NOTES

NOTES
LIVER DISEASES

GENERALLY, WHAT ARE THEY?

(e.g. increase in free calcium)
PATHOLOGY & CAUSES ▪ Decreased hepatic metabolism of
circulating estrogens → hyperestrogenism
▪ Diseases affecting hepatic parenchymal
▫ Spider nevi: vascular lesions, central
tissue or vasculature
arteriole surrounded by smaller vessels
▪ Variable insults
▫ Palmar erythema
▫ Impairment in function of/destruction
▫ Gynecomastia
of liver parenchyma → inflammation →
scarring (cirrhosis) → liver failure ▪ Fetor hepaticus (breath odor due to
increased dimethyl sulfide levels)
▫ Obstruction or restriction of blood flow
through liver → hypertension in portal ▪ Jaundice (cellular necrosis → reduced
circuit producing secondary systemic hepatic ability to metabolize, excrete
effects bilirubin → buildup of unconjugated
bilirubin in the blood)
▫ Diseases caused by anomalies in
absorbing, storing, converting or ▪ Decreased production of coagulation
detoxification → accumulation of factors → easy bruising, bleeding
substances in the liver and other tissues ▪ Hepatic encephalopathy
causing damage ▫ Ammonia, related nitrogenous
substances not cleared from blood →
accumulate in brain → impaired cerebral
SIGNS & SYMPTOMS function

▪ Early stages generally asymptomatic

▪ Non-specific symptoms MNEMONIC: ABCDEFGHIJ
▫ Weakness, weight loss, fatigue Common signs of liver
disease
Portal hypertension Asterixis, Ascites, Ankle
▪ Abdominal distension (ascites) edema, Atrophy of testicles
▪ Splenomegaly Bruising
▪ Esophageal varices → trouble swallowing, Clubbing/ Color change of nails
hematemesis, dark stools (leukonychia)
▪ Caput medusae Dupuytren’s contracture
▫ Dilated periumbilical collateral veins Encephalopathy / palmar
▪ Cruveilhier–Baumgarten murmur Erythema
▫ Venous hum heard in epigastric region Fetor hepaticus
with stethoscope Gynecomastia
Liver cellular dysfunction Hepatomegaly
▪ Decreased hepatic albumin production Increase size of parotids
▫ Decreased osmotic pressure → edema Jaundice
▫ Increase in levels of free circulating
compounds normally bound to albumin

OSMOSIS.ORG 289
 ▫ Neglect of personal appearance MNEMONIC: 3Cs & 3Cs
▫ Unresponsive, forgetful, trouble Hepatomegaly common
concentrating causes
▫ Changes in sleeping habits Cirrhosis
▫ Psychosis Carcinoma
▫ Asterixis (bilateral asynchronous Cardiac failure
flapping of outstretches, dorsiflexed
hands) Hepatomegaly rare causes
▪ Decreased metabolism of active Cholestasis
compounds → increased sensitivity to Cysts
certain medications
Cellular infiltration
▪ Pruritus

anti-hepatitis B core IgM

DIAGNOSIS
▫ Hepatitis C: hepatitis C antibody,
DIAGNOSTIC IMAGING hepatitis C RNA
▪ CT scan with contrast, MRI, ultrasound, ▫ Hepatitis D & E: IgM, IgG antibodies
radionuclide imaging ▪ Autoimmune panel
▫ Rheumatoid factor (RF), anti-cyclic
citrullinated peptide antibody (CCP),
LAB RESULTS anti-nuclear antibody (ANA), anti-
▪ Complete blood count (CBC) double stranded DNA (anti-dsDNA),
▪ Liver function tests anti-extractable nuclear antigen (anti-
▫ Tests of synthetic function: serum ENA), antineutrophil cytoplasmic
albumin level, international normalized antibody (ANCA)
ratio (INR) ▪ Liver biopsy
▫ Hepatocellular enzymes: aspartate
transaminase (AST), alanine
transaminase (ALT), total bilirubin, direct TREATMENT
bilirubin
▫ Ductal enzymes: alkaline phosphatase ▪ Initially disease-specific; see individual
(ALP), gamma glutamyl transpeptidase disorders
(GGT)
▪ Hepatitis virus serology SURGERY
▫ Hepatitis A: anti-hepatitis A IgM, anti- ▪ Advanced disease → liver transplant
hepatitis A IgG
▫ Hepatitis B: hepatitis B surface antigen,
anti-hepatitis B core/surface antibodies,

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ALCOHOLIC LIVER DISEASE

osms.it/alcoholic-liver-disease
▪ Large vacuoles coalesce → fatty cysts →
PATHOLOGY & CAUSES irreversible lesions
▪ Macrovesicular steatosis most commonly
▪ Abnormal lipid retention in hepatocytes
associated with alcohol, diabetes, obesity,
(steatosis) → large triglyceride fat vacuoles
corticosteroids
accumulate in liver cells → fatty liver
▪ Severe fatty liver may be accompanied by
▪ Fat content of liver exceeds 5–10% by
inflammation, steatosis → steatohepatitis
weight
▫ Steatohepatitis → hepatocyte
▪ Can be accompanied by progressive
ballooning, necrosis → liver cell death,
inflammation (hepatitis) → steatohepatitis
inflammatory response → hepatic
stellate cell activation → fibrosis →
RISK FACTORS cirrhosis
▪ Glycogen storage diseases, acute fatty liver
during pregnancy, malnutrition, obesity, COMPLICATIONS
HIV, hepatitis C
▪ Hepatocellular carcinoma
Alcohol
▪ Most common cause
SIGNS & SYMPTOMS
▪ Chronic alcohol use → production of toxic
metabolites (e.g. aldehydes)
▪ Fatigue, malaise, dull right-upper-quadrant
▫ Damages mitochondria, cellular pain, mild jaundice (rare), significant
structures → impaired cellular energy damage → hepatomegaly, ascites
mechanisms
▫ Alcohol metabolised to aldehyde hepatic
enzymes (reaction facilitates conversion DIAGNOSIS
of NAD+ → NADH; lower NAD+
concentration → less fatty acid oxidation DIAGNOSTIC IMAGING
→ fatty acids accumulate → steatosis)
Ultrasound
STAGING ▪ Steatosis → bright liver with increased
echogenicity
▪ Stages of intracytoplasmic accumulation of
triglycerides → fatty change ▪ Fibrosis → coarse echo pattern
▪ Cirrhosis → nodules → irregular outline of
Initial stage liver surface
▪ Hepatocytes contain small fat vacuoles
(liposomes) around nucleus (microvesicular CT scan
fatty change) ▪ Lower density than spleen on CT scan

Late stage MRI

▪ Vacuoles enlarge → nucleus pushed to ▪ Fat → bright on T1 and T2-weighted
cell periphery → signet ring appearance images
(macrovesicular fatty change)
▪ Vesicles well-delineated, optically empty LAB RESULTS
▫ Fats dissolve during tissue processing
Liver function tests
▪ Serum aminotransferases normal/

OSMOSIS.ORG 291
 moderately elevated
▫ AST usually more elevated than ALT in
TREATMENT
alcoholic fatty liver disease
▪ Hepatic steatosis reversible, non-
▫ GGT often elevated in alcoholic fatty progressive if underlying cause controlled
liver disease (e.g. cease alcohol use)
Secondary causes of steatosis
▪ Hepatitis C virus antibodies
▪ Hepatitis A IgG
▪ Hepatitis B surface antigen, surface
antibody, core antibody
▪ Plasma iron, ferritin, total iron-binding
capacity

Biopsy
▪ Early changes
▫ Accumulation of membrane bound large
droplet steatosis (Large macrovesicular
drops → alcoholic steatosis; small
microvesicular droplets → acute fatty Figure 36.1 A Mallory–Denk body is a feature
liver of pregnancy, tetracycline toxicity, of many liver pathologies including alcoholic
Reye’s syndrome) hepatitis and alcoholic cirrhosis.
▫ Proliferation of smooth endoplasmic
reticulum
▫ Gradual distortion of mitochondria
▪ Steatohepatitis
▫ Presence of neutrophils → alcoholic
steatohepatitis, unusual in chronic viral
hepatitis
▫ Mallory-Denk bodies (clusters of
intracellular cytoskeletal protein
aggregates)
▪ Advanced changes
▫ Fibrosis: accumulation of scar tissue
or extracellular matrix, potentially
reversible if individual stops drinking Figure 36.2 Histological appearance of fatty
alcohol, not true cirrhosis characterized liver. The numerous white spaces represent
by presence of regenerative nodules the accumulation of lipid.
(irreversible)

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 Chapter 36 Liver Diseases

AUTOIMMUNE HEPATITIS
osms.it/autoimmune-hepatitis

PATHOLOGY & CAUSES DIAGNOSIS

▪ Inflammation of the liver tissue caused by LAB RESULTS
autoimmunity ▪ ↑↑ALT, ↑ AST, ↓ albumin, ↑ prothrombin
time
TYPES ▪ Type 1
▪ Type 1: 80% of cases ▫ Antinuclear antibodies (ANAs),
▪ Type 2: most common in young antibodies against smooth muscle
biologically-female individuals proteins, or (ASMAs)
▪ Type 3: different antibodies but presents as ▪ Type 2
Type 1 ▫ Antibodies to the microsomes of the
▪ Type 4: no detectable antibodies liver or kidney (ALKM-1), liver cytosol
antigen (ALC-1)
▪ Type 3
CAUSES ▫ Soluble liver antigen positive
▪ Combination of environmental triggers and
genetic predisposition
TREATMENT
RISK FACTORS
▪ Young biologically-female individuals; MEDICATIONS
presence of HLA-DR3.DR4 Immunosuppressants
▪ Corticosteroids, azathioprine
COMPLICATIONS
▪ Acute liver failure, chronic liver failure, SURGERY
hepatocellular carcinoma, long term
immunosuppression can lead to Liver transplantation
malignancies ▪ If resistant to drug therapies

SIGNS & SYMPTOMS

▪ Wide spectrum of presentation, from
asymptomatic to cirrhosis and liver failure
▪ Common moderate symptoms
▫ Fever, jaundice, and
hepatosplenomegaly
▪ Chronic disease symptoms
▫ Coagulation disturbance, impaired
immunity
▪ Type 2 is associated with other diseases
(Hashimoto’s thyroiditis, Grave’s disease)

OSMOSIS.ORG 293
 Figure 36.3 The histological appearance of
autoimmune hepatitis. There is an infiltration
of lymphocytes and plasma cells at the
interface between the hepatic lobule and the
portal tract i.e. lymphoplasmacytic interface
hepatitis.

BUDD–CHIARI SYNDROME
osms.it/budd-chiari-syndrome
▪ Trauma
PATHOLOGY & CAUSES ▪ Pregnancy
▪ Contraceptive therapy
▪ Congestive hepatic disease caused by
obstruction of hepatic venous outflow
▪ Usually > one hepatic vein or hepatic COMPLICATIONS
section of vena cava ▪ Cirrhosis and liver failure
▪ Venous congestion leads to ▪ Esophageal, gastric and rectal varices
▫ Ischemia and centrilobular necrosis ▪ Kidney dysfunction (hepatorenal syndrome)
▫ Increased pressure in portal system →
portal hypertension
SIGNS & SYMPTOMS
CAUSES ▪ Can present acutely or chronically
▪ Occlusion (primary)
▪ Classic triad
▫ Thrombosis (most common)
▫ Hepatomegaly
▪ Compression (secondary)
▫ Abdominal pain
▫ Tumor mass, granuloma
▫ Ascites
▪ Jaundice
RISK FACTORS ▪ Fever
▪ Myeloproliferative and hematologic ▪ Other signs and symptoms of portal
disorders (e.g. polycythemia vera) hypertension (e.g. splenomegaly,
▪ Hypocoagulative disorders encephalopathy)
▪ Tumors
▪ Infections (e.g. tuberculosis)
▪ Inflammatory diseases

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DIAGNOSIS TREATMENT
DIAGNOSTIC IMAGING ▪ Treat the underlying cause

Doppler ultrasound
▪ Thrombus MEDICATIONS
▪ Alteration of hepatic venous outflow ▪ Usually insufficient
▪ ‘Spider web’ formation around the ▪ Anticoagulants
obstruction duto collateral vessels ▪ Diuretics
proliferation

Venography
SURGERY
Liver transplantation
CT scan, MRI
▪ In case of fulminant liver failure

LAB RESULTS Portosystemic shunt

▪ Elevated aminotransferases ▪ Divert the flow away from the obstruction
▪ Liver biopsy ▪ Transjugular intrahepatic portosystemic
shunt (TIPS)
▪ Surgical shunt

OTHER INTERVENTIONS
Thrombolytic therapy
▪ Dissolve clots
▪ Balloon angioplasty

Figure 36.4 An abdominal CT scan in the

axial plane demonstrating hypoperfusion of
the right lobe of the liver secondary to Budd-
Chiari syndrome.

OSMOSIS.ORG 295
 CHOLESTATIC LIVER DISEASE
osms.it/cholestatic-liver-disease
malignancy (biliary tree/head of
PATHOLOGY & CAUSES pancreas), strictures, cystic fibrosis
(impaired secretory function of biliary
▪ Cholestasis: decrease in bile flow through epithelium), primary sclerosing
bile ducts into duodenum cholangitis (immune system attacks
▪ Hepatic retention, spillage into systemic bile ducts → inflammation, scar tissue),
circulation of cholesterol, bile salts → biliary atresia (≥ one newborn infant’s
incorporation into biological membranes bile ducts narrow/blocked/absent)
→ altered membrane fluidity → injury to ▫ Complications: prolonged obstruction
biological membranes, impaired function → biliary cirrhosis; subtotal/intermittent
of membrane channels → bile secretion obstruction → ascending cholangitis
impaired in liver (secondary bacterial infection of biliary
▪ No bile reaches small intestine → intestinal tree) → sepsis, if untreated
malabsorption → nutritional deficiencies of
fat soluble vitamins (A, D, E, K)
SIGNS & SYMPTOMS
CAUSES
▪ Jaundice
Hepatocellular cholestasis ▫ Individual components of bile enter
▪ Impaired secretion of bile by hepatocytes serum (e.g. conjugated bilirubin)
▫ Intracellular accumulation of bile ▪ Pain
acids → ↓ regulation of bile synthesis ▫ Right upper quadrant (RUQ) pain,
→ ↓ total bile production/secretion radiates to right shoulder, minutes to
→ accumulation of bile components hours in duration (often after fatty meal)
(e.g. conjugated bilirubin) → diffuse/ ▪ Pruritus
exocytose into interstitium → diffuse
▫ Systemic accumulation of bile salts/
into blood
endogenous opioids/lysophosphatidic
Elevated levels of estrogen acid
▪ Breakdown of cholesterol → cholic acid ▪ Skin xanthomas
(bile acid) ▫ Focal accumulations of cholesterol
▪ ↑ estrogen → inhibition of export pump → (common in obstructive jaundice)
estrogen-induced cholestasis ▪ Pale stools/dark urine
▪ Risk factors ▫ Absence of bile in gut → conjugated
▫ Oral contraceptives (increase estrogen bilirubin (water soluble) not excreted
exposure), pregnancy (pregnancy- with bile, excreted via kidneys
induced cholestasis), anabolic steroids
(similar in structure to estrogen)
▪ Extrahepatic cholestasis
▫ Physical obstruction blocks bile flow
▫ Ductal obstruction → bile accumulates
in liver → ↑ pressure in bile ducts → bile
leaks through tight junctions between
hepatocytes → enters serum, interstitial
space
▫ Causes: cholelithiasis (gallstones),

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DIAGNOSIS TREATMENT
LAB RESULTS MEDICATIONS
▪ Associated vitamin deficiency
Liver function tests (LFTs)
▫ Fat-soluble vitamin supplementation
▪ Elevated membrane-bound enzymes
▪ Children
(sensitive to hepatocyte damage) → ↑
serum alkaline phosphatase (ALP), gamma- ▫ Ursodeoxycholic acid → increased bile
glutamyl transpeptidase (GGT) formation

Histology
SURGERY
▪ Individual hepatocytes take on brownish-
▪ Extrahepatic obstruction
green stippled appearance (due to
trapped bile), canalicular bile plugs form ▫ Surgical correction of obstruction
between individual hepatocytes/bile ducts (e.g. cholecystectomy; if gallstone
(excreted bile cannot travel further due to obstructing common bile duct, removal
obstruction) of gallbladder)
▫ Under sufficient pressure, canalicular
plugs may rupture → spillage of bile into OTHER INTERVENTIONS
surrounding tissue → hepatic necrosis ▪ Pregnancy-induced cholestasis
▫ Early delivery (around week 36 of
gestation)

CIRRHOSIS
osms.it/cirrhosis
fibrotic material in extracellular matrix
PATHOLOGY & CAUSES ▪ Fibrotic cascade → formation of fibrous
septa → separation of hepatocyte nodules
▪ Hepatic parenchyma replaced by scar → distortion of liver architecture →
tissue → scar tissue blocks portal flow of decrease blood flow throughout → splenic
blood through liver → raised blood pressure congestion → hypersplenism, splenic
and disturbance of function sequestration of platelets
▪ Reversible phase → hepatitis/fatty liver ▪ Injured liver cells group together →
(steatosis) often precedes cirrhosis regenerative nodules (clumps of cells
▪ Long term accumulation of liver damage → between fibrotic tissue, collagen) → bumpy
disruption of liver architecture → functional cirrhotic liver
impairment
▪ Develops over months to years
RISK FACTORS
▪ Damage to parenchyma → activation of
▪ Chronic alcohol use, chronic hepatitis C
stellate cells (sit between sinusoids and
infection, chronic hepatitis B (+/- hepatitis
hepatocytes in perisinusoidal space) →
D) infection, autoimmune hepatitis,
secretion of
hereditary hemochromatosis, Wilson
▫ TGF-β1 → production of myofibroblasts disease, alpha 1-antitrypsin deficiency,
→ increased fibrosis, proliferation of medications
connective tissue
▫ TIMP 1 & 2 (matrix metalloproteinase
inhibitors) → prevents breakdown of

OSMOSIS.ORG 297
 COMPLICATIONS (ERCP) /magnetic resonance
▪ Portal hypertension, hepatic cholangiopancreatography (MRCP))
encephalopathy, increased blood levels of
Diagnostic paracentesis
estrogens, hepatocellular carcinoma
▪ Determine ascitic fluid origin
▪ Portal hypertension
MNEMONIC: HEPATIC ▪ Suspected spontaneous bacterial peritonitis
Causes of Cirrhosis ▫ Cell count, gram stain, culture
Hemochromatosis (primary) ▫ Serum: ascites albumin gradient (SAAG)
Enzyme deficiency (alpha-1- > 1.1 g/dL → portal HTN
anti-trypsin)
Post hepatic (infection + drug LAB RESULTS
induced) ▪ AST, ALT moderately elevated, AST > ALT
Alcoholic ▪ ALP 2–3x normal
Tyrosinosis ▪ GGT very high in chronic alcoholic liver
Indigenous people in America disease
(galactosemia) ▪ Bilirubin increases as cirrhosis worsens
Cardiac/ Cholestatic (biliary)/ ▪ Albumin decreases as synthetic function
Cancer/ Copper (Wilson’s) declines
▪ Prothrombin time increases as synthetic
function declines
SIGNS & SYMPTOMS ▪ Hyponatremia from inability to excrete free
water (high levels of antidiuretic hormone,
▪ Early stages generally asymptomatic aldosterone)
▫ Liver may be enlarged, shrinks as ▪ Serum biomarkers correlate with degree of
cirrhosis progresses liver damage in variety of liver diseases
▫ Non-specific symptoms: weakness, ▪ A2-macroglobulin, haptoglobin,
weight loss, fatigue apolipoprotein A1, bilirubin, GGT, age,
▪ Portal hypertension biological sex
▪ Liver cellular dysfunction Histology
▪ Nail changes (Muehrcke’s lines, Terry’s ▪ Macroscopic appearance
nails, clubbing)
▫ Surface irregular, consistency firm
▪ Hypertrophic osteoarthropathy
▫ Yellow color (in steatosis)
▪ Dupuytren’s contracture
▫ Nodular
▪ Liver biopsy
DIAGNOSIS ▫ Microscopic appearance of hepatocytes
(regenerating nodules) and fibrosis/
DIAGNOSTIC IMAGING connective tissue deposits between
nodules
Ultrasound ▪ Cause specific abnormalities
▪ Small nodular liver (advanced cirrhosis), ▫ Chronic hepatitis B: infiltration of liver
increased echogenicity, irregular- looking parenchyma with lymphocytes
areas, widening fissures, splenomegaly, ▫ Cardiac cirrhosis: erythrocytes, greater
imaging of blood flow in portal vein amount of fibrosis in tissue surrounding
Endoscopy hepatic vein
▪ Esophagogastroduodenoscopy (EGD) ▫ Primary biliary cholangitis: fibrosis
around bile duct, presence of
▫ Exclude esophageal varices
granulomas, pooling of bile
▪ Imaging of bile ducts (endoscopic
▫ Alcoholic cirrhosis: neutrophilic
retrograde cholangiopancreatography
infiltration

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OTHER DIAGNOSTICS
Child-Pugh score
▪ Grading of cirrhosis
▫ Class A (5–6 points): one year survival
100%, two year survival 85%
▫ Class B (7–9 points): one year survival
81%, two year survival 57%
▫ Class C (10–15 points): one year
survival 45%, two year survival 35%

Figure 36.5 Gross pathology of micronodular

TREATMENT liver cirrhosis.
MEDICATIONS
▪ Antiviral medication (e.g. interferon)
▫ For hepatitis B, C
▪ Corticosteroids
▫ For autoimmune hepatitis
▪ Diuretics, antibiotics, laxatives, enemas,
thiamine, steroids, acetylcysteine,
pentoxifylline
▫ For decompensation (compensated
cirrhosis—no jaundice, ascites, variceal
bleeding, hepatic encephalopathy;
development of any of above →
decompensated)
Figure 36.6 Histological appearance of liver
cirrhosis (trichrome stain). The blue highlights
OTHER INTERVENTIONS the bands of fibrosis between islands of
▪ Abstain from alcohol hepatocytes.
▫ For alcoholic hepatitis
▪ Chelation therapy (e.g. penicillamine)
▫ For Wilson disease
▪ Dissolve gallstones
▫ Blockage of bile ducts

OSMOSIS.ORG 299
 FITZ–HUGH–CURTIS SYNDROME
osms.it/fitz-hugh-curtis-syndrome
▪ Causative organisms
PATHOLOGY & CAUSES ▫ Commonly: Chlamydia trachomatis,
Neisseria gonorrhoeae, Mycobacterium
▪ Pelvic inflammatory disease (PID) → tuberculosis (endemic areas)
inflammation of local structures → anterior
▫ Reported: Trichomonas vaginalis,
liver capsule inflammation (perihepatitis)
Ureaplasma urealyticum, Mycoplasma
→ patchy purulent, fibrinous exudate →
hominis, Bacteroides spp., Gardnerella
adhesions form
vaginalis, E. coli and Streptococcus spp.

CAUSES
RISK FACTORS
▪ Etiology of inflammation poorly understood
▪ Biological females of reproductive age
▪ Thinning of cervical mucus → bacteria
colonizing vagina enters uterus, fallopian
tubes → infection, inflammation → possibly SIGNS & SYMPTOMS
spreads via
▫ Direct intraperitoneal spread from initial ▪ Vomiting, nausea, hiccupping, headaches
pelvic inflammation and infection
▪ Acute onset right upper quadrant
▫ Bacterial seeding via lymphatic abdominal pain; aggravated by breathing,
bloodstream coughing, laughing (pleuritic pain), may
▫ Autoimmune response to PID refer to right shoulder, tenderness to

300 OSMOSIS.ORG
 Chapter 36 Liver Diseases

palpation, tenderness to percussion of

overlying ribs TREATMENT
▪ Fever, chills, night sweats, malaise, vaginal
discharge, lower abdominal pain, cervical
MEDICATIONS
motion tenderness ▪ Organism-specific antibiotics
▪ Pain management
▫ Appropriate analgesia
DIAGNOSIS ▫ Laparoscopy for lysis of adhesions for
refractory pain
▪ History of pelvic inflammatory disease

DIAGNOSTIC IMAGING
Abdominal ultrasound
▪ Typically normal

Abdominal CT scan with contrast

▪ Perihepatic
▫ Subtle enhancement of liver capsule,
inflammatory stranding and fluid along
right paracolic gutter and perihepatic
region, gallbladder wall thickening,
pericholecystic inflammatory change
▪ Pelvic Figure 36.7 A laparoscopic view of intra
▫ Possible tubo-ovarian abscess abdominal adhesions caused by Fitz-Hugh-
Curtis syndrome.

LAB RESULTS
▪ Liver function tests
▫ Typically normal
▪ D-dimer
▫ Markedly raised
▫ Often ordered due to pleuritic chest pain
▪ Endocervical/low vaginal swab
▫ Culture causative organism

OTHER DIAGNOSTICS
Laparoscopy
▪ “Violin string” adhesions of parietal
peritoneum to liver/diaphragm

OSMOSIS.ORG 301
 HEMOCHROMATOSIS
osms.it/hemochromatosis

PATHOLOGY & CAUSES SIGNS & SYMPTOMS

▪ Excessive iron absorption in the intestine → ▪ Initially asymptomatic
iron deposited in organs and tissues → free ▫ Biogically male: symptoms appear
radical generation → cellular damage → around age 50
cell death → tissue fibrosis ▫ Biologically female: eliminate iron
through menstrual bleeding →
TYPES symptoms appear 10-20 years after
menopause
Primary (hereditary: autosomal recessive) ▪ Signs and symptoms of liver disease
▪ Variety of possible mutations (C282Y ▪ Altered glucose homeostasis (hyper/
being the most common) in HFE gene on hypoglycemia)
chromosome 6 regulating iron absorption ▪ Fatigue
from food → most of the iron in the food
▪ Arthralgia
is absorbed by enterocytes in the gut and
pass into the bloodstream → iron overload ▪ Sexual dysfunction
▪ Abdominal pain
Secondary (not genetic) ▪ Cardiac arrhythmias
▪ Multiple blood transfusions → erythrocytes
contain iron bound to the hemoglobin →
heme is released in bloodstream when DIAGNOSIS
erythrocytes die after 120 days
▪ Chronic hemolytic anemias LAB RESULTS
▪ Excessive iron intake (very rare) ▪ High levels of serum iron
▪ Elevated ferritin
COMPLICATIONS ▪ High transferrin saturation
▪ Caused by deposition of iron in tissues ▪ Decreased total iron binding capacity
▫ Liver: cirrhosis, cancer
Liver biopsy
▫ Pancreas: altered endocrine and
▪ Iron can be seen as brown spots inside
exocrine function
hepatocytes → it becomes blue with a
▫ Skin: bronze pigmentation Prussian blue stain
▫ Heart: cardiomyopathy, arrhythmias
▫ Gonads (related to impaired pituitary
OTHER DIAGNOSTICS
function): amenorrhea in biologically-
female individuals, testicular atrophy in ▪ Genetic analysis and screening of family
biologically-male individuals members
▫ Adrenal gland: gland insufficiency
▫ Joints: degenerative joint disease

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TREATMENT
MEDICATIONS
Deferoxamine
▪ Chelating agent binds iron molecules →
deferoxamine excreted by kidneys → urine
excretion → decreases iron load

SURGERY
▪ Advanced liver damage → transplantation
Figure 36.8 Iron deposition (hemosiderosis)
in the liver parenchyma in a case
hemochromatosis. There is associated OTHER INTERVENTIONS
hepatocyte damage. ▪ Phlebotomy
▪ Dietary changes to reduce iron absorption

Figure 36.9 Prussian blue stain on a liver

biopsy highlights iron deposits in a case of
hemochromatosis.

OSMOSIS.ORG 303
 HEPATITIS B
osms.it/hepatitis

PATHOLOGY & CAUSES DIAGNOSIS

▪ Infection of the liver caused by hepatitis B LAB RESULTS
virus (HBV) ▪ HBV virions found in blood serum, proves
▪ DNA virus from the hepadna group viral replication
▪ Incubation is 1–6 months, long term carrier ▪ ↑ ALT, ↑ AST
state established after, transmitted through ▪ ↑ CRP, ↑ ESR, ↑ WBC
blood or semen ▪ HBsAg (surface antigen); present in acute
▪ Immune system attacks infected infection then cleared in recovery; if present
hepatocytes over six months → chronic infection; used
to create vaccine
RISK FACTORS ▪ Anti-HBc IgM (core antigen); present in
▪ Intravenous drug users, unprotected active infection for six months; if present
sexual intercourse, blood transfusions; longer individual is carrier; used for
hemodialysis screening because present most of the time
▪ Anti-HBc IgG develop after IgM, lifelong
secretion indicates individual is immune
COMPLICATIONS ▪ Anti-HBe secreted core antigen, appears
▪ Liver cirrhosis, hepatocellular carcinoma during viral replication, indicates active
infection
▪ Bilirubin normal to increased
SIGNS & SYMPTOMS
▪ General infection OTHER DIAGNOSTICS
▫ Low grade fever, malaise, lethargy, ▪ Physical exams shows hepatomegaly
anorexia
▪ Liver related
▫ Fatty stool, dark urine, jaundice,
TREATMENT
hepatomegaly, scleral icterus, pruritus,
right upper quadrant tenderness
MEDICATIONS
▪ Interferon alpha, nucleoside reverse
transcriptase inhibitors (NRTI)
▪ Post exposure prophylaxis available with
HBV immunoglobulins
▪ Vaccine available

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HEPATITIS C
osms.it/hepatitis

PATHOLOGY & CAUSES DIAGNOSIS

▪ Viral hepatitis caused by hepatitis C virus LAB RESULTS
(HCV) ▪ Enzyme-linked immunosorbent assay
▪ RNA virus from the class of flaviviridae (ELISA) used to detect antibodies in
▪ Incubation is 6–7 weeks, lifelong infectious chronic cases, may be false negative in
carrier state immunosuppressed
▪ Virus mutates often to bypass the host ▪ Specific hepatitis C antigens immunoassay
immune system ▪ HCV RNA test with PCR
▪ Minority of individuals develop acute ▪ ↑ ALT
hepatitis symptoms, due to this majority ▪ ↑ CRP, ↑ ESR, ↑ WBC
progress to chronic infection
OTHER DIAGNOSTICS
RISK FACTORS ▪ Physical exam shows enlarged liver
▪ Intravenous drug use, sexual contact, from
mother to child in neonatal period (vertical
transmission); chronic hemodialysis TREATMENT

COMPLICATIONS MEDICATIONS
▪ Cirrhosis, hepatocellular carcinoma, renal ▪ Interferon alfa, ribavirin
dysfunction (HCV immune complexes ▪ Screen for HBV, HIV and HAV; vaccinate
involved in pathogenesis) against HBV and HAV if tests are negative
▪ No HCV vaccine available

SIGNS & SYMPTOMS SURGERY

▪ Liver transplant in case of liver failure
▪ General infection
▫ Low grade fever, malaise, lethargy,
anorexia
▪ Liver related
▫ Fatty stool, dark urine (iron), jaundice,
hepatomegaly, icterus, pruritus

OSMOSIS.ORG 305
 HEPATITIS E
osms.it/hepatitis

PATHOLOGY & CAUSES DIAGNOSIS

▪ Viral hepatitis caused by hepatitis E virus LAB RESULTS
(HEV) ▪ Anti - HEV IgM assay in acute infection,
▪ RNA virus from the class hepeviridae PCR in chronic cases
▪ Transmitted via fecal-oral route ▪ ↑ ALT
▪ ↑ CRP, ↑ ESR, ↑ WBC
RISK FACTORS
▪ Consuming contaminated food and water OTHER DIAGNOSTICS
in endemic areas, blood transfusions, from ▪ Physical exam shows enlarged liver
mother to child in neonatal period

COMPLICATIONS TREATMENT
▪ Rare but if present then cholestatic
MEDICATIONS
hepatitis, chronic infection in
immunosuppressed individuals, liver failure, ▪ Ribavirin used in immunosuppressed
high mortality rate in pregnant individuals individuals

SURGERY
SIGNS & SYMPTOMS ▪ Liver transplant in case of liver failure

▪ General infection
▫ Low grade fever, malaise, lethargy,
anorexia
▪ Liver related
▫ Fatty stool, dark urine (iron), jaundice,
hepatomegaly, icterus, pruritus
▪ Other
▫ Diarrhea, arthralgia, urticarial rash

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HEPATOCELLULAR ADENOMA
osms.it/hepatocellular-adenoma

PATHOLOGY & CAUSES DIAGNOSIS

▪ Rare, benign liver tumor DIAGNOSTIC IMAGING
▪ Formed from hepatic epithelial cells, often ▪ Often incidental finding on abdominal
in healthy liver imaging
▫ Enlarged, nonfunctional epithelial cells
Ultrasound
▫ More glycogen, lipids than expected
▪ Solitary well-demarcated heterogeneous
▫ Surrounding tissue highly vascularized mass with variable echogenicity
▫ Bile ducts, portal triads absent
CT scan
CAUSES ▪ Well-marginated isoattenuating hepatic
lesions; fat content → hypoattenuation
▪ Exact mechanisms unknown; associated
with estrogen-based drugs: oral
contraceptives, anabolic steroids LAB RESULTS
▪ Genetic diseases
Histology (definitive)
▫ Glycogen storage disease type I (von
▪ Well-circumscribed nodules
Gierke’s disease): glucose cannot
be generated from glycogen via ▫ Sheets of hepatocytes with bubbly
gluconeogenesis vacuolated cytoplasm
▪ Lack portal tracts/central veins
RISK FACTORS
▪ Diabetes, metabolic syndrome, obesity TREATMENT

COMPLICATIONS SURGERY
▪ Rupture, bleeding; malignant ▪ Surgical resection
transformation (rare)
OTHER INTERVENTIONS
▪ Estrogen-associated
SIGNS & SYMPTOMS ▫ Cessation of estrogen-based medication
→ adenoma regression
▪ Usually asymptomatic
▪ Von Gierke’s disease
▪ Abdominal pain (esp. epigastric/RUQ),
▫ Strict dietary management → adenoma
palpable mass
regression
▪ If adenoma ruptures, bleeds
▫ Hypotension, tachycardia, diaphoresis

OSMOSIS.ORG 307
 Figure 36.10 Intraoperative photograph of
a large, well-circumscribed hepatocellular
adenoma of the left lobe of the liver. There
is a rim of normal liver surrounding the
adenoma. The right lobe of the liver is just
visible to the left of the image.

NEONATAL HEPATITIS
osms.it/neonatal-hepatitis
COMPLICATIONS
PATHOLOGY & CAUSES ▪ If untreated > six months
▫ Chronic liver disease → hepatic cirrhosis
▪ Inflammation of liver in newborns (usually
→ liver failure
1–2 months after birth)

CAUSES SIGNS & SYMPTOMS

▪ Viruses (20%)
▫ Infect mother during pregnancy/baby ▪ Jaundice, pruritus, rashes, dark urine,
shortly after birth pale stools, hepatomegaly (due to liver
▫ Rubella; Cytomegalovirus (CMV); inflammation)
hepatitis A,B,C ▪ Decreased intestinal bile flow → impaired
▪ Idiopathic (80%) fat digestion, vitamin absorption → failure
to grow
▫ Unknown origin
▫ Viral
▫ Neonatal cholestasis DIAGNOSIS
▫ Newborn bile production immature → ↓
bile production DIAGNOSTIC IMAGING
▫ Developing liver more sensitive to injury
→ ↓ bile synthesis, flow Ultrasound
▪ Genetic ▪ Check bile ducts for obstruction, correct
development
▫ Alpha 1-antitrypsin deficiency:
malformation → cannot be transported
out of hepatocytes → accumulation
within cells → cell death → hepatitis

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LAB RESULTS
TREATMENT
Liver biopsy
▪ Multinucleated giant cells MEDICATIONS
▫ Arise from combination of neighboring ▪ Ursodeoxycholic acid
cells (hepatocytes) ▫ Increase bile formation
▫ Signs of cholestatic liver disease

Blood tests
SURGERY
▪ Cirrhotic liver disease/liver failure requires
▪ ↑ serum bilirubin
liver transplant

OTHER INTERVENTIONS
▪ Optimize nutrition/vitamin supplementation

NON-ALCOHOLIC FATTY LIVER

DISEASE
osms.it/non-alcoholic-fatty-liver

NAFL → NASH
PATHOLOGY & CAUSES
▪ Second hit hypothesis
▪ Disease due to fat accumulation in liver, ▫ Initial fatty change benign → oxidative
associated inflammation stress, hormonal imbalances,
mitochondrial abnormalities →
progression
TYPES ▪ Hepatocytic fat vulnerable to degradation
Non-alcoholic fatty liver (NAFL) ▫ Unsaturated fatty acids: ≥ one double
bond, hydrogen atoms vulnerable to
▪ Steatosis without inflammation
initiators (e.g. reactive oxygen species)
Non-alcoholic steatohepatitis (NASH) ▫ Process damages cell lipid membranes
▪ Steatosis with hepatic inflammation, → mitochondrial dysfunction → cell
indistinguishable from alcoholic death → inflammation → steatohepatitis
steatohepatitis (NASH)

Subtype
RISK FACTORS
▪ Liver steatosis without evident secondary
▪ NAFL → NASH
cause (e.g. chronic alcohol use/persistent
viral infection) ▫ Age > 50
▫ Liver large, soft, yellow greasy ▫ BMI ≥ 28kg/m2 (5.7lbs/ft2)
▫ Bloating, hepatocyte necrosis ▫ Diabetes mellitus
▫ Mallory–Denk bodies ▫ Elevated serum aminotransferases
▫ Damage attracts neutrophils → more ▫ Ballooning degeneration, Mallory–Denk
inflammation bodies or fibrosis on biopsy
▫ Inflammation → hepatic stellate cells ▪ NAFL (general)
activate → fibrosis → cirrhosis ▫ Insulin resistance, metabolic syndrome,
▫ ≥ Three of: obesity, hypertension,

OSMOSIS.ORG 309
 diabetes, hypertriglyceridemia, Liver biopsy
hyperlipidemia, excessive soft drink ▪ > 5% fat content → NAFL
consumption (high concentration of ▪ Iron deposits
fructose), diet rich in saturated fats,
▪ NAFL
medications (corticosteroids)
▫ Steatosis alone
▫ Steatosis with lobular/portal
COMPLICATIONS inflammation without hepatocyte
▪ Liver cirrhosis, hepatocellular carcinoma ballooning
▫ Steatosis with hepatocyte ballooning
but without inflammation
SIGNS & SYMPTOMS ▪ NASH
▪ Usually asymptomatic ▫ Hepatocyte ballooning degeneration,
hepatic lobular inflammation,
▪ Fatigue, malaise, dull right upper quadrant
apoptotic bodies, mild chronic portal
pain, mild jaundice (rare), significant liver
inflammation, perisinusoidal collagen
damage → hepatomegaly, ascites
deposition → zone 3 accentuation
(chicken wire pattern), portal fibrosis
without perisinusoidal or pericellular
DIAGNOSIS fibrosis, cirrhosis (macronodular
or mixed), Mallory–Denk bodies,
▪ Typically diagnosed as incidental finding on megamitochondria, vacuolated nuclei in
liver function panel periportal hepatocytes

DIAGNOSTIC IMAGING OTHER DIAGNOSTICS

▪ Identify fatty infiltrates ▪ Alcohol consumption > 25 ml/day pure
Ultrasound ethanol excludes diagnosis
▪ Increased echogenicity → bright appearing
liver → diffuse fatty infiltration TREATMENT
CT scan
▪ Decreased hepatic attenuation
OTHER INTERVENTIONS
Dietary changes
MRI
▪ Avoid high fructose-corn syrup, trans-fats
▪ Increased fat signal
▪ Omega 3 fatty acid supplementation →
improvement in liver fat deposition
LAB RESULTS ▪ Coffee and olive oil consumption may be
▪ Destruction of hepatocytes → increase in protective
liver enzymes AST/ALT
▪ Serum ALT > AST level = NAFL Treat insulin resistance
▪ Weight-loss
▪ Insulin sensitizers

Treat hyperlipidemia
▪ Statins

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PORTAL HYPERTENSION
osms.it/portal-hypertension

PATHOLOGY & CAUSES SIGNS & SYMPTOMS

▪ Elevation of blood pressure in the portal ▪ GI bleeding (secondary to esophagogastric
venous system above 5mmHg varices) → most life-threatening
complication
CAUSES ▫ Hematemesis
▫ Melena
Prehepatic causes ▪ Jaundice
▪ Portal vein obstruction (e.g. thrombosis) ▪ Ascites
Intrahepatic causes ▪ Periumbilical caput medusae
▪ Cirrhosis (most common of all causes) ▪ Signs and symptoms of encephalopathy
▪ Schistosomiasis ▫ Altered level of consciousness
▪ Sarcoidosis ▫ Lethargy
▫ Hand tremor when the wrist is extended
Posthepatic causes (aka asterixis)
▪ Right-sided heart failure ▫ Seizure, coma and death
▪ Constrictive pericarditis
▪ Budd–Chiari syndrome
DIAGNOSIS
COMPLICATIONS DIAGNOSITC IMAGING
▪ Portosystemic shunts and development of
collateral channels Liver ultrasound
▫ Esophageal varices ▪ Nodules in case of cirrhosis
▫ Hemorrhoids CT scan, MRI
▫ Caput medusae (distension of ▪ Ascites
abdominal wall veins)
▪ Cirrhosis
▪ Increased hydrostatic pressure and
▪ Splenomegaly
hypoalbuminemia → ascites
▪ Vascular alteration such as inferior vena
▪ Splenomegaly (blood drainage backs up to
cava dilatation
spleen due to high pressure portal system)
→ sequestration of blood elements →
anemia, thrombocytopenia, leukopenia LAB RESULTS
▪ Liver disease and blood shunting away ▪ Full blood count
from liver → decreased blood detoxification ▪ Liver enzymes and serology
→ increased ammonia in the blood → ▪ Perform emergent upper GI endoscopy, to
encephalopathy diagnose/treat varices
▪ Spontaneous bacterial peritonitis

OSMOSIS.ORG 311
 OTHER DIAGNOSTICS
TREATMENT
Diagnostic paracentesis
▪ Will determine if ascites is due to portal ▪ Prevent and treat the complications
HTN or other etiology
▪ Serum ascites albumin gradient (SAAG) > MEDICATIONS
1.1 mg/dL ▪ Beta-blockers
▫ Portal HTN is likely ▫ → decrease portal venous pressure
▪ IV octreotide
▫ If bleeding, non-selective beta blockers
(prophylaxis), antibiotics (prophylaxis for
spontaneous bacterial peritonitis)
▫ For esophageal varices
▪ Diuretics and sodium restriction
▫ For ascites

SURGERY
▪ Transjugular intrahepatic portosystemic
shunt
▫ Communication between portal vein
and hepatic vein → blood bypasses the
liver circulation → reduced intrahepatic
pressure
▪ Balloon tamponade, sclerotherapy, variceal
ligation/banding
Figure 36.11 Ascites as a consequence of
▫ For esophageal varices
portal hypertension caused by cirrhosis of
the liver.

MNEMONIC: ABCDE
Features of Portal
hypertension
Ascites
Bleeding (haematemesis, piles)
Caput medusae
Diminished liver
Enlarged spleen

Figure 36.12 Barium swallow demonstrating

esophageal varices.

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Figure 36.13 Endoscopic appearance of

esophageal varices.

PRIMARY BILIARY CIRRHOSIS

osms.it/primary-biliary-cirrhosis
COMPLICATIONS
PATHOLOGY & CAUSES ▪ Osteoporosis, hyperlipidemia, fat soluble
vitamin deficiencies
▪ Autoimmune disease of liver → progressive
destruction of cells lining small intrahepatic
bile ducts → leakage of bile, toxins into SIGNS & SYMPTOMS
liver parenchyma, blood → inflammation,
fibrosis → cirrhosis
▪ Fatigue, pruritus, jaundice, right upper
▪ AKA primary biliary cholangitis quadrant pain
▪ Loss of bone density → fractures
CAUSES ▪ Hypercholesterolemia → xanthelasma,
▪ Failure of immune tolerance against xanthoma
mitochondrial pyruvate dehydrogenase ▪ Liver cirrhosis → ascites, splenomegaly,
complex (PDC-E2), other hepatic proteins esophageal varices, hepatic
→ destruction of cells lining bile ducts → encephalopathy
autoimmunity

RISK FACTORS DIAGNOSIS

▪ Biological female, family history of disease,
DIAGNOSTIC IMAGING
extrahepatic autoimmune disease
▫ Previous infection with environmental Abdominal ultrasound/MRCP/CT scan
gram-negative Novosphingobium ▪ Rule out bile duct obstruction
aromaticivorans → cross-reaction
between bacterial antigens, hepatic
mitochondrial proteins LAB RESULTS
▪ Antimitochondrial antibodies (most
individuals)

OSMOSIS.ORG 313
 ▪ Other autoantibodies may be present
▫ Antinuclear antibody, anti-
TREATMENT
glycoprotein-210 antibodies, anti-p62
antibodies (suggests more severe
MEDICATIONS
disease → liver failure), anticentromere ▪ Ursodeoxycholic acid
antibodies (correlates with developing ▫ Reduces intestinal absorption of
portal hypertension), anti-np62 and cholesterol → reduces cholestasis,
anti-sp100 improves liver function tests
▪ Elevated IgM, total cholesterol, HDL, GGT, ▪ Cholestyramine
ALP (released from damaged bile ducts), ▫ Bile acid sequestrant → reduces bile
bilirubin = advanced disease acid absorption in gut → relieves itching
due to bile acids in circulation
Liver biopsy (percutaneous/laparoscopic)
▪ Modafinil
▪ Interlobular bile duct destruction, bile duct
▫ For fatigue
inflammation (intraepithelial lymphocytes),
periductal epithelioid granulomas
OTHER INTERVENTIONS
▪ Cease all alcohol intake

Figure 36.14 The histological appearance

of primary biliary cirrhosis. The bile duct
is surrounded by epithelioid macrophages
which in turn are surrounded by a rim of
lymphocytes, indicative of granulomatous
inflammation.

WILSON'S DISEASE
osms.it/wilsons-disease
▪ Reduced copper elimination in the bile
PATHOLOGY & CAUSES ▪ Copper accumulation in hepatocytes → free
radical generation → hepatocyte damage
▪ Autosomal recessive mutation in ATP7B → spilling of free copper into the blood
gene → defect in ATP7B transport protein → copper accumulation in organs and
action in the hepatocyte tissues → free radical generation → tissues
▪ AKA hepatolenticular degeneration damage
▪ Reduced copper incorporation into
apoceruloplasmin and reduction of its
copper-bound form (ceruloplasmin)

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COMPLICATIONS
▪ Liver: cirrhosis, liver failure
DIAGNOSIS
▪ Brain: movement disorders, dementia, and LAB RESULTS
psychiatric issues
▪ Signs of liver dysfunction (e.g. high liver
▪ Kidney: renal disease enzymes)
▪ Eye: Kayser–Fleischer’s ring, sunflower ▪ Low serum ceruloplasmin
cataract
▪ High 24-hour copper excretion
▪ Blood: hemolytic anemia

TREATMENT
SIGNS & SYMPTOMS
MEDICATIONS
▪ Presents at a young age (< 30 years old)
▪ Chelating agents → make it easier to
▪ Signs and symptoms of cirrhosis and portal excrete copper
hypertension (e.g. hepatosplenomegaly,
▫ Penicillamine (penicillin metabolite
jaundice, ascites, esophageal varices)
without antibiotic properties)
▪ Signs of renal dysfunction
▫ Trientine hydrochloride
▪ Parkinsonian-like movement disorders
▪ Agents that block intestinal absorption of
▫ Tremors copper
▫ Rigidity ▫ Ammonium tetrathiomolybdate
▪ Psychiatric illness ▫ Zinc
▫ Depression
▫ Personality changes
SURGERY
▫ Psychosis
▪ Advanced liver damage → transplantation
▫ Cognitive dysfunctions
▪ Kayser–Fleischer ring
▫ Ring of copper deposition in the cornea
OTHER INTERVENTIONS
(Descemet’s membrane) ▪ Eliminate copper-rich food (e.g.
mushrooms, nuts, shellfish)
▫ Appears to encircle the iris

Figure 36.15 Copper deposition in

Descemet’s membrane of the sclera results in
a Kayser–Fleischer ring.

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