pass effect on the liver.
To avoid endometrial hyperplasia and reduce the risk of endometrial
cancer, prescribe 10 mg of medroxyprogesterone acetate for the first
12 calendar days of each month to induce regular menses
• OCPs contain more hormone than is needed for physiologic replace-
ment and should not be prescribed for this purpose. Furthermore,
they have not been shown to be safe and effective as a contraceptive
in this group and cannot be relied upon for this purpose. Patients
who desire to avoid pregnancy should use a barrier method or an
intrauterine device
• Have patients keep a menstrual calendar. If expected menses fails to
occur, get a pregnancy test and have them stop the hormone replace-
ment therapy. Approximately 5−10% of women with POI conceive
without medical intervention. The hormone replacement regimen noted
previously does not inhibit ovulation in these women, and there are
theoretical reasons and evidence to suspect it may in fact increase the
chance of ovulation
• If patients are interested in conceiving, prescribe intercourse 2 or
3 times a week to assure there are always sperm waiting for that
intermittent and unpredictable ovulation that may occur. Sperm live in
the female genital track for 3−5 days. Efforts to time intercourse are
stress-inducing, ineffective, and not indicated
• Other associated endocrine deficiencies may develop
° In women with documented adrenal autoimmunity, there is a 50%
risk of developing AI, a potentially fatal disorder. Patients with
evidence of adrenal autoimmunity need annual corticotropin stimu-
lation tests indefinitely. All patients with POI should be educated
regarding the symptoms of AI
° Approximately 20% develop thyroid autoimmunity, most commonly
Hashimoto’s thyroiditis and associated hypothyroidism. If TPO
antibodies are positive, check TFTs yearly. If TPO antibodies are
negative, check TFTs every 4−5 years, or sooner if symptoms of
hypothyroidism develop
• Approximately 20% develop dry eye syndrome; refer those with
symptoms to an ophthalmologist
• Maintain BMD
° 1200 milligrams of elemental calcium per day
° 1000 units of vitamin D3 per day
° 30 minutes of weight bearing exercise per day
° Bisphosphonates are not advised
■ Unexpected pregnancies occur
■ Long serum half-life
■ Fetal effects uncertain
48565_ST05_199-250.indd 242 5/1/13 9:33 PM

Acknowledgments 243
• Maintain cardiovascular health

° Regular exercise
° Healthy diet to avoid obesity
° Attend to metabolic risk factors
• Family planning
° Contraception
■ Use a barrier method or perhaps an IUD
■ Oral contraceptives not proven effective in this population
° Creating a family
■ No proven markers to define increased rate of remission
■ No proven therapies to restore ovarian function
■ Attempts at egg retrieval for in vitro fertilization are not
indicated
■ Spontaneous remission resulting in pregnancy occurs in 5−10%
of cases; generally remissions are temporary, but rarely may

last for years
■ Couples need time to adjust to the diagnosis emotionally and to
consider their options. Many couples are relieved to have the cli-
nician remove urgency from the situation by suggesting a plan to
attempt conception as detailed previously for three years while
they make other plans if this does not result in a pregnancy.
■ Some couples will decide to nurture other dreams rather
than adopt, foster a child, or employ advanced reproductive

technologies
■ There is no medical urgency to proceed to egg donation; the
pregnancy rates depend on the egg donor’s age rather than

the recipient
■ Women who become pregnant by egg donation may have an
increased risk of delivering infants who are small for gestational

age and of having pregnancy-induced hypertension and postpar-
tum hemorrhage, although these findings are controversial
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program on
Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National
Institute of Child Health and Human Development, NIH, Bethesda, MD
48565_ST05_199-250.indd 243 5/1/13 9:33 PM

REFERENCES
Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med,
2009;360(6):606−14.
Sterling EW, Nelson LM. From victim to survivor to thriver: helping women
with primary ovarian insufficiency integrate recovery, self-management,
and wellness. Semin Reprod Med, 2011;29(4):353−61.
Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation
and reproduction. Fertil Steril, 2007;87(3):456−65.
48565_ST05_199-250.indd 244 5/1/13 9:33 PM

42 ■ FEMALE INFERTILITY
Wendy Vitek, MD
PATHOPHYSIOLOGY
• Infertility is defined as the failure to conceive after ≥1 year of regular,
unprotected intercourse (10−15% of healthy young couples will
experience infertility)
• Causes of infertility
° Ovulatory dysfunction (20−40%)
■ Oligomenorrhea (>35-day intervals between periods) or amenor-
rhea (>6 months without a period)

• PCOS, thyroid dysfunction, hyperprolactinemia, hypothalamic
amenorrhea (obesity, eating disorder, stress, exercise),
premature ovarian insufficiency
° Tubal, uterine, cervical and peritoneal factors (30−40%)
■ Tubal factors
• Pelvic infection, ruptured appendix, surgical trauma,

endometriosis
■ Uterine factors
• Fibroids, polyps, intrauterine adhesions, mullerian anomalies

■ Cervical factors
• Cervical stenosis, surgical trauma

■ Peritoneal factor
• Endometriosis
° Male factors (30−40%)
■ Genital anomalies, trauma, surgical trauma, sexual dysfunction,
genetic abnormalities, endocrine disorders

° Unexplained infertility (10%)
■ Couples with patent fallopian tubes, without cervical or uterine
factors, adequate sperm production, regular ovulation

• Female fertility declines with age due to a decline in follicular pool and
an increase in aneuploid oocytes with chromosomal abnormalities,
young women with infertility may exhibit advanced ovarian aging or
diminished ovarian reserve (DOR)
° FSH may be elevated on cycle day 2 or 3 due to less feedback inhibi-
tion from a declining follicular pool
° antral follicles
Inhibin B and AMH are derived from granulosa cells of small
and decrease with a declining follicular pool;
likewise, antral follicle counts (AFC) decrease with a declining
follicular pool
48565_ST05_199-250.indd 245 5/1/13 9:33 PM

246 Female Infertility
• Evaluation can be initiated after the definition for infertility has
been met
• Earlier evaluation is warranted for
° Women >35 years old who have not conceived after 6 months of
regular unprotected intercourse
° Women with oligomenorrhea
Women with or amenorrhea
° Men with knownhistory of pelvic infection or endometriosis
° or suspected subfertility
• General health should be optimized prior to conception. Assess for
° Medical conditions
° Teratogenic medications
° Caffeine, tobacco, alcohol, illicit drug use
° Family history of birth defects or mental retardation
° Obesity (BMI ≥30 kg/m )
2
• Infertility evaluation
° Ovulatory dysfunction
■ Assess for signs and symptoms of thyroid disease, hyperprolac-
tinemia, androgen excess, or menopause

• TSH, PRL, total testosterone, day 2 or 3 FSH and estradiol
° Tubal, uterine, cervical, peritoneal factors
■ Tubal factors
• Evaluate tubal patency by hysterosalpingogram (HSG)

■ Antibiotic prophylaxis (doxycycline 100 mg po BID × 5 days)
is indicated if history of pelvic inflammatory disease or

dilated fallopian tubes noted on HSG
■ Uterine factors
• Assess for menorrhagia (fibroids), metrorrhagia (polyps), and

hypomenorrhea (intrauterine adhesions)
• Bimanual exam may reveal fibroids
• Fibroids can be characterized by transvaginal ultrasound
(TVUS) or MRI
• Submucosal myomas, polyps and intrauterine adhesions can
be detected by HSG or saline sonohysterogram (SHG)
• Mullerian anomalies can be diagnosed by MRI or HSG and TVUS
• Assess for history of abnormal pap smears and treatment
48565_ST05_199-250.indd 246 5/1/13 9:33 PM

Management 247
• Assess for dysmenorrhea, dyspareunia, and dyschezia
• Bimanual exam may reveal adnexal mass (endometrioma),
tenderness, or nodularity (endometriotic implant) in
cul-de-sac
• Laparoscopy may be performed to diagnose and treat
enometriosis
° Male factors
■ Semen analysis × 2
• Azospermia: absence of sperm

• Oligospermia: sperm concentration <15 million/ml or total
sperm number <39 million/ejaculate
• Asthenozoospermia: progressive motility <32%
• Teratospermia: normal morphologic forms <4%
■ The likelihood of male infertility increases with the number of
abnormal parameters and should prompt referral to a urologist

for evaluation
° Unexplained infertility
■ Infertility despite evidence of ovulation, patent fallopian tubes,
normal uterine cavity, and adequate sperm production

■ DOR can be diagnosed by any of the following ovarian reserve tests
• Day 2 or 3 FSH >10 mIU/ml and/or estradiol >80 pg/ml

• AFC (number of follicles measuring 2−10 mm in diameter by
TVUS) is abnormal if <5−10 antral follicles/ovary are noted
■ Other tests that can be considered
• AMH <0.02−0.07 ng/ml (cycle day independent)

• Day 2 or 3 inhibin B <40−45 pg/ml
• Clomid challenge test (clomiphene 100 mg/day days 5−9) is
abnormal if FSH is elevated on day 3 or 10
MANAGEMENT
• Preconception counseling
° Optimize the management of medical disorders
° Transition to medications that are safe in pregnancy
° tobacco, alcohol,
Limit caffeine intake (~two 8-ounce cups of coffee) and discontinue
and illicit drug use
° Genetic counseling if family history of birth defects or mental
retardation
° Weight loss to achieve BMI between 20 and 25 kg/m
2
48565_ST05_199-250.indd 247 5/1/13 9:33 PM

• Treatment of infertility
° Ovulatory dysfunction
■ Treat thyroid dysfunction and hyperprolactinemia
■ Counseling and weight management for hypothalamic amenorrhea
■ Weight loss of 5−10% may restore ovulation in women with
PCOS
■ Ovulation induction
• Clomiphene citrate
■ 80% will ovulate, cycle fecundity (i.e., probability of
achieving a live birth in a single cycle) is ~15%

■ Risks: multiple gestations (8%)
■ Side effects: hot flushes, mood swing, discontinue therapy
if visual disturbance develops

■ Protocol
– If negative pregnancy test, initiate progestin-induced

withdrawal bleed with medroxyprogesterone 10 mg
po × 5−10 days
– Start with clomiphene citrate 50 mg/day cycle days
5−9 with timed intercourse
– Monitor for ovulation with urinary LH kit, luteal proges-
terone (>3 ng/ml) or serial ultrasounds
- If ovulatory and no conception, repeat cycle and limit
lifetime clomiphene exposure to 12 cycles
- If anovulatory, increase clomiphene to 100 mg/day on
days 5−9 and monitor for ovulation; if no ovulation,
increase clomiphene to 150 mg/day days 5−9 and
monitor for ovulation
• Resistance to clomiphene (i.e., no ovulation in response
to clomiphene) in women with PCOS can be managed with
clomiphene plus metformin (1000−2000 mg/day in divided
dose), letrozole, ovarian drilling, or gonadotropins
■ Ovulation induction in patients with hypothalamic amenor-
rhea can be achieved with gonadotropins

° Tubal, uterine, or peritoneal factors
■ Tubal factors
• Tubal cannulation can treat isolated proximal tubal blockage

• Laparoscopic fimbroplasty or neosalpingostomy can treat mild
hydrosalpinges
• Microsurgical tubal reanastomosis can be performed for tubal
ligation reversal in appropriate candidates
• Large hydosalpinges can be removed or proximally occluded to
improve in vitro fertilization (IVF) pregnancy rates
48565_ST05_199-250.indd 248 5/1/13 9:33 PM

References 249
■ Uterine
• Myomectomy for submucosal fibroids and large intramural
fibroids may improve pregnancy rates
• Hysteroscopic polypectomy for polyps may improve pregnancy
rates
• Hysteroscopic lysis of adhesions may improve pregnancy rates
with intrauterine adhesions
• Treatment of mullerian anomalies should be individualized
• Cervical dilation or intrauterine insemination (IUI) may be

indicated for cervical stenosis after treatment for dysplasia
• Laparoscopic excision or ablation of endometriotic implants

may improve pregnancy rates
• Superovulation/IUI or IVF may be indicated based on severity
of endometriosis and additional prognostic factors
° Male factors
■ Medical treatment, surgical correction, and/or genetic counsel-
ing as recommended by a urologist

■ IUI may improve pregnancy rates with oligospermia
■ IVF/ICSI is indicated for severe oligospermia and testicular
extraction sperm aspiration (TESA) specimens

■ Donor sperm is an option for severe male factor
° Unexplained infertility
■ Superovulation (i.e., ovulating multiple oocytes in a single cycle)
/IUI with clomiphene may improve the pregnancy rate in couples

with unexplained infertility, but clomiphene alone or natural
cycle IUI do not improve pregnancy rates
■ Gonadotropin/IUI may improve pregnancy rates when there is a
failure to achieve multifollicular development with clomiphene;

otherwise the cycle fecundity is similar to clomiphene/IUI
■ IVF is the most effective treatment for couples with unexplained
infertility
■ Women with DOR may have lower pregnancy rates with super-
ovulation/IUI and IVF; donor oocyte IVF is an option
REFERENCES
Committee on Gynecologic Practice of American College of Obstetricians and
Gynecologists; Practice Committee of American Society for Reproductive
Medicine. Age-related fertility decline: a committee opinion. Fertil Steril,
2008;90(Suppl 5):S154−5.
Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization
reference values for human semen characteristics. Hum Reprod Update,
2010;16(3):231−45.
48565_ST05_199-250.indd 249 5/1/13 9:33 PM

Practice Committee of the American Society for Reproductive Medicine.

Committee opinion: role of tubal surgery in the era of assisted reproduc-
tive technology. Fertil Steril, 2012;97(3):539−45.
Practice Committee of the American Society for Reproductive Medicine.
Optimal evaluation of the infertile female. Fertil Steril, 2006;86(5 Suppl 1):
S264−7.
Practice Committee of the American Society for Reproductive Medicine. Use
of clomiphene citrate in women. Fertil Steril, 2006;86(5 Suppl 1):S187−93.
Practice Committee of American Society for Reproductive Medicine. Use
of exogenous gonadotropins in anovulatory women: a technical bulletin.
Fertil Steril, 2008;90(Suppl 5):S7−12.
48565_ST05_199-250.indd 250 5/1/13 9:33 PM

SECTION VI: DIABETES, METABOLISM,
AND OBESITY
48565_ST06_251-352.indd 251 5/1/13 9:32 PM

48565_ST06_251-352.indd 252 5/1/13 9:32 PM
43 ■ ENDOCRINE PANCREAS AND FUEL
METABOLISM ESSENTIALS
Robert J. Smith, MD
• Normal growth and metabolic homeostasis require precise regulation of

° The assimilation of macronutrients absorbed from the diet
(e.g., glucose, amino acids, and free fatty acids [FFA])
° The appropriate storage or synthesis of these body fuels
° The exchange of body fuels between organs and tissues
• The pancreatic islets (islets of Langerhans) have a central role in
regulating body fuel metabolism
° Islets are vascularized, innervated organelles containing multiple
secretory endocrine cell types
° approximately
The islets are scattered throughout the pancreas, accounting for
2% of pancreatic mass
• The most common islet cell type, the β cell, synthesizes and stores the
peptide hormone insulin
° Insulin is comprised of A and B chains that are cleaved from the
precursor peptide, proinsulin, and linked together by disulfide bonds
° amounts
Connecting peptide (C-peptide) is also cleaved from proinsulin, in
equal to insulin, when insulin is formed
° plasma as has
C-peptide uncertain functions, but can be measured in the
an index of insulin synthesis
■ Low plasma C-peptide (consult individual lab reference range)
indicates β-cell deficiency and can be useful in distinguishing

type 1 from type 2 diabetes
■ Simultaneous insulin and C-peptide measurements can be use-
ful in identifying causes of hypoglycemia

• Hypoglycemia from injected insulin occurs with high plasma
insulin and low C-peptide levels (pharmacological insulin
contains no C-peptide)
• Hypoglycemia from endogenous insulin overproduction (e.g., with
an insulinoma) has high levels of C-peptide as well as insulin
° Insulin is secreted from β cells primarily in response to glucose
and also in response to ketone bodies and certain amino acids. The
actions of insulin include
■ In skeletal muscle: stimulation of glucose uptake, glycogen
synthesis, and glucose metabolism for energy

■ In liver: stimulation of glycogen synthesis and glucose
metabolism for energy; suppression of glycogen breakdown and

gluconeogenesis
■ In adipose tissue: stimulation of glucose uptake and fat
(triglyceride) synthesis; suppression of triglyceride breakdown

and FFA release
48565_ST06_251-352.indd 253 5/1/13 9:32 PM

254 Endocrine Pancreas and Fuel Metabolism Essentials
• The second most common islet cell type, the α cell, secretes the pep-
tide hormone glucagon.; insulin and glucagon have generally opposing
actions in the regulation of body fuel metabolism
° Glucagon secretion from a cell is suppressed by glucose. Glucagon
actions occur mostly in the liver and include
■ Breakdown of glycogen and release of glucose from the liver to
the blood stream

■ Synthesis of glucose from lactate, pyruvate, and amino acids
(gluconeogenesis) with resulting glucose release from the liver

to the blood stream
■ Stimulation of ketone body formation from FFAs in the liver
• Changes in insulin and glucagon levels are important for metabolic

adjustments during transitions between fed and fasted states
° During fasting, a low insulin/glucagon ratio contributes to
■ Diminished uptake of glucose from the circulation
■ Release of glucose from the liver to the circulation (from glyco-
genolysis and gluconeogenesis)

■ Breakdown of adipose tissue triglyceride stores and release of
FFAs to the circulation

■ Increased use of FFAs as metabolic fuels (instead of glucose)
■ Formation of ketone bodies in the liver (an important alternative
to glucose as a metabolic fuel in the brain and other tissues)

° In■ the fed state, a high insulin/glucagon ratio contributes to
Removal of absorbed glucose from the circulation, with its
metabolism for energy and storage as glycogen
■ Suppression of hepatic glucose production from glycogenolysis
and gluconeogenesis
■ Conversion of glucose and absorbed FFAs to triglyceride stores
■ Suppression of fat breakdown (lipolysis)
■ Suppression of ketone body formation (ketogenesis)
• Incretins are peptide hormones secreted into the blood stream from
the intestine in response to glucose and nutrient ingestion with
important effects on body fuel metabolism
° Incretins account for a greater insulin secretory response to oral
than IV glucose (designated the “incretin effect”)
° gastric inhibitory
The two major incretins are glucagon-like peptide 1 (GLP-1) and
peptide (GIP)
° Incretin actions include
■ Stimulation of β-cell glucose-dependent insulin secretion and
insulin biosynthesis
■ Inhibition of α-cell glucagon secretion
■ Delay of gastric emptying
■ Decreased appetite and weight loss
■ Additional potential (unproven) actions
• Increased β-cell number

• Increased peripheral insulin sensitivity
48565_ST06_251-352.indd 254 5/1/13 9:32 PM

Endocrine Pancreas and Fuel Metabolism Essentials 255
° In type 2 diabetes, there is loss of effectiveness of GIP, but retained

responsiveness to GLP-1. This forms the mechanistic basis for two
classes of oral hypoglycemic agents
■ GLP-1 analogues (forms of GLP-1 stable to degradation)
■ Dipeptidyl dipeptidase inhibitors (delay endogenous GLP-1
degradation)
• Other hormones with important roles in body fuel homeostasis include
glucocorticoids, catecholamines, and GH
° Each of these hormones has individualized actions with distinct
pathological consequences when deficient or present in excess
° As a group, together with glucagon, they are designated “insulin
counter-regulatory hormones,” since a part of their actions directly
or indirectly inhibits the actions of insulin
° In some patients, excess of one or more of these counter-regulatory
hormones (e.g., as part of a stress response with severe illness,
or as a result of a hormone-secreting tumor) can result in a state
of “relative insulin deficiency” and lead to the development of
diabetes mellitus. In uncontrolled diabetes mellitus, it therefore is
important to identify clinical conditions that may be contributing by
increasing counter-regulatory hormone levels. These include
■ Sources of infection or stress (e.g., silent myocardial infarc-
tion [MI]) that result in elevated levels of counter-regulatory

hormones
■ Conditions with primary hypersecretion of counter-regulatory
hormones (e.g., Cushing’s syndrome or acromegaly)

■ Pharmacologic administration of glucocorticoids for treatment
of another disorder
• Counterposed to the role of insulin in regulating body fuel homeosta-
sis, excess nutrient intake is of major clinical importance in causing
insulin deficiency and diabetes
° This is thought to result from both insulin resistance secondary to
obesity, and a loss of insulin-secreting pancreatic β cells possibly
caused by the demand for excess insulin secretion or a pancreatic
islet inflammatory process precipitated by obesity
° The role of obesity is most evident in type 2 diabetes, with obesity
present in more than 80% of patients prior to the development of
diabetes
° Obesity can also accelerate the time of presentation of incipient
type 1 diabetes, or result in the development of combined types
1 and 2 diabetes in some individuals
° Since the amount of insulin required for metabolic control relates
to the quantity of ingested glucose and other nutrients in addition
to the overall sensitivity to insulin, reducing calorie intake can have
benefit in the correction of hyperglycemia in obese individuals even
before there has been significant change in the degree of obesity
48565_ST06_251-352.indd 255 5/1/13 9:32 PM

256 Endocrine Pancreas and Fuel Metabolism Essentials
REFERENCES
American Diabetes Association. Standards of medical care in diabetes—
2012. Diabetes Care, 2012;35(Suppl 1):S11−63.
Ferrannini E. Physiology of glucose homeostasis and insulin therapy in type 1
and type 2 diabetes. Endocrinol Metab Clin North Am, 2012;41(1):25−39.
Phillips LK, Prins JB. Update on incretin hormones. Ann NY Acad Sci,
2011;1243:E55−74.
48565_ST06_251-352.indd 256 5/1/13 9:32 PM

44 ■ DIABETES MELLITUS
Lillian Lien, MD and Mark Feinglos, MD
BACKGROUND
• Diabetes mellitus (DM) is a complex multiorgan system process, with
defects in pancreatic insulin secretion, central and peripheral insulin
action, and glucose utilization and production
° Infl ammation has now been recognized as an underlying patho-
physiologic process
° organs, including
Chronic hyperglycemia is associated with damage to various end
the eyes, kidneys, nerves, blood vessels, and heart
• Diagnosing type 1 versus type 2 versus other forms of DM is important
for optimal care
° However, this distinction is not always possible
PATHOPHYSIOLOGY OF TYPE 1 DM
• Fundamentally an immune-mediated process: T-cell mediated autoimmune
destruction of pancreatic β cells leads to an absolute insulin deficiency
• Patients must receive exogenous insulin therapy
• Accounts for only 5−10% of those with DM
• Autoantibodies can be detected in as many as 85−90% of these
patients
° Islet cell autoantibodies, autoantibodies to insulin, autoantibodies
to GAD (GAD65), and autoantibodies to the tyrosine phosphatases
IA-2 and IA-2β
• Patients may have additional autoimmune disorders
CLINICAL PRESENTATION OF TYPE 1 DM

• Typically <40 years of age, although not exclusively a disease of childhood
• Nonspecific symptoms often associated with type 1 DM: polyuria, poly-
dipsia, weight loss, fatigue, blurred vision, susceptibility to infection
• Diabetic ketoacidosis (DKA; see Chapter 46, Hyperglycemic Emergencies)
may be the initial presentation of type 1 diabetes
PATHOPHYSIOLOGY OF TYPE 2 DM
• Multifactorial, including both defects in insulin action and insulin
secretion
° Resistance to insulin action is generally present, but failure of the
β cell to compensate causes hyperglycemia
48565_ST06_251-352.indd 257 5/1/13 9:32 PM

258 Diabetes Mellitus
• Accounts for approximately 90% of those with DM

• Often associated with caloric excess and obesity
° These conditions lead directly to visceral adiposity and insulin
resistance
• Due to insulin resistance, insulin levels may be normal or elevated at
diagnosis
• Complex genetics with strong familial predisposition
CLINICAL PRESENTATION OF TYPE 2 DM

• Often associated with weight gain, being overweight, or obesity; or in
women with a history of GDM
• Similar nonspecific symptoms as in type 1, but may be undiagnosed
for many years
• May present with hyperosmolar hyperglycemic syndrome (HHS; see
Chapter 46, Hyperglycemic Emergencies); DKA can also occur, usually
in association with a specific stressor such as infection
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION

OF OTHER FORMS OF DM
• Maturity-onset diabetes of the young (MODY) (see Chapter 45)
Monogenic Diabetes)
° Autosomal
secretion
dominant monogenic diabetes with defects in insulin
° Often managed effectively

Age of presentation is usually <25 years old
° with diet alone or sulfonylurea drugs
• Latent autoimmune diabetes of the adult (LADA)
° Usually diagnosed in patients 25 years of age or older
° Initial presentation may mimic type 2 DM, but patients are not
obese and often progress rapidly to insulin requirement
° Autoimmune pathophysiology
• Nonimmune causes of pancreatic destruction
° Wide variety of causes such as pancreatectomy, pancreatitis,
hemochromatosis, and cystic fibrosis (cystic fibrosis-related
diabetes [CFRD])
° Patients often require treatment with insulin depending on extent
of β-cell loss
° ties in glycemic control α cells may lead to additional difficul-
Loss of glucagon-producing
• Drug-induced DM: many potential causative agents including corti-

costeroids, immunosuppressive agents, protease inhibitors, atypical
antipsychotics, antineoplastics, anticonvulsants, pentamidine, niacin,
thiazide diuretics, β-adrenergic blockers
48565_ST06_251-352.indd 258 5/1/13 9:32 PM

ADA Criteria for the Diagnosis of DM 259
• Gestational DM
° Glucose intolerance first recognized in pregnancy
° Diagnosis of gestational DM is made from an OGTT performed at 24−28
weeks gestation in women not previously diagnosed with overt DM
■ High-risk women found to have DM at the initial prenatal visit
are considered to have “overt,” not gestational, DM
AMERICAN DIABETES ASSOCIATION (ADA) CRITERIA

FOR DM SCREENING IN ADULTS
• Adults with BMI ≥25 kg/m2 and one or more additional risk factor
° Physical inactivity
° First-degree relative with DM
° High-risk race/ethnicity (e.g., African American, Latino, Native
American, Asian American, Pacific Islander)
° Women who delivered a baby weighing >9 lbs or who were diag-
nosed with gestational DM
° Hypertension (BP ≥140/90 mm Hg or on therapy for hypertension)
° HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglycer-
ide level >250 mg/dL (2.82 mmol/L)
° Women with PCOS
° A1c >5.7%, impaired glucose tolerance (IGT), or impaired fasting
glucose (IFG)
° Clinical conditions associated with insulin resistance (e.g., severe
obesity, acanthosis nigricans)
° History of CVD
• In the absence of the above, testing for DM should begin at age 45
• If results are normal, testing should be repeated at least at 3-year intervals
ADA CRITERIA FOR THE DIAGNOSIS OF DM

1. A1C ≥ 6.5%*
° The test should be performed in a laboratory using a method that is
National Glycohemoglobin Standardization Program (NGSP)–certified
and standardized to the Diabetes Control and Complications Trial assay
2. Fasting plasma glucose (PG) (at least 8 hours fasting)*
° Normal <100 mg/dL
° “Prediabetes (IFG)” 100–125 mg/dL
° DM ≥126 mg/dL (7.0 mmol/l)*
3. OGTT: 2-hour PG after a 75-gram glucose load*
° Normal <140 mg/dL
° “Prediabetes (IGT)” 140–199 mg/dL
° DM ≥200 mg/dL (11.1 mmol/L)*
4. Random PG ≥200 mg/dL (11.1 mmol/L), with symptoms of
hyperglycemia/crisis
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
48565_ST06_251-352.indd 259 5/1/13 9:32 PM

ADDITIONAL LABORATORY TESTING FOR THE DIAGNOSIS

AND MANAGEMENT OF GLYCEMIA IN DM
• PG: obtained by venipuncture; to avoid false lows, must process
promptly; serum glucose is more stable
• Point-of-care testing (POCT) glucose: POCT glucose, or capillary
glucose, measures whole blood glucose by a portable glucose meter;
usually obtained by fingerstick
° POCT glucose can differ by 10–15% from plasma glucose
° Less reliable at extremes: <60 mg/dL (3.3 mmol/L) or >500 mg/dL
(27.7 mmol/L)
• Hemoglobin A1c: a measure of glycosylation of the hemoglobin
molecule; with increased ambient blood glucose levels, glycosylation
rates rise
° Refl ects average glucose over lifetime of a red blood cell ~120 days
° A1c
to DM
levels of 5.7–6.5% are considered “at risk” for progression
° Causes
ADA targets A1c levels <7% as the goal for most patients with DM
° sion, anemia,
of inaccurate A1cs: abnormal hemoglobin, blood transfu-
early pregnancy, splenectomy
• C-peptide
° insulin moleculeprecursor
Proinsulin, the molecule to insulin, consists of the future
and a 31-amino acid polypeptide known as C-peptide
° Thus, C-peptide reflects endogenous insulin production
° Should be measured either 1 hour after a 75-gm carbohydrate load
or when glucose is at least 150 mg/dL
° In patients with type 2 DM, it may be useful to see whether detect-
able C-peptide levels are present to evaluate whether there is a role
for oral agent therapy
° C-peptide measurement may be required by an insurance company
for coverage of insulin pump therapy initiation
• Antibody testing
° Various antibodies associated with autoimmune forms of diabetes:
islet cell autoantibodies, autoantibodies to insulin, autoantibodies
to GAD (GAD65), and autoantibodies to the tyrosine phosphatases
IA-2 and IA-2β
° Not always present in type 1 diabetes and no data to support rou-
tine use, though elevated levels are consistent with an autoimmune
etiology (type 1 DM or LADA)
° ADA states that testing for islet cell autoantibodies may be
appropriate in high-risk cases: those with transient hyperglycemia,
relatives with type 1 DM, or enrolled in clinical research studies
48565_ST06_251-352.indd 260 5/1/13 9:32 PM

Pharmaceutical Options for Diabetes Management 261
PHARMACEUTICAL OPTIONS FOR DIABETES MANAGEMENT
TABLE 44.1 Insulin Formulations

Type Product Brand
Rapid-Acting Lispro Humalog
Aspart Novolog
Glulisine Apidra
Short-Acting Regular “R” Humulin, Novolin, ReliOn
Intermediate-Acting NPH “N” Humulin, Novolin, ReliOn
Long-Acting (Basal) Glargine Lantus

Detemir Levemir
Premixed 70/30 regular Humulin 70/30, Novolin 70/30
75/25 lispro Humalog Mix 75/25
70/30 aspart Novolog Mix 70/30
50/50 lispro Humalog Mix 50/50
Lispro (Humalog),
Aspart (Novolog), GlargineDetemir
Insulin Type Glulisine (Apidra) Regular NPH (Lantus)(Levemir)
Onset 15–30 min 30 min 1–2 hours 1–2 hours
~1 hour
Time to Peak 1–2 hours 2–4 hours 4–10 hours No peak No/little
peak
Duration 3–5 hours 4–8 hours 12–20 hours ~24 hours Up to
24 hours
Administration ≤15 min before, 30–60 min 30–60 min Without Without
or right after before before regard regard to
meals meals meals or to meals meals
at bedtime
48565_ST06_251-352.indd 261 5/1/13 9:32 PM

TABLE 44.2 Noninsulin Antidiabetic Medications
262
Noninsulin Antidiabetic % A1c

Medication Drug Class Route Common Adverse Effects Contraindications lowering
48565_ST06_251-352.indd 262
Glipizide (Glucotrol), Sulfonylurea Oral Hypoglycemia Type 1 diabetes, DKA 1–2%
glimepiride (Amaryl),
glyburide (Diaβeta, Glynase
Diabetes Mellitus
PresTabs, Micronase)
Metformin (Glucophage, Biguanide Oral GI (N/V, diarrhea, abdominal Type 1 diabetes, DKA, Cr >1.5 in men, 1.5–2%
Glucophage XR) pain), Vitamin B12 Cr >1.4 in women, acute or chronic
deficiency metabolic acidosis
Pioglitazone (Actos*), Thiazolidinedione Oral Edema, weight gain, bone Type 1 diabetes, DKA, symptomatic CHF 1.5%
rosiglitazone (Avandia†) fractures
Repaglinide (Prandin), Meglitinide Oral Hypoglycemia Type 1 diabetes, DKA 0.5–1%
nateglinide (Starlix)
Acarbose (Precose), Alpha- Oral GI (flatulence, diarrhea, Type 1 diabetes, DKA, hepatic cirrhosis, 0.5–1%
miglitol (Glyset) glucosidase abdominal discomfort) chronic intestinal diseases
inhibitor
Sitagliptin (Januvia), DPP-4 inhibitor Oral Hypersensitivity Type 1 diabetes, DKA, pancreatitis, 0.5–1%
saxagliptin (Onglyza), hypersensitivity
linagliptin (Tradjenta)
Liraglutide (Victoza) GLP-1 mimetic SQ GI pancreatitis (rare) Type 1 diabetes, DKA, personal or 1–2%
family history of MTC or MEN2,
pancreatitis
5/1/13 9:32 PM
Exenatide (Byetta) GLP-1 mimetic SQ GI pancreatitis (rare) Type 1 diabetes, DKA, pancreatitis 1–2%
Exenatide extended-release Long-acting SQ GI pancreatitis (rare) Type 1 diabetes, DKA, personal or 1–2%
(Bydureon) GLP-1 mimetic family history of MTC or MEN2,
48565_ST06_251-352.indd 263
(once weekly) pancreatitis
Pramlintide (Symlin) Amylin mimetic SQ GI, headache Confirmed gastroparesis, hypoglycemic 0.5–1%
unawareness
Bromocriptine mesylate Dopamine Oral GI, orthostatic hypotension, Type 1 diabetes, DKA, syncopal 0.5%
(Cycloset) receptor agonist somnolence, psychosis, migraines, lactating women
dizziness
Colesevelam (Welchol) Bile acid Oral Constipation, Type 1 diabetes, DKA, history of bowel 0.5%
sequestrant hypertriglyceridemia, obstruction, hypertriglyceridemia,
absorption of medicines pancreatitis
DPP-4 = Dipeptidyl peptidase-4
* Pioglitazone (Actos): possible association with bladder cancer.
† Rosiglitazone (Avandia): use highly restricted, as may increase risk of MI.
Pharmaceutical Options for Diabetes Management
263
5/1/13 9:32 PM
GLYCEMIC MANAGEMENT IN TYPE 1 DIABETES:

INITIATING OUTPATIENT REGIMENS
• DCCT showed intensive insulin therapy to be associated with better
microvascular outcomes
• Intensive insulin therapy requires the use of multiple-dose insulin
injections daily or insulin pump therapy
• Multiple-dose insulin therapy
° The ADA recommends the use of insulin analogues in order to
reduce the risk of hypoglycemia
■ However, if financial issues preclude the above, a 4-shot regimen
using regular insulin TID with meals and NPH Insulin at bedtime
can still be considered
° Total daily dose (TDD): in type 1, the TDD can be estimated at
0.3–0.5 units/kg/day
■ Type 1 DM patients are often insulin sensitive; it is reasonable to
start on the low end

° Using
as follows
analogue insulins, the TDD is divided into 4 daily injections
■ 50% of the TDD is given as one basal (long-acting, peakless,
analogue) insulin injection every 24 hours

■ The remaining 50% of the TDD is divided into three mealtime
injections of prandial (rapid-acting analogue) insulin (i.e.,

~17% of TDD is administered at each meal)
• Alternatively, the dose for each mealtime injection can be
matched to carbohydrate intake using insulin to carbohydrate
ratios (the ratio reflects the amount of insulin needed to cover
a specific amount of carbohydrate, i.e., 1:15 ratio, represent-
ing 1 unit of insulin per 15 g carbohydrate intake)
° Inventtypethe1,development
always give basal insulin, even if the patient is NPO, to pre-
of DKA; IV calories may be needed in association
° 24 hours; in this case,
In some patients, a single injection of basal insulin may not last a full
it is reasonable to divide the basal into 2 sepa-
rate injections given 12 hours apart (of note, this then is a 5-injection
daily regimen: 2 basal and 3 prandial injections daily)
• Continuous SQ insulin therapy (i.e., insulin pump)
° An insulin pump is a small mechanical device that delivers a continu-
ous infusion of SQ insulin to the patient through a flexible catheter.
° Requires a thorough understanding of the hardware and a proven
ability to perform self-care
48565_ST06_251-352.indd 264 5/1/13 9:32 PM

Glycemic Management in Type 2 Diabetes: ADA Guidelines 265
° In most cases, a rapid-acting analogue insulin is used in the pump.

Even though only one type of insulin is used, the pump can deliver
both basal and bolus (prandial) components
■ Basal insulin is infused at programmed hourly rates; usually
multiple different basal rates throughout the day

■ Bolus insulin is infused at discrete (meal) times; calculation of
the dose is based on factors including: the insulin-to-carbohy-

drate ratio, target blood glucose range, active insulin time, and
insulin sensitivity factor
GLYCEMIC MANAGEMENT IN TYPE 2 DIABETES: ADA GUIDELINES

• Choice of regimen must account for multiple patient factors: patient
attitude and expected treatment effects, risk of hypoglycemia, disease
duration, comorbidities, life expectancy, established complications,
and resources
• The ADA recommends lifestyle intervention and metformin therapy
both be initiated at the time of initial type 2 DM diagnosis; as long as
metformin is not contraindicated, it is first-line therapy
• If metformin monotherapy does not achieve control over 3 months,
the ADA recommends adding a second oral agent, a GLP-1 receptor
agonist, or basal insulin
° There are few data regarding comparative long-term effectiveness
of different drugs combined with metformin. Thus, no standard
recommendations regarding combinations are available. The ADA
suggests that the advantages and disadvantages of specific drugs
for each patient should be considered in order to improve glycemic
control while minimizing side effects (see Table 44-2 for choices).
• Adding a third noninsulin agent to a two-drug regimen that has not
achieved control can be considered, but ADA states a more robust
response may be achieved by adding insulin
• The higher the hemoglobin A1c (i.e., A1c ≥9%), the more likely insulin
will be needed
° Before moving to more complex regimens, ADA suggests first using
basal insulin, added onto noninsulin therapies; the noninsulin
therapies are necessary to cover prandial needs, which cannot be
safely covered by basal insulin
° Basal insulin is usually added at a low dose (estimated
0.1−0.2 units/kg/day)
• If the patient is still having significant postprandial hyperglycemia
despite the previous recommendation, intensification may be needed
in patients willing to take more than 1 injection
° Apremixed
2-injection regimen can be achieved with the use of twice-daily
insulins
48565_ST06_251-352.indd 265 5/1/13 9:32 PM

° Alternatively, a 2-injection regimen could consist of basal insulin

plus a single prandial insulin injection at the largest meal
■ If still insuffi cient, another prandial injection could be added at
another meal (i.e., 3 injections daily: 1 basal plus 2 prandial)

■ If still insufficient, intensification up to a full 4-shot basal-bolus regi-
men may be needed (see dosing instructions in the section Glycemic

Management in Type 1 Diabetes: Initiating Outpatient Regimens)
• Individualization of therapy is essential, accounting for the degree of
hyperglycemia versus overall patient capabilities
REFERENCES
American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care, 2012;35:Suppl:1:S64−71.
American Diabetes Association. Standards of medical care in diabetes—2012.
Diabetes Care, 2012;35(Suppl 1):S11−63.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in
type 2 diabetes: a patient-centered approach: position statement of the
American Diabetes Association (ADA) and the European Association for
the Study of Diabetes (EASD). Diabetes Care, 2012;35(6):1364−79.
Pearce SH, Merriman TR. Genetics of type 1 diabetes and autoimmune
thyroid disease. Endocrinol Metab Clin North Am, 2009;38(2):289−301.
48565_ST06_251-352.indd 266 5/1/13 9:32 PM

45 ■ MATURITY ONSET DIABETES
OF THE YOUNG
Rebecca McEachern, MD
PATHOPHYSIOLOGY
• Heterogeneous group of disorders causing diabetes due to single gene
defects in pancreatic β cell causing insulin secretory deficits
• Now subtyped according to gene involved but old nomenclature persists
• Autosomal dominant genetic transmission with variable penetrance
and expression
• Represents 2−5% of all cases of diabetes although exact prevalence
unknown and may be misdiagnosed as type 2 diabetes or antibody-
negative type 1 diabetes
• Young age of onset (<25 years of age)
° Usually nonobese individuals without signs of insulin resistance
(e.g., no acanthosis nigricans)
° Slow disease progression
° Low insulin requirements
• Family history of diabetes over 2 generations consistent with autoso-
mal dominant inheritance is mandatory for diagnosis
• Subtype determines presentation
° MODY 2 (GCK subtype)
■ Lifelong mild hyperglycemia
■ Often presents with incidentally detected hyperglycemia
■ Typical symptoms of diabetes are rare
° ■ Normoglycemia
Other forms of MODY
early in childhood and adolescence
■ Overt diabetes symptoms of polyuria and polydipsia
■ Progressive hyperglycemia
• Patients who do not fulfill classic criteria for either type 1 or type 2
diabetes should be screened (see previous section)
• Serum glucose +/− A1C levels in the diabetic range (although gluco-
kinase [GCK] mutations may only have impaired glucose levels)
• Some have disproportionate glycosuria (MODY 1 or hepatocyte nuclear
factor 1α [HNF-1α] subtype)
• Genetic testing is commercially available for the most common subtypes
48565_ST06_251-352.indd 267 5/1/13 9:32 PM

268 Maturity Onset Diabetes of the Young
MANAGEMENT
• Correctly diagnosing MODY (rather than type 1 or type 2 diabetes) has
a significant impact on treatment options and monitoring
• Treatment is geared towards improving hyperglycemia
° MODY 1 and 3
■ Sulfonylurea can be considered in MODY 1 and 3
■ Insulin is required with progression in MODY 1 and 3
° Insulin is recommended for all other forms of MODY

TABLE 45.1 Pathophysiology of MODY Subtypes
Original Additional
Name Gene Pathogenesis Affected Sites Features
MODY 1 HNF-4α Defect in Pancreas, liver Lipid
(rare) transcription abnormalities,
factor gain of function
regulating β cell mutations
development and cause neontatal
differentiation hypoglycemia
⇒ severe insulin and macrosomia
secretory defect
MODY 2 GCK (15−32% Decreased Pancreas, liver Low birth
of MODY sensitivity of β weight, hepatic
subtypes) cell to glucose glycogen
⇒ change in storage defects,
glucose threshold neonatal
for normal insulin diabetes in
secretion homozygotes
MODY 3 HNF-1α Defect in Pancreas, Glycosuria,
(52−65% transcription kidneys impaired
of all MODY factor regulating β glucagon
subtypes) cell development secretion,
and differentiation pancreatic
⇒ severe insulin exocrine
secretory defect dysfunction
MODY 4 Insulin promoter Defect in Pancreas Pancreatic
factor-1 (IPF-1) transcription agenesis in
(rare) factor homozygotes
regulating β cell
development and
differentiation
⇒ insulin
secretory defect
(continues)
48565_ST06_251-352.indd 268 5/1/13 9:32 PM

Management 269
Original Additional
Name Gene Pathogenesis Affected Sites Features
MODY 5 HNF-1β (rare) Defect in Pancreas, Polycystic
transcription liver, kidney, kidney disease,
factor genitalia urogenital tract
regulating β cell anomalies,
development and hepatic
differentiation dysfuntion,
⇒ severe insulin hyperuricemia
secretory defect
MODY 6 Neurogenic Defect in Pancreas CNS defects in
differentiation transcription homozygotes
factor 1 factor
(NeuroD1) regulating β cell
(rare) development and
differentiation
⇒ severe insulin
secretory defect
None Preproinsulin Defect in insulin Pancreas Unknown
gene (INS) precursor folding
(unknown and processing
frequency)
Other CEL, PAX4, Pancreatic β Pancreas Unknown
KLF11, BLK nuclear factor
defects
TABLE 45.2 Clinical Features of MODY

Long-Term
Presentation Age of Onset Treatment Complications
HNF-1α Overt diabetes Adolescence− Responsive to Screening for
subtype with progression early sulfonylurea but diabetes
(MODY 1) in some adulthood 1/3 eventually complications is
individuals require insulin required
GCK Mild fasting Very young Often no Very low risk
subtype hyperglycemia pharmacologic
(MODY 2) (due to glycogen intervention
abnormalities) required
and impaired
glucose
tolerance, GDM in
50% carriers
(continues)
48565_ST06_251-352.indd 269 5/1/13 9:32 PM

270 Maturity Onset Diabetes of the Young
Long-Term
Presentation Age of Onset Treatment Complications
HNF-1α Overt diabetes Adolescence− Responsive to Screening for
subtype with progression early sulfonylurea but diabetes
(MODY 3) adulthood 1/3 eventually complications
require insulin is required
IPF-1 Ranges from Early adulthood Insulin therapy Unknown and
subtype impaired thus screening
(MODY 4) glucose for diabetes
tolerance to complications
overt diabetes suggested
HNF-1β Progressive Early adulthood Insulin therapy Unknown and
subtype hyperglycemia, thus screening
(MODY 5) renal cysts for diabetes
(which may complications
precede suggested
diagnosis of
diabetes)
NeuroD1 Progressive Variable age Insulin therapy Unknown and
subtype hyperglycemia of onset thus screening
(MODY 6) for diabetes
complications
suggested
REFERENCES
Giuffrida FM, Reis AF. Genetic and clinical characteristics of maturity-onset
diabetes of the young. Diabetes Obes Metab, 2005;7(4):318−26.
Nyunt O, Wu JY, McGown IN, et al. Investigating maturity onset diabetes of
the young. Clin Biochem Rev, 2009;30(2):67−74.
Rubio-Cabezas O, Edghill EL, Argente J, Hattersley AT. Testing for monogenic
diabetes among children and adolescents with antibody-negative clini-
cally defined Type 1 diabetes. Diabet Med, 2009;26(10):1070−4.
Steck AK, Winter WE. Review on monogenic diabetes. Curr Opin Endocrinol
Diabetes Obes, 2011;18(4):252−8.
Vaxillaire M, Bonnefond A, Froguel P. The lessons of early-onset monogenic
diabetes for the understanding of diabetes pathogenesis. Best Pract Res
Clin Endocrinol Metab, 2012;26(2):171−87.
Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics
and relevance to multifactorial forms of type 2 diabetes. Endocr Rev,
2008;29(3):254−64.
48565_ST06_251-352.indd 270 5/1/13 9:32 PM

46 ■ HYPERGLYCEMIC EMERGENCIES:
DIABETIC KETOACIDOSIS (DKA) AND THE
HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)
Steven Kaufman, MD
PATHOPHYSIOLOGY
• Results from decreased ratio of insulin to counterregulatory hormones
(most importantly glucagon)
° Can result from decreased insulin, increased counterregulatory
hormones, or both
• Development of hyperglycemia
° Decreased glucose uptake by peripheral tissues, increased glycoge-
nolysis, and gluconeogenesis
° Volume depletion leads to impaired glucose excretion
• Development of ketoacidosis
° Increased lipolysis → increased FFA delivered to liver → ketogen-
esis (in setting of significant insulinopenia)
■ β hydroxybutyrate: predominant ketoacid in DKA, can be mea-
sured quantitatively but not by standard ketone assay

■ Acetoacetate: usually minor portion of acid load in DKA,
assessed by ketone assay

■ Acetone: not a weak acid, most notable for causing “fruity” odor
on breath of patients with DKA

° βserum
hydroxybutyrate and acetoacetate are weak acids → decrease
alkali reserve (decrease bicarbonate) → metabolic acidosis
° Ketoacidosis is typical presentation of hyperglycemic emergency
in type 1 diabetes; can also occur in type 2 diabetes but there is
usually sufficient insulin to suppress ketogenesis
• Development of hyperosmolarity
° Hyperglycemia results in osmotic diuresis, leading to water loss →
solute loss → hyperosmolarity
° in type 2 diabetes;is can
Hyperosmolarity typical presentation of hyperglycemic emergency
also occur in type 1 diabetes but patients
typically present with DKA before significant water loss occurs
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272 Diabetic Ketoacidosis (DKA) and the Hyperosmolar Hyperglycemic State (HHS)
TABLE 46.1 Diagnosis
DKA HHS
Glucose >250 mg/dl >600 mg/dl
pH <7.30 >7.3
CO2 <18 mmol/L >15 mmol/L
Serum osmolality Normal >320 mOsm/kg
Anion gap Elevated Normal
Serum ketones Elevated Normal
Mental status Alert to stuporous/coma Stuporous/coma
TYPICAL PRECIPITATING FACTORS

• Inadequate insulin: new-onset diabetes, omission of insulin, insulin
pump failure
• Infections: especially pneumonia or urinary tract infection (UTI)
• Other acute medical conditions: especially MI, pancreatitis, cerebro-
vascular accident (CVA)
• Drugs: especially corticosteroids, thiazide diuretics, atypical
antipsychotics
• Other: including parenteral nutrition, substance abuse, and various
endocrine conditions
EVALUATION
• Initial laboratory studies: glucose, electrolytes, phosphorus, BUN,
creatinine, urinalysis, CBC with differential, ECG, urine for ketones or
serum for β hydroxybutyrate
• Assessment for precipitating factors, especially infection or MI
TABLE 46.2 Common Calculations
Calculations Formula
Anion gap Na+− (Cl−+ HCO3−)
Serum osmolality 2 × [measured Na+] + [glucose (mg/dl)/18] +
[BUN (mg/dl)/2.8]
“Corrected” serum sodium Corrected Na+ = [(serum glucose − 100) × 1.6] +
measured Na+
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Management 273
COMMONLY SEEN LABORATORY ABNORMALITIES

• Anion gap: elevated in DKA, normal in HHS
• Bicarbonate: can be very low in DKA, usually normal in HHS
unless there is another supervening condition such as lactic
acidosis
• Potassium: serum levels may vary from frankly low to frankly elevated,
but all patients have had loss of total body potassium
• Phosphate: levels may initially be normal to elevated, but usually
decline with treatment
• Sodium: measurement is “diluted” by water drawn into circulation by
excess glucose
° “Corrected” serum sodium used to estimate what serum sodium
will be when glucose is removed
° Clinical implication: patient with normal serum sodium and
very high glucose will likely be hypernatremic when glucose
levels fall
• Amylase: increased in up to 90% of patients with DKA
• Lipase may also be elevated in DKA
• Leukocytosis of 10,000−15,000 mm is common
° WBC >25,000 mm or greater than 10% band neutrophils should
increase the clinical suspicion for an active infection
• Mild increases in creatinine kinase and troponin may occur in the
absence of myocardial damage
MANAGEMENT
• Goals
° Goal of management of DKA is correction of the acidosis
° Goal of management of HHS is correction of the hyperosmolar state
and electrolyte imbalances
° Management of DKA or HHS with appropriate fluid, insulin, and
electrolyte replacement will improve the hyperglycemia as well
• IV fluids
° Fluids
pending
can be started while initial laboratory assessment is
° 1 liter per hour)

Start normal saline at 15−20 ml/kg body weight/hour (maximum of
° Reduce infusion rate to 250–500 cc per hour once BP stabilizes

° Once the sodium corrects to the eu- or hypernatremic level, change
the IV fluid to ½ normal saline
° Titrate
status
fluid rates based on the response to treatment and volume
° an acute MI,with
Use caution aggressive fluid replacement in patients with CHF,
evidence of volume overload, or anuria
48565_ST06_251-352.indd 273 5/1/13 9:32 PM

° Add dextrose to the IV fluids once the glucose drops to below

250 mg/dL to avoid hypoglycemia while allowing the insulin infusion
to continue until the acidosis or hyperosmolarity has resolved
° Cerebral edema occurs primarily in children, but has been
described in adults
• Insulin
° Do not start IV insulin until serum potassium measured
° Regular insulin IV bolus at 0.1−0.15 units/kg body weight
° InitiallyIV the
Start insulin infusion at 0.1 units/kg body weight/hour
° expansion; thereafter,
glucose level may fall precipitously due to volume
glucose levels should make a steady decline
of 50−75 mg/dL each hour
° downward at an appropriate
Adjust the rate of insulin infusion to allow the glucose to trend
rate
• Bicarbonate
° formation
Bicarbonate is largely regenerated as insulin reverses ketone
° Routine bicarbonate replacement is not recommended (and may be

detrimental), but can be considered if pH <6.9
TABLE 46.3 Potassium

Potassium Level Potassium Replacement
<3.3 mmol/L Hold insulin, give 20–30 mmol of K + /hr until K +
>3.3 mmol/L, then start insulin
3.3−5.0 mmol/L 20–30 mmol of K + /L
>5.0 mmol/L Hold potassium repletion, repeat K + in 2 hours
• Phosphate
° Routine use of phosphate replacement not recommended
° Selective replacement suggested in patients with phosphate levels
<1.0 mg/dL, anemia, respiratory failure, or CHF
COMPLICATIONS OF MANAGEMENT
• Hypoglycemia
° Reduce
250 mg/dL
risk by adding dextrose to IV fluids as glucose falls below
• Hypokalemia
° Reduce risk by frequent assessment of potassium level and atten-
tion to potassium repletion
48565_ST06_251-352.indd 274 5/1/13 9:32 PM

Transition from IV Insulin Infusion 275
• Hyperchloremic acidosis
° Chloride (Cl−) in saline solution replaces the lost negative charge of
bicarbonate (HCO3−) to help maintain electroneutrality
° Anion gap has improved, but bicarbonate levels remain low
° This benign process resolves gradually in the hours to days after
the saline infusion is reduced or stopped
• Cerebral edema
° Cerebral edema occurs primarily in children, but has been
described in adults
° Etiology is unclear, but cerebral edema is not related to the degree
of hyperosmolality
° Avoid rapid changes in glucose and osmolarity
RESOLUTION OF THE HYPERGLYCEMIC CRISIS

• Resolution of DKA: normalization of the anion gap and/or drop in the
β hydroxybutyrate level to less than 3 mmol/L
• Resolution of HHS: correction of the fluid and electrolyte
abnormalities
TRANSITION FROM IV INSULIN INFUSION

• Transition to SQ insulin regiment once the acute abnormalities (acid-
base, osmolar, and electrolyte) have resolved and the glucose level
has improved
• Do not stop IV insulin until adequate time for absorption of SQ insulin
° At least 30 minutes for short-acting insulin or 2 hours for longer-
acting insulin
• Start a physiologic insulin regimen consisting of
° Basal insulin (NPH, glargine, or detemir)
° Mealtime, or “nutritional,” insulin (regular, lispro, apidra, or aspart)
• Use of corrective (“sliding scale”) insulin as the sole SQ insulin strat-
egy is never appropriate in a patient recovering from a hyperglycemic
emergency
• Calculate TDD of insulin requirements
° TDD = stable IV insulin infusion rate (over last 4−6 hours) ⫻ 20
° ½ of TDD as basal insulin given once daily as either (1) glargine
daily or (2) detemir or NPH twice daily in divided doses
° ½ of TDD as mealtime insulin given in three equal doses at break-
fast, lunch, and dinner
° ticipated hyperglycemia
Supplemental insulin doses can be administered to correct unan-
48565_ST06_251-352.indd 275 5/1/13 9:32 PM

REFERENCES
DeSantis AJ, Schmeltz LR, Schmidt K, et al. Inpatient management
of hyperglycemia: the Northwestern experience. Endocr Pract,
2006;12(5):491−505.
Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty years
of personal experience in hyperglycemic crises: diabetic ketoacido-
sis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab,
2008;93(5):1541−52.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult
patients with diabetes. Diabetes Care, 2009;32(7):1335−43.
O’Malley CW, Emanuele M, Halasyamani L, Amin AN; Society of Hospital
Medicine Glycemic Control Task Force. Bridge over troubled waters: safe
and effective transitions of the inpatient with hyperglycemia. J Hosp Med,
2008;3(Suppl 5):55−65.
Trachtenbarg DE. Diabetic ketoacidosis. Am Fam Physician, 2005;71(9):
1705−14.
Wilson JF, Laine C, Turner BJ, et al. Diabetic ketoacidosis. Ann Int Med, 2010;
152(1):ITC1-16.
48565_ST06_251-352.indd 276 5/1/13 9:32 PM

47 ■ HYPOGLYCEMIA IN PATIENTS
WITH DIABETES
Hilary Whitlatch, MD and Geetha Gopalakrishnan, MD
DEFINITION
• PG concentration ≤70 mg/dL with or without symptoms
SYMPTOMS OF HYPOGLYCEMIA
• Increased Epi secretion: tremor, palpitations, diaphoresis
• Neuroglycopenic symptoms: confusion, behavior change, seizure, coma
CLASSIFICATION OF HYPOGLYCEMIA IN PATIENTS WITH DIABETES

• Severe: requires assistance of another person
• Documented symptomatic: typical symptoms and measured
PG ≤70 mg/dL
• Asymptomatic: measured PG ≤70 mg/dL without symptoms
• Probable symptomatic: typical symptoms but PG not measured
• Relative: typical symptoms but measured PG >70 mg/dL
° People with chronic hyperglycemia may experience hypoglycemic
symptoms when blood sugars decline to the physiologic range
° Although uncomfortable, likely poses no direct harm, as there is
adequate glucose supply to vital organs
ETIOLOGIES OF HYPOGLYCEMIA IN DIABETES

• Insulin excess
° Excess/mistimed exogenous insulin or medications that stimulate
release of endogenous insulin from the pancreas independently of
blood glucose (sulfonylureas and meglitinides)
° Situations of increased insulin sensitivity or glucose utilization
(exercise, weight loss)
° Decreased insulin clearance (renal failure)
• Decreased glucose availability
° Decreased exogenous glucose intake (overnight fast, missed meal)
° Decreased
consumption)
endogenous glucose production (liver failure, alcohol
• Abnormal counterregulatory response to hypoglycemia

° Exogenous insulin is not subject to normal physiologic feedback
regulation in response to hypoglycemia
48565_ST06_251-352.indd 277 5/1/13 9:32 PM

278 Hypoglycemia in Patients with Diabetes
° Lack of hypoglycemia-induced glucagon secretion from pancreatic

α cells results in failure to stimulate liver glycogenolysis and
gluconeogenesis.
■ Develops within 5 years of type 1 diabetes onset and more
slowly in type 2 diabetes (>10 years), mirroring β-cell

failure
■ The pathogenesis is unknown; hypotheses include inhibition
of glucagon secretion by exogenous insulin or by intraislet

sympathetic neuropathy
° Lack of hypoglycemia-induced Epi secretion occurs as a result
of alteration in the function of glucose-sensing receptors on
autonomic neurons
■ Results in a failure to appropriately stimulate liver glycogenoly-
sis and gluconeogenesis

■ Reduces autonomic symptoms of hypoglycemia (tremor, dia-
phoresis, palpitations), causing hypoglycemic unawareness and

delayed recognition and treatment of hypoglycemia
HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE (HAAF)

• Occurs when the glycemic threshold for sympathetic autonomic activa-
tion is shifted to a lower PG concentration by a prior hypoglycemic
event, prior exercise, or sleep
° Mechanism is not clearly defined, but is thought to reside in the
brain, possibly the ventromedial hypothalamus
• Results in reduced sympathetic neural response to hypoglycemia,
reducing symptoms and leading to hypoglycemic unawareness
• Results in a cycle of recurrent hypoglycemia and is associated with a
sixfold increased risk for severe hypoglycemia
• Risk factors for HAAF include absolute endogenous insulin deficiency
(type 1 diabetes, postpancreatectomy, long-standing type 2 diabetes),
history of severe hypoglycemia, recent antecedent hypoglycemia, prior
exercise or sleep, and aggressive glycemic therapy to achieve lower
glycemic goals
• 2−3 weeks of strict avoidance of treatment-induced hypoglycemia
can reverse HAAF and restore the Epi counterregulatory
response
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Prevention of Hypoglycemia in Diabetes 279
ACUTE TREATMENT OF HYPOGLYCEMIA IN DIABETES

• In general, all hypoglycemic episodes, with the exception of relative
hypoglycemia, should be treated
° HAAF can lead to a cycle of recurrent hypoglycemia
• If conscious, treat with 15−20 g of oral glucose (4 ounces of juice,
3 glucose tablets, 1 tube of glucose gel)
° Clinical improvement usually occurs within 15 minutes; a finger-
stick can confirm resolution (FS > 70 mg/dL)
° may be required
Given risk of recurrent hypoglycemia, a subsequent snack or meal
• If unconscious or unable to take glucose by mouth at home, a trained

family member/associate can administer 1 mg of glucagon SQ or IM
• If unconscious and IV access available, 12.5−25 g IV 50% dextrose
can be administered by medical personnel.
PREVENTION OF HYPOGLYCEMIA IN DIABETES

• Individualize glycemic goals
° Balance the risk of complications from hypoglycemia and the risk of
long-term complications of hyperglycemia
° Aappropriate
higher glycemic treatment target, such as a A1C of 7−8% is
in the elderly, those at high risk of hypoglycemia, and
those with hypoglycemic unawareness
• Individualize therapy
° Among the sulfonylureas, hypoglycemia is less frequent with
glimepiride and glipizide than with glyburide
° in less hypoglycemia
Use of a long-acting insulin analogue (glargine or detemir) results
than use of NPH insulin
° Use of a rapid-acting insulin analogue (aspart, lispro, glulisine) for
mealtime insulin coverage is associated with less hypoglycemia
than use of regular insulin
• Patient and family education
° Frequent self-monitoring of blood glucose
° Recognition of early symptoms of hypoglycemia
° should be altered
Recognition of situations in which dose or timing of medication
(exercise, illness, fasting)
° Recognition of situations in which a preemptive snack or glucose
load is appropriate (exercise, alcohol consumption)
° Ready availability of treatment (glucose tablets, gel)
° Instruction of family members on glucagon administration
° Consider medical alert identification, particularly in those with a
prior history of severe hypoglycemia or hypoglycemic unawareness
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280 Hypoglycemia in Patients with Diabetes
REFERENCES
Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes.
Diabet Med, 2008;25(3):245−54.
Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of
adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2009;94(3):709−28.
McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes. Diabetes,
2010;59(10):2333−9.
Workgroup on Hypoglycemia, American Diabetes Association. Defining
and reporting hypoglycemia in diabetes: a report from the American
Diabetes Association Workgroup on Hypoglycemia. Diabetes Care,
2005;28(5):1245−9.
48565_ST06_251-352.indd 280 5/1/13 9:32 PM

48 ■ DIABETIC RETINOPATHY
Harikrashna Bhatt, MD and Geetha Gopalakrishnan, MD
PATHOPHYSIOLOGY
• Diabetic retinopathy is the leading cause of adult blindness in the
United States
• 95% of type 1 diabetics and 60% of type 2 diabetics will develop
diabetic retinopathy after 20 years of diabetes
° Long-term hyperglycemia causes diabetic retinopathy
° Progression of diabetic retinopathy can be delayed by improving
glycemic control and by reducing A1C; target goal for A1C is <7%
• Diabetic retinopathy can occur in those with impaired glucose
tolerance
• Damage to the retinal vasculature by chronic hyperglycemia is the
underlying cause of diabetic retinopathy
° Proposed mechanisms: sorbitol accumulation, advanced glycation
end products (AGEs), reactive oxygen species
° may play role
Retinal microthrombosis and certain growth factors such as VEGF
• Two types of retinopathy: nonproliferative and proliferative

° General progression from mild nonproliferative diabetic retinopathy
to proliferative diabetic retinopathy
• Patients may have no symptoms in the early stages of retinopathy
• With progression, patients may experience poor visual acuity and
blindness
• Diabetic retinopathy progresses with hyperglycemia; monitor A1C and
target levels <7%
• Comprehensive dilated eye exam necessary
° Nonproliferative diabetic retinopathy ophthalmoscopic features:
retinal hemorrhages, macular edema, hard exudates, microaneu-
rysms, venous beading, and cotton wool spots
° Proliferative diabetic retinopathy ophthalmoscopic features:
preretinal hemorrhages, macular edema, fibrovascular proliferation,
and neovascularization
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282 Diabetic Retinopathy
TABLE 48.1 Retinal Findings
Retinal Findings Etiology Descriptions
Retinal hemorrhages Bleeding from retinal Appear as red dots
vessels
Microaneurysms Leakage of serum from Small dots along retinal
retinal capillaries capillaries
Hard exudates Lipid deposits within Appear yellow with clear
retina edges
Venous beading Retinal hypoxia Dilated retinal veins
Cotton wool spots Retinal ischemia White/soft-edged spots
(transient)
Preretinal hemorrhages Vitreous blood Red areas
Macular edema Fluid within the intraretinal Loss of central vision
portion of macula
MANAGEMENT
• BP and blood glucose control is essential for the prevention and
progression of diabetic retinopathy
• Start ophthalmologic evaluation
° At time of diagnosis for patient with type 2 diabetes
° 3−5 yrs after diagnosis of type 1 diabetes
• Follow up interval is based on severity of retinopathy, ranging from 3 to
12 months
• Pregnant women can get worsening of retinopathy as pregnancy
progresses
° Reasons postulated include lower retinal blood flow (due to physi-
ologic systemic lowering of BP in pregnancy) worsening retinal
ischemia/hypoxia
° Pregnant women with type 1 or 2 diabetes should get an eye exam
prior to conception or in the early first trimester
° Follow-up ophthalmologic evaluation every trimester may be necessary
• Treatment
° Mild and moderate nonproliferative diabetic retinopathy is generally
not treated; focal laser photocoagulation can be considered if
macular edema present
° Panretinal photocoagulation can be used in the treatment of severe
nonproliferative diabetic retinopathy; potential side effects include
poor adaptation to dark and reduced peripheral vision/central vision
° Laser photocoagulation can be performed during pregnancy
° Retinal detachment or vitreous hemorrhage may require surgical
intervention
° Future therapeutic directions: antiplatelet agents, protein kinase
C inhibitors, anti-VEGF agents (anti-VEGF agents have shown the
most promise)
48565_ST06_251-352.indd 282 5/1/13 9:32 PM

References 283
REFERENCES
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med,
2012;366(13):1227−39.
Bhavsar AR. Diabetic retinopathy: the latest in current management. Retina,
2006;26(Suppl 6):S71−9.
Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy:
a systematic review. JAMA, 2007;298(8):902−16.
48565_ST06_251-352.indd 283 5/1/13 9:32 PM

48565_ST06_251-352.indd 284 5/1/13 9:32 PM
49 ■ DIABETIC NEPHROPATHY
M. Luiza Caramori, MD, MSc, PhD
EPIDEMIOLOGY
• Diabetic nephropathy develops in 25–35% of patients with a peak in
incidence around 20 years of diabetes duration
• Rates of diabetic nephropathy are similar in type 1 and type 2 diabetes
• Diabetic nephropathy is the most common cause of ESRD in adults
• Patients with diabetic nephropathy have increased mortality, mainly
due to cardiovascular disease
RISK FACTORS
• Glycemic control, systemic BP, and genetic factors are very important
determinants of diabetic nephropathy risk
• Other factors (smoking, obesity, lipid levels) may modulate this risk
• There is a high concordance in diabetic nephropathy risk among
siblings with diabetes
• Diabetic nephropathy risk is greater in patients with family history of
hypertension and CVD
PATHOPHYSIOLOGY
• Renal lesions in diabetes are mainly related to extracellular matrix
accumulation in the glomerular and tubular basement membranes,
mesangium, and interstitium
• Expansion of the mesangium reduces the glomerular capillary luminal
space, decreasing glomerular filtration surface and GFR
• There is a strong relationship between renal structure and function in
patients with type 1 diabetes
• Progressive tubular atrophy, interstitial fibrosis, renal glomerular
arteriolar hyalinosis, arteriosclerosis, and glomerulosclerosis are also
important components of diabetic nephropathy that may contribute to
the reduction in GFR
• Larger vessel atherosclerosis, especially in type 2 diabetes, may lead
to ischemic renal tissue damage
• Hyperglycemia, AGEs, and increased oxidative stress have all been
associated with diabetic nephropathy
48565_ST06_251-352.indd 285 5/1/13 9:32 PM

286 Diabetic Nephropathy
• Didactically, the course of diabetic nephropathy in type 1 diabetes can
be divided in 5 stages (Table 49.1)
• Patients with type 2 diabetes can have microalbuminuria or proteinuria
at diagnosis, generally attributed to a prior period of undiagnosed
diabetes; GFR decline is also more variable, reflecting the heterogene-
ity of renal lesions in these patients
TABLE 49.1 Stages of Diabetic Nephropathy
Diabetes Duration Stage Manifestations Characteristics
0 to 3−5 years I • Renal hypertrophy • Present at diagnosis
• Increased-to-normal GFR
3−5 to 7 years II • Normal urinary albumin • Common in all
excretion patients with
• Basement membrane diabetes
thickening
• Mesangial expansion
7 to 15−20 years III • Microalbuminuria • 20−45% progression
• Increases in blood to Stage IV in 10 years
pressure levels
• Normal-to-declining GFR
15−20 to 25 years IV • Proteinuria • Increased
• Hypertension cardiovascular
• Decreased GFR mortality
• Dyslipidemia • Progression to ESRD
in 5−15 years
• Associated with other
chronic complications
of diabetes
After 25 years V • ESRD
Adapted from: Caramori ML, Maver M. Pathogenesis and pathophysiology of diabetic nephropathy. In:
Greenberg A, ed. Primer on Kidney Diseases, 5th ed. Philadelphia, PA: Saunders Elsevier; 2009:214–223.
GFR = glomerular filtration rate; ESRD = end-stage renal disease
• Diagnosis is based on the presence of increased urinary albumin
excretion (UAE) (Table 49.2) and/or reduced GFR
• Renal biopsies may be necessary for diagnosis in patients with an
atypical clinical course, since, although not common, other nephropa-
thies can be present
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Management 287
TABLE 49.2 Categories of Urinary Albumin Excretion
Category/Urine Spot Collection 24-h Collection Timed Collection
Collection (μg/mg creatinine) (mg/24h) (μg/min)
Normoalbuminuria <30 <30 <20
Microalbuminuria 30−300 30−300 20−200
Macroalbuminuria/ >300 >300 >200
Proteinuria
Adapted from: Caramori ML, Maver M. Pathogenesis and pathophysiology of diabetic nephropathy. In:
Greenberg A, ed. Primer on Kidney Diseases, 5th ed. Philadelphia, PA: Saunders Elsevier; 2009:214–223.
MANAGEMENT
• Blood glucose control: primary prevention of diabetic nephropathy is
mainly achieved by intensive blood glucose control (A1c around 7%)
• All patients with overt diabetic nephropathy (proteinuria and/or
reduced GFR) should be treated with ACEIs or ARBs
• BP control: in patients with hypertension, BP control is key
° For most patients, a BP goal of <130/80 is acceptable; however, the
BP target may vary depending on the presence of comorbidities
° Most
goals
patients need multiple antihypertensive agents to reach BP
° frequentlydiuretics,
Thiazide calcium channel blockers, and/or β blockers are
used in combination with an ACEI or ARB
° Although the combination of an ACEI and ARB may further reduce
proteinuria, mortality is increased and, in most instances, these
agents should not be used together
° Patients may have other clinical conditions for which a specific
class of antihypertensive agent is indicated (e.g., ACEIs or ARBs if
proteinuria or elevated creatinine, β blockers following MI)
• Lipid control: control of lipid levels (low-density lipoprotein [LDL]
<100 mg/dL), in association with other measures, is associated with
slower rates of diabetic nephropathy development and progression
• Smoking cessation
• Patients with progressive nephropathy, especially when estimated GFR
is <60 ml/min/1.73m2, should be referred to a nephrologist if there is
concern for the presence of non-diabetic kidney disease
• All patients with estimated GFR <30 ml/min/1.73m2 should be
referred to a nephrologist
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288 Diabetic Nephropathy
REFERENCES
American Diabetes Association. Standards of medical care in
diabetes—2013. Diabetes Care, 2013;36(Suppl 1):S11−63.
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations
for Diabetes and Chronic Kidney Disease. Am J Kidney Dis, 2007;49
(2 Suppl 2):S12−154.
US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic
Kidney Disease and End-Stage Renal Disease in the United States.
Bethesda, MD: National Institutes of Health, National Institute of Diabetes
and Digestive and Kidney Diseases; 2010. Available at: hwww.usrds.org/
atlas10.aspx.
48565_ST06_251-352.indd 288 5/1/13 9:32 PM

50 ■ DISTAL SYMMETRIC POLYNEUROPATHY
Elias S. Siraj, MD
PATHOPHYSIOLOGY
• Hyperglycemia is clearly associated with the development of diabetic
neuropathy
• Proposed mechanisms include
° Formation of AGEs; increased sorbitol production via the aldose
reductase pathway
° Increased activation
Activation of protein kinase C
° Increased oxidative stress
of the hexosamine pathway
°
• Other mechanisms may include: vascular factors such as ischemia and
hypertension, autoimmunity, and defects in nerve fiber repair mechanisms
• Presentation tends to be “glove and stocking” distribution with
feet much more frequently affected than hands; symptoms include
numbness, pain (usually burning and sometimes pronounced at night),
altered sensation, and paresthesias
• Impairment of pain, light touch, and temperature is secondary to
loss of small fibers and tends to appear early even though it may be
asymptomatic and undetected
• Loss of vibratory sensation and altered proprioception reflect large-
fiber loss
• Decreased or absent ankle reflexes may be noted
• In severe cases, muscle weakness may be seen
SCREENING AND MONITORING OF DISTAL SYMMETRIC

POLYNEUROPATHY (DSPN)
• DSPN is usually diagnosed clinically based on symptoms and physical
exam findings
• All patients with type 2 diabetes should be screened for DSPN at the
time of diagnosis and those with type 1 diabetes should be screened
five years after diagnosis
• After initial screening, all patients should be followed at least annually by
examining sensory function in the feet and checking ankle reflexes. One or
more of the following tests can be used to assess sensory function:
° Pinprick
° Temperature
48565_ST06_251-352.indd 289 5/1/13 9:32 PM

290 Distal Symmetric Polyneuropathy
° Vibration perception (using a 128-Hz tuning fork)

° Pressure sensation (using a 10-g monofilament pressure sensation
at the distal halluces)
• Nerve conduction studies are occasionally useful to exclude other
types of neuropathy
MANAGEMENT OF DSPN
• All patients with DSPN require comprehensive foot care
• Glycemic control reduces the onset and progression of DSPN
° Rapid improvement of glycemic control may lead to a transient
worsening of neuropathic symptoms
• Pain management
° Antidepressants:
■ Tricyclics
used as first-line agents in most cases
• Amitriptyline 25−100 mg /day

■ Dual serotonin and NE reuptake inhibitors
• Duloxetine 60−120 mg/day

• Venlafaxine 75−225 mg/day
° tion with antidepressants
Anticonvulsant therapy: can be used as monotherapy or combina-
■ Pregabalin 300−600 mg/day
■ Gabapentin 900−3600 mg/day
■ Sodium valproate 500−1200 mg/day
° Others
■ Capsaicin cream 0.075%: a naturally occurring component of
some types of hot peppers that causes analgesia by depleting

substance P
• Can be added if refractory to antidepressants or
anticonvulsants
• Applied up to 4 × daily
■ Opiods: oxycodone, morphine sulphate
■ Topical lidocaine
■ Others: dextromethorphan, tramadol
REFERENCES
Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment
of painful diabetic neuropathy—report of the American Association of
Neuromuscular and Electrodiagnostic Medicine, the American Academy
of Neurology, and the American Academy of Physical Medicine &
Rehabilitation. Muscle Nerve, 2011;43(6):910–7.
Consensus statement: Report and recommendations of the San Antonio con-
ference on diabetic neuropathy. American Diabetes, Association American
Academy of Neurology. Diabetes Care, 1988;11(7):592–7.
48565_ST06_251-352.indd 290 5/1/13 9:32 PM

References 291
England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy:

a definition for clinical research: report of the American Academy of
Neurology, the American Association of Electrodiagnostic Medicine, and
the American Academy of Physical Medicine and Rehabilitation. Neurology,
2005;64(2):199–207.
Hartemann A, Attal N, Bouhassira D, et al. Painful diabetic neuropathy:
diagnosis and management. Diabetes Metab, 2011;37(5):377–88.
Said G. Diabetic neuropathy—a review. Nat Clin Pract Neurol,
2007;3(6):331–40.
48565_ST06_251-352.indd 291 5/1/13 9:32 PM

48565_ST06_251-352.indd 292 5/1/13 9:32 PM
51 ■ CARDIOVASCULAR DISEASE
IN TYPE 2 DIABETES
Tessey Jose, MD, Raymond R. Russell, MD, and Silvio E. Inzucchi, MD
DIABETES AND CARDIOVASCULAR RISK: OVERVIEW

• CVD is the leading cause of mortality in diabetes (responsible for nearly
70% in individuals >65 years old)
• Diabetes imparts a ~2- to 4-fold risk of CVD: MI, stroke, peripheral
arterial disease (PAD), and CHF
• Outcomes after CVD events, including mortality, are more adverse in
the diabetic population
• In general, atherosclerosis is more diffuse and advanced in the pres-
ence of diabetes
PATHOPHYSIOLOGY
FIGURE 51.1 Pathophysiology of Insulin Resistance and its Association with

Cardiovascular Disease
48565_ST06_251-352.indd 293 5/1/13 9:32 PM

294 Cardiovascular Disease in Type 2 Diabetes
• Type 2 diabetes and atherosclerosis (attributed to the following risk fac-

tors and intermediaries, each exhibiting complex interrelationships)
° Insulin resistance/metabolic syndrome
° Obesity
° Dyslipidemia (and AGEs)
Hyperglycemia
° Hypertension
° Proinflammatory state
° Hypercoagulability (prothrombotic state)
° Microvascular/endothelial dysfunction
° Oxidative stress
°
• Diabetic cardiomyopathy
° MI (sometimes silent) → regional and global ventricular
dysfunction
° Microvascular disease
° Cardiac autonomic neuropathy
and fatty acids → glucolipotoxicity
° Elevated glucose
GLYCEMIC CONTROL
• Glycemic control and CVD outcomes: implications of major trials
° UKPDS: in newly diagnosed patients with type 2 DM, sulfonylureas
or insulin therapy showed neutral effect on MI risk as compared to
standard diet therapy; in contrast, metformin reduced MI risk in
overweight patients
° UKPDS 10-year follow-up study: group previously treated more
intensively with sulfonylureas/insulin (A1c ~7%) demonstrated
modestly reduced cardiovascular risk, as compared to standard diet
therapy group (A1c ~8%); metformin’s cardiovascular advantage
persisted as well
° ACCORD, ADVANCE, VADT: in patients with longstanding type 2 DM
and higher cardiovascular risk, there is no apparent cardiovascular
advantage to A1c targets more intensive than ~7% (or slightly
higher); the risks of intensive glycemic control may outweigh
benefits in some patients: advanced age (>70–75 years), long
disease duration (>20 years), established CVD, increased risk of
hypoglycemia
48565_ST06_251-352.indd 294 5/1/13 9:32 PM

Glycemic Control 295
TABLE 51.1 CV Considerations of the Most Commonly Used
Antihyperglycemic Medications
CV Considerations
Mechanism HbA1c Potential
Drug Class of Action Efficacy Benefi ts Concerns
Biguanides Decreases –1 to 2% • Insulin- • Contraindicated
hepatic sensitizing in unstable/
glucose properties severe CHF
production • Improved CVD • Possible
outcomes in lactic acidosis
UKPDS in patients
• Retrospective with renal
studies dysfunction
show ↓ receiving
cardiovascular contrast
mortality
Sulfonylureas Binds to –1 to 2% – • Hypoglycemia
sulfonylurea risk
receptors on • Weight gain
pancreatic • ? Impairs
β cells, ischemic
stimulating preconditioning
insulin • Retrospective
release studies show ↑
cardiovascular
mortality
Thiazolidinediones Activates, –1 to 1.5% • Insulin- • Edema/heart
PPARγ, sensitizing failure
increasing properties • Weight gain
peripheral • Beneficial • Question of
insulin effects on ↑ MIs with
sensitivity multiple rosiglitazone
intermediate
CVD markers/
surrogates
• ↓ TGs ,
↑ HDL-C
• ↓ MACE* in
PROactive
(pioglitazone)
(continues)
48565_ST06_251-352.indd 295 5/1/13 9:32 PM

CV Considerations
Mechanism HbA1c Potential
Drug Class of Action Efficacy Benefi ts Concerns
GLP-1 Receptor Activates –1 to 1.5% • Weight loss • Slight ↑ heart
Agonists GLP-1 • Beneficial rate
receptors, effects on
stimulating several
insulin intermediate
release CVD markers/
(glucose- surrogates
dependent), • ? benefits
suppressing from
glucagon, activating
slowing cardiac GLP-1
gastric receptors
emptying,
and
enhancing
satiety
DPP-4 Inhibitors Inhibits –0.6 to 0.8% • ? benefits –
enzyme that from inhibiting
deactivates degradation
endogenous of SDF-1α,
incretins, increasing
GLP-1 circulating
and GIP, endothelial
augmenting progenitor
their activity cells
• ? benefits
from
activating
cardiac GLP-1
receptors
Insulin Activates Theoretically • Anti- • Hypoglycemia
insulin limitless inflammatory risk
receptors, action • Weight gain
increasing • ↓ AMI • Retrospective
peripheral mortality in studies show ↑
glucose DIGAMI cardiovascular
uptake and mortality in
decreasing heart failure
hepatic
glucose
production
*Major adverse cardiovascular events
48565_ST06_251-352.indd 296 5/1/13 9:32 PM

Hypertension Management 297
HYPERTENSION MANAGEMENT
• Major risk factor for both CVD and microvascular complications
• Lowering BP with various antihypertensive regimens has been shown
to be effective in reducing cardiovascular events (UKPDS, HOT)
• No benefit in reduction of cardiovascular events with intense BP
control (systolic blood pressure [SBP] <120 mm Hg) compared to SBP
of 130−140 mm Hg in type 2 DM patients at high CVD risk (ACCORD)
• Goals: ADA and 7th Report of the Joint National Committee (JNC)
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC-7) – in patients with diabetes
° Systolic BP <130 mm Hg (JNC), <140* (ADA)
° Diastolic BP <80 mm Hg
° Screening and diagnosis
During pregnancy 110–129/65–79 mm Hg
° ■ BP should be measured at every office visit
■ Elevated levels should be confirmed on a separate day
° Treatment
■ Patients with SBP of 130–139 mm Hg or diastolic blood pressure
(DBP) of 80–89 may be given a 3-month period of lifestyle

modification
■ Lifestyle therapy for hypertension includes weight loss, diet rich
in fruits and vegetables, increased physical activity, reduced

sodium intake (<1500 mg/day), increased potassium intake, and
moderation of alcohol consumption
■ Patients with higher BP (SBP ≥140 or DBP ≥90) should be
treated with pharmacological therapy

■ Most patients will need combination therapy with at least
3 agents for optimal control

■ First-line therapy is with an ACEI (or an ARB if an ACEI is not
tolerated)
• During pregnancy, ACEIs and ARBs are contraindicated
• In patients with microalbuminuria or established nephropathy,
either ACEIs or ARBs are considered first-line therapy
■ Second-line agent after ACEI/ARB: usually a thiazide diuretic
■ Third-line agents: Ca + channel blockers and β-blockers
*Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger
patients, if achieved without undue treatment burden.
48565_ST06_251-352.indd 297 5/1/13 9:32 PM

DYSLIPIDEMIA
• Type 2 DM patients have an increased prevalence of lipid abnormali-
ties, contributing to their higher CVD risk
• Major abnormalities include increased triglycerides (TG), low HDL
cholesterol (HDL-C), and more atherogenic LDL particles
• Major reductions in CVD event rates from statin therapy has been
reported in multiple trials focused on or including large numbers of
diabetic patients (CARDS, Heart Protection Study, TNT, PROVE IT)
• Fasting lipid profile should be measured annually
LIPID GUIDELINES
• ADA Standards of Medical Care in Diabetes (2013)
° Reduction of CVD events with statins correlates well with lowering
of LDL cholesterol (LDL-C), so targeting LDL remains the preferred
strategy. Secondary goals include
■ TG <150 mg/dL
■ HDL >40 mg/dL in men; >50 mg/dL in women
° with overt
Statin therapy should be added to lifestyle therapy for DM patients
CAD and those without CVD who are > age 40 who have
≥1 CVD risk factors (family history of CVD, hypertension, smoking,
dyslipidemia, or albuminuria)
° In individual without overt CVD, primary LDL goal is <100 mg/dL
° In very high-risk individuals (e.g., with overt CVD), lower LDL goal of
<70 mg/dL is recommended
° If30−40%
patients do not reach the above goals, then a reduction in LDL of
from baseline is an acceptable goal
° acid sequestrants)
Additional pharmacological agents (fibrates, niacin, ezetimibe, bile
may improve lipid parameters but no evidence
that such therapy will reduce event rates or that combinations of
these agents with statins is beneficial
TABLE 51.2 ADA Lipid Management Recommendations

Assessment Frequency Goal Drug Rx Initiation*
LDL-C
• With CVD Yearly <70 mg/dL ≥70 mg/dL
• No CVD Yearly <100 mg/dL ≥100 mg/dL
TG Yearly <150 mg/dL >400 mg/dL
HDL-C Yearly >40 mg/dL (men) Uncertain
>50 mg/dL (women)
* Irrespective of baseline lipid profile, statin therapy should be added to lifestyle therapy for DM patients
with overt CAD and those without CVD who are > age 40 who have ≥1 CVD risk factor (family history of
CVD, hypertension, smoking, dyslipidemia, or albuminuria).
48565_ST06_251-352.indd 298 5/1/13 9:32 PM

Antiplatelet Therapy 299
TABLE 51.3 Natioxnal Cholesterol Education Program (NCEP)—Adult
Treatment Panel III
LDL-C level to initiate lifestyle change ≥100 mg/dL
LDL-C level to initiate a statin ≥100mg/dL
TG Goal < 150 mg/dL (initiate once LDL-C treated)
(or non–HDL-C goal <130 mg/dL)
TG 150−199 mg/dL 1° aim: LDL-C goal
2° aim: Lifestyle modification (diet,
weight loss)
TG 200−499 mg/dL 1° aim: LDL-C goal
2° aim: Non−HDL-C goal by adding fibrate,
nicotinic acid or increasing dose of
LDL-C drug
TG ≥500 mg/dL 1° aim: Reduce risk of pancreatitis by
starting low-fat diet, weight loss, and
fibrate or nicotinic acid
2° aim: LDL-C goal
Low HDL-C (men <40 mg/dL, Consider adding fibrate or nicotinic acid if
women <50 mg/dL) LDL-C and non−HDL-C goals are met
ANTIPLATELET THERAPY
• 2010 Position Statement of the ADA, American Heart Association
(AHA), and American College of Cardiology (ACC). Aspirin therapy
(75−162 mg/day) as primary prevention in patients with types
1 or 2 diabetes at increased CV risk (10-year risk >10%: most men
>50 and women >60 who have at least 1 of the following additional
major risk factors: smoking, hypertension, dyslipidemia, family history
of premature CVD, albuminuria)
• Aspirin not recommended for CVD prevention for adults at low CVD risk
(10-year risk <5%: most men <50 and women <60 who have no other
major CVD risk factor)
• Clinical judgment required for patients in these age groups at interme-
diate risk with a 10-year risk of 5−10%
• Aspirin therapy recommended as secondary prevention in those with
diabetes and a history of CVD
• For those with an aspirin allergy, clopidogrel 75 mg/day should
be used
• Combination therapy with aspirin and clopidogrel may be used for up
to 1 year following an acute coronary syndrome
• Aspirin for patients <21 is contraindicated due to the associated risk
of Reye’s syndrome
48565_ST06_251-352.indd 299 5/1/13 9:32 PM

CORONARY HEART DISEASE (CHD) SCREENING

• Standards of Medical Care in Diabetes—2013
° In asymptomatic patients, routine screening for CAD is not recom-
mended, since it does not improve CVD outcomes as long as risk
factors are treated (DIAD study)
° Patients with typical or atypical cardiac symptoms or an abnormal
resting ECG should be tested
° hypertension,
In patients with diabetes, CVD risk factors, including dyslipidemia,
smoking, family history of premature CAD, and the
presence of albuminuria, should be assessed at least annually
MANAGEMENT OF DM IN ACUTE CORONARY SYNDROME

• Unstable angina (UA)/non-ST elevation myocardial infarction
(NSTEMI): 2011 ACCF/AHA Guidelines
° Treatment of hyperglycemia is associated with improved outcomes
■ However, it is unclear whether hyperglycemia is a marker
of underlying health status or whether it is a mediator of

complications
° glucosethere
Since is a paucity of well-designed trials of target-driven
control in UA/NSTEMI patients, goals are in accordance
with the current standard of care as per the ADA guidelines for
critically ill patients
■ Insulin therapy should be initiated for hyperglycemia at a thresh-
old no greater than 180 mg/dL

■ Target glucose level of 140−180 mg/dL
■ Stringent goals, such as 110−140 mg/dL, may be appropriate
for selected patients as long as targets are achieved without

hypoglycemia
■ An IV insulin protocol has shown to demonstrate effi cacy
and safety in achieving glycemic targets without significant

hypoglycemia
■ Consider obtaining an A1c on patients with diabetes if testing
within the last 2−3 months is not available

• UA/ST elevation myocardial infarction (STEMI): 2009 ACC/AHA Focused
Update: STEMI and PCI Guidelines
° Due to the lack of randomized trials with target-driven glucose
control in STEMI patients, it is reasonable to use an insulin-based
regimen to achieve and maintain blood sugars <180 mg/dL while
avoiding hypoglycemia
48565_ST06_251-352.indd 300 5/1/13 9:32 PM

References 301
REFERENCES
ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of com-
bination lipid therapy in type 2 diabetes mellitus. N Engl J Med,
2010;362(17):1563−74.
ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood
glucose control and vascular outcomes in patients with type 2 diabetes.
N Engl J Med, 2008;358(24):2560−72.
Anderson JL, Adams CD, Antman EM, et al. 2011 ACC/AHA Focused Update
Incorporated Into the ACC/AHA 2007 Guidelines for the Management of
Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction:
a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation,
2011;123(18):e426−579.
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. Hypertension, 2003;42(6):1206−52.
Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute
coronary syndrome: a scientific statement from the American Heart
Association Diabetes Committee of the Council on Nutrition, Physical
Activity, and Metabolism. Circulation, 2008;117(12):1610−9.
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascu-
lar complications in veterans with type 2 diabetes. N Engl J Med,
2009;360(2):129−39.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-
up of intensive glucose control in type 2 diabetes. N Engl J Med,
2008;359(15):1577−89.
Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/
AHA Guidelines for the Management of Patients With ST-Elevation
Myocardial Infarction (updating the 2004 Guideline and 2007 Focused
Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary
Intervention (updating the 2005 Guideline and 2007 Focused Update):
a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation,
2009;120(22):2271−306.
National Heart Lung and Blood Institute. Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III ) . Available at. www.nhlbi.nih.gov/guidelines/
cholesterol.
48565_ST06_251-352.indd 301 5/1/13 9:32 PM

Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of
cardiovascular events in people with diabetes: a position statement of the
American Diabetes Association, a scientific statement of the American
Heart Association, and an expert consensus document of the American
College of Cardiology Foundation. Circulation, 2010;121(24):2694−701.
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and
the prevention of cardiovascular events: implications of the ACCORD,
ADVANCE, and VA diabetes trials: a position statement of the American
Diabetes Association and a scientific statement of the American College
of Cardiology Foundation and the American Heart Association. Circulation,
2009;119(2):351−7.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-
glucose control with metformin on complications in overweight patients
with type 2 diabetes (UKPDS 34). Lancet, 1998;352(9131):854−65.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose con-
trol with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet, 1998;352(9131):837−53.
48565_ST06_251-352.indd 302 5/1/13 9:32 PM

52 ■ DIABETES IN PREGNANCY
Kenneth Chen, MD and Geetha Gopalakrishnan, MD
CLASSIFICATION
• Preexisting type 1 (7.5%) or type 2 diabetes (5%)
• Gestational Diabetes (GDM) (87.5%)
° Placental production of human placental lactogen increases
maternal tissue resistance and leads to the development of glucose
intolerance in pregnancy
° Resolves after the delivery of baby
° Overt diabetes will develop in 20−30% of women who experience
GDM within 5 years
RISK FACTORS FOR GDM

• BMI >30kg/m2
• Previous macrosomic baby weighing 9 lbs (4.1 kg) or above
• Previous GDM
• Family history of type 2 diabetes in first-degree relatives
• Ethnic origin with a high prevalence of type 2 diabetes (African American,
Asian American, Hispanic, Native American, or Pacific Islander)
• PCOS
• Presence of glycosuria in routine urinalysis testing
• Previous unexplained perinatal death or severe polyhydramnios
DIAGNOSIS OF GDM
• No universally accepted criteria as yet but International Association of
Diabetes in Pregnancy Study Groups (IADPSG) has been convened to
resolve this issue
• The following criteria has been proposed by the IADPSG and is cur-
rently endorsed by the ADA but not yet by the American College of
Obstetrics & Gynecology (ACOG)
° 2-hour 75 g OGTT between 24 and 28 weeks gestation
° Woman has GDM if any one of these are met
■ Fasting ≥92 mg/dL (5.1 mmol/l)
■ 1-hour post 75 g OGTT ≥180 mg/dL (10.0 mmol/l)
■ 2-hour post 75 g OGTT ≥153 mg/dL (8.5 mmol/l)
• Diagnostic algorithm as currently endorsed by ACOG

° 1-hour 50-g glucose challenge test (nonfasting)
■ If blood glucose level ≥140 mg/dL or 7.8 mmol/l on 50-g challenge,
then proceed to 3-hour 100-g OGTT
48565_ST06_251-352.indd 303 5/1/13 9:32 PM

304 Diabetes in Pregnancy
°Woman has GDM if two or more of these are met on 100-g OGTT
■ Fasting ≥95 mg/dL (5.3 mmol/l)
■ 1-hour post 100-g OGTT ≥180 mg/dL (10.0 mmol/l)
• All pregnant women with risk factors should be screened with an OGTT
and A1C for preexisting diabetes at first prenatal visit using standard
diagnostic criteria for DM (2 fasting PG levels ≥126 mg/dL confirmed on
separate days, any random PG level ≥200 mg/dL or A1C >6.5%). Patients
with normal results should then have screening for GDM at 24–28 weeks
• All women with previous GDM should be offered early self-monitoring
of blood glucose levels or an OGTT at 16−18 weeks followed by a
repeat OGTT at 28 weeks if the results are normal
PRECONCEPTION CARE OF WOMEN WITH PREEXISTING DIABETES

• Women with diabetes who are planning to become pregnant should
° Ideally have baseline BMI ≤27 kg/m2
° Take folic acid supplements 5 mg/day until 12 weeks gestation to
reduce incidence of neural tube defects
° Be self-monitoring blood glucose levels on a regular basis
° Have baseline A1C as close to 6.0% as possible
° miscarriages
Use contraception until glycemic control is optimized as risk of
and congenital anomalies are significantly increased
in women whose preconception A1C is >7%
° Have preconception complications screening with regards to reti-
nopathy and nephropathy as presence of these can worsen during
the course of pregnancy
° Be screened for concurrent disorders such as thyroid disease or
celiac disease
° insulin therapy
Women on oral hypoglycemic agents should be switched over to
preconception
■ There is evidence that both metformin and glyburide cross the
placenta (cord blood studies)

■ There is no data to confirm that either of these agents is harmful
to the fetus in the long run

■ Therefore, some experts consider the use of these agents in patients
who are unwilling or unable to take insulin during pregnancy

° ACEIs and angiotensin-II receptor antagonists should be discontin-
ued before conception and switched to alternative antihypertensive
agents such as labetalol, methyldopa, or nifedipine; statins should
also be discontinued before conception
MANAGEMENT OF DIABETES IN PREGNANCY

• Monitor blood glucose levels regularly
° Fasting levels should be <95 mg/dL
° 1−2-hour postprandial levels should be <120 mg/dL consistently
48565_ST06_251-352.indd 304 5/1/13 9:32 PM

Postnatal Care 305
• A1C can be monitored monthly to achieve target goals of <6.0%

throughout pregnancy
• If target glycemic goals are not met
° Recommend counseling to address diet and exercise regimen
° Insulin therapy (Gold standard)
■ Approximately 15% of women with GDM will require insulin
■ Insulin approved for use in pregnancy
• Rapid-acting insulin analogues (aspart and lispro)

• Regular insulin
• NPH insulin
• Insulin detemir
• Insufficient evidence supporting the use of glargine in preg-
nancy but increasing data suggests that it does not cause any
issues for the fetus
■ Metformin or glyburide can be considered in GDM and type 2 DM
if patient unable or unwilling to take insulin; there is insufficient

data to support the use of any other oral agents in pregnancy
• Suboptimally controlled blood glucose level will lead to an increased
risk of a large-for-gestational-age baby (increasing the risk of shoul-
der dystocia, induction of labor, and Cesarean section), polyhydram-
nios, preeclampsia, neonatal hypoglycemia, perinatal complications
such as respiratory tract infections or neonatal jaundice, and an
increased risk of the baby developing obesity and/or diabetes in later
life (fetal programming effect, Barker’s hypothesis)
SPECIAL PRENATAL CONSIDERATIONS FOR DIABETIC PATIENTS

• Routine high resolution level 2 ultrasound at 18−20 weeks looking at
4-chamber view of fetal heart and outflow tracts
• Regular ultrasounds every 4 weeks from 28 to 36 weeks to assess fetal
growth and amniotic fluid volumes
• Women on insulin therapy or whose blood glucose levels are not well
controlled on dietary therapy may require twice weekly nonstress tests
from 32 weeks to assess fetal well-being
• Delivery is usually recommended at 39 weeks; provided that baby is
normal size, Cesarean section does not confer any advantages over
vaginal delivery and hence the latter is preferred mode of delivery
POSTNATAL CARE
• Women with GDM can discontinue all hypoglycemic treatments
immediately after birth but keep monitoring their blood glucose levels
for 48 hours on a normal diet
° Women who required insulin or oral medications during pregnancy
should be offered an OGTT 6−12 weeks postpartum to ensure that
their glucose tolerance has returned to normal. If 6−12 week OGTT
is normal, they should be offered OGTT every 1−3 years thereafter.
48565_ST06_251-352.indd 305 5/1/13 9:32 PM

306 Diabetes in Pregnancy
° Women who did not require insulin or oral medications during

pregnancy should be offered OGTT at 1-year postpartum and every
1–3 years thereafter
° Ifshould
OGTT results are abnormal postpartum, prediabetes and diabetes
be treated appropriately with lifestyle intervention and
medical management
• Women with preexisting diabetes (on insulin therapy) should have
their insulin doses reduced back to prepregnancy levels; some oral
agents can be restarted postpartum in type 2 diabetes based on the
breastfeeding status
• Breastfeeding
° Breastfeeding utilizes an additional 500 Kcal per day; women who
breastfeed will usually require lower-than-baseline insulin dose
° breastfeeding and canand
Metformin (preferred) glyburide are generally safe with
be considered for the management of type 2
DM postpartum.
• Women with preexisting DM or GDM can use any form of contraception
postpartum
REFERENCES
American Diabetes Association. Detection and diagnosis of gestational
diabetes mellitus (GDM). Diabetes Care, 2012;35(Suppl 1):S15–S16.
Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gesta-
tional diabetes mellitus on pregnancy outcomes. N Engl J Med,
2005;352(24):2477–86.
HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al.
Hyperglycemia and adverse pregnancy outcomes. N Engl J Med,
2008;358(19):1991–2002.
International Association of Diabetes and Pregnancy Study Groups
Consensus Panel, Metzger BE, Gabbe SG, et al. International association
of diabetes and pregnancy study groups recommendations on the diag-
nosis and classification of hyperglycemia in pregnancy. Diabetes Care,
2010;33(3):676–82.
Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treat-
ment for mild gestational diabetes. N Engl J Med, 2009;361(14):1339–48.
Löbner K, Knopff A, Baumgarten A, et al. Predictors of postpartum diabetes
in women with gestational diabetes mellitus. Diabetes, 2006;55(3):792–7.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators.
Metformin versus insulin for the treatment of gestational diabetes. N Engl
J Med, 2008;358(19):2003–15.
48565_ST06_251-352.indd 306 5/1/13 9:32 PM

53 ■ GLYCEMIC ISSUES IN HOSPITALIZED
PATIENTS
Steven Kaufman, MD and Marc Laufgraben, MD, MBA
FOR HOSPITALIZED PATIENTS OUTSIDE THE ICU

• Glucose goals
° Fasting or premeal glucose less than 100–140 mg/dL
° Random glucose less than 180 mg/dL
° Blood glucose goals should be individualized; higher goals are
reasonable for patients with limited life expectancy or who have
recurrent hypoglycemia
• POCT glucose is recommended for patients under the following
circumstances: history of diabetes, PG >140 mg/dL on lab testing,
risk factors for diabetes, tube feeds or parenteral nutrition, or starting
glucocorticoids
° Testing can be reduced or discontinued if patient not started on
insulin regimen and glucoses remain <140 mg/dL after 48 hours
• Frequency of POCT
° IfIf NPO
eating: test premeal and at bedtime
° or on continuous nutrition: test q 4−6 h
• Check an A1C (if not performed in past 3 months) for patients with
diabetes or glucose >140 mg/dL
° For patients with prior history of diabetes, helps to determine
efficacy of outpatient diabetes regimen
° For hyperglycemic patients without a history of diabetes, an
elevated A1C is consistent with undiagnosed diabetes preceding
the hospitalization
° Hemoglobin A1C unreliable in patients with anemia, hemogolobin-
opathies, or who have received transfusions
• Discontinue oral antidiabetic agents and noninsulin injectable
medications in most patient
° Exception is the patient with good outpatient glycemic control,
glucose levels <140 mg/dL during hospitalization, no contraindica-
tion to the use of their outpatient medications, ability to tolerate
orals, and not expected to be NPO
° Switch to insulin therapy if clinical condition changes
• Start insulin for glucose levels above goal
48565_ST06_251-352.indd 307 5/1/13 9:32 PM

308 Glycemic Issues in Hospitalized Patients
TABLE 53.1 Currently Available Preparations of Insulin
INJECTABLE INSULINS*
Onset (h) Peak (h) Duration (h)
Rapid/short- Insulin aspart (NovoLog) <0.2 1–3 3–5
acting Insulin glulisine (Apidra) 0.30–0.4 1 4–5
Insulin lispro (Humalog) 0.25–0.5 0.5–2.5 ≤5
Regular (Novolin R, Humulin R) 0.5–1 2–3 3–6
Intermediate/ NPH (Novolin N, Humulin N) 2–4 4–10 10–16
long-acting Insulin detemir (Levemir) n.a. flat action up to 23†
profile
Insulin glargine (Lantus) 2–4 peakless 24
Mixtures Insulin aspart protamine 0.25 1–4 up to 24
susp/aspart (NovoLog (biphasic)
Mix 70/30)
Insulin lispro protamine <0.25 1–3 10–20
susp/insulin lispro (biphasic)
(HumaLog Mix 75/25,
HumaLog Mix 50/50)
NPH/Reg (Humulin 70/30, 0.5–1 2–10 10–20
Novolin 70/30) (biphasic)
*These are general guidelines, as onset, peak, and duration of activity are affected by the site of injection,
physical activity, body temperature, and blood supply.
†Dose dependent duration of action, range from 6 to 23 h.
n.a., not available.
• Protocol for initiating insulin if the patient has glucose levels above
goal or a history of diabetes
° Consider resuming home basal-bolus regimen if the patient reports
good glucose control
° Weight-based insulin regimen
■ Calculate TDD of insulin
• Standard: 0.4 units/kg body weight (BMI 25−30)

• Insulin-sensitive (BMI <25, decreased GFR [CrCl <30]),
hepatic insufficiency): 0.3 units/kg body weight
• Insulin-resistant (BMI >30): 0.5 units/kg body weight
■ Divide insulin into basal and nutritional components
• ½ TDD as basal insulin: glargine daily, detemir divided BID, or

NPH divided BID
• ½ TDD divided into 3 equal mealtime doses (regular, lispro,
aspart, or glulisine)
■ Use correction-dose insulin (“sliding scale”) as supplement to
basal-bolus regimen
• Do not use correction-dose insulin as the sole insulin strategy
in hospitalized patients
48565_ST06_251-352.indd 308 5/1/13 9:32 PM

For Patients in ICU S 309
• Correctional insulin doses should be proportional to the basal and

mealtime insulin doses (i.e., an insulin-resistant patient requires
higher supplemental doses than a patient who is insulin sensitive)
■ Glycemic data should be reviewed daily with insulin dose
adjusted for occurrence of hypoglycemia or hyperglycemia, or use

of correctional-dose insulin
• Special considerations: parenteral nutrition, enteral nutrition, and
glucocorticoids
° Enteral and parenteral feedings
■ Enteral and parenteral feeding preparations are associated with
an increase in glucose
■ SQ regimens: glargine daily, detemir every 12−24 hours, or NPH
every 8−12 hours

■ The initial dose of insulin is calculated at ½ the TDD
• Standard: 0.2 units/kg body weight (BMI 25−30)

• Insulin-sensitive (BMI <25, decreased GFR [CrCl < 30]),
hepatic insufficiency): 0.15 units/kg body weight
• Insulin-resistant (BMI >30): 0.25 units/kg body weight
■ The shorter half-life of NPH allows for more frequent titration of
the insulin doses in response to changes in nutrition

■ Regular insulin may be added directly to the parenteral nutrition
bag at an initial dose of 1 unit for each 15 grams of dextrose

■ When nutrition is held or discontinued, reduce the insulin dose
and/or provide dextrose-containing IV fluid

° Glucocorticoids
■ Glucocorticoids cause hyperglycemia by increasing insulin
resistance and promoting gluconeogenesis

■ SQ insulin therapy may be started for glucocorticoid-induced hyper-
glycemia with an initial TDD of 0.3−0.5 units per kg body weight

■ IV insulin infusion is appropriate for moderate−severe
hyperglycemia
■ Insulin doses will need to be titrated for changes in steroid dose
• Insulin doses should be lowered to decrease the risk of hypo-

glycemia as the dose of the glucocorticoid decreases
FOR PATIENTS IN ICU S

• Background and goals
° Hyperglycemia is associated with increased morbidity and mortality
in critically ill patients
° However, despite initial enthusiasm, intensive insulin therapy
aimed at normalizing blood glucose in ICU patients has not been
demonstrated to improve outcomes, and hypoglycemia from insulin
therapy is associated with increased mortality
° Current recommendations are to start an IV insulin infusion for
glucose >180 mg/dL with a goal of 140−180 mg/dL
48565_ST06_251-352.indd 309 5/1/13 9:32 PM

310 Glycemic Issues in Hospitalized Patients
• IV insulin protocols
° Amaintain
standardized insulin protocol should be employed in order to
goal glucose levels and reduce hypoglycemia
° glucose
The insulin protocol should allow for titration of IV insulin as
levels change
° Multiple published protocols are available
■ The protocol should be adapted to fi t the needs of the local
institution
• Transitioning from IV insulin to SQ insulin is appropriate as critical
illness resolves
° See section Transition from IV Insulin Infusion in Chapter 46
REFERENCES
Donaldson S, Villanuueva G, Rondinelli L, Baldwin D. Rush University guide-
lines and protocols for the management of hyperglycemia in hospitalized
patients: elimination of the sliding scale and improvement of glycemic
control throughout the hospital. Diabetes Educ, 2006;32(6):954−62.
Jakoby MG 4th, Nannapaneni N. An Insulin Protocol for Management of
Hyperglycemia in Patients Receiving Parenteral Nutrition Is Superior to Ad
Hoc Management. J Parenter Enteral Nutr. 2011 Aug 8. PMID: 21825091.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association
of Clinical Endocrinologists and American Diabetes Association
consensus statement on inpatient glycemic control. Endocr Pract,
2009;15(4):353−69.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive
versus conventional glucose control in critically ill patients. N Engl J Med,
2009;360(13):1283−97.
Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of
hyperglycemia in hospitalized patients in non-critical care setting: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab,
2012;97(1):16−38.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in
critically ill patients.
48565_ST06_251-352.indd 310 5/1/13 9:32 PM

54 ■ PREDIABETES AND DIABETES
PREVENTION
Jennifer M. Argumedo, MD
PATHOPHYSIOLOGY
• Increased insulin resistance
° Impaired Fasting Glucose (IFG): higher hepatic insulin resistance
° Impaired Glucose Tolerance (IGT): higher muscle insulin resistance
• Decreased insulin secretion
° Secondary to β-cell failure
° IFG and IGT both with impaired first-phase insulin secretion
° IGT has impaired second-phase insulin secretion
• Environmental factors that aggravate genetic components
° Weight gain
° Physical inactivity
° Aging
• Those with prediabetes are typically asymptomatic
• Screening for prediabetes is based on screening criteria for diabetes in
asymptomatic patients
TABLE 54.1 Diagnostic Evaluation
Test Results
IFG 100−125 mg/dL (5.6−6.9 mmol/L)
IGT* 140−199 mg/dL (7.8−11.0 mmol/L)
HbA1c 5.7−6.4% (6−6.4% considered high-risk for diabetes)
*2-h value in the 75-g OGTT.
ASSOCIATED CONDITIONS
• Obesity
• CVD
° IGT: strong predictor of CVD
° Higher incidence of both microvascular (microalbuminuria,
retinopathy, and neuropathy) and macrovascular complications as
compared to those with normoglycemia
• Dyslipidemia with high TG levels ± low HDL-C
• Hypertension
48565_ST06_251-352.indd 311 5/1/13 9:32 PM

312 Prediabetes and Diabetes Prevention
RECOMMENDATIONS FOR DELAY OF DM TYPE 2

• Lifestyle modifications with goal of 7% weight loss and moderate
physical activity of at least 150 minutes per week
• Medical nutrition therapy (MNT)
° Reduced caloric intake
° Reduced dietary fat intake
° Aim to achieved US Department of Agriculture’s (USDA) recommen-
dation for dietary fiber (14 g fiber/1000 kcal) and foods containing
whole grains
° Limited intake of sugar-sweetened beverages
• Follow-up counseling
• Consider initiation of metformin
° ADA does not advocate use of other drug therapies such as
thiazolidinediones, sulfonylureas, α-glucosidase inhibitors, GLP-1
analogues at this time
• At least annual monitoring for the development of diabetes
TABLE 54.2 High-Risk Patients Who May
Benefi t from Metformin
BMI >35 kg/m2
Age <60 years old
Women with history of GDM
Those with more severe or progressive hyperglycemia
MANAGEMENT OF CVD IN PREDIABETES

• High risk of adverse cardiac events in prediabetic state similar to that
seen in type 2 diabetes
• Try to achieve same lipid-lowering goals as in diabetic patients
° LDL-C lowering to <100 mg/dL with statins
° Consider fibrates if low HDL-C or high TG
° At least annual monitoring of fasting lipid concentrations
• Monitor for hypertension at least annually
° Same BP goals as in diabetic patients, ≤130/80
° First-line
■ ACEIs
agents include
■ ARBs
° Avoid thiazides and β blockers: may increase risk of developing

diabetes in prediabetics
• At least annual monitoring for microalbuminuria
TREATMENT GOALS WITH PHARMACOLOGIC THERAPY

• Normalize glucose levels
• Prevent progression to diabetes
• Prevent microvascular and macrovascular complications
48565_ST06_251-352.indd 312 5/1/13 9:32 PM

References 313
REFERENCES
DeFronzo RA, Abdul-Ghani MA. Preservation of β-cell function: the key to
diabetes prevention. J Clin Endocrinol Metab, 2011;96(8):2354−66.
Grundy SM. Prediabetes, metabolic syndrome, and cardiovascular risk. J Am
Coll Cardiol 2012; 59:635–43.
Moutzouri E, Tsimihodimos V, Rizos E, Elisaf M. Prediabetes: to treat or not to
treat? Eur J Pharmacol, 2011;672(1-3):9−19.
Rhee SY, Woo JT. The prediabetic period: review of clinical aspects. Diabetes
Metab J, 2011;35(2):107−16.
48565_ST06_251-352.indd 313 5/1/13 9:32 PM

48565_ST06_251-352.indd 314 5/1/13 9:32 PM
55 ■ DIABETIC FOOT DISEASE
William Jeffcoate, MRCP
DIABETIC FOOT ULCERATION AND INFECTION

• Background
° An ulcer is a break in the epidermis that does not promptly heal
° Between 2.5 and 5.0% of the population with diabetes have an
ulcer at any one time
° It is a major,
Incidence ~20 per 1000 person-years
° and sometimes neglected, source of suffering and cost
• Pathophysiology: predisposing factors
° PAD
■ Leading to skin and SQ tissue that is thinned and dysmorphic
■ PAD is both macrovascular (atheromatous occlusion of large and
medium arteries) and microvascular (both structural [basement

membrane thickening] and functional [abnormal vasomotor
regulation caused by neuropathy])
° ■ Sensory:
Distal symmetrical neuropathy
making the person unaware of incipient skin damage
(e.g., from ill-fitting shoes, unnoticed sharp objects, burns from
walking barefoot in very hot weather)
■ Motor: altered balance of long fl exor and extensor muscles,
combined with small muscle atrophy and shortening of con-

nective tissue caused by glycation leads to clawing of the
foot, dislocation of metatarsophalangeal joints and abnormal
distribution of plantar forces during walking; build of callus at
pressure points increases the forces and can lead to ulceration
through pressure necrosis
■ Vasomotor: abnormal regulation of the microvasculature
■ Autonomic: loss of skin integrity through reduced sweating
° Other complications or comorbidities of diabetes including impaired

vision and immobilization through ill health
■ Pressure sores on the heel are a common complication of hospital
admission; the median time to healing of a heel ulcer is 200 days

• Pathophysiology: precipitating factors
° Trauma/pressure
° Tinea pedis: causing breaks in the skin that can lead to secondary
bacterial infection
° Spontaneous
neuropathy
cracks in the heel that can complicate distal
• Pathophysiology: failure to heal

° Infection (see next section)
° PAD: leading to delayed healing
48565_ST06_251-352.indd 315 5/1/13 9:32 PM

316 Diabetic Foot Disease
°Continued trauma to the wound bed from

■ Failure to provide adequate off-loading (protection)
■ Inability of the patient to reduce weight-bearing
■ Distal sensory neuropathy: reduced sensation makes the patient
less aware of the need to reduce weight-bearing

■ Acquisition of the biology of the chronic wound, which is an ill-
defined change resulting in the process of healing being arrested

in a phase of chronic inflammation
• Pathophysiology: infection
° Infection is a complication of foot ulceration and not a cause
° Once it occurs, infection can seriously worsen the condition of the
wound, as well as worsen the prognosis for healing
° Two broad categories of infection
■ Soft tissue infection
■ Osteomyelitis
° Diagnosis of infection is clinical

■ Microbiologic studies should only be used to determine the
pathogen
• Management of diabetic foot ulcers
° exposed toofcontinuing
Provision adequate off-loading to prevent the ulcer site being
trauma
° Debridement of the wound edge and removal of necrotic material
° Dressing of the wound with simple dressing products
■ There is no robust scientifi c evidence to justify the use of any
dressing product, application, or other advanced wound care

procedure on a routine basis (even though these are frequently
selected by experts)
■ Negative pressure therapy may improve healing of postoperative
wounds
° Use of appropriate antibiotic therapy or other modalities to elimi-
nate infection (see section on soft tissue infection)
° Organization
Consider revascularization for significant PAD
° of frequent review of the status of the wound
• Soft tissue infection (STI)
° In newly occurring STI, the infecting organisms are usually aerobic
Gram-positive cocci and empiric treatment can be based on narrow
spectrum antibiotics such as flucloxacillin (dicloxacillin in the US)
or erythromycin, but must be governed by local prescribing policy
° When the patient has already been exposed to antibiotic treatment
and/or the wound is deeper or necrotic, the responsible pathogens
may be Gram-positive, Gram-negative, aerobic or anaerobic, and
therefore empiric antibiotic choice must broad spectrum, such as
ampicillin/sulbactam or clindamycin plus quinolone, but must be
guided by local prescribing policy
° specimen
Treatment should ideally be based on microbiologic examination of
of deep soft tissue
■ Swabs (either superfi cial or deep) are not useful
48565_ST06_251-352.indd 316 5/1/13 9:32 PM

Charcot Neuroosteoarthropathy (CN; The Charcot Foot) 317
° Antibiotic therapy can be administered orally for mild infections,

but IV treatment is preferred for severe as well as for some moder-
ate infections
■ Initial therapy should not be continued for more than 1−2 weeks
without expert review

• Osteomyelitis
° Osteomyelitis frequently complicates neuropathic ulcers (pedal
pulses palpable) on the forefoot and can complicate ulcers of the
heel
° Diagnosis rests on clinical features reinforced by imaging
° The clinical features are of local inflammation, usually of the
forefoot (typically the “sausage-shaped toe”)
■ Systemic symptoms and signs are uncommon
° Plain X-rays may be normal for several weeks following the onset
of the disease
° The mostX-rays
If plain are normal, the diagnosis may established by MRI
° gens may common
be involved
infecting organism is S. aureus but other patho-
° Traditionally, experts have emphasized the need for surgical exci-

sion of infected bone, but in recent years, an increasing percentage
attempt eradication with prolonged (two months or more) courses
of systemic antibiotics either alone or in combination with limited
surgery
■ Ideally, prolonged antibiotic therapy should be targeted at
organisms isolated from bone biopsy, as soft tissue sampling is

of limited value
• Long-term care
° the succeeding
When the wound is healed, there is a 40% chance of recurrence in
12 months and the patient should ideally remain
under expert care
° Cardiovascular risk factor reduction is crucial because of reduced
life expectancy in this group.
° only ~50% at 5 yearsof people presenting with a new foot ulcer is
The overall survival
° The patient should be instructed to seek care immediately if a new

ulcer occurs
■ The rate of healing correlates with ulcer area and duration at the
time of first expert assessment
CHARCOT NEUROOSTEOARTHROPATHY (CN; THE CHARCOT FOOT)

• Background
° Diagnosis is frequently delayed in routine practice, often for weeks
or months, with the inflammation being variously attributed to
infection, sprain, gout, or thrombosis
48565_ST06_251-352.indd 317 5/1/13 9:32 PM

318 Diabetic Foot Disease
°People with diabetes complicated by neuropathy should be

instructed to seek medical evaluation to rule out CN should they
develop inflammation of the foot that is not explained by obvious
trauma
° Diagnosis relies on the demonstration of characteristic fracture and
dislocation of the bones of the foot; or if the skeletal architecture
appears normal on X-ray by demonstrating edema of bone marrow
on MRI and/or microfractures of pedal bones on CT
° When CN is suspected, the patient should be referred for urgent
expert assessment and urged not to bear weight in order to limit
damage to the foot
• Pathophysiology
° CN is a complication of neuropathy
■ Diabetes is the most common cause, but essentially any cause of
neuropathy (e.g., alcohol abuse, leprosy, etc.) can cause CN

° Manifest by the occurrence of inflammation in foot, associated with
fracture and dislocation of the bones and joints of the foot, and
especially of the mid- and hind-foot
° Hypothesized that a person with neuropathy is predisposed to exag-
gerated release of proinflammatory cytokines (IL-1β, TNF-α) and
consequent activation osteoclasts through the RANKL-NFkappaB
pathway
■ Neuropathy is associated with decreased release of neuropep-
tides (e.g., calcitonin gene-related peptide [CGRP]) that oppose

the RANKL-NFkappaB activation
■ When the affected person continues to bear weight on the
inflamed foot (because of reduced protective sensation), the pro-

cess of inflammation and resultant bone breakdown continues,
leading to the skeletal damage that characterizes the condition
■ The condition can also be triggered by other causes of inflamma-
tion such as infection, ulceration, or surgery

• Diagnosis
° person
The diagnosis should be suspected and actively pursued in any
with neuropathy who presents with foot or ankle inflamma-
tion with or without obvious associated deformity, which occurs
spontaneously or following minimal trauma
• Management
° The role of surgery in the acute phase is not established
° Most experts manage CN simply by immobilizing the foot in a
nonremovable, below-knee fiberglass cast
■ The cast needs to be changed after a few days (because there
will be a rapid resolution of local inflammation), and then

replaced every 1−2 weeks for a period of months
■ The duration of casting may be up to 12 months, sometimes
longer
■ Patients often suffer marked frustration and depression because
of the limitation of their activity
48565_ST06_251-352.indd 318 5/1/13 9:32 PM

References 319
° Secondary ulceration complicates the deformity in approximately

25% and can itself be complicated by osteomyelitis
° Gross deformity or intractable infection may lead to below-knee
amputation
° Although some experts have recommended the use of bisphospho-
nates, available data suggest that bisphosphonates may actually
delay resolution
° The condition eventually settles although it may occur on contralat-
eral side in approximately 20% of patients
■ Long-term ipsilateral recurrence is very uncommon
° Late corrective surgery may be used to minimise the deformity
REFERENCES
Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society
of America clinical practice guideline for the diagnosis and treatment of
diabetic foot infections. Clin Infect Dis, 2012;54:e132–73.
Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot foot in diabetes.
Diabetes Care, 2011;34(9):2123−9.
48565_ST06_251-352.indd 319 5/1/13 9:32 PM

48565_ST06_251-352.indd 320 5/1/13 9:32 PM
56 ■ HYPOGLYCEMIA DISORDERS
Kevin Donohue, DO and Serge Jabbour, MD
DEFINED BY WHIPPLE’S TRIAD

• Symptoms/signs consistent with hypoglycemia
• PG concentration <55 mg/dL (not a fingerstick glucose)
• Relief of symptoms after the PG is raised
SYMPTOMS
• Neurogenic symptoms are the result of adrenergic response, i.e.,
release of NE, Epi, and acetylcholine, in response to hypoglycemia
• Neuroglycopenic symptoms are the result of CNS glucose deprivation
TABLE 56.1 Neurogenic Versus Neuroglycopenic Symptoms
Neurogenic Symptoms Neuroglycopenic Symptoms
Sweating Confusion, irritability
Tremulousness Psychotic behavior
Palpitations Motor incoordination, paresis
Anxiety and confusion Diplopia
Hunger Seizure, coma
CLASSIFICATION OF HYPOGLYCEMIAS IN ADULTS

• Fasting hypoglycemia
° Drugs: insulin, insulin secretagogues (sulfonylureas, glinides),
ethanol (interferes with gluconeogenesis), quinine, gatifloxacin,
pentamidine (direct injury to pancreatic β cells with subsequent
insulin release)
° Critical illnesses: sepsis (including malaria); hepatic, renal, or
cardiac failure; inanition (all decrease glycogen stores and impair
gluconeogenesis)
° Hormone deficiency: cortisol, glucagon, and Epi (associated with
poor glycogenolysis and gluconeogenesis)
° ducing large tumors:
Nonislet cell bulky mesenchymal or epithelial tumors pro-
amounts of IGF-2 with insulin-like activity (alternative
hypothesis is that the tumors utilize large amounts of glucose)
Endogenous hyperinsulinism, insulinoma, β-cell hypertrophy/
° hyperplasia, autoantibody to insulin or insulin receptor (excess
insulin production)
48565_ST06_251-352.indd 321 5/1/13 9:32 PM

322 Hypoglycemia Disorders
• Reactive (postprandial) hypoglycemia: delayed insulin release after a

meal has been absorbed, occurs 4−6 hours after eating
° Postgastric bypass (PGB): nesidioblastosis
° Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS):
β-cell hypertrophy
• Factitious hypoglycemia: surreptitious or even malicious administra-
tion of insulin or an insulin secretagogue
• Artifactual hypoglycemia: incorrect collection of blood samples or
interfering substances in the blood causing glycolysis in vitro (i.e.,
leukemia, chronic hemolytic anemia, etc.)
DIAGNOSIS
• Document Whipple’s triad (draw labs before administering glucose)
• Labs: glucose, insulin, C-peptide, proinsulin, insulin secretagogue
screen, β hydroxybutyrate (and if indicated: ethanol, insulin antibod-
ies, and IGF-2)
• If unable to draw labs during a spontaneous episode, perform 72-hour
fast
° Check serum glucose, insulin, and β hydroxybutyrate every 6 hours
until blood glucose <60
° Increase frequency of lab draws to every 2 hours until blood
glucose <45, then check glucose, insulin, proinsulin, C-peptide,
and β hydroxybutyrate
° 1-mg IV glucagon injection given after labs drawn to relieve symp-
toms and correct hypoglycemia (check PG 10, 20, and 30 minutes
after glucagon injection)
TABLE 56.2. Results

C-Peptide Insulin Proinsulin SU Screen Misc.
Insulinoma. NIPHS,
↑ ↑ ↑ –
PGBH
Sulfonylurea ↑ ↑ ↑ +
Exogenous insulin ↓ ↑ ↓ –
Nonislet cell tumors ↓ ↓ ↓ – ↑ IGF-2
Insulin autoimmune + insulin
↑ ↑ ↑ –
antibody
48565_ST06_251-352.indd 322 5/1/13 9:32 PM

Treatment 323
IMAGING (LOCALIZING STUDIES)

• CT, MRI, and transabdominal ultrasonography can detect most
insulinomas
° Negative imaging does not rule out insulinoma (proceed with arte-
rial calcium stimulation)
• Arterial calcium stimulation
° Calcium gluconate is selectively injected into the gastroduodenal,
splenic, and superior mesenteric arteries with concurrent sampling
of insulin in the hepatic vein
■ Can distinguish between a focal abnormality (insulinoma) and
a diffuse process (Islet cell hypertrophy/nesidioblastosis) when

imaging is negative
■ Also used to localize nonimaged but focal lesion and aid surgical
resection
TREATMENT
• Acute episode
° If4-ounce
patient awake and able to take oral meds: glucose tabs (~15 g) or
juice or soda
° IfD50 IV
patient not able to take oral meds but has IV access: ½ amp
(1/2 amp = 12.5 g)
° IfSQ/IM
patient cannot take oral meds and no IV access: glucagon 1 mg
° Repeat glucose level in 15 minutes, repeat treatment if needed

• Carefully review patient’s medications, and remove any possible
offending agents (e.g., insulin, insulin secretagogues, fluoroquinolones)
• Consider and correct any underlying critical illness (e.g., AI, sepsis,
and liver failure)
• Preferred treatment for insulinoma is surgical resection based on
imaging and/or arterial calcium stimulation
• Preferred treatment for NIPHS is medical management with an
α-glucosidase inhibitor, diazoxide, calcium channel blocker, β blocker
or octreotide; or partial pancreatectomy guided by imaging and arterial
calcium stimulation if medical therapy fails to relieve symptoms
• If patient has insulin antibodies, consider anti-inflammatory agents,
steroids, and referral to an endocrinologist
48565_ST06_251-352.indd 323 5/1/13 9:32 PM

324 Hypoglycemia Disorders
REFERENCES
Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of
adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2009;94(3):709−28.
Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am,
2006;35(4):753−6.
Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk
factors and outcomes. Crit Care Med, 2007;35(10):2262−7.
Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: drug-induced
hypoglycemia: a systematic review. J Clin Endocrinol Metab,
2009;94(3):741−5.
48565_ST06_251-352.indd 324 5/1/13 9:32 PM

57 ■ LIPID ESSENTIALS
Charlotte Boney, MD
LIPID PROFILE REFLECTS THE LIPOPROTEINS CARRYING

CHOLESTEROL AND TRIGLYCERIDE
• Total cholesterol (TC) largely reflects LDL and HDL; fasting has no
effect on TC and HDL levels
• LDL can be measured directly or estimated by the Friedewald equation
(LDL = TC – HDL − TG/5), which is accurate only when TG are
<400 mg/dL
• HDL is measured directly; if elevated, it is a protective factor in CVD
and can be a significant proportion of TC
• TG measured in the fasting state largely reflects very low-density
lipoproteins (VLDL); in the nonfasting state, TG reflects chylomicrons
(CM), which are synthesized from dietary fat; TG carried in CM can take
8−10 hours to return to baseline after eating
• Plasma lipoproteins contain cholesterol esters (CE), some free
cholesterol (FC), and TG in precise proportions as well as specific
apolipoproteins that confer structure and function (enzyme cofactor,
receptor binding). See Table 57-1.
• Lipoprotein (a) is not measured in a lipid profile, but is a modified LDL
particle that is an independent risk factor for CVD. Its unique lipopro-
tein Apo(a) has substantial homology to plasminogen
TABLE 57.1 Lipoprotein Structure and Function

Lipoprotein % Cholesterol % TG Major Protein Source Function
Chylomicron 5 85 ApoB48 Diet Deliver FFA
(CM) (intestine) to tissues
CM Remnant 20 60 ApoB48, ApoE Plasma Deliver FFA
(derived to liver
from CM
hydrolysis)
VLDL 20 55 ApoB100, Liver Deliver FFA
ApoE to tissue;
pick up CE
from HDL
(continues)
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326 Lipid Essentials

Lipoprotein % Cholesterol % TG Major Protein Source Function
Intermediate 35−40 20−25 ApoB100, Plasma Deliver FFA
– density ApoE (derived to tissue;
lipoprotein from VLDL pick up CE
(IDL) hydrolysis) to form LDL
LDL 60 5 ApoB100 Plasma Deliver CE to
(derived tissues
from IDL
hydrolysis)
HDL 20 5 ApoAI, ApoCI, Liver, Return CE
ApoCII intestine to liver;
transfer CE
to VLDL/
IDL to form
LDL
Lipoprotein (a) 60 5 ApoB100, Liver: Apo(a) Promotes
Apo(a) linked to thrombosis
LDL at cell
surface
PLASMA LIPOPROTEINS ARE DETERMINED

BY 3 INTERRELATED PATHWAYS
• Transport of dietary or exogenous fat (Figure 57.1)
° CM are synthesized in the intestine from dietary fat and hydrolyzed
in plasma by lipoprotein lipase (LPL), releasing FFA for uptake by
peripheral tissues and adipose tissue
° CM remnants are removed quickly by the binding of apolipoprotein
E to the remnant receptor, delivering TG to the liver for repackaging
as VLDL
° Defects in the pathway can occur due to mutations in LPL or
its cofactor apolipoprotein C-II. These defects result in lipemic
plasma and increased risk of pancreatitis but not increased CVD.
Defects in the lipoprotein ApoE can produce excess remnants,
which lower LDL clearance and elevate TG, increasing risk of
pancreatitis and CVD
48565_ST06_251-352.indd 326 5/1/13 9:32 PM

Plasma Lipoproteins Are Determined by 3 Interrelated Pathways 327
Dietary Fat and

Cholesterol
Intestine
Liver
Chylomicrons CM–Remnant
LPL
FFA
Peripheral Adipose
Tissue Tissue
FIGURE 57.1 Exogenous (Dietary) Pathway
• Transport of hepatic or endogenous fat (Figure 57.2)

° VLDL is synthesized and secreted from the liver and contains
mostly TG, some CE, and the lipoprotein ApoB100. VLDL undergoes
hydrolysis by LPL and picks up CE from HDL by cholesterol ester
transport protein (CETP) to become intermediate density lipoprotein
(IDL), which is further hydrolyzed by LPL and hepatic lipase (HL)
with transfer of more CE from HDL by CETP to become LDL
° LDL is removed from the blood by binding of ApoB100 to the LDL
receptor (LDLR) on tissues, including liver. Oxidized LDL particles
are taken up by scavenger receptors on macrophages, promoting
foam cell formation, inflammation, and CVD. Small, dense LDL is
more prone to the scavenger pathway and is taken up more slowly
by the LDLR
° VLDL is synthesized and secreted from the liver and contains
mostly TG, some CE, and the lipoprotein ApoB100. VLDL undergoes
hydrolysis by LPL and picks up CE from HDL by CETP to become IDL,
which is further hydrolyzed by LPL and HL with transfer of more CE
from HDL by CETP to become LDL
48565_ST06_251-352.indd 327 5/1/13 9:32 PM

328 Lipid Essentials
° LDL is removed from the blood by binding of ApoB100 to the LDLR

on tissues, including liver. Oxidized LDL particles are taken up by
scavenger receptors on macrophages, promoting foam cell forma-
tion, inflammation, and CVD. Small, dense LDL is more prone to the
scavenger pathway and is taken up more slowly by the LDLR
° The hepatic cholesterol pool is determined by endocytosis of
LDL bound to its receptor, de novo cholesterol synthesis, and CE
delivered by CM and bile. HMG Co-A reductase is the rate-limiting
step in cholesterol synthesis and the target of “statin” cholesterol-
lowering therapy. Treatments that decrease the intracellular
cholesterol pool, such as dietary restriction or statin therapy,
increase LDLR expression and thus decrease circulating LDL levels.
° Defects in this pathway may be genetic (single defects in the LDLR
or the LDLR ligand ApoB100; polygenic defects that increase VLDL
production or reduce LDL clearance) or acquired (VLDL overproduc-
tion from excessive dietary fat, poor LPL activity due to insulin
resistance impairs VLDL metabolism). Defects can increase levels
of TG or LDL or both
Peripheral
Tissue
Liver
LDL
LPL, HL CETP (HDL)
VLDL IDL
LPL
FFA
Peripheral
Adipose
Tissue
Tissue
FIGURE 57.2 Endogenous Pathway
48565_ST06_251-352.indd 328 5/1/13 9:32 PM

Plasma Lipoproteins Are Determined by 3 Interrelated Pathways 329
• Reverse cholesterol transport (Figure 57.3)

° Nascent HDL (nHDL) particles are synthesized in the liver and intes-
tines and acquire FC from cells via the cholesterol transport protein
ATP-binding cassette transporter A1 (ABCA1). Lecithin cholesterol
acyltransferase (LCAT) converts FC to CE to form a stable, mature
HDL (also referred to as HDL 3)
° HDL delivers CE back to the liver (“reverse cholesterol transport”)
or to cholesterol-requiring tissues via its specific receptor, scaven-
ger receptor B-1 (SR-B1). Its major lipoprotein, ApoA1, has crucial
functions, including structure, binding the HDL receptor SR-B1 and
activating LCAT
° HDL also transfers CE via CETP to VLDL and IDL particles to
form LDL
° Defects in this pathway include mutations in ABCA1 (Tangier
Disease), ApoA1, and LCAT (“Fish eye” disease), all of which result
in very low HDL levels and increased CVD risk. Acquired defects,
such as insulin resistance, increase HDL clearance by the kidney to
lower HDL levels. Elevated ApoA1 or deficiency in CETP results in
high levels of HDL, which is cardioprotective
Adrenal Testis
Ovary Peripheral
Tissue
Liver LCAT
HDL nHDL ABCA1
CE FC
CETP
LDL VLDL
FIGURE 57.3 Reverse cholesterol (HDL) Pathway
REFERENCES
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on
(Adult Treatment Panel III). JAMA, 2001;285(19):2486−97.
Knopp RH. Drug treatment of lipid disorders. N Engl J Med, 1999;341(7):498−511.
Kwiterovich, PO. The American Journal of Cardiology, Volume 86, Issue 12,
Supplement 1, 21 December 2000, Pages 5–10.
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48565_ST06_251-352.indd 330 5/1/13 9:32 PM
58 ■ LIPID DISORDERS
Rajesh M. Kabadi, MD and Perry J. Weinstock, MD
LIPID COMPONENTS
• Cholesterol is a fat-like substance that is present in cell membranes
• Precursor of bile acids and steroid hormones
• Travels in the blood as distinct particles called lipoproteins
° LDL
■ Accounts for 60−70% of plasma cholesterol
■ Contains a single apolipoprotein: ApoB-100
■ Major atherogenic lipoprotein
■ Primary target for treatment per National Cholesterol Education
Program (NCEP) guidelines

° HDL
■ Accounts for 20−30% of plasma cholesterol
■ Made up of two apolipoproteins: ApoA-I and A-II
■ Inversely correlated with risk for CHD
■ Felt to protect against development of atherosclerosis
° VLDL
■ Contains 10−15% of total serum cholesterol
■ Produced by liver
■ Triglyceride-rich precursor of LDL
■ Major lipoproteins are: ApoB-100, ApoCs (C-I, C-II, C-III), and
ApoE
■ Atherogenic, especially VLDL remnants
° ■ Resides between VLDL and LDL

IDL
■ In usual practice it is included in the LDL measurement
■ Like VLDL, tends to be atherogenic
° Chylomicrons
■ Triglyceride (TG) rich
■ Formed in the intestine from dietary fat
■ Same apolipoproteins as VLDL except ApoB-48 instead of B-100
CLASSIFICATION OF TOTAL CHOLESTEROL AND LDL CHOLESTEROL

• LDL: the primary target for cholesterol lowering therapy
° Elevated LDL is a strong risk factor for CHD and stroke
° Various angiographic trials have shown that LDL-lowering reduces
the volume of plaque
° NCEP classification
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332 Lipid Disorders
TABLE 58.1 Classifi cation of Total Cholesterol and LDL Cholesterol
Total Cholesterol
<200 Desirable
200−239 Borderline high
≥240 High
LDL Cholesterol
70* Optional goal in very high-risk individuals*
<100 Optimal
100−129 Near optimal
130−159 Borderline high
160−189 High
≥190 Very high
*Very high risk: recent MI or known CAD + history of DM, metabolic syndrome, or current smoking.
TABLE 58.2 Triglyceride Level Categories

Triglyceride Category Levels
Normal <150 mg/dl
Borderline−high 150−199
High 200−499
Very high >500
• TG: energy storage unit of fatty acids

° Particularly well-defined risk factor for CHD in women
° Carried in blood primarily as VLDL
° May cause pancreatitis when >500 mg/dL
• VLDL: major carrier of TG derived from the endogenous pathway
° Produces atherogenic remnant lipoproteins as it gives up triglycer-
ides to become IDL
• IDL: result of action of lipoprotein lipase on VLDL to liberate free fatty
acids
• HDL: responsible for reverse cholesterol transport
° Low levels (<40 mg/dL) → increased CAD morbidity/mortality
° High level (≥60 mg/dL:) → decreased CAD morbidity/mortality
• Non-HDL: defined as Total Cholesterol minus HDL and is equivalent to
total of VLDL, IDL, and LDL
° Useful clinical measure when TG >200 mg/dL
48565_ST06_251-352.indd 332 5/1/13 9:32 PM

Classifi cation of Total Cholesterol and LDL Cholesterol 333
TABLE 58.3 Frederickson’s Classifi cation of Lipoprotein Disorders
Lipoprotein
Type Serum Elevation Syndrome Elevation
I Cholesterol and Familial hyperchylomicronemia CMs
triglycerides
IIa Cholesterol Familial hypercholesterolemia LDL
IIb Cholesterol and Familial combined hyerplipdemia LDL and VLDL
triglycerides
III Cholesterol and Dysbetalipoproteinemia IDL
triglycerides
IV Triglycerides Familial hypertriglyceridemia VLDL
V Cholesterol and Metabolic syndrome VLDL and CMs
triglycerides
• Type I (familial hyperchylomicronemia)

° Severely elevated fasting plasma TG levels, mainly chylomicrons
° Reduced or absent LPL activity or ApoC-II activity
° xanthomas,with:
Associated recurrent bouts of pancreatitis, eruptive
xerostomia, or xerophthlamia; occasionally behavioral
disturbances
° Treatment centered around diet and lifestyle modification (low-fat
diet, avoidance of alcohol)
° reduces the riskcan
Fibrate therapy also be particularly effective and especially
of pancreatitis in such individuals
• Type II
° Two types: both involve elevated LDL (may exceed >220 mg/dL in
adults)
■ Type IIa (familial hypercholesterolemia)
• Elevation in LDL only

■ Type IIb (familial combined hyperlipidemia)
• Elevation in LDL and VLDL

° High risk of developing CAD in men in the third and fourth decades
and 10 years later in women
■ Treatment end points revolve around CAD risk factors
° Manifest clinically with premature CAD, corneal arcus, xanthomas

over extensor tendons, xanthelasmas
° Autosomal dominant transmission
48565_ST06_251-352.indd 333 5/1/13 9:32 PM

334 Lipid Disorders
• Type III (dysbetalipoproteinemia)

° Rare genetic disorder (defect in ApoE)
° Associated with increased CHD risk and CVA at young age
° ■ Lab findings:byincreased
Characterized elevation of remnant lipoprotein particles
total cholesterol, TG, and IDL; reduced
HDL; LDL measurements usually unreliable
° Clinical
xanthomas
findings: tuberous xanthomas and striated palmar
° ■ Dietary modifi
Treatment involves diet and medical therapy
cation with special attention to
• Low-fat diets, especially saturated fats and trans fats
• Restriction of carbohydrates
• Increased fiber
■ Correction of metabolic abnormalities (diabetes, obesity,
hypothyroid)
■ Medical therapy includes the use of fibrate drugs, statins, and
niacin
• Type IV (familial hypertriglyceridemia)
° Elevated VLDL-related serum TG level
° Association with diabetes
° No specific physical
Association with CHD is not as strong as with type II disorders
° Treatment centered around
exam findings
° ■ Limit alcohol and encourage lifestyle modifications
low-fat dieting
■ Increasing physical activity
° Medical therapy is second-line if lifestyle modification fails, and

includes niacin, fibrates, fish oil
• Type V
° Severe elevation in plasma TG levels (both VLDL and CMs)
° Usually associated with: high-fat diet, obesity, diabetes
° Dietary modification generally advised
° options
As previously, fibrates and nicotinic acid are effective treatment
48565_ST06_251-352.indd 334 5/1/13 9:32 PM

Common Pharmacologic Therapies 335
TABLE 58.4 ATP III LDL-C Goals and Cutpoints for Therapy
Initiate TLC* Pharmacologic
Risk Category LDL-C Goal (mg/dL) (mg/dL) Therapy (mg/dL) †
High: CHD‡ or CHD§ <100 (optional <70) ≥100 ≥100 (consider drug
risk equivalents option if <100)
(10 year risk >20%)
Moderately high: 2+ <130 ≥130 ≥130 (consider drug
risk factors (10 year option if 100−129)
risk 10–20%)
Moderate: 2+ risk <130 ≥130 ≥160
factors (10 year risk
<10%)
Low: 0−1 risk factors <160 ≥160 ≥190
(10-year risk <10%)
Risk factors include cigarette smoking, hypertension (BP >140/90), low HDL (<40 mg/dL), family history
of premature CAD (first-degree male relative <55 yrs old; first-degree female relative <65 yrs), and age
(men ≥45, women ≥55).
* TLC = therapeutic lifestyle changes.
† Drug therapy should be sufficient to achieve 30−40% LDL reduction.
‡ CHD = history of MI, unstable angina, stable angina, revascularization, or evidence of ischemia.
§ CHD risk equivalents: clinical manifestations of noncoronary forms of atherosclerotic disease (PAD,
AAA, carotid artery disease), diabetes.
COMMON PHARMACOLOGIC THERAPIES

• HMG-CoA reductase inhibitors (“statins”)
° Prevent
synthesis
formation of mevalonate, rate-limiting step in sterol
■ Body responds by increasing LDL receptors
■ End result is decreased LDL production and increased clearance
° Commonly referred to as “statin” drugs (see Table 58.5)

° Ant-infl ammatory effects as well
48565_ST06_251-352.indd 335 5/1/13 9:32 PM

336
48565_ST06_251-352.indd 336
Lipid Disorders
TABLE 58.5 Common Statin Forms and Their Doses

Atorvastatin Simvastatin* Rosuvastatin Pravastatin Fluvastatin Lovastatin Pitavastatin ~% LDL ↓
10 mg 20 mg 40 mg 20 mg 1 mg 30%
10 mg 20 mg 40 mg 80 mg 40 mg 2 mg 38%
20 mg 40 mg 5 mg 80 mg 80 mg 4 mg 41%
40 mg 10 mg 47%
80 mg 20 mg 55%
40 mg 63%
*Recent FDA warning recommends limiting the use of simvastatin doses >40 mg; should not exceed 10-mg dose with diltiazem, verapamil, and
amiodarone; should not exceed 20-mg dose with amlodipine, ranolazine.
5/1/13 9:32 PM
Common Pharmacologic Therapies 337
° Common side effects include transaminitis and myositits

■ Liver function should be monitored at regular intervals for all
patients on statin therapy

■ If suspicion for myositis, serum CPK levels should be obtained
° ■ Inhibitors byof the

Metabolized cytochrome P-450 system
this system will increase statin levels in the plasma
• Cholesterol absorption inhibitor (Ezetimibe)
° Limits selective uptake of cholesterol and other sterols at intestinal
epithelial level
° Improves LDL cholesterol numerically but data do not demonstrate
improvement in CHD outcomes
• Bile acid–binding resins
° Cholestyramine, colestipol, and colesevelam
° Inhibit bile acid resorption at intestinal level
° Adjunctive therapy for patients with severe hypercholesterolemia
caused by increased LDL
■ Can be taken in conjunction with statin therapy
° Side effects are gastrointestinal discomfort, constipation, fullness

■ May interfere with absorption of other medications
• Other medications should be taken 1 hour before or 3 hours

after administration of bile acid–binding resin
• Fibric acid derivatives (“Fibrates”)
° Indicated
states
in treatment of hypertriglyceridemia and in low HDL
° and ApoA-I genes

Interacts with PPARα, which regulates transcription of LPL, ApoC-III,
° Examples include gemfibrozil and fenofibrate

° Common side effects include
■ Abdominal discomfort
■ Transaminitis
■ Erectile dysfunction
■ When administering gemfibrozil concurrently with statin therapy,
may increase risk of rhabdomyolysis due to interference with

statin elimination
• Nicotinic acid (Niacin)
° levels for increasing HDL levels, lowering TG, and lowering LDL
Indicated
° Typical effective doses include 1500–3000 mg/day in divided

separate doses
° mia, acanthosis
Common side effects include flushing, hyperuricemia, hyperglyce-
nigricans, and gastritis
■ Usually started at low doses with plan to titrate to maximum over
2–3 weeks due to side effect tolerability

■ Slow-release formulations also aid with tolerability but may be
associated with liver toxicity, particularly at doses exceeding 2 g

■ Flushing may be attenuated by pretreatment with aspirin
48565_ST06_251-352.indd 337 5/1/13 9:32 PM

338 Lipid Disorders
° The Coronary Drug Project had previously shown that use of niacin
improved mortality at 15 years
° Recent data (AIM-HIGH study) have called into question the
concept that the addition of niacin to statin therapy would improve
CHD outcomes
REFERENCES
AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients
with low HDL cholesterol levels receiving intensive statin therapy. N Engl J
Med, 2011;365(24):2255−67.
Cholesterol in Adults. Executive Summary of the Third Report of the
FDA. “Drug Safety and Availability > FDA Drug Safety Communication:
New restrictions, contraindications, and dose limitations for Zocor
(simvastatin) to reduce the risk of muscle injury.” 12/15/11. FDA. 6/28/12.
Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
Frederickso DS, Lees RS. A system for phenotyping hyperlipoproteinemia.
Circulation, 1965;31:321−7.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials
for the National Cholesterol Education Program Adult Treatment Panel III
guidelines. Circulation, 2004;110(2):227−39.
Quehenberger O, Dennis EA. The human plasma lipidome. N Engl J Med,
2011;365(19):1812−23.
48565_ST06_251-352.indd 338 5/1/13 9:32 PM

59 ■ ESSENTIALS OF ADIPOSE TISSUE
ENDOCRINOLOGY
Mark Herman MD and Eleftheria Maratos-Flier MD
TYPES OF ADIPOSE TISSUE

• White adipose tissue
° Adipocytes with predominantly large solitary lipid droplet
° Adapted for energy storage
■ Storage of dietary fat as triglyceride
■ Conversion of excess dietary glucose to fatty-acids for storage
(de novo lipogenesis)

° Other functions
■ Insulation
■ Mechanical cushion
■ Regulation of appetite, energy expenditure, and hypothalamic-
pituitary axes via leptin secretion

■ Metabolism of sex steroids
• Brown adipose tissue

° Adipocytes with small, multilocular lipid droplets
° Rich in mitochondria
° Adapted for thermogenesis
• Beige or Brite Cells
° White adipocytes with an intermediate phenotype
° May participate in thermogenesis
ENDOCRINE REGULATION OF LIPID STORAGE
AND RELEASE IN ADIPOCYTES
• Chylomicrons or VLDL deliver triglyceride to adipose tissue depots
• The activity of lipoprotein lipase (LPL) present on the luminal surface
of adipose tissue vascular endothelial cells is stimulated by insulin
and hydrolyzes triglyceride to release free fatty acids
• FFAs are transported across the adipocyte membrane by diffusion
and/or facilitation by fatty acid transporters with the assistance of
intracellular fatty acid binding proteins
• Insulin stimulates translocation of the insulin-responsive glucose
transporter (Glut4) to the adipocyte plasma membrane to permit
adipocyte glucose uptake. This glucose is used to produce glycerol-
3-phosphate, which is then esterified with fatty acyl-CoAs to form
triglyceride for storage purposes
48565_ST06_251-352.indd 339 5/1/13 9:32 PM

340 Essentials of Adipose Tissue Endocrinology
• Insulin inhibits lipolysis by multiple mechanisms including decreasing cAMP

levels through induction of a phosphodiesterase, which catabolizes cAMP
• Catecholamines bind to β-adrenergic receptors, which activate cAMP-
dependent Protein Kinase A (PKA); this phosphorylates perilipin, a lipid
droplet surface protein, and hormone-sensitive lipase (HSL), resulting
in hydrolysis of triglyceride to glycerol and FFAs
ADIPOSE TISSUE DERIVED EFFERENT SIGNALS

• Adipokines: adipocyte-derived secreted proteins with endocrine or
paracrine functions
° Cytokine related proteins: leptin (see below), TNFα, IL-6
° Proteins involved in fibrinolysis: PAI-1, tissue factor
° Others: resistin,
Complement related proteins: adipsin, adiponectin (see below)
° RBP4, FGF21
• Enzymes involved in steroid metabolism
° 17βHSD (conversion of of
Aromatase (conversion androgens to estrogens)
° 11βHSD1 (conversion ofandrostenedione to testosterone)
° inactive to active glucocorticoids)
• Nonesterified fatty acids released as a result of lipolysis
LEPTIN
• A circulating peptide hormone with structural homology to cytokines
• Secreted into the circulation in proportion to adipose tissue mass and
is also regulated acutely by nutritional status
• Effects of leptin are mediated through actions on leptin receptors
present in the hypothalamus
• Its primary role is to serve as a signal of energy sufficiency
° Leptin levels rapidly decline with weight loss
° Aexpenditure
decline in leptin levels increase appetite and reduce energy
• A decline in leptin suppresses the thyroid and gonadal axes

• Other functions
° Leptin regulates immune function, hematopoiesis, angiogenesis,
and bone development
• Rare genetic mutations in leptin cause morbid obesity which are
reversible with leptin
• Leptin is ineffective at reducing weight in most obese humans due to a
state of leptin resistance associated with high circulating leptin levels
ADIPONECTIN
• Adipocyte secreted protein that circulates at high concentrations
in multimeric complexes, which suppresses hepatic glucose production
• Circulating levels decrease in obesity and increase with weight loss or
thiazolidinedione treatment
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Adipose Tissue Endocrinology in Obesity 341
OBESITY
• Defined as excess adiposity
• Produced by a combination of adipocyte hyperplasia and hypertrophy
• Clinical definitions
° Overweight: BMI >25 kg/m2
° Obesity: BMI >30 kg/m2
• A key component of the “metabolic syndrome,” which is a cluster of
cardiovascular disease risk factors including hypertriglyceridemia,
hypertension, low HDL-C, and insulin resistance (see Chapter 61,
Metabolic Syndrome)
• Increased risk for early mortality with increasing obesity
• Rapidly increasing prevalence over the last three decades
° In the United Sates, the prevalence of obesity is >30%
° The explanation for the rapidly increasing prevalence of obesity
remains uncertain. Potential contributors include
■ Environmental factors: changes in diet and exercise
■ Genetic factors: may contribute to ~60 % of the variation in BMI
in a population
• Variants in the melanocortin 4 receptor (MC4R) gene and
the fat mass and obesity−associated (FTO) gene account for
~2% of the variation in BMI
• Genome wide association scans have identified an additional
8 genetic loci associated with BMI; however, variants in
these genes appear to account for only a small fraction of the
heritability of BMI
ADIPOSE TISSUE ENDOCRINOLOGY IN OBESITY

• In obesity, adipocytes are resistant to the effects on insulin to inhibit
lipolysis, resulting in an increase in the release of FFAs; increased cir-
culating FFAs can contribute to the development of insulin resistance
in muscle and liver
• Obesity is a state of leptin resistance
• Decreased adiponectin secretion in obesity may contribute to insulin
resistance
• Increased TNFα and RBP4 secretion in obesity may contribute to
insulin resistance
• Increased adipose tissue inflammation obesity may contribute to
insulin resistance
• Expression of Glut4, the insulin-responsive glucose transporter, is
down-regulated in adipocytes in obese patients contributing to insulin
resistance
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342 Essentials of Adipose Tissue Endocrinology
LIPODYSTROPHIES
• Disorders characterized by selective or generalized absence or loss of
body fat
• May be genetic or acquired and partial or generalized
• The most prevalent form of lipodystrophy is associated with HIV infec-
tion and treatment with highly active antiretroviral therapy (HAART),
particularly protease inhibitors
• Causes insulin resistance and its associated complications such as
DM, hypertriglyceridemia, and often severe hepatic steatosis
• Use of a methylated form of leptin is currently under investigation as
replacement therapy of several varieties of lipodystrophy
REFERENCES
Barbatelli G, Murano I, Madsen L, et al. The emergence of cold-induced
brown adipocytes in mouse white fat depots is determined predominantly
by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol
Metab, 2010;298(6):E1244−53.
Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of
lipolysis in adipocytes. Annu Rev Nutr, 2007;27:79−101.
Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends
Genet, 2010;26(6):266−74.
Garg A. Clinical review: lipodystrophies: genetic and acquired body fat
disorders. J Clin Endocrinol Metab, 2011;96(11):3313−25.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol
Metab, 2004;89(6):2548−56.
48565_ST06_251-352.indd 342 5/1/13 9:32 PM

60 ■ OBESITY MANAGEMENT
David W. Lam, MD and Robert T. Yanagisawa, MD
PATHOPHYSIOLOGY
• Obesity involves a complex interaction between genetics, behavior,
and environment. Ultimately, it results from chronic energy imbalance
where intake exceeds expenditure.
° Energy intake can be estimated with dietary journals reviewed
by the practitioner or a registered dietician; accuracy hinges on
patient motivation and perceptions of intake
° Energy expenditure is a product of the resting metabolic rate (RMR)
and a physical activity factor
■ Resting metabolic rate (kcal/day) = 10 X weight (kg) + 6.25 X
height (cm) – 5.0 X age (yr) + s (s = 5 for males and –161 for
females)
■ Physical activity factor (range 1.2–1.9): sedentary = 1.2, moder-
ate exercise 3–5x/wk = 1.55, extra active = 1.90

° Calculating energy intake and expenditure helps patients concep-
tualize and quantify the efficacy of caloric reductions in diet and
increasing physical exercise
• Pathologic and iatrogenic factors can contribute to obesity and make
treatment more difficult
° Pathologic conditions: Cushing’s syndrome, hypothyroidism, PCOS,
and hypothalamic obesity
° ine, risperidone, lithium),
Iatrogenic causes: antipsychotics (thioridazine, clozapine, olanzap-
tricyclic antidepressants, antiepileptic
(carbamazepine, valproate), antidiabetic drugs (insulin, sulfonyl-
ureas, thiazolidinediones), and glucocorticoids
DIAGNOSIS
• BMI = weight (kg)/height (m) squared
• BMI is the current standard for classification of obesity by the WHO
and the National Heart, Lung, and Blood Institute
° Overweight (BMI 25.0–29.9)
° Obesity class I (BMI 30.0–34.9)
° Obesity class III
Obesity class II (BMI 35.0–39.9)
° (BMI ≥40.0)
• Increased BMI and waist circumference (WC) are independently asso-
ciated with increased risk for type 2 DM, hypertension, and CVD
48565_ST06_251-352.indd 343 5/1/13 9:32 PM

344 Obesity Management
• Relative risk varies depending on population sampled; however,

patients with a BMI ≥25.0, males with WC >102 cm and females with
WC > 88 cm should be evaluated for possible comorbid conditions
• Sole use of BMI has limitations in muscular patients and those with
significant loss of muscle mass. In addition it has ethnic limitations,
particularly with Asian populations (e.g., Asian males with WC >90
cm and Asian females with WC >80 cm are considered higher risk).
Despite these limitations, BMI cut-offs are still recommended for
international use
TABLE 60.1 History at Clinical Presentation of Obesity
History Components Evaluate for Comorbidities
• Age of onset of obesity • Coronary heart disease
• Weight loss attempts including • Type 2 DM
methods, successes, and failures • Sleep apnea
• Food intake with attention to skipped • Nonalcoholic steatohepatitis
meals, portion size, beverage choices, • PCOS
food consumed between scheduled
meals, and dining out
• Physical activity including duration,
intensity, and frequency of activities
• Triggers for increased food
consumption and decreased physical
Assess Factors Increasing CVD Risk
activity
• Perceived impact of obesity on health • Tobacco use
and body image • Hypertension
• Willingness and motivation to lose • Hyperlipidemia (LDL >160, LDL
weight 130–159 with 2 additional risk factors,
• Medications and supplements HDL <35)
• Targeted review of systems to evaluate • Impaired fasting glucose
for secondary contributors of obesity • Family history of CAD (Men ≥45,
such as hypothyroidism and Cushing’s women ≥55)
syndrome
° Height, weight, WC (measured at the level of the iliac crest at the
end of expiration) should be measured in addition to standard vital
signs.
° Aattention
complete physical examination should be performed with specific
to signs that maybe consistent with a secondary contribu-
tor of obesity such as Cushing’s syndrome and hypothyroidism
48565_ST06_251-352.indd 344 5/1/13 9:32 PM

Treatment 345
• Laboratory evaluation
° Electrolytes, LFTs, TSH, fasting lipid panel, fasting BG
° Ifsalivary
clinically suspected, a 24-hour urine-free cortisol or midnight
cortisol should be collected to screen for Cushing’s disease
TREATMENT
• Patient involvement and investment are critical for success; goals
of treatment and a treatment plan should be made jointly with the
patient and discussed at each visit
• Injury prevention should be reviewed and the necessity for pretreat-
ment cardiovascular assessment should be determined by the
practitioner
• Goals of therapy
° Apounds
10% decrease from baseline weight with a rate between 1 and 2
per week is recommended for initial weight loss
° Plan adjustment may be required after initial weight loss because
of an adjustment of the energy balance
• Lifestyle modifications
° Diet
■ Total energy intake should be reduced by 500–1000 kcal/day for
obese patients and 300–500 kcal/day for overweight patients;

intake from fat should be limited to 25–35% of the total
■ Education for the patient on appropriate food choices, reading
food labels, and making healthy decisions when dining out is

essential
■ Weight loss from diet is more related to the restriction of energy
intake over specific macronutrient modification (e.g., low fat or

low carbohydrate diets)
° ■ 30 minutes of moderate-to-vigorous physical activity 5–7 days
Exercise
a week is recommended. Moderate intensity: 3.0–5.9 Metabolic

Equivalent of Tasks (METS) (walking 3 miles/hour = 3.3 METS).
Vigorous intensity: >6.0 METS (running at 6 miles/hour = 6 METS)
■ Exercise can offset lean body mass loss and the lowering of the
RMR from caloric restriction; in addition, exercise leads to more

percent weight lost as fat compared to caloric restriction
° (BWL) are behavioral
Cognitive therapy (CBT) and behavioral weight loss
psychological interventions for weight management
■ CBT seeks to identify emotions that facilitate overeating and
manage patient expectations

■ BWL includes self-monitoring and reinforcing positive diet/
exercise behaviors
48565_ST06_251-352.indd 345 5/1/13 9:32 PM

TABLE 60.2 Pharmacotherapy for Obesity
Class of Medication Effi cacy Side Effects Indication
Intestinal fat 5–10 kg loss, Oily spotting, Long-term treatment
absorption inhibitor less for over the intestinal cramps, of obesity
(orlistat*) counter. gas, loose stools
CNS stimulants/ Variable Palpitations, Short-term
appetite increased blood treatment of
suppressants pressure, insomnia. obesity (less than
(benzphetamine*, • Scheduled drugs 12 weeks)
diethylpropion*, given abuse
phendimetrazine*, potential.
phentermine*)
Appetite 5% body weight Headache, Upper BMI ≥30 or
suppressant, loss respiratory BMI ≥27 with
selective serotonin infection (URI) weight-related
(5-HT2c) agonist symptoms. comorbidity
(lorcaserin*) Consider baseline
echocardiogram
(ECHO)
Biguanide 0.6–2.7 kg loss Abdominal Type 2 DM
(metformin) discomfort,
diarrhea, anorexia
Alpha-glucosidase 0.5 kg loss Abdominal pain, Type 2 DM
inhibitors (1–3 years) flatulence,
(Acarbose, diarrhea
miglitol)
GLP-1 analogs 1.8–6.0 kg loss Nausea, vomiting, Type 2 DM
(exenatide, dyspepsia.
liraglutide) Serious reactions:
pancreatitis
Amylin mimetic 1.5 kg loss Nausea, vomiting, Type 2 DM
(pramlintide) anorexia
*Approved by United States Food and Drug Administration (FDA) for the treatment/management of obesity
° Most nutraceutical supplements lack rigorous scientific data dem-

onstrating their safety and efficacy in weight loss. It is important to
educate patients regarding the use of nutraceutical supplements
° Dietary fiber (25 g/day for women and 38 g/day for men) may
enhance weight loss by slowing the absorption of macronutrients
and decreasing appetite
48565_ST06_251-352.indd 346 5/1/13 9:32 PM

References 347
• Surgical treatment of obesity

° Bariatric surgery should be considered in patients with BMI
≥40 kg/m2, or BMI ≥35 kg/m2 with a significant obesity-related
comorbidity
° Patients should have preoperative measurement of iron, vitamins
B12, C, and D, and zinc. Postoperatively they should be screened
for complications at 6 months and then annually
TABLE 60.3 Surgical Treatment of Obesity

Excess Body Type 2 DM Micronutrient
Procedure Weight Loss Resolution Complications
Gastric banding 46% 57% Vitamins C, D,
B12, B6, Folate,
and Iron
Sleeve gastrectomy 55% 80% Zinc, Vitamin D,
Folate, Vitamin
B12, Iron
Gastric bypass 60% 80% Iron, Folate,
Vitamins A, B1,
B12, B6, C, D,
E, Zinc
Biliopancreatic 64% 95% Vitamins A, B12, D,
diversion/ E, K, Iron, Zinc,
duodenal switch Selenium, Copper,
Folate
REFERENCES
Bray GA. Medications for weight reduction. Med Clin North Am,
2011;95(5):989−1008.
Donnelly JE, Blair SN, Jakicic JM, et al. American College of Sports Medicine
Position Stand. Appropriate physical activity intervention strategies for
weight loss and prevention of weight regain for adults. Med Sci Sports
Exerc, 2009;41(2):459−71.
Laddu D, Dow C, Hingle M, Thomson C, Going S. A review of evidence-based
strategies to treat obesity in adults. Nutr Clin Pract, 2011;26(5):512−25.
48565_ST06_251-352.indd 347 5/1/13 9:32 PM

Leblanc ES, O’Connor E, Whitlock EP, Patnode CD, Kapka T. Effectiveness

of primary care-relevant treatments for obesity in adults: a systematic
evidence review for the U.S. Preventive Services Task Force. Ann Intern
Med, 2011;155(7):434−47.
Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of
Clinical Endocrinologists, The Obesity Society, and American Society for
Metabolic & Bariatric Surgery Medical guidelines for clinical practice for
the perioperative nutritional, metabolic, and nonsurgical support of the
bariatric surgery patient. Endocr Pract, 2008;14(Suppl 1):1−83.
Strohmayer E, Via MA, Yanagisawa R. Metabolic management following
bariatric surgery. Mt Sinai J Med, 2010;77(5):431−45.
48565_ST06_251-352.indd 348 5/1/13 9:32 PM

61 ■ METABOLIC SYNDROME
George A. Bray, MD
INTRODUCTION
• Metabolic syndrome is a cluster of risk factors that predict the risk for
cardiovascular and metabolic disease
• A list of the primary components and other factors that are often
present but not included in the definition of metabolic syndrome are
shown in Table 61-1
• Metabolic syndrome is highly prevalent in obese individuals
• The higher the number of abnormal components, the greater is the risk
of cardiometabolic diseases
° Fasting glucose alone may be as good as the metabolic syndrome in
predicting diabetes
° Low HDL-C and elevated BP are strong predictors of CVD
• Acarbose has a stronger association with diabetes than with CHD
TABLE 61.1 Features of the Metabolic Syndrome

Major Components Factors Frequently Found
Abdominal obesity Microalbuminuria
Glucose intolerance Small dense LDL
High triglycerides Inflammatory markers
Low HDL-cholesterol Thrombotic factors
High blood pressure Endothelial dysfunction
Insulin resistance Hyperuricemia
PREVALENCE
• The prevalence of the metabolic syndrome has been estimated at
23.7% of the adult population or 47 million US adults
• The prevalence increases with age
° 6.7% in those aged 20–29 years
° 43.5% in those aged 60–69 years
° 42% in people older than 70 years
• The overall prevalence is similar in men and women (24.0% versus
23.4%)
• Ethnic variation with higher prevalence in African-American and
Mexican-American women (57%) and men (30%)
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350 Metabolic Syndrome
DIAGNOSIS
• The NCEP Adult Treatment Panel III has provided defining values for
5 components of the metabolic syndrome including WC, plasma TG,
plasma HDL-C, fasting glucose, and BP. When 3 of the 5 criteria are
abnormal, the patient has metabolic syndrome
• Other diagnostic criteria for metabolic syndrome were developed by the
WHO and the International Diabetes Federation
• The agreed upon international diagnostic criteria are shown below.
The diagnosis requires that 3 of the 5 measures listed in below be
abnormal and allows different definitions of WC to be employed. In
general, WC >40 inches (102 cm) in men and >35 inches (88 cm) in
women is the risk level in the US
° International criteria for The Metabolic Syndrome (Drug treatments
for any of these conditions are considered alternate indicator criteria)
■ ↑ waist circumference (population- and country-specific definitions)
■ ↑ triglycerides (≥ 150 mg/dL)
■ ↓ HDL-cholesterol (Males, < 40 mg/dL; Females, <50 mg/dL)
■ ↑ blood pressure (>130 mm Hg systolic and/or > 85 mm Hg
diastolic)
■ ↑ fasting blood glucose (> 100 mg/dL)
• Obesity, hypertension, dyslipidemia, and hyperglycemia
• Focus history on symptoms of diabetes and its complications, obesity
and its complications, CAD (angina), and polycystic ovary syndrome
(PCOS)
• Other complications include cognitive decline in the elderly, fatty liver
disease, obstructive sleep apnea, gout, and chronic kidney disease
• Complete physical examination, including height, weight, waist
circumference, and BP
LABORATORY TESTING
• Fasting lipid profile (TC, LDL-C, HDL-C, and TG)
• Fasting glucose
TREATMENT
• Weight loss will improve all of the markers of the metabolic syndrome
and reduces the risk of developing diabetes
• Diet and exercise is the first step in management
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References 351
• Surgically induced weight loss via laparoscopic gastric banding or

gastric bypass can be particularly effective in reversing diabetes and
metabolic syndrome (Table 61.2)
• If BP, dyslipidemia, diabetes, or IGT persist, they may need to be
treated individually
TABLE 61.2 The Effect of Substantial Weight Loss After Surgery on the Incidence
of the Metabolic Syndrome in Randomized Control Trials
Reduction in the
Study Population Incidence of Diabetes Signifi cance
Mild-to-moderately obese
From 40% → 3% P = 0.006
adults (BMI 30–35)
Obese adults with type 2
97% → 28% P < 0.001
diabetes
Obese adolescents 36% → 0% P = 0.03
REFERENCES
Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome:
a joint interim statement of the International Diabetes Federation
Task Force on Epidemiology and Prevention; National Heart, Lung, and
Blood Institute; American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International Association for
the Study of Obesity. Circulation, 2009;120(16):1640−45.
Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after
bariatric surgery: systematic review and meta-analysis. Am J Med,
2009;122(3):248−56.
Cholesterol in Adults. Executive Summary of The Third Report of The
Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome
among US adults: findings from the third National Health and Nutrition
Examination Survey. JAMA, 2002;287(3):356−9.
Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current
state of the evidence. Diabetes Care, 2008;31(9):1898−904.
Franssen R, Monajemi H, Stroes ES, Kastelein JJ. Obesity and dyslipidemia.
Gu D, Reynolds K, Wu X, et al. Prevalence of the metabolic syndrome and
overweight among adults in China. Lancet, 2005;365(9468):1398−405.
Koster A, Leitzmann MF, Schatzkin A, et al. Waist circumference and mortal-
ity. Am J Epidemiol, 2008;167(12):1465−75.
48565_ST06_251-352.indd 351 5/1/13 9:32 PM

352 Metabolic Syndrome
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive
protein and low-density lipoprotein cholesterol levels in the prediction of
first cardiovascular events. N Engl J Med, 2002;347(20):1557−65.
Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and
cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med,
2004;351(26):2683−93.
48565_ST06_251-352.indd 352 5/1/13 9:32 PM

SECTION VII: MISCELLANEOUS
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48565_ST07_353-368.indd 354 5/1/13 9:32 PM
62 ■ PANCREATIC NEUROENDOCRINE
TUMORS AND CARCINOID SYNDROME
Matthew H. Kulke, MD
PATHOPHYSIOLOGY
• Neuroendocrine tumors (NETs) are generally subcategorized as either
carcinoid tumors or pancreatic endocrine tumors
• The release of substances such as serotonin, gastrin, glucagon, and
insulin into the systemic circulation results in the unique systemic
syndromes associated with NETs
• NETs can be further classified according to histology. The majority are
well-differentiated and pursue a relatively indolent course. A minority,
however, are poorly differentiated and pursue an aggressive course;
these tumors are treated with aggressive surgery and/or traditional
chemotherapy
TABLE 62.1 Histologic Classifi cation of Neuroendocrine Tumors
Mitotic Ki-67
Differentiation Grade Count Index Traditional ENETS, WHO
Low grade <2 per ≤2% Carcinoid, islet Neuroendocrine
(G1) 10 HPF cell, pancreatic tumor,
(neuro) grade 1
endocrine
tumor
Well- Intermediate 2–20 per 3–20% Carcinoid, Neuroendocrine
differentiated grade (G2) 10 HPF atypical tumor,
carcinoid, grade 2
islet cell,
pancreatic
(neuro)
endocrine
tumor
High grade >20 per >20 % Small cell Neuroendocrine
(G3) 10 HPF carcinoma carcinoma,
grade 3,
Poorly small cell
differentiated Large cell Neuroendocrine
neuroendocrine carcinoma
carcinoma grade 3, large
cell
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356 Pancreatic Neuroendocrine Tumors and Carcinoid Syndrome
• Pancreatic NET
° Pancreatic NET may arise either sporadically or, less commonly, in
patients with MEN-1
° The clinical presentations of pancreatic endocrine tumors
are diverse and are often related to symptoms of hormonal
hypersecretion (Table 62.2)
° Diagnostic tests and initial treatment of symptoms of hormonal
hypersecretion depend on the type of tumor (Table 62.2)
TABLE 62.2 Clinical Presentation and Initial Treatment of Pancreatic
Neuroendocrine Tumors
Tumor Symptoms or Signs Diagnostic Tests
Insulinoma Hypoglycemia resulting in Insulin/glucose ratio;
intermittent confusion, C-peptide; 48–72 hour
sweating, weakness, inpatient fast if necessary
nausea; loss of
consciousness may occur
in severe cases
Glucagonoma Rash (necrotizing migratory Serum glucagon
erythema), cachexia,
diabetes, deep venous
thrombosis
VIPoma, Verner-Morrison Profound secretory Serum VIP
syndrome, WDHA diarrhea, electrolyte
syndrome disturbances
Gastrinoma, Acid hypersecretion Basal gastrin; stimulated
Zollinger-Ellison syndrome resulting in refractory gastrin level if basal
peptic ulcer disease, gastrin inconclusive
abdominal pain, and
diarrhea
• Carcinoid tumors
° Aaccording
commonly used classification scheme groups carcinoid tumors
to their presumed derivation from the embryonic gut:
foregut (bronchial and gastric), midgut (small intestine and
appendiceal), and hindgut (rectal)
° The clinical presentation and management of these tumors varies,
depending upon their site of origin (see Table 62.3)
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Diagnosis 357
TABLE 62.3 Clinical Presentation of Carcinoid Tumors

Tumor Symptom
Foregut
Bronchial Carcinoids Cough, hemoptysis, post-obstructive pneumonia,
Cushing’s syndrome. Carcinoid syndrome rare
Gastric Carcinoids Usually asymptomatic and found incidentally
Midgut
Small Intestine Intermittent bowel obstruction or mesenteric ischemia.
Carcinoids Carcinoid syndrome common when metastatic.
Appendiceal Carcinoids Usually found incidentally; may cause carcinoid syndrome
when metastatic
Hindgut
Rectal Carcinoids Either found incidentally or discovered due to bleeding,
pain, and constipation; rarely cause hormonal symptoms,
even when metastatic
DIAGNOSIS
• Laboratory esting
° Urinary 5-Hydroxyindole acetic acid (5-HIAA) levels
■ Elevated levels of 5HIAA in a 24-hour urine collection are highly
specific for carcinoid tumors, but not particularly sensitive

■ 5-HIAA levels are generally elevated in patients with primary
midgut carcinoid tumors but not useful in patients with either

foregut (bronchial, gastric) or hindgut (rectal) carcinoid tumors
that only rarely secrete serotonin
° Serum chromogranin A (CGA)
■ Serum CGA concentrations are a more sensitive marker than
urinary 5-HIAA levels in patients with carcinoid tumors, and can

also be used as a marker in patients with both functional and
nonfunctional pancreatic endocrine tumors
■ However, CGA is nonspecifi c and may be elevated in patients on
PPIs, with chronic renal disease, and in other medical conditions

° Measurement of specific hormones (glucagon, vasoactive intestinal
peptide (VIP), insulin, gastrin) may be helpful in the diagnosis and
follow-up of patients with specific secretory symptoms related to
the hormone of interest
• Imaging
° The type and sequence of diagnostic imaging tests depend in part
on tumor stage (localized versus metastatic) and the suspected
location of the primary tumor
48565_ST07_353-368.indd 357 5/1/13 9:32 PM

° For evaluation of suspected localized disease, direct imaging with

the potential for diagnostic biopsy is preferred
■ Endoscopic ultrasound may be helpful both to visualize and
facilitate biopsy in patients with pancreatic NET

■ Bronchoscopy can be used to diagnose patients with bronchial
carcinoid
■ Colonoscopy is appropriate in patients with suspected rectal or
small bowel carcinoid tumors

° Patients with localized disease or suspected metastatic disease
should generally be evaluated first with cross sectional imaging
■ CT scanning remains the standard cross-sectional imaging tech-
nique for baseline staging of patients with neuroendocrine tumors

■ NET liver metastases are often hypervascular and may become
isodense relative to the liver with the administration of IV con-

trast materials. CT scans should thus be performed both before
and after the administration of IV contrast agents. If CT results
are inconclusive or CT is not easily feasible, MRI scan is highly
sensitive for liver metastases and may be used for staging
° Somatostatin receptor scintigraphy is generally used as an adjunct
to cross-sectional imaging at baseline. It is not generally used or
recommended for the routine follow-up of patients with neuroen-
docrine tumors
■ With the exception of insulinomas (of which only 50% express
type 2 somatostatin receptors), over 90% of NETs, including

nonfunctioning pancreatic tumors and carcinoid tumors, contain
high concentrations of somatostatin receptors, and can be
imaged with a radiolabeled form of the somatostatin analogue
octreotide (111-indium pentetreotide)
■ The uptake of radiolabeled octreotide is also predictive of a clini-
cal response to therapy with somatostatin analogues
GENERAL MANAGEMENT APPROACH

• Surgery is the only curative treatment option for patients with NETs,
and should be considered for patients with localized disease; the type
and extent of surgery is dependent on the location and size of the tumor
• Treatment for patients with advanced disease focuses both on treat-
ment of symptoms of hormone hypersecretion (if present) and direct
antitumor therapies
TREATMENT OF SYMPTOMS OF HORMONAL

HYPERSECRETION BY TUMOR TYPE
• Insulinoma: diazoxide is generally used as an initial treatment to
stabilize blood glucose levels. Recent data suggest that everolimus
may have a direct and rapid effect in improving glucose control
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Systemic Treatment Options for Tumor Control 359
Somatostatin analogues are not universally effective in treating

patients with insulinoma and should be used with caution
• Glucagonoma: somatostatin analogues are generally effective in treat-
ing symptoms associated with glucagon hypersecretion
• VIPoma: somatostatin analogues are generally effective in treating the
diarrhea associated with VIP hypersecretion
• Gastrinoma: PPIs are generally used first-line; the addition of octreo-
tide can also be considered
• Carcinoid syndrome: the flushing and diarrhea associated with
carcinoid syndrome has been attributed to serotonin secretions, and is
generally highly responsive to treatment with somatostatin analogues
TREATMENT OF PATIENTS WITH HEPATIC-PREDOMINANT

METASTATIC DISEASE
• In selected cases, metastatic liver disease can be surgically resected
• Hepatic arterial embolization is commonly used as a palliative tech-
nique in patients with hepatic metastases who are not candidates for
surgical resection, and can be performed with or without the adminis-
tration of concurrent chemotherapy. More recently, radioembolization
has also shown promise in patients with advanced NETs
SYSTEMIC TREATMENT OPTIONS FOR TUMOR CONTROL

• Somatostatin analogues
° Octreotide improved time to tumor progression in patients with
advanced small bowel carcinoid tumors and is often used first-line
to slow tumor growth in this setting
• Interferon α
° Interferon α has been used as a treatment for advanced carcinoid
for several decades
° While not approved for this indication in the United States, reports
suggest that single-agent IFN therapy can provide symptomatic
control of carcinoid syndrome, and induce a biochemical response
in at least 30–35% of patients
° Prospective studies evaluating the efficacy and toxicity of interferon
in advanced neuroendocrine tumors have been limited by relatively
small patient numbers
• Cytotoxic chemotherapy
° Cytotoxic chemotherapy has, in general, been minimally active
in patients with advanced carcinoid tumors; most studies have
focused on regimens incorporating streptozocin, dacarbazine, or
temozolomide
° In contrast to carcinoid tumors, pancreatic NETs are clearly respon-
sive to cytotoxic chemotherapy; active regimens include those
containing streptozocin or temozolomide
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• Molecularly targeted therapy

° Molecularly targeted therapies, including VEGF pathway inhibi-
tors and the mammalian target of rapamycin (mTOR) inhibitor
everolimus, are currently under investigation for the treatment of
advanced carcinoid tumors
° Sunitinib, a TKI-targeted against the VEGF receptor and related
receptors, was approved for use in patients with advanced
pancreatic NET
° The mTOR inhibitor everolimus is approved for use in patients with
advanced pancreatic NET. Everolimus may also independently
improve glycemic control in patients with functioning insulinomas
REFERENCES
Chan JA, Kulke MH. New Treatment Options for Patients with Advanced
Neuroendocrine Tumors. Curr Treat Options Oncol, 2011;12:136–48.
Halperin DM, Kulke MH. Management of Pancreatic Neuroendocrine Tumors.
Gastroenterol Clin North Am, 2012;41:119–31.
Kulke MH, Benson AB 3rd, Bergsland E, et al. Neuroendocrine tumors. J Natl
Compr Canc Netw, 2012;10(6):724−64.
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63 ■ AUTOIMMUNE POLYGLANDULAR
SYNDROMES AND MULTIPLE ENDOCRINE
NEOPLASIAS
Catherine J. Owen, MBBS, MRCP, MRCPCH, PhD
AUTOIMMUNE POLYGLANDULAR SYNDROMES (APS)

• Encompass a wide spectrum of clinical diseases, whereby more than
one organ-specific autoimmune disease occurs in an affected individual
TABLE 63.1 Comparison of Features in APS1 and APS2
APS2 APS1
Age of onset Adulthood (16–40 + yrs) Childhood (4–10 yrs)
Female : male ratio 3:1 1:1
Main manifestations Addison’s disease + either Candidiasis,
hypothyroidism or type 1 hypoparathyroidism,
diabetes Addison’s disease (2 of 3 OR
1 + 2 minor manifestations)
Aetiology Multifactorial — multiple Monogenic (autosomal
genes (including HLA, recessive) – AIRE gene
CTLA-4, CYP21B) and mutation (important role
environmental factors. in central induction of
Familial clustering. self-tolerance).
Prevalence 4–5/100,000 Very rare estimated 3 per million
AUTOIMMUNE POLYGLANDULAR SYNDROMES TYPE 2 (APS2)

• The presence of autoimmune primary adrenal insufficiency (AI) with
either autoimmune thyroid disease (AITD) or type 1 diabetes
Clinical Presentation of APS2
• AI occurs in 100% and is the first endocrine abnormality in ~50%
• AITD (usually hypothyroidism) occurs in 70–90%
• Type 1 DM in 30–50%
• Complete triad (AI, AITD, and type 1 DM) noted in 10%
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362 Autoimmune Polyglandular Syndromes and Multiple Endocrine Neoplasias
• Other autoimmune conditions may also be associated (Table 63.2)

TABLE 63.2 Other Autoimmune Conditions Associated with APS2
More Common Rare Manifestations
Manifestations Endocrine Pituitary involvement,
(1–20 %) hypophysitis, empty sella
Pernicious anemia syndrome,
Gonadal failure late-onset hypoparathyroidism
(male and female) Gastrointestinal Ulcerative colitis, primary bilary
Vitiligo cirrhosis
Alopecia Dermatological Granuloma annulare, dermatitis
Autoimmune herpatiformis
hepatitis Neurology Myositis, myasthenia gravis,
Malabsorption neuropathy, stiff man syndrome
(inc. celiac disease) Other Sarcoidosis, serositis, selective IgA
Sjögren syndrome deficiency, idiopathic heart block,
idiopathic thrombocytopenia
Neoplasia
purpura, rheumatoid arthritis
• Related conditions
° Incomplete APS2: presence of AITD or type 1 DM with adrenal
autoantibodies; or patients with AI with thyroid and/or islet cell
autoantibodies (but not overt AITD or type 1 DM)
■ Many will develop APS2 in the future; around 30% with positive
adrenal antibodies will develop AI over the next 6 years

° thantype
APS
AI
3: association of AITD with an autoimmune disease other
Diagnosis of APS2
• History and examination essential
° Ask about family history of autoimmunity
° All patients with a single autoimmune disease are at risk for others
° Number of disorders and age of onset is unpredictable
° Long-term follow-up is needed to decrease morbidity and mortality,
especially from undiagnosed AI
• Autoantibody screening depends on the likelihood of finding another
autoimmune disease and of reducing morbidity and mortality
° AI: 50% have second autoimmune endocrinopathy, so screen
for AITD and type 1 DM at diagnosis and at periodic intervals.
Autoantibodies (i.e., TPO, GAD65, insulin, islet cell, and IA-2) can
develop at any time, so period screening is indicated even if initial
testing is negative. The optimal interval for retesting is not clear.
Some advocate checking antibodies every 5 years in adults, with
further testing yearly if positive. However, others recommend yearly
TSH testing with or without antibody screening.
° Patients with type 1 DM: at risk for AITD, therefore screen annually
with TSH; only screen for other conditions if clinical concern
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Autoimmune Polyglandular Syndromes Type 2 (APS2) 363
° Isolated AITD: rarely develop a second autoimmune condition, there-

fore only do autoantibody screening if clinical concern, not routinely
° Consider intermittent autoantibody screening in women with
premature ovarian insufficiency or young patients with vitiligo
° biochemically should also be assessed clinically and
Family members
• Clear link between the presence of organ-specific autoantibodies and

the progression to disease; often a latent period of months or years
• Screen antibody-positive patients annually as per the individual condition
• Also investigate if clinical symptoms suggestive of associated autoim-
mune condition as antibodies not 100% sensitive
TABLE 63.3 Screening Tools (Both Autoantibodies and End-Organ Testing) for the
Main Diseases Associated with the Autoimmune Polyglandular Syndromes
Associated
Disease Component Autoantibodies End-Organ Testing
AI P450c21, P450scc, P450c17 BP, U&E, ACTH, plasma
renin activity, annual
synacthen test
AITD Thyroid peroxidase, fT3, fT4, and TSH
thyroglobulin, thyrotropin
receptor
T1DM GAD65, insulin, 1A-2, islet cell HbA1c, fasting blood glucose
Hypoparathyroidism Possibly the calcium- Serum Ca2+, phosphate, PTH
sensing receptor and Mg2+
Gonadal failure P450c17, P450scc Gonadotropin levels,
testosterone/estradiol
Autoimmune hepatitis CYP1A2*, CYP2A6, AADC*, LFTs
LKM
Autoimmune gastritis/ H/K-ATPase of gastric CBC
pernicious anaemia parietal cells, intrinsic factor
Celiac disease Endomysial, Intestinal biopsy
transglutaminase, gliadin
Autoantibodies marked * are almost exclusive to APS1 and thus helpful in differentiating APS1 from other
autoimmune diseases.
#
The presence of anemia on complete blood count requires further investigation with ferritin, transferrin,
and serum iron levels if the anemia is microcytic, and vitamin B12 levels if macrocytic.
P450c21, steroid 21-hydroxylase; P450scc, cholesterol side-chain cleaving enzyme; P450c17, steroid
17α-hydroxylase; GAD65, glutamic acid decarboxylase 65; 1A-2, tyrosine phosphatase-like protein 1A-2;
CYP1A2, cytochrome P450 1A2; CYP2A6, cytochrome P450 2A6; AADC, aromatic L-amino acid decarboxyl-
ase; LKM, liver–kidney microsomal.
• Other key points

° Recurrent hypoglycemia and ↓ insulin dose in type 1 DM: consider AI
° Conversely, in AI, TSH levels often ↑ (~5−10 mU/L) in absence of
thyroid disease, as cortisol inhibits thyrotrophin release
48565_ST07_353-368.indd 363 5/1/13 9:32 PM

Management of APS2
• Hormone replacement or other therapies for the component diseases
of APS2 are similar whether the disease occurs in isolation or in
association with other conditions, and disorders should be treated as
they are diagnosed
° In patients with AITD and subclinical adrenocortical failure, LT4
initiation can precipitate an adrenal crisis (by ↑ cortisol clearance)
AUTOIMMUNE POLYGLANDULAR SYNDROMES TYPE 1 (APS1)

• Autosomal recessive condition, also known as the autoimmune polyen-
docrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED)
Clinical Presentation of APS1
• Three major manifestations: chronic mucocutaneous candidiasis
(CMC), autoimmune hypoparathyroidism, and AI
• Spectrum of associated endocrine and nonendocrine minor manifestations
TABLE 63.4 Major and Minor Manifestations Associated with APS1 Frequencies
Seen in North American and European Patients Are Shown in Parentheses
Major — Chronic mucocutaneous candidiasis (72–
Manifestations 100%), autoimmune hypoparathyroidism
(76–93%), autoimmune adrenal failure
(73–100%)
Minor Endocrine Hypergonadotrophic hypogonadism
Manifestations (17–69%), AITD (4–31%), type 1 DM
(0–33%), pituitary defects (7%)
Gastrointestinal Pernicious anemia (13–31%),
malabsorption (10–22%), cholelithiasis
(44%), chronic active hepatitis (5–31%)
Dermatological Vitiligo (8–31%), alopecia (29–40%),
urticarial-like erythema with fever (15%)
Ectodermal Dysplasia Nail dystrophy (10–52%), dental enamel
hypoplasia (40–77%), tympanic
membrane calcification (33%)
Other Keratoconjunctivitis (2–35%), hypo/
asplenia (15–40%)
• CMC tends to develop in infancy, hypoparathyroidism ~age 7, and AI

by 13 years
° All three major manifestations occur in ~60% of subjects
° CMC is often mild and intermittent, may need to ask about
specifically
° AI can develop gradually,
Hypoparathyroidism is often the first endocrine feature of APS1
° can appear in either orderdefi ciencies of cortisol and aldosterone
up to 20 years apart
48565_ST07_353-368.indd 364 5/1/13 9:32 PM

Clinical Presentation of MEN-1 365
• Minor manifestations present throughout life, until about the fifth decade
° Median number of disease components is 4 but can be up to 10
° Chronic active hepatitis varies from asymptomatic to cirrhosis or
fulminant hepatic failure with a potentially fatal outcome. Beware
↑ transaminase levels
• Great variability in the clinical picture makes diagnosis challenging
Diagnosis of APS1
• Clinical diagnosis requires 2 of the 3 major manifestations OR 1 major
and 2 minor manifestations OR 1 major manifestation + affected sibling
• Confirm with DNA screening for autoimmune regulator (AIRE) muta-
tions and autoantibody screen
° Since genetic testing often looks for only the most common muta-
tions, a negative result may not exclude the diagnosis
° prevalence
Interferon autoantibodies (IFN-α and IFN-ω) have almost 100%
in APS1 and are disease-specific, so should be mea-
sured to help identify those with negative genetic screening
• After diagnosis, close follow-up is essential, as some manifestations
(particularly AI and chronic active hepatitis) are life threatening
° New components recognized by standard surveillance methods
° Presence of autoantibodies indicates need for at least annual
screening for the relevant condition
° Absence of antibodies does not exclude disease development
• All siblings should be assessed
Management of APS1
• Treat individual disorders
• Treat oral candidiasis because of the risk of oral carcinoma
• Ca 2+ levels in APS1 hypoparathyroidism are often labile, probably due
to malabsorption
° Monitor frequently (2–3 times monthly) and maintain around lower
end of the normal range (2.0–2.2 mmol/L) to avoid hypercalciuria
° ↓ Mg may contribute to resistance to Ca and require replacement
2+ 2+
• In AI, alteration of the HC dose changes Ca2+ absorption

° ↑ Ca may be the first sign of the AI developing
2+
• Avoid live vaccines in view of underlying immunodeficiency
MULTIPLE ENDOCRINE NEOPLASIAS (MEN)

• Autosomal-dominant disorders, with high penetrance, leading to develop-
ment of glandular hyperplasia and malignant neoplasia of endocrine organs
CLINICAL PRESENTATION OF MEN-1

• Association of parathyroid hyperplasia (>90%), pituitary adenomas
(15–50%) and pancreatic islet cell tumours (60–80%)
° May also develop carcinoid, adrenocortical hyperplasia, and lipomas
• ~50% present <20 years of age
• Hypercalcemia due to hyperparathyroidism most common presenting
feature
48565_ST07_353-368.indd 365 5/1/13 9:32 PM

CLINICAL PRESENTATION OF MEN-2

• Associated with MTC, subdivided into
° MEN-2A: MTC with pheochromocytoma (50%) and/or hyperparathy-
roidism (~35%)
° neuromas (mainlyMTC
MEN-2B (rarer): with pheochromocytoma, multiple mucosal
tongue and GI tract), Marfanoid habitus and dys-
morphic facies, with multiple facial neuroma leading to thickened
lips and eyelids
■ MTC presents earlier and is more aggressive in MEN-2B
° Familial MTC: MTC alone

TABLE 63.5 Main Endocrine Associations in MEN-1 and MEN-2 Together with
Their Clinical Presentation and Screening/Diagnostic Tools
Screening/ Important
Organ Neoplasia Symptoms Diagnosis Points
Parathyroid Hyperpara- Bones and joint Ca2+, PTH Occurs in
thyroidism pain, renal >90% of
stones cases
Pituitary Prolactinoma Galactorrhea, Prolactin 60% pituitary
hypogonadism tumours in
MEN-1
GH-secreting Acromegaly, IGF-1, GH 25% pituitary
tumour gigantism tumours in
MEN-1
ACTH- Cushing’s Urinary-free <15% pituitary
secreting or disease cortisol, 9 AM tumours in
nonfunctioning and midnight MEN-1
cortisol
MEN-1 Pancreas Insulinoma Hypoglycaemia Glucose/ ~30%
insulin pancreatic
tumours in
MEN-1
Gastrinoma Zollinger-Ellison Gastrin ~50%

syndrome pancreatic
tumours in
MEN-1, main
cause death
PP producing, Usually Plasma PP and Rare, most other
VIP producing asymptomatic, VIP, imaging pancreatic
diarrhea tumors are
nonfunctioning
(continues)
48565_ST07_353-368.indd 366 5/1/13 9:32 PM

Diagnosis of MEN-2 367
TABLE 63.5 (continued)
Screening/ Important
Organ Neoplasia Symptoms Diagnosis Points
Parathyroid Hyperpara- Bones and Ca2+, PTH Occurs in
thyroidism joint pain, ~35% of
renal stones cases
Thyroid Medullary Neck mass Calcitonin Occurs in nearly
carcinoma 100% fg
MEN-2 MEN-2 cases
Adrenal Phaeochromo- Hypertension, Catecholamine Occurs in 50%
cytoma headache, measurement of cases,
adrenergic and/or frequently
paroxysms imaging bilateral, rarely
malignant
DIAGNOSIS OF MEN-1
• Due to inactivating mutation of tumor suppressor gene MEN-1.
• In 70%, MEN-1 mutation is identified, the remainder diagnosed clinically
° Genetic test if ≥2 MEN-1 associated tumors or positive family his-
tory of MEN-1. Age of screening children depends on family wishes
and local practice
• Once diagnosed, regular screening can detect tumors ~10 years before
symptom onset
• If patient with known mutation, begin screening at age 5 with history,
examination and annual Ca2+ and PTH, add in PRL, IGF-1 and pancre-
atic ultrasound after age of 10. Other tests only performed in children
if clinically indicated
• Begin screening for pancreatic neuroendocrine markers ~aged 20 by
annual measurement of gastrin, VIP, glucagon, pancreatic polypeptide,
CGA, insulin, and glucose. Also pancreas MRI every 3 years, pituitary
MRI every 3–5 years, and chest CT or MRI every 1–2 years
• If screen positive, further studies, including imaging, are necessary
DIAGNOSIS OF MEN-2
• MEN-2 caused by a gain of function mutation of the RET proto-oncogene
• Early genetic testing important as prophylactic thyroidectomy can
prevent MTC
• Close relationship between mutation and phenotype, with different
RET gene mutations correlating with time of onset of MTC, aggressive-
ness of MTC, and the presence or absence of other endocrine tumors
° Complete thyroidectomy recommended for all patients
° Timing of surgery (age < 1 yr, 1–5 yrs, 5–10 yrs) depends on the
particular RET mutation
° Annual calcitonin level also recommended
48565_ST07_353-368.indd 367 5/1/13 9:32 PM

• Annually screen for pheochromocytoma with fractionated urine or

plasma MNs
• Annually screen for primary hyperparathyroidism with serum calcium
• Genetically test all those with sporadic MTC, as 5–10% RET mutation
positive
MANAGEMENT OF MEN
• As per the individual condition or tumor, preferably by a multidisciplinary
team involving the relevant specialists experienced in managing MEN
• Other key points
° Hyperparathyroidism gradually involves multiple glands, so need
subtotal (3½ glands) parathyroidectomy or total parathyroidectomy
with gland reimplantation in forearm
° Zollinger-Ellison
disease
syndrome has high mortality from peptic ulcer
° In MEN-2, complete thyroidectomy is recommended, as develop-

ment of MTC is inevitable and has a poor prognosis once clinically
evident
REFERENCES
Burgess J. How should the patient with multiple endocrine neoplasia type 1
(MEN 1) be followed? Clin Endocrinol (Oxf), 2010;72(1):13−6.
Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations
and management of patients with autoimmune polyendocrine syndrome
type I. J Intern Med, 2009;265(5):514−29.
Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol,
2009;161(1):11−20.
Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectoder-
mal dystrophy: known and novel aspects of the syndrome. Ann N Y Acad
Sci, 2011;1246:77−91.
Lankisch TO, Jaeckel E, Strassburg CP. The autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy or autoimmune polyglandular syndrome
type 1. Semin Liver Dis, 2009;29(3):307−14.
Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev
Endocrinol, 2010;6(5):270−7.
Owen CJ, Cheetham TD. Diagnosis and management of polyendocrinopathy
syndromes. Endocrinol Metab Clin North Am, 2009;38(2):419−36.
Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam
Cancer, 2010;9(3):449−57.
48565_ST07_353-368.indd 368 5/1/13 9:32 PM

INDEX
Note: Italicized page locators indicate figures; tables are noted with t
A Adipose tissue endocrinology,

Abdominal scan, 138 essentials of
α blockade, preoperative adiponectin, 340
management, 140 derived efferent signals, 340
ACC. See Adrenocortical endocrine regulation of lipid
carcinoma storage, 339–340
ACCORD, 294 leptin, 340
Acromegaly lipodystrophies, 342
clinical presentation, 19–20 obesity, 341
diagnostic evaluation, 20–21 types of, 339
management, 21–24 Adjuvant mitotane for tumors, 157
medical therapy options, 24t Adjuvant radiotherapy
pathophysiology, 19 for adrenocortical carcinoma, 158
physical exam, 20 for craniopharyngiomas, 35
signs and symptoms of, 20 Adrenal adenoma, 127
testing for, 23t Adrenal androgens, 115
ACTH. See Adrenocorticotropic replacement, 119
hormone Adrenal cortex, 113
ACTH-dependent Cushing’s Adrenalectomy, 96
syndrome, 123, 126 Adrenal essentials
ACTH-independent Cushing’s anatomy, 113
syndrome, 123, 126 function of hormones, 115–116
Actonel, 192t, 198 histology, 113
Acute adrenal crisis, AI, 120 hormone synthesis, 113, 114
Acute coronary syndrome, regulation of adrenal function,
DM in, 300 114–115
Acute illness, NTIS, 70 Adrenal incidentaloma, 136
Acute treatment of adrenal masses, 149
hypercalcemia, 172 benign vs. malignant adrenal
ADA. See American Diabetes masses, 151, 152
Association hormone hypersecretion
ADA Standards of Medical Care in assessment, 149
Diabetes (2013), 298 patients
Adenohypophysis. See Anterior evaluation and management
pituitary with, 151, 152
ADH. See Antidiuretic hormone history and follow-up of, 153
Adipocytes, release in, 339–340 pheochromocytoma, 149–150
Adipokines, 340 primary aldosteronism, 150
Adiponectin, 340 SCS, 150
48565_IDXx_369-396.indd 369 5/1/13 9:35 PM

370 Index
Adrenal insufficiency (AI) Adults
acute adrenal crisis, 120 classification of hypoglycemia in,
with AITD, 362 321–322
causes of, 117 DM screening in, 259
chronic treatment of, 119–120 Adult Treatment Panel III, 299t
critical illness-related ADVANCE, 294
corticosteroid AGHD. See Adult growth hormone
insufficiency, 121 deficiency
diagnosis of, 118–119 AI. See Adrenal insufficiency
HC dosing conditions, 120 AIT. See Amiodarone-induced
patient education and “sick day thyrotoxicosis
management,” 120 AITD. See Autoimmune thyroid
symptoms and finding in, 117t disease
Adrenal medulla, 113 Aldosterone antagonists, 150
Adrenal steroidgenesis, 114 Aldosterone-producing
Adrenal ultrasound, 235 adenoma, 150
Adrenocortical carcinoma (ACC) Alemtuzumab, 76
adjuvant mitotane/radiotherapy Alendronate (Fosamax), 192t, 197
and follow-up, 157–158 Alpha-glucosidase inhibitors, 346t
advanced disease, 158 Aluminum-based antacids, 74
clinical presentation, 155–157 American Diabetes Association
epidemiology and (ADA)
pathophysiology, 155 for DM, 259, 264–266
hormonal evaluation, 156t guidelines for ill patients, 300
initial therapy and surgical lipid management
approach, 157 recommendations, 298t
mitotane effect on endocrine American Thyroid Association (ATA),
function, 158–159 89, 90
pathological evaluation, 157 Aminobisphosphonates, 197
staging for adult, 156t Amiodarone
Adrenocorticotropic hormone hypothyroidism, 75
(ACTH) pharmacology, 75
deficiency, 9, 9t Amiodarone-induced thyrotoxicosis
manifestations of, 8t (AIT)
Adult care, transition from pediatric classification, 75
to, 30 diagnosis, 75
Adult growth hormone deficiency management, 75–76
(AGHD) Amylin mimetic (pramlintide), 346t
causes of, 25 Anaplastic thyroid cancers (ATCs)
clinical presentation, 25–26, 26t clinical presentation, 97
diagnosis, 27 diagnostic evaluation, 98–99
GH replacement therapy in, differences between PDTC
recommendations for, 29t and, 99t
imaging, 29 external radiation therapy,
management, 29 100–101
provocative dynamic tests for, 28t on FNAB, 98t
signs and symptoms of, 26t management, 100
48565_IDXx_369-396.indd 370 5/1/13 9:35 PM

Index 371
pathophysiology, 97 Arteries, blood supply, 113
signs and symptoms of, 98t Artifactual hypoglycemia, 322
surgery, 100 Aspirin therapy, 299
treatment options and Asymptomatic primary
suggestions, 101t hyperparathyroidism,
Anatomical imaging of parathyroidectomy in,
pheochromocytoma, 138 171, 172t
Androgen replacement ATA. See American Thyroid
adrenal, 119 Association
risks of, 213–215, 214t–215t ATCs. See Anaplastic thyroid
Androgens, 223 cancers
Angiotensin-converting enzyme Atherosclerosis, 293, 294
inhibitors (ACEIs), 297, 304 ATP-binding cassette transporter
Angiotensin-II receptor, 304 A1 (ABCA1), 329
Anorgasmia, 220 ATP III LDL-C, goals and cutpoints
Anterior pituitary, 3 for therapy, 335t
cells and hormones, 5–6 Autoantibody, screening of,
control of, 4 362–363
Antiadrenal medical therapy, 128 Autocrine regulation, 204
Antiandrogens, 230, 236–237 Autoimmune adrenalitis, 117
Antibiotic therapy for STI, 317 Autoimmune polyendocrinopathy–
Antibody testing, glycemia candidiasis–ectodermal
in DM, 260 dystrophy syndrome
Anticonvulsant therapy, 290 (APECED), 364
Antidepressants, 290 Autoimmune polyglandular
Antidiabetic medications, syndromes (APS), 361
noninsulin, 262t–263t diseases associated with, 363t
Antidiuretic hormone (ADH) type 1 (APS1)
deficiency, 9t, 10 clinical presentation of,
manifestations of, 8t 364–365
Antihyperglycemic medications, diagnosis of, 365
cardiovascular features in, 361t
considerations of, major and minor
295t–296t manifestations associated
Antiplatelet therapy, 299 with, 364t
Appendiceal carcinoids tumors, 357t management of, 365
APS. See Autoimmune polyglandular type 2 (APS2)
syndromes autoimmune conditions
Aredia, 197 associated with, 362t
Arginine test for GH secretion clinical presentation of,
in adults, 28t 361–362
Arginine vasopressin receptor diagnosis of, 362–363
(AVPR) antagonists, 40 features in, 361t
ARR testing. See Plasma management of, 364
aldosterone/renin ratio Autoimmune thyroid disease (AITD),
testing AI with, 362
Arterial calcium stimulation, 323 Autoimmune thyroiditis, 103
48565_IDXx_369-396.indd 371 5/1/13 9:35 PM

372 Index
Autosomal recessive condition. Paget’s disease of. See Paget’s
See autoimmune disease of bone
polyendocrinopathy– PTH, 165
candidiasis–ectodermal Bone mineral density (BMD)
dystrophy syndrome by DEXA, 189t
(APECED) maintenance of, 242
Boniva, 192t
B Breastfeeding, 306
Barbiturates, 74 Brite cells, 339
Bariatric surgery for obesity, 347 Bronchial carcinoids tumors, 357t
Basal insulin, 264–265 Bronchoscopy, 358
β blockade, preoperative Brown adipose tissue, 339
management, 140 Bulbourethral glands, 202
Behavioral weight loss Burned out Paget’s disease, 195
(BWL), 345 BWL. See Behavioral weight loss
Beige cells, 339
Bexarotene, 77
Bicarbonate, hyperglycemic C
emergencies CAH. See Congenital adrenal
management, 274 hyperplasia
Biguanides, 295t, 346t Calcidiol, 165
Bilateral adrenalectomy, Cushing’s Calcifediol, 165
syndrome, 128 Calcitonin, 96, 167, 192t
Bilateral inferior petrosal sinus Calcitonin receptor (CTR), 167
sampling (IPSS), 127 Calcium balance, maintenance of,
Bilateral primary aldosteronism, 163–164
131, 133, 134 Calcium carbonate, 73
Bile acid–binding resins, 337 Calcium gluconate, 323
Bile acid sequestrants, 74 Calcium infusion, 183
Biliopancreatic diversion/duodenal Calcium intakes, 163, 164t
switch for obesity, 347t Calcium metabolism essentials
Biopsy, 358 calcitonin, 167
Blood glucose control, 287, calcium balance, maintenance
304, 305 of, 163–164
Blood pressure (BP), 136 PTH, 164–165
close monitoring, 141 vitamin D, 165–166
control, 287 Calcium-sensing receptor
Blood supply, 3, 113 (CaSR), 163
Blood tests for male infertility, Carbamazepine, 74
218–219 treatment for central DI, 45
BMD. See Bone mineral density Carcinoembryonic antigen
Body mass index (BMI), 259, (CEA), 96
343–344 Carcinoid syndrome, 359
Bolus insulin, 265 Carcinoid tumors
Bone clinical presentation,
calcitonin, 167 356–357, 357t
metabolism, 190 diagnosis, 357–358
48565_IDXx_369-396.indd 372 5/1/13 9:35 PM

Index 373
general management Central hypothyroidism, causes
approach, 358 of, 63
hepatic-predominant metastatic Cerebral edema, 275
disease treatment, 359 Cervical factors, female infertility,
hormonal hypersecretion 245, 246, 249
treatment symptoms of, CETP. See Cholesterol ester
358–359 transport protein
pathophysiology, 355 CGA. See Chromogranin A
treatment options for control of, Charcot neuroosteoarthropathy
359–360 background, 317–318
Cardiovascular complications, 196 diagnosis, 318
Cardiovascular disease (CVD), 311 management, 318–319
management in prediabetes, 312 pathophysiology, 318
in type 2 diabetes CHD. See Coronary heart disease
antiplatelet therapy, 299 Chemotherapy, 141
CHD screening, 300 Chlorpropamide, treatment for
DM in acute coronary central DI, 45
syndrome, 300 Cholecalciferol, 165
dyslipidemia, 298 Cholesterol, 331
glycemic control, 294 absorption inhibitor, 337
hypertension management, 297 lipoproteins carrying, 325
lipid guidelines, 298, 298t Cholesterol esters (CE), 325
NCEP, 299t Cholesterol ester transport protein
overview, 293 (CETP), 327, 329
pathophysiology, 293, 294 Cholestyramine, 74
risk factors, 300 Chromogranin A (CGA), 357
Cardiovascular health, maintenance Chronic hypercalcemia, symptoms
of, 243 of, 170, 170t
Carney complex, 86 Chronic illness, NTIS, 70
Catecholamine Chronic mucocutaneous candidiasis
neurotransmitters, 221 (CMC), 364
Catecholamine-producing Chronic treatment
tumors, 135 of AI, 119–120
Catecholamines for hypercalcemia, 172
binding to β-adrenergic Chvostek’s sign, 182
receptors, 340 Chylomicrons (CM), 326, 331, 339
function of adrenal hormones, 116 Clofibrate, treatment for central
synthesis, 113 DI, 45
CBT. See Cognitive behavioral Clomiphene
therapy citrate, 248
C-cell hyperplasia (CCH), 93 resistance to, 248
C cells, 49 CMC. See Chronic mucocutaneous
CEA. See Carcinoembryonic antigen candidiasis
Central diabetes insipidus, 43 CNS stimulants/appetite
etiologies of, 43t suppressants, 346t
interpretation of test results, 44 Cognitive behavioral therapy (CBT),
treatment, 45 for obesity, 345
48565_IDXx_369-396.indd 373 5/1/13 9:35 PM

374 Index
Colonoscopy, 358 Cushing’s syndrome, 95
Combined oral contraceptives, 230 causes, management of,
Computed tomography (CT) 127–128
scans, 156 clinical features, 123
abdominal, 138 diagnostic strategy, 124–125
adrenal, 126, 133 differential diagnosis, 126–127
anatomical imaging, 138 etiologies, 123
of chest, 94 standard diagnostic tests for,
of neck, 57, 99 125–126
for NET liver metastases, 358 Cyproterone acetate (CPA), 236
parathyroid, 177 Cytokines, 69
Congenital adrenal hyperplasia Cytotoxic chemotherapy, 359
(CAH)
clinical presentation, 144–145 D
laboratory testing and Debulking surgery, 141
diagnostic evaluation, Deficient hormones, manifestations
145, 145t of, 8t
management, 145–147 Demeclocycline, managing SIADH, 39
pathophysiology, 143–144, 143 Denosumab (Prolia), 192t
types of, 144 DEXA. See Dual-energy X-ray
Congenital hypothyroidism, 63 absorptiometry
Conivaptan, 40 Dexamethasone, 118
Connecting peptide DI. See Diabetes insipidus
(C-peptide), 253 Diabetes
glycemia in DM, 260 hypoglycemia in
Coronary heart disease (CHD), acute treatment of, 279
screening, 300 classification of, 277
Correction-dose insulin, 308–309 etiologies, 277–278
Corticotrophin-releasing hormone prevention of, 279
(CRH) testing, 127 preexisting. See Preexisting
Corticotrophs, 6 diabetes
Cosmetic therapies for in pregnancy
hirsutism, 237 classification, 303
Cosyntropin stimulation test diagnosis of GDM, 303–304
(CST), 118 management of, 304–305
Counter-regulatory hormones, 255 postnatal care, 305–306
Cowden’s syndrome, 86 preconception care, 304
CPA. See Cyproterone acetate prenatal considerations for, 305
C-peptide. See Connecting peptide risk factors for GDM, 303
Craniopharyngiomas type 1
background, 34 glycemic management in,
presentation and TDD of, 264
evaluation, 35 type 2
CST. See Cosyntropin stimulation cardiovascular disease in.
test See Cardiovascular disease,
Cushing’s disease, 126–128 in type 2 diabetes
48565_IDXx_369-396.indd 374 5/1/13 9:35 PM

Index 375
glycemic management in, management, 273–274, 274t
265–267 complications of, 274–275
Diabetes insipidus (DI) pathophysiology, 271
clinical manifestations, 43 resolution of, 275
definition, 43 transition from IV insulin
diagnosis, 44 infusion, 275
etiologies of, 43t typical precipitating factors, 272
treatment, 45 Diabetic nephropathy
types of, 43 clinical presentation, 286
Diabetes mellitus (DM), 255 diagnostic evaluation, 286
in acute coronary syndrome, 300 epidemiology, 285
ADA for, 259 management, 287
background, 257 pathophysiology, 285
drug-induced, 258 risk factors, 285
gestational, 259 stages of, 286t
glycemia in, 260 Diabetic retinopathy
pharmaceutical options clinical presentation, 281
for, 261t diagnostic evaluation, 281
type 1 management, 282
glycemic management in, nonproliferative and
264–265 proliferative, 281
pathophysiology and clinical pathophysiology, 281
presentation of, 257 retinal findings, 282t
type 2 Diet
glycemic management in, for metabolic syndrome, 350
265–266 for obesity, 345
pathophysiology and clinical Dietary fiber, 346
presentation of, 257–258 Differentiated thyroid cancer
recommendations for (DTC), 85
delay, 312 features indicating risk of
Diabetes prevention recurrence of, 90t
associated conditions, 311 initial treatment of, 89–90
clinical presentation, 311 Diminished ovarian reserve
diagnostic evaluation, 311t (DOR), 249
pathophysiology, 311 Discontinue oral antidiabetic
Diabetic cardiomyopathy, 294 agents, 307
Diabetic foot ulceration and Distal sensory neuropathy, 316
infection Distal symmetrical neuropathy, 315
background, 315 Distal symmetric polyneuropathy
long-term care, 317 (DSPN)
management of, 316 clinical presentation, 289
osteomyelitis, 317 management of, 290
pathophysiology, 315–316 pathophysiology, 289
Diabetic ketoacidosis (DKA), 257 screening and monitoring of,
diagnosis, 272t 289–290
evaluation, 272, 272t DKA. See Diabetic ketoacidosis
laboratory abnormalities, 273 DM. See Diabetes mellitus
48565_IDXx_369-396.indd 375 5/1/13 9:35 PM

376 Index
Dopamine, 77 Endoscopic ultrasound, 358
Dopamine agonists Energy expenditure,
for acromegaly, 22, 24t calculating, 343
for nonfunctioning Energy intake, calculating, 343
macroadenomas, 33 Enteral feeding, 309
for ovulation, 16 Enzymes in steroid
treatment for metabolism, 340
hyperprolactinemia, 15 Epididymis, 202
DOR. See Diminished ovarian reserve Erectile dysfunction, 220
Doxazosin, 140 Ergocalciferol, 165
DPP-4 inhibitors, 296t Estradiol, 222
Drospirenone, 230, 237 Estrogen, 221, 222
Drug-induced DM, 258 HRT, 192t
Drugs affecting thyroid function skeletal protection, 178
absorption, 73–74 symptoms of deficiency, 240
causing central Euvolemia, 38
hypothyroidism, 77 Everolimus, mTOR inhibitor, 360
directly, 75–77 Evista, 192t
hormone metabolism, 74 Exercise
DSPN. See Distal symmetric for metabolic syndrome, 350
polyneuropathy for obesity, 345
DTC. See Differentiated thyroid Exocrine function, 201
cancer Exogenous fat. See Transport
Dual-energy X-ray absorptiometry of dietary fat
(DEXA), BMD by, 189t External beam radiation
Dysbetalipoproteinemia, 334 therapy (EBRT), 85,
Dyslipidemia, 298 96, 141
Extracellular fluid (ECF) volume,
E classification of
Early postnatal period, 202 hypoosmolality by, 38
EBRT. See External beam radiation Ezetimibe, 337
therapy
Ectopic ACTH syndrome, 128 F
Eflornithine cream, hirsutism, 237 Factitious hypoglycemia, 322
Ejaculatory duct, 202 Factitious thyrotoxicosis, 53t
Ejaculatory dysfunction, 217, 219 Familial combined
11-hydroxylase deficiency (11OHD), hyperlipidemia, 333
144, 147 Familial hyperaldosteronism
Endocrine type I, 131
function, 201 type II, 131
in MEN-1 and MEN-2, 366t–367t Familial hypercholesterolemia, 333
pancreas, 253–255 Familial hyperchylomicronemia, 333
Endocrinopathies, 217 Familial hypertriglyceridemia, 334
therapies for, 219–220 Familial medullary thyroid cancer
Endogenous fat. See Transport (FMTC), 93
of hepatic fat Family planning, 243
Endometrium, menstrual cycle, 224t Fasting hypoglycemia, 321
48565_IDXx_369-396.indd 376 5/1/13 9:35 PM

Index 377
Female infertility. See also Male pathological features, 86–87
infertility persistent/recurrent disease
causes of, 245 management, 91–92
clinical presentation, 246 prognosis, 87–88
diagnostic evaluation, 246–247 risk factors, 85–86
management, 247–249 TNM classification, 88
pathophysiology, 245 Forteo, 192t
preconception counseling, 247 Fosamax, 192t, 197
treatment of, 248 Fracture, risk factors for, 191t
Female reproduction essentials Frederickson’s classification of
development in embryo, 221 lipoprotein disorders, 333t
menopause, 224–226 type I, 333
menstrual cycle hormones, type II, 333
221–224, 223t–224t, type III, 334
225 –226 type IV, 334
puberty, 221 type V, 334
Ferriman Gallwey hirsutism scoring Free cholesterol (FC), 325
system, 234, 235 Free fatty acids, 339
Fibrates. See Fibric acid derivatives Free thyroxine index (FTI), 52t
Fibric acid derivatives, 337 FTC. See Follicular thyroid
Fibroblast growth factor (FGF), 5 carcinoma
Finasteride, 237 FTI. See Free thyroxine index
Fine needle aspiration (FNA), Fuel homeostasis, insulin
81, 151 roles in, 255
5-Hydroxyindole acetic acid Fuel metabolism, essentials,
(5-HIAA), 357 253–255
Fludrocortisone suppression Functional imaging,
testing, 133 pheochromocytoma, 138
Fluid restriction, managing
SIADH, 39 G
Flutamide, 237 Gastric banding procedure for
FMTC. See Familial medullary obesity, 347t
thyroid cancer Gastric bypass procedure for
FNA. See Fine needle aspiration obesity, 347t
Follicles, 49 Gastric carcinoids tumors, 357t
Follicular stimulating hormone Gastrinoma, 359
(FSH), 222 GDM. See Gestational diabetes
deficiency, 9t, 10 mellitus
manifestations of, 8t Genetic testing,
Follicular thyroid carcinoma pheochromocytoma,
(FTC), 85 138, 139
clinical presentation and Gestation, 202
diagnosis, 87 Gestational diabetes mellitus
definition, 85 (GDM), 259
epidemiology, 85 diagnosis of, 303–304
long-term management, 90–91 risk factors for, 303
pathogenesis, 86 women with, 305–306
48565_IDXx_369-396.indd 377 5/1/13 9:35 PM

378 Index
GH receptor antagonist, 22, 23, 24t Growth hormone–releasing
Glucagon hormone (GHRH), 28t
actions of, 254 Gynecomastia
secretion, hypoglycemia clinical presentation, 206
lack, 278 diagnostic evaluation, 206
test for GH secretion in history and physical examination
adults, 28t in, 206t
Glucagon-like peptide 1 (GLP-1) management, 207
analogs, 346t pathogenesis of, 205t
receptor agonists, 296t
Glucagonoma, 359 H
Glucocorticoid-remediable HAAF. See Hypoglycemia-associated
aldosteronism (GRA), 131, autonomic failure
133, 134 HDDST. See High-dose
Glucocorticoids, 77, 114, 115, dexamethasone test
237, 309 HDL. See High-density lipoprotein
equivalency chart for, 120t Hemoglobin A1c, glycemia in
replacement of AI, 119 DM, 260
Glucose, 307, 339 Hepatic cholesterol pool,
Glycemia in DM, diagnosis and determination of, 328
management of, 260 Hepatic-predominant metastatic
Glycemic control disease, 359
in type 1 diabetes, 264–265 Heterogeneous syndrome, 227
in type 2 diabetes, 265–266, 294 HHS. See Hyperosmolar
Glycemic issues in hospitalized hyperglycemic state
patients High-density lipoprotein (HDL),
in ICU, 309–310 325, 331, 332
outside ICU, 307–309 High-dose dexamethasone test
Goiter effects, lithium, 76 (HDDST), 126
Gonadotrophs, 6 Highly active antiretroviral therapy
Gonadotropin, 249 (HAART), 342
Gonadotropin-releasing hormone High-risk patients, benefit from
(GnRH), 221, 237 metformin, 312
regulation of, 203 Hirsutism
GRA. See Glucocorticoid-remediable clinical presentation, 233–235
aldosteronism diagnostic evaluation, 235
Granulomatous disease, 172 management, 236–238
Graves’ disease, 53t pathophysiology, 233
Growth hormone (GH) in PCOS, 230
manifestations of, 8t HMG-CoA reductase inhibitors,
measurement of, 20–21 335–337, 336t
replacement therapy Hormonal assessment for pituitary
in AGHD, 29t hypofunction, 9t
Growth hormone deficiency (GHD), Hormone hypersecretion
25–26, 26t assessment for, 149
in adults. See Adult growth biochemical evaluation for, 153
hormone deficiency treatment symptoms of, 358–359
48565_IDXx_369-396.indd 378 5/1/13 9:35 PM

Index 379
Hormone replacement, 9–10 Hyperosmolar hyperglycemic
thyroid, 71, 73–77 state (HHS)
Hormone replacement therapy diagnosis, 272t
(HRT), 242 evaluation, 272, 272t
for females, 10 laboratory abnormalities, 273
Hormones management, 273–274, 274t
counter-regulatory, 255 complications of, 274–275
of menstrual cycle, 221–224, pathophysiology, 271
223t–224t resolution of, 275
secretion, adrenal transition from IV insulin
incidentalomas, 153 infusion, 275
Hospitalized patients outside, ICU, typical precipitating
307–309 factors, 272
HPA axis. See Hypothalamic- Hyperparathyroidism, 94
pituitary-adrenal axis clinical presentation, 176
HPT axis. See Hypothalamic- diagnostic evaluation,
pituitary-thyroid (HPT) axis 176–178
H2 receptor antagonists, 73 management, 178
Hungry bone syndrome, 181 pathophysiology, 175
Hurthle cell cancer, 87 Hyperprolactinemia, 220
Hydrocortisone (HC), 146 pathophysiology, 13
dosing conditions of AI, 120 symptoms due to, 13t, 14
IV, 67 Hypertension, 131, 141
Hyperandrogenism, 227–228 management, 297
OCPs reducing, 236 monitor for, 312
Hypercalcemia Hyperthyroidism
clinical presentation, 170 clinical features of, 54
crisis, 178 in pregnancy
diagnostic evaluation, 170–172 clinical presentation, 106
incidence, 169 diagnosis, 106
management, 172 etiology and
pathophysiology, 169–170 pathophysiology, 105
Hyperchloremic acidosis, 275 laboratory evaluation, 106
Hyperfunction, screening for, 32 management, 107
Hyperglycemia for patients in ICU, subclinical, 60–61
309–310 Hypertonic saline, managing
Hyperglycemic emergencies SIADH, 39
diagnosis, 272t Hypertrichosis, 233
evaluation, 272, 272t Hypervolemia, 38
laboratory abnormalities, 273 Hypocalcemia
management, 273–274, 274t clinical presentation, 182
complications of, 274–275 diagnostic evaluation scheme
pathophysiology, 271 for, 183, 183
resolution of, 275 laboratory testing, 182–183
transition from IV insulin management, 183, 184
infusion, 275 pathophysiology, 181
typical precipitating factors, 272 specific causes, 181
48565_IDXx_369-396.indd 379 5/1/13 9:35 PM

380 Index
Hypoglycemia, 253, 274 Hypothalamic-pituitary-testicular
development of, 271 axis, 203
disorders in male, 209, 209
classification in adults, Hypothalamic-pituitary-thyroid
321–322 (HPT) axis, 69, 70
defined, 321 Hypothalamopituitary disease, 219
diagnosis, 322 Hypothyroidism, 75, 76
imaging, 323 background, 63–64
neurogenic vs. neuroglycopenic clinical presentation of, 64t
symptoms, 321t diagnosis, 64
treatment, 323 myxedema coma, 66–67
lack of, 278 in pregnancy
in patients with diabetes clinical presentation, 103
acute treatment of, 279 diagnosis, 104
classification of, 277 etiology and
definition, 277 pathophysiology, 103
etiologies of, 277 laboratory evaluation, 104
prevention of, 279 management, 104–105
symptoms of, 277 screening for, 103
treatment of, 268, 300 subclinical, 66
Hypoglycemia-associated treatment, 65–66
autonomic failure (HAAF), Hypovolemia, 38
risk factors for, 278
Hypogonadism, prevalence of, I
211–212 Ibandronate (Boniva), 192t
Hypokalemia, 131, 274 ICU
Hyponatremia treatment guidelines hospitalized patients outside,
for SIADH, 41 307–309
Hypoosmolality patients in, 309–310
classification by ECF Idiopathic hirsutism, 233
volume, 38 Idiopathic hyperandrogenemia, 233
clinical presentation, 37 IDL. See Intermediate density
diagnostic evaluation, 38 lipoprotein
pathophysiology, 37 Imatinib, 74
Hypophyseal portal vessels, 3 Immobilization, 172
Hypopituitarism Impaired Fasting Glucose (IFG), 311
background, 7 Impaired Glucose Tolerance
causes of, 7 (IGT), 311
clinical presentation, 7–8 IMRT. See Intensity-modulated
diagnostic evaluation, 9 radiation therapy
hormone replacement, 9–10 Inactivating enzyme. See Type 3
pathophysiology, 7 deiodinase (D3) catalyses
screening for, 32 Infection, diabetic foot, 315–317
surgery for, 33 Infertility, 146
Hypotension, 141 female. See Female infertility
Hypothalamic-pituitary-adrenal male. See Male infertility
(HPA) axis, 115 in PCOS, 231
48565_IDXx_369-396.indd 380 5/1/13 9:35 PM

Index 381
Insulin Intraoperative hypertensive crisis,
actions of, 253 140–141
defects, 257–258 Intrauterine insemination (IUI), 249
basal, 264, 265 Intravenous (IV) fluids,
bolus, 265 hyperglycemic emergencies
cardiovascular considerations management, 273–274
of, 296t Intravenous (IV) insulin infusion,
excess, 277 transition from, 275
formulations, 261t Intravenous (IV) insulin protocols
hyperglycemic emergencies for patients in ICU,
initial dose of, 309 Intravenous (IV) saline infusion
measurements, 253 testing, 132
mixtures of, 308t In vitro fertilization (IVF), 249
preparations of, 308t Iodine, 53t
protocol for initiating, 308 deficiency, 63
roles in fuel homeostasis, 255 Islets of Langerhans, 253
TDD of, 275 Isotonic saline, managing
use in pregnancy, 305 SIADH, 39
Insulin-like growth factor-1 (IGF-1) ITT. See Insulin tolerance test
testing, 20 IUI. See Intrauterine insemination
Insulin-lowering medications, 237 IVF. See In vitro fertilization
Insulinoma, 358–359
Insulin pump. See SQ insulin
Insulin resistance, pathophysiology K
of, 293 Ketoacidosis
Insulin-responsive glucose development of, 271
transporter (Glut4), 339 diabetic. See Diabetic
Insulin therapy, 305 ketoacidosis
multiple-dose, 264 Kidney
Insulin tolerance test (ITT) calcitonin, 167
for AGHD, 27, 28t PTH, 165
for diagnosis of AI, 118
Intensity-modulated radiation L
therapy (IMRT), 100 Lactotrophs, 5
Interferon-α, 76–77, 359 LADA. See Latent autoimmune
Interleukin-2, 77 diabetes of adults
Intermediate/long-acting Lanthanum carbonate, 73
insulin, 308t Laser photocoagulation, 282
Intermediate density lipoprotein Latent autoimmune diabetes
(IDL), 327, 331, 332 of adults (LADA), 258
Interpretation of test for diagnosis LCAH. See Lipoid CAH
of DI, 44 LDL. See Low-density lipoprotein
Interstitial compartment, LDLR. See Low-density lipoprotein
testes, 201 receptor
Intestinal fat absorption Leptin, 340
inhibitor, 346t Leydig cells, 201
48565_IDXx_369-396.indd 381 5/1/13 9:35 PM

382 Index
Lifestyle modifications, treatment M
for obesity, 345 Macroadenomas, 16, 19
Lipid nonfunctioning, 33
control, 287 Magnetic resonance imaging
disorders (MRI) scan
components, 331 anatomical imaging, 138
pharmacologic therapies, 335, craniopharyngiomas, 35
336t, 337–338 for NET liver metastases, 358
TC and LDL cholesterol, pituitary, 127
classification, 331–335 tumor size monitored, 16
essentials, 325–329 Malabsorption syndromes,
guidelines, 298, 298t evaluation of, 186
Lipid-poor adrenal tumors, 151 Male factors, causes of infertility,
Lipodystrophies, 342 245, 247, 249
Lipoid CAH (LCAH), 144, 147 Male infertility. See also Female
Lipomastia, 205 infertility
Lipoprotein clinical presentation, 218
disorders, Frederickson’s definition of, 217
classification of, diagnostic evaluation,
333–334, 333t 218–219
lipid profile reflects, 325 diagnostic imaging, 219
structure and function, pathophysiology of, 217
325t–326t treatment of, 219–220
Lipoprotein lipase (LPL), Male reproduction essentials
326, 339 neuroendocrine regulation,
Lithium 203–204
effects, 76 reproductive outflow tract, 202
mechanisms, 76 sexual differentiation, 202–203
Liver metastases, NETs, 358 testes, 201
Long-term care, diabetic Males
foot ulceration and hypothalamic-pituitary-
infection, 317 testicular axis in,
Low-density lipoprotein (LDL), 325, 209, 209
327–328, 331 testosterone replacement for, 10
Low-density lipoprotein (LDL) Mammalian target of rapamycin
cholesterol (mTOR) inhibitor
ATP III, goals and cutpoints for everolimus, 360
therapy, 335t Mammosomatotrophs, 6
classification of, 331–335, 332t Maturity-onset diabetes of the
Low-density lipoprotein receptor young (MODY), 258
(LDLR), 327 clinical presentation of, 267,
LPL. See Lipoprotein lipase 269t–270t
Luteinizing hormone (LH), 222 diagnostic evaluation, 267
deficiency, 9t, 10 management, 268
manifestations of, 8t pathophysiology of, 267,
Lymphoma, 172 268t–269t
48565_IDXx_369-396.indd 382 5/1/13 9:35 PM

Index 383
Medical comorbidities, Mitotane effect on endocrine
management for function, 158–159
acromegaly, 23 MNT. See Medical nutrition therapy
Medical nutrition therapy MODY. See Maturity-onset diabetes
(MNT), 312 of the young
Medical therapy for acromegaly, 22 Molecularly targeted therapy, 360
Medullary thyroid cancer (MTC) Monitoring serum in hospitalized
clinical features, 95 patients with SIADH,
clinical presentation, 94 41–42
diagnosis, 94 Motor, distal symmetrical
epidemiology, 93 neuropathy, 315
features of, 93t MTC. See Medullary thyroid cancer
follow-up, 96 Multiple-dose insulin therapy, 264
pathophysiology, 93 Multiple endocrine neoplasias-1
staging, 95 (MEN-1)
therapy, 95–96 clinical presentation of, 365, 366
Meiosis arrests, 221 diagnosis of, 367
MEN. See Multiple endocrine endocrine associations in, 366t
neoplasias Multiple endocrine neoplasias-2
Menopause, 224–226 (MEN-2)
Menstrual abnormalities, 228 clinical presentation of, 366, 367
Menstrual cycle hormones, diagnosis of, 367–368
221–224, 223t–224t, endocrine associations in, 367t
225 –226 Multiple endocrine neoplasias
Menstrual irregularity in PCOS, 231 (MEN)
Metabolic syndrome management of, 368
clinical presentation, 350 Myxedema coma, 66
component of, 341 diagnosis, 67
diagnosis, 350 management, 67
features of, 349t
incidence in randomized control N
trials, 351t Nascent HDL (nHDL), 329
international criteria for, 350t National Cholesterol Education
laboratory testing, 350 Program (NCEP) Adult
prevalence of, 349 Treatment Panel III,
treatment, 350–351 299t, 350
Metanephrine (MN) testing, Neoplastic cell, 196
interpretation of, 137 Nephrogenic diabetes insipidus, 43
Metformin, 230, 237, 305, 312, 346t etiologies of, 43t
Metyrosine, 140 interpretation of test results, 44
Miacalcin, 198 treatment, 45
Microadenomas, 16 Nephropathy, diabetic. See Diabetic
nonfunctioning, 32–33 nephropathy
Mineralocorticoid, 114, 116 NETs. See Neuroendocrine tumors
antagonist, 147 Neuroendocrine regulation,
replacement of AI, 119 203–204
48565_IDXx_369-396.indd 383 5/1/13 9:35 PM

384 Index
Neuroendocrine tumors (NETs), 355 Normocalcemic
classification of, 355t hyperparathyroidism, 176
liver metastases, 358 NSAIDs. See Nonsteroidal anti-
pancreatic. See Pancreatic inflammatory drugs
neuroendocrine tumors NSTEMI. See Non-ST elevation
Neurohypophysis. See Posterior myocardial infarction
pituitary NTIS. See Nonthyroidal illness
Neurologic symptoms, 196 syndrome
Neuropathy
CN complication of, 318 O
distal sensory, 316 Obesity
distal symmetrical, 315 adipose tissue endocrinology
Niacin. See Nicotinic acid in, 341
Nicotinic acid, 337–338 clinical definitions, 341
Nonesterified fatty acids, 340 male infertility, 220
Nonfunctioning macroadenoma management
management of, 33–34 clinical presentation,
signs or symptoms of, 33 344–345, 344t
Nonfunctioning microadenoma diagnosis, 343–344
management of, 33 pathophysiology, 343
presentation and natural treatment, 345–347
history, 32 pharmacotherapy for, 346t
Nonfunctioning pituitary adenomas rapidly increasing prevalence, 341
management of, 33–34 roles of, 255
presentation and natural history surgical treatment of, 347, 347t
of, 32–33 OCPs. See Oral contraceptive pills
Non-high-density lipoprotein, 332 ODS. See Osmotic demyelination
Noninsulin antidiabetic syndrome
medications, 262t–263t Oral contraceptive pills (OCPs), 242
Noninsulinoma pancreatogenous reducing hyperandrogenism, 236
hypoglycemia syndrome Oral contraceptives, 236
(NIPHS), 323 Oral salt loading, 132
Nonislet cell tumors, 321 Osmoreceptors, 3
Nonproliferative diabetic Osmotic demyelination syndrome
retinopathy, 281 (ODS), 41
Non-ST elevation myocardial Osteitis deformans. See Paget’s
infarction (NSTEMI), 300 disease of bone
Nonsteroidal anti-inflammatory Osteomyelitis, 317
drugs (NSAIDs), 45 Osteoporosis
Nonthyroidal illness syndrome bone metabolism, 190
(NTIS) definition, 189–190
background, 69 epidemiology, 189
diagnostic evaluation, 70–71 medical therapy for use in, 192t
management, 71 risk factors for, 191, 191t
pathophysiology, 69–70 screening, 191
treatment of, 71 secondary causes of, 190t
TSH levels, 70–71 treatment, 191–192
48565_IDXx_369-396.indd 384 5/1/13 9:35 PM

Index 385
Osteoporotic fractures, 189 definition, 85
Ovarian hormones, menstrual epidemiology, 85
cycle, 223 long-term management,
Ovarian ultrasound, 145 90–91
Ovary, menstrual cycle, 223 pathogenesis, 86
Overnight metyrapone test, 118 pathological features, 86–87
Ovulation induction, 248 persistent/recurrent disease
Ovulatory dysfunction, 245, management, 91–92
246, 248 prognosis, 87–88
Oxytocin, 5 risk factors, 85–86
TNM classification, 88
P Paracrine regulation, 204
PAD. See Peripheral arterial disease Parathyroidectomy, 96
Paget’s disease of bone in asymptomatic primary
assessment of therapeutic hyperparathyroidism,
response, 197–198 171, 172t
clinical presentation, 195–196 Parathyroid gland anatomy, 164
diagnostic evaluation, 196 Parathyroid hormone (PTH),
etiology, 195 164–165, 171
management, 197–198 Parathyroid hormone 1-receptor
pathophysiology, 195 (PTH-1R), 164
physical examination, 196 Parenteral feeding, 309
Painful subacute thyroiditis, 53t Patient education of AI, 120
Painless thyroiditis, 76 PCOS. See Polycystic ovary
Pamidronate (Aredia), 197 syndrome
Pancreas PDTC. See Poorly differentiated
endocrine, 253–255 thyroid cancer
nonimmune causes of, 258 Pelvic ultrasound, 235, 241
Pancreatic islets, 253 Perimenopause, 224
Pancreatic neuroendocrine Peripheral arterial disease
tumors (NETs) (PAD), 315
clinical presentation, Peritoneal factor, female infertility,
356–357, 356t 245, 247, 249
diagnosis, 357–358 P450-oxidoreductase deficiency
general management (PORD), 144, 147
approach, 358 PG. See Plasma glucose
hepatic-predominant metastatic Pharmacological therapy,
disease treatment, 359 57–58, 192
hormonal hypersecretion hirsutism, 236
treatment symptoms of, for lipid disorders, 335–338
358–359 treatment goals with, 312
pathophysiology of, 355 Pharmacotherapy
treatment of, 356t, 359–360 for obesity, 346t
Panretinal photocoagulation, 282 for Paget’s disease of bone,
Papillary thyroid carcinoma (PTC) 197–198
clinical presentation and Phenoxybenzamine, 140
diagnosis, 87 Phenytoin, 74
48565_IDXx_369-396.indd 385 5/1/13 9:35 PM

386 Index
Pheochromocytoma, 94 Plasma lipoproteins, 325
adrenal incidentalomas, determined by
149–150 reverse cholesterol transport,
clinical presentation, 136 329, 329
diagnostic evaluation transport of dietary fat,
anatomical imaging, 138 326, 327
functional imaging, 138 transport of hepatic fat,
genetic testing, 138, 139 327–328, 328
screening test strategy, 137 Plasma methoxytyramine, 137
follow-up, 141 Plateau response, 198
malignant POCT glucose. See Point-of-care
pheochromocytomas, 141 testing glucose
management POI. See Primary ovarian
operative, 140–141 insufficiency
postoperative, 141 Point-of-care testing (POCT)
preoperative, 140 glucose, 307
pathophysiology, 135 glycemia in DM, 260
Phosphate, hyperglycemic Polycystic ovaries, characteristics
emergencies of, 229
management, 274 Polycystic ovary syndrome
PHPT. See Primary (PCOS)
hyperparathyroidism background, 227
Physical activity factor, energy definitions, 227
expenditure, 343 hirsutism in, 230
PI. See Pituitary incidentalomas imaging, 229
Pituitary essentials infertility in, 231
basic facts, 3 investigations, 228–229
control of, 3–5, 4 management of, 229–230
function, 5–6 menstrual irregularity in, 231
MRI, 127 signs, 228
Pituitary hormones, menstrual symptoms, 227–228
cycle, 223 Poorly differentiated thyroid
Pituitary hypofunction, hormonal cancer (PDTC)
assessment for, 9t clinical presentation, 97
Pituitary incidentalomas (PI) diagnostic evaluation, 98–99
definition of, 31 differences between ATC
differential diagnosis, 31 and, 99t
evaluation, 31–32 external radiation therapy,
Plasma aldosterone/renin ratio management, 100
(ARR) testing, pathophysiology, 97
131–132 surgery, 100
Plasma calcium, 163 PORD. See P450-oxidoreductase
Plasma catecholamines, 137 deficiency
Plasma chromogranin A, 137 Positron emission tomography
Plasma glucose (PG), glycemia (PET) scanning,
in DM, 260 pheochromocytoma, 138
48565_IDXx_369-396.indd 386 5/1/13 9:35 PM

Index 387
Posterior pituitary, 3 Primary hyperparathyroidism
control of, 4 (PHPT), 94, 169, 172
hormones, 5 clinical presentation, 176
Postnatal care, 305–306 pathophysiology, 175
Postpartum thyroiditis symptomatic, 176
clinical presentation, 109 treatment in, 178
diagnostic evaluation, 109 in young adults/children, 177
etiology and Primary hypothyroidism,
pathophysiology, 109 causes of, 63
in pregnancy, 109 Primary medical therapy for
treatment and monitoring, 110 acromegaly, 21
Postprandial hypoglycemia. See Primary ovarian insufficiency (POI)
Reactive hypoglycemia clinical presentation, 239–240
PPI. See Proton pump inhibitors definition, 239
Pramlintide. See Amylin mimetic diagnostic evaluation,
Preconception care of women with 240–241
diabetes, 304 management, 241–243
Prediabetes pathophysiology, 239
associated conditions, 311 Primary polydipsia, 43, 44
clinical presentation, 311 diagnosis, 44
diagnostic evaluation, 311t treatment, 45
management of CVD in, 312 Primary testicular defect
pathophysiology, 311 in sperm production, 217
treatment goals with therapies for, 219
pharmacologic Progesterone, 222
therapy, 312 Progestins, 236
Preexisting diabetes, women with, Prolactin (PRL)
304, 306 inhibition of, 13
Pregnancy, 16 levels during pregnancy, 16
diabetes in. See Diabetes, Prolactinemia
in pregnancy clinical presentation, 13–14
thyroid disorders in. See Thyroid diagnostic evaluation, 14
disorders in pregnancy follow-up, 16
21OHD, 144 pathophysiology, 13
Premixed insulin for treatment, 15
DM, 261t Prolactinomas
Pressure sores on heel, 315 diagnostic evaluation, 14
Primary AI, 117, 118 pathophysiology, 13
Primary aldosteronism, 150 treatment, 15
ARR testing, 131–132 Prolia, 192t
clinical presentation, 131 Proliferative diabetic
confirmatory testing options, retinopathy, 281
132–133 Prostate glands, 202
management, 134 Proton pump inhibitors (PPI), 73
subtype differentiation, 133 Provocative tests
subtypes of, 131t, 132t for diagnosis of DI, 44
unilateral vs. bilateral, 133 for GH secretion in adults, 28t
48565_IDXx_369-396.indd 387 5/1/13 9:35 PM

388 Index
Pseudogynecomastia, 205 Sellar imaging, male infertility, 219
Psuedo-Cushing’s syndrome, 124 Seminal fluid analysis for male
PTC. See Papillary thyroid carcinoma infertility, 218–219
Puberty, 203, 221 Seminal vesicle, 202
Seminiferous tubules, 201
R Sensory, distal symmetrical
Radiation therapy (RT) neuropathy, 315
for acromegaly, 23 Sequential gene testing, clinical
Cushing’s syndrome, 128 algorithm for, 138, 139
external, 100–101 SERM-Raloxifene (Evista), 192t
for prolactinemia, 15 Sertoli cells, 201
Radioactive iodine therapy, 58–59 Serum calcium, 182
Raloxifene, 74 Serum chromogranin A (CGA), 357
Rapid-acting insulin for DM, 261t, 265 Serum 25-hydroxyvitamin D, 186
Rapid/short-acting insulin, 308t Serum osmolality and sodium, for
Reactive hypoglycemia, 322 diagnosis of DI, 44
Rearranged during transfection Serum phosphorous, 177
(RET), 93 Sevelamer hydrochloride, 73
Reclast, 192t, 197 17-hydroxylase/17,20-lyase
Rectal carcinoids tumors, 357t deficiency (17OHD),
Regulation of adrenal function, 144, 147
114, 115 Sex hormone–binding globulin
Renal fluid excretion, increased, 40 (SHBG), variations in,
Reproductive outflow tract, 202 212, 212t
Resting metabolic rate (RMR), 343 Sexual differentiation, 202–203
RET. See Rearranged during Sexual disorders, 217
transfection therapies for, 220
Retinopathy, diabetic. See Diabetic Short-acting insulin for DM, 261t
retinopathy “Sick day management” of AI, 120
Reverse cholesterol transport, Silent subacute thyroiditis, 53t
329, 329 Skeletal X-rays, 196
Rifampicin, 74 Sleeve gastrectomy procedure
Risedronate (Actonel), 192t, 198 for obesity, 347t
RMR. See Resting metabolic rate Small intestine carcinoids
tumors, 357t
Soft tissue infection (STI), 316–317
S Somatostatin
Salmon calcitonin (Miacalcin), 198 analogues, 24t, 359
Screening guidelines for men for acromegaly, 22
and women, 191, 191t for nonfunctioning
Scrotal ultrasound, 219 macroadenomas, 34
SCS. See Subclinical Cushing’s receptor scintigraphy, 358
syndrome Somatotrophs, 5
Secondary adrenal insufficiency Sperm defect transport, 217
(AI), 117, 119 therapies for, 219
Secondary hyperparathyroidism, Spironolactone, 147, 236
175, 176 Sporadic tumors, 141
48565_IDXx_369-396.indd 388 5/1/13 9:35 PM

Index 389
SQ insulin hypertonic saline, 39
therapy, 264–265 isotonic saline, 39
transitioning from IV insulin to, tolvaptan, 40–41
275, 310 urea, 40
Standards of Medical Care in Systemic arterial blood supply, 3
Diabetes, 300 Systemic chemotherapy, 159
ST elevation myocardial infarction
(STEMI), 300 T
Steroid biosynthesis pathway, 143 TBG. See Thyroid hormone binding
Steroidgenesis, adrenal, 114 globulin
Steroid metabolism, enzymes TC. See Total cholesterol
involved in, 340 TDD. See Total daily dose
STI. See Soft tissue infection Technetium bone scan, 196
Struma ovarii, 53t Teriperatide (Forteo), 192t
Subclinical Cushing’s syndrome Tertiary hyperparathyroidism,
(SCS), 150 175, 176
Subclinical hyperthyroidism, Testes, 201
60–61 Testicular descent, 202
Subclinical hypothyroidism, 66 Testing
Sucralfate, 74 for acromegaly, 23t
Sulfonylureas, 295t antibody, 260
Sunitinib, 360 CRH, 127
Superovulation, 249 end-organ, 363t
Surgery fludrocortisone suppression, 133
for acromegaly, 21 genetic, 138
ATC, 100 glycemic, 229
for DTC, 89 interpretation of MN, 137
gynecomastia, 207 plasma ARR, 131–132
for hyperthyroidism, 59 Testosterone, 212
MTC, 95 deficiency in men
for nonfunctioning androgen replacement, risks
macroadenomas, 33 of, 213, 214t–215t, 215
persistent/recurrent assays/tests, 212
disease, 91 chronic conditions with
transsphenoidal, 15 hypogonadism prevalence,
Syndrome of inappropriate 211–212
antidiuretic hormone diagnosis, 212–213
secretion (SIADH) etiology, 210t, 213t
clinical criteria, 39 history, 211
disorders associated with, 39 pathophysiology, 209
monitoring serum in hospitalized physical exam, 211
patients with, 41–42 prevalence, 209
treatment screening for, 211–212
arginine vasopressin receptor replacement for males, 10
antagonists, 40 therapy, avoidance, 213
demeclocycline, 40 Thiazide diuretics, treatment for
fluid restriction, 39 central DI, 45
48565_IDXx_369-396.indd 389 5/1/13 9:35 PM

390 Index
Thiazolidinediones, 295t Thyroid essentials
3β-hydroxysteroid dehydrogenase anatomy of, 49
deficiency (3βHSDD), histology of, 49
144, 147 physiology of, 49–50
THRT. See Thyroid hormone Thyroid FNA, decision-making
replacement therapy for, 81t
Thyroglobulin (Tg), 49 Thyroid function
Thyroid absorption, drugs affecting, drugs affecting, 73–77
73–74 tests
Thyroid cancer anatomy of, 49
clinical presentation, 108 histology of, 49
diagnosis and management, 108 physiology of, 49–50
etiology and use and interpretation of,
pathophysiology, 107 51–52t
history of, 109 Thyroid hormone
Thyroid disorders in pregnancy effect of drugs on, 71t
hyperthyroidism metabolism, drugs affecting, 74
clinical presentation, 106 resistance, 53t
diagnosis, 106 therapy, 67
etiology and Thyroid hormone binding globulin
pathophysiology, 105 (TBG), 51t
laboratory evaluation, 106 Thyroid hormone replacement
management, 107 therapy (THRT), 73
hypothyroidism Thyroid nodule
clinical presentation, 103 clinical presentation, 108
diagnosis, 104 diagnosis and management, 108
etiology and etiology and
pathophysiology, 103 pathophysiology, 107
laboratory evaluation, 104 evaluation
management, 104–105 clinical presentation, 79–80
screening for, 103 diagnostic evaluation, 80–81
postpartum thyroiditis epidemiology and
clinical presentation, 109 pathophysiology, 79
diagnostic evaluation, 109 malignancy risk by cytologic
etiology and diagnosis, 82t
pathophysiology, 109 management, 81–82
treatment and monitoring, 110 history of, 109
thyroid nodules and thyroid Thyroid-stimulating hormone
cancer (TSH), 51t
clinical presentation, 108 conditions of, 54–55t
diagnosis and deficiency, 9t, 10
management, 108 manifestations of, 8t
etiology and suppression, 91
pathophysiology, 107 Thyroid storm, treatment of, 60, 60t
history of, 109 Thyrotoxicosis
Thyroid dysfunction, male clinical presentation of, 54
infertility, 220 diagnosis, 54–57
48565_IDXx_369-396.indd 390 5/1/13 9:35 PM

Index 391
etiology and pathophysiology newborn, 146
of, 53 treatment principles, 145–146
management options of, 57–59 Type 1 deiodinase (D1) catalyses, 69
subclinical hyperthyroidism, Type 2 deiodinase (D2) catalyses, 69
60–61 Type 3 deiodinase (D3) catalyses, 69
thyroid storm, 60 Type 1 diabetes
Thyrotrophs, 6 glycemic management in, 264–265
TNM. See Tumor node metastasis TDD of, 264
Tolvaptan, 40–41 Type 2 diabetes
Total cholesterol (TC), 325, cardiovascular disease in. See
331–335, 332t Cardiovascular disease,
Total daily dose (TDD) in type 2 diabetes
calculation, 309 glycemic management in, 265–267
of insulin, 275
in type 1 diabetes, 264 U
Total thyroxine, 51t UA. See Unstable angina
Toxic adenoma/toxic goiter, 53t UAE. See Urinary albumin excretion
Transient receptor potential UK Prospective Diabetes Study
channels, 166 (UKPDS), 294
Transport of dietary fat, 326, 327 Ulceration, diabetic foot, 315–317
Transport of hepatic fat, Unilateral primary aldosteronism,
327–328, 328 131, 133, 134
Transrectal ultrasound, 219 Unstable angina (UA), 300
Transsphenoidal surgery Urea, managing SIADH, 39
for acromegaly, 21 Urinary albumin excretion (UAE),
for prolactinemia, 15 categories of, 285, 286t
Triglyceride Urinary 5-Hydroxyindole acetic acid
categories, 332t (5-HIAA), 357
lipoproteins carrying, 325 Urine catecholamines, 137
Trophoblastic disease, 53t Urology, 215
Trousseau’s sign, 182 Uterine factors, female infertility,
TSH-secreting pituitary adenoma, 53t 245, 246, 249
T3 resin uptake (T3RU), 52t
Tubal factors, female infertility,
245, 246, 248 V
Tumor node metastasis (TNM) VADT, 294
classification, 88 Vascular endothelial growth
staging, 88t, 99, 100t factor (VEGF), 86
Tumors Vasomotor, 315
carcinoid. See Carcinoid tumors Vasopressin, 5
pancreatic neuroendocrine. See Veins, 113
Pancreatic neuroendocrine Venous drainage, 3
tumors Very low-density lipoproteins
21-hydroxylase deficiency (VLDL), 325, 327, 331,
(21OHD), 144 332, 339
adult, 146–147 VIPoma, 359
child/adolescent, 146 Visual field testing for PI, 32
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392 Index
Vitamin D, 165–166 Weight-based insulin regimen,
deficiency, 181 308–309
clinical presentation, 186 Weight loss
diagnosis, 186 from diet, 345
management, 186–187 effect of substantial, 351
pathophysiology, 185 PCOS management, 229–230
prevalence of, 185 Weight reduction, hirsutism, 236
risk factors for, 185 Werner syndrome, 86
recommended intakes Whipple’s triad, 321
for, 166t White adipose tissue, 339
Vitamin D receptor (VDR), 166 World Health Organization (WHO), 189
VLDL. See Very low-density
lipoproteins Z
Zoledronic acid, 192t, 197
W Zometa, 192t
Waist circumference, increased, 343 Zona fasciculata, 113
Water deprivation test for diagnosis Zona glomerulosa, 113
of DI, 44 Zona reticularis, 113
48565_IDXx_369-396.indd 392 5/1/13 9:35 PM

Tarascon Adult Endocrinology

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Tarascon Adult

Marc J. Laufgraben, MD, MBA, FACE, FACP

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Production Credits Composition: CAE Solutions Corp.

To order this product, use ISBN:

Printed in the United States of America

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° Venous drainage: inferior petrosal sinuses

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Action Stress rresponse

directly on G-protein coupled surface receptors on anterior pituitary

■ Miscellaneous: oxytocin receptor widely expressed in central nervous

system (CNS) and inﬂuences reproductive behavior in some species

gogue, coagulation regulator

circulatory volume, nausea and emesis

contact with the circulation via local gaps in blood-brain barrier

• Stimulatory: GHRH and ghrelin

• Somatotrophs make up ~50% of anterior pituitary cells

• Inhibitory: dopamine (DA)

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■ Role: linear and organ growth and lactation

• Indistinguishable from somatotrophs by conventional histology

(POMC) including melanocyte-stimulating hormone, lipotrophic

■ Role: regulate sex steroid synthesis and ovulation/

hormone (LH)-expressing gonadotrophs equal in female fetus, LH

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• Presentation of hypopituitarism varies from subclinical (diagnosed

TABLE 2.1 Manifestations of Deﬁ cient Hormones

Deﬁ cient Hormone Manifestations

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TABLE 2.2 Hormonal Assessment for Pituitary Hypofunction

° Adequacy of replacement assessed by checking for manifestations

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• For TSH deﬁciency

° thyroxine (T4) replacement

■ Do not start therapy in patients with palpable prostate nodule

or induration, haematocrit >50%, untreated severe obstructive

active thromboembolism, active endometrial cancer, breast

or past history of thromboembolism, ischemic heart disease,

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