LONG ANSWER QUESTIONS

LAQ 1: Viruses Causing Hepatitis

Introduction

Hepatitis A Virus (HAV)

• Type: ssRNA virus (Picornaviridae family)
• Transmission: Fecal-oral route (contaminated food/water)
• Incubation period: 2-6 weeks
• Chronicity: Never causes chronic liver disease
• Clinical: Produces self-limited acute hepatitis; most patients recover fully. No carrier state.
• Diagnosis: Serum IgM anti-HAV in acute phase; IgG anti-HAV indicates past infection/immunity
• Pathology: Lobular hepatitis with spotty necrosis, Kupffer cell hyperplasia, periportal inflammation, cholestasis. Councilman (acidophil) bodies (apoptotic hepatocytes) may be seen.
• Complications: Rarely causes fulminant hepatitis. No progression to cirrhosis.

Hepatitis B Virus (HBV)

• Type: Partially double-stranded DNA virus (Hepadnaviridae)
• Transmission: Parenteral (blood/blood products), sexual contact, perinatal (vertical)
• Incubation period: 2-26 weeks
• Chronicity: 5-10% of adults develop chronic infection; higher in neonates (up to 90%)
• Virology: The virion (Dane particle) consists of:
  • HBsAg - surface antigen (envelope)
  • HBcAg - core antigen (not detectable in serum)
  • HBeAg - secreted antigen indicating active replication
• Serologic markers:
  • HBsAg: present in acute and chronic infection
  • Anti-HBs: indicates recovery/immunity
  • IgM anti-HBc: acute infection
  • IgG anti-HBc: past or chronic infection
  • HBeAg: active replication, high infectivity
  • Anti-HBe: lower replication activity
• Pathogenesis: HBV is not directly cytopathic; liver injury is mediated by cytotoxic T-lymphocytes (CTL) attacking HBV-infected hepatocytes expressing viral antigens.
• Morphology (acute): Diffuse hepatocyte swelling (ballooning degeneration), spotty necrosis, Councilman bodies, lobular disarray, sinusoidal lymphocytosis, and portal tract inflammation.
• Morphology (chronic): Ground-glass hepatocytes (HBsAg accumulation in smooth ER - characteristic finding), "sanded nuclei" (HBcAg accumulation in nucleus). Progressive portal fibrosis leading to cirrhosis.
• Complications: Cirrhosis, hepatocellular carcinoma (200x increased risk), membranous glomerulonephritis, polyarteritis nodosa (extrahepatic immune complex deposition).

Hepatitis C Virus (HCV)

• Type: ssRNA virus (Flaviviridae family)
• Transmission: Parenteral; intranasal cocaine use; rarely sexual contact
• Incubation period: 4-26 weeks
• Chronicity: >80% develop chronic infection - highest chronicity of all hepatitis viruses
• Clinical: Most primary infections are asymptomatic or mild (20-30% have jaundice; 10-20% have nonspecific symptoms like anorexia, malaise, abdominal pain)
• Diagnosis: ELISA for anti-HCV antibodies (cannot distinguish acute/chronic/resolved); RT-PCR for HCV RNA (detects active infection, used for monitoring)
• Morphology (chronic): Lymphoid follicles in portal tracts (characteristic), steatosis, mild portal inflammation, bile duct damage. Fibrosis progresses to cirrhosis.
• Complications: Cirrhosis in 20-30% over 20 years; HCC; essential mixed cryoglobulinemia; membranoproliferative glomerulonephritis

Hepatitis D Virus (HDV)

• Type: Defective circular ssRNA virus; requires HBsAg coat to infect cells
• Transmission: Parenteral (same as HBV)
• Occurs as:
  • Co-infection: Simultaneous HBV+HDV infection - usually self-limited; 10% chronicity
  • Superinfection: HDV in chronic HBV carrier - 90-100% progress to chronic hepatitis; worse prognosis
• Clinical: Accelerates liver disease; associated with fulminant hepatitis and rapid progression to cirrhosis

Hepatitis E Virus (HEV)

• Type: ssRNA virus
• Transmission: Fecal-oral (contaminated water; endemic in developing countries)
• Incubation period: 4-5 weeks
• Chronicity: Not observed in immunocompetent patients; can persist in immunosuppressed (transplant, AIDS)
• Special feature: Mortality rate approaching 20% in pregnant females (especially third trimester) - a key distinguishing feature
• Diagnosis: IgM anti-HEV at onset of symptoms; PCR for HEV RNA

Summary Table

Clinicopathologic Syndromes

1. Acute asymptomatic infection with recovery - subclinical; verified by serology
2. Acute symptomatic hepatitis with recovery - 4 phases: incubation, preicteric (malaise, anorexia, nausea, RUQ pain), icteric (jaundice, dark urine, pale stools), convalescence
3. Chronic hepatitis - persistence of hepatitis >6 months; defined by ongoing liver inflammation; caused primarily by HBV and HCV
4. Fulminant hepatic failure - massive hepatic necrosis; HBV, HDV superinfection; rare with HCV
5. Carrier state - HBsAg carriers with HBV; HCV chronic infection

LAQ 2: Non-Alcoholic Steatohepatitis (NASH)

Introduction and Terminology

Epidemiology

• Most common metabolic liver disorder worldwide
• Strongly associated with metabolic syndrome, obesity, type 2 diabetes mellitus, and hyperlipidemia
• Prevalence mirrors the obesity epidemic, including in pediatric populations
• Major cause of chronic liver failure and indication for liver transplantation, after alcohol-associated liver disease

Pathogenesis

• Insulin resistance causes increased free fatty acid delivery to the liver
• Increased de novo lipogenesis within hepatocytes
• Decreased fatty acid oxidation
• Result: triglyceride accumulation as macro- and microvesicular steatosis

• Lipotoxicity: Saturated fatty acids, ceramides, and reactive lipid intermediates directly injure hepatocytes
• Oxidative stress: Mitochondrial dysfunction generates reactive oxygen species (ROS); beta-oxidation overload
• Endoplasmic reticulum (ER) stress: Triggers unfolded protein response and hepatocyte apoptosis
• Gut-liver axis: Gut dysbiosis leads to increased intestinal permeability, allowing endotoxins (LPS) to enter the portal circulation, activating Kupffer cells via TLR4 receptors
• Adipokines: Leptin promotes fibrosis; adiponectin (reduced in obesity) is hepatoprotective
• Innate immunity activation: Kupffer cell activation releases TNF-alpha, IL-6, IL-1 - promoting hepatocyte injury, stellate cell activation, and fibrosis

• Activated hepatic stellate cells (Ito cells) deposit collagen - initially pericellular/perisinusoidal ("chicken wire" pattern), then bridging fibrosis, ultimately cirrhosis

Morphology

1. Macrovesicular steatosis - large fat droplets displacing nucleus to periphery (predominant); mixed micro- and macrovesicular patterns
2. Hepatocyte ballooning degeneration - hepatocytes show cytoplasmic clearing, swelling, and loss of intermediate filaments (Mallory-Denk bodies may be present, indistinguishable from alcoholic hepatitis)
3. Lobular inflammation - scattered mixed inflammatory infiltrate (neutrophils and lymphocytes) within lobules
4. Pericellular/perisinusoidal fibrosis - "chicken wire" collagen deposition surrounding individual hepatocytes, seen on Masson trichrome stain
5. Portal inflammation - may be present but usually mild

Clinical Features

• Most patients with only steatosis are asymptomatic
• MASH patients may have fatigue, nonspecific right-sided abdominal discomfort from hepatomegaly
• Signs/symptoms of metabolic syndrome predominate: obesity, insulin resistance/diabetes, dyslipidemia, hypertension
• Serum AST and ALT elevated in most MASH patients; AST:ALT ratio typically <1 (unlike alcoholic hepatitis where it is usually >2)
• Liver biopsy is required for definitive diagnosis of MASH
• Imaging (ultrasound, MRI) can detect steatosis but cannot reliably diagnose MASH or stage fibrosis

Disease Spectrum and Progression

• ~20-30% of patients with simple steatosis develop MASH
• ~10-15% of MASH patients develop cirrhosis over 10-15 years
• HCC can develop even in absence of cirrhosis (unlike HCV-related HCC)
• Cardiovascular disease is the most frequent cause of death in MASH (due to shared metabolic risk factors)

Treatment

• Weight loss, diet modification (Mediterranean diet), and exercise are the cornerstones - can reverse histologic abnormalities
• Correction of underlying metabolic risk factors: treat diabetes, dyslipidemia, hypertension
• Pharmacologic agents under investigation: GLP-1 receptor agonists, pioglitazone (for T2DM patients), vitamin E (non-diabetic patients), FXR agonists
• Bariatric surgery for eligible obese patients
• Liver transplantation for end-stage disease
• Resmetirom (THR-beta agonist) received FDA approval in 2024 for MASH with liver fibrosis

SHORT NOTES

1. Hepatitis C

Virology

• Genome: Positive-sense ssRNA, ~9.5 kb; member of Flaviviridae
• Genotypes: 6 major genotypes (1-6); genotype 1 most common globally; genotyping guides treatment duration and regimen
• Envelope glycoproteins: E1 and E2 - highly variable (hypervariable region 1); responsible for viral escape from neutralizing antibodies, explaining inability to clear infection

Transmission

• Primarily parenteral (IV drug use most common in developed countries; blood transfusions historically)
• Intranasal cocaine use (shared straws)
• Sexual transmission is inefficient but occurs
• Perinatal transmission: ~5% from HCV-viremic mothers

Clinical Course

• Most primary infections (70-80%) are asymptomatic
• 20-30% develop jaundice; 10-20% have nonspecific symptoms (anorexia, malaise, abdominal pain)
• >80% develop chronic infection - the hallmark of HCV
• Anti-HCV antibodies detectable in 50-70% at symptom onset; delayed by 3-6 weeks in some

Diagnosis

• ELISA: Detects anti-HCV antibodies (cannot distinguish acute/chronic/resolved)
• RT-PCR: Detects HCV RNA - used for acute infection diagnosis, confirming active infection, monitoring treatment response
• Genotyping by nucleic acid assays guides therapy

Morphology (Chronic HCV)

• Lymphoid follicles in portal tracts (characteristic feature)
• Mild portal/periportal inflammation
• Bile duct damage (lymphocytic cholangitis)
• Steatosis (especially with genotype 3)
• Progressive fibrosis - bridging fibrosis - cirrhosis (20 years average)

Complications

• Cirrhosis (20-30% over 20 years)
• Hepatocellular carcinoma (annual incidence ~1-3% in cirrhotics)
• Essential mixed cryoglobulinemia (type II): vasculitis, purpura, arthralgias, neuropathy
• Membranoproliferative glomerulonephritis
• Lichen planus, porphyria cutanea tarda

Treatment

• Direct-Acting Antivirals (DAAs): pangenotypic regimens (e.g., sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) achieve >95% sustained virological response (SVR12) - effectively a cure
• Interferon-free regimens; 8-12 week course
• SVR12 markedly reduces (but does not eliminate) HCC risk in cirrhotics

2. Tumour-Like Conditions of the Liver

1. Focal Nodular Hyperplasia (FNH)

• Definition: Benign, non-neoplastic lesion; most common in adult females
• Pathogenesis: Thought to result from altered (increased) blood flow leading to hyperplastic changes in hepatocytes. Associated with hemangiomas, vascular malformations.
• Gross: Well-circumscribed, no capsule; characteristic central stellate scar in up to 80% of cases; most lesions ≤5 cm
• Microscopy: Fibrous septa radiate from the central scar dividing parenchyma into nodules; septa contain thick-walled arteries with intimal/fibromuscular hyperplasia; bile ductules at periphery of fibrous bands (ductular reaction); hepatocytes are normal
• Imaging: Characteristic central scar with spoke-wheel vascularity on contrast CT/MRI; intense arterial enhancement
• Behavior: Benign; no malignant potential; spontaneous hemorrhage is rare; no treatment usually needed

2. Hepatic Adenoma (Hepatocellular Adenoma)

• Definition: Benign neoplasm of hepatocytes; classified as a benign neoplasm but described here due to non-cirrhotic background
• Associations: Oral contraceptive use (women); anabolic steroid use (men); glycogen storage disease
• Molecular subtypes:
  • HNF1-alpha inactivated (most common; ~35-40%): steatotic, absent LFABP by immunostain; low malignant risk
  • Beta-catenin activated (~10-15%): highest risk of malignant transformation to HCC
  • Inflammatory (~40-45%): elevated CRP immunostaining; sinusoidal dilatation; associated with obesity
  • Unclassified
• Gross: Pale-yellow, soft, often subcapsular; no central scar
• Microscopy: Normal or slightly atypical hepatocytes in cords/trabeculae; no portal tracts; unpaired arteries; dilated vascular spaces; no bile ducts
• Complications: Spontaneous hemorrhage (rupture - surgical emergency); malignant transformation (especially beta-catenin activated, >5 cm)
• Management: Resection for males, beta-catenin-activated, or >5 cm tumors; cessation of OCP/steroids for others

3. Regenerative Nodules

• Form in cirrhotic livers as a response to hepatocyte loss
• Surrounded by fibrous bands; normal or slightly enlarged hepatocytes
• Dysplastic nodules (low-grade and high-grade) represent premalignant lesions on the spectrum to HCC; high-grade dysplastic nodules may contain small foci of HCC

4. Hepatic Abscess

• Pyogenic: Most commonly from biliary infection (ascending cholangitis); organisms: E. coli, Klebsiella; presents with fever, RUQ pain, jaundice
• Amoebic: Entamoeba histolytica; "anchovy paste" content; right lobe predilection
• Clinically important to distinguish from neoplasms

5. Hydatid Cyst

• Echinococcus granulosus; multiloculated cyst with outer ectocyst (host derived) and inner germinal layer; daughter cysts; calcification on imaging; constitutes important liver mass in endemic areas

3. Types of Gallstones

Classification

A. Cholesterol Stones (~75-80% in Western countries)

• Composition: Pure cholesterol (>50% cholesterol monohydrate crystals) or mixed (cholesterol + calcium salts + bile pigment)
• Gross: Single large stone or multiple faceted stones; pale yellow to white; radiolucent on plain X-ray (but may calcify peripherally)
• Pathogenesis (4 F's of risk factors): Fat, Forty, Female, Fertile (and also: rapid weight loss, total parenteral nutrition, Crohn's disease, drugs - fibrates)
• Lithogenic factors:
  1. Supersaturation of bile with cholesterol - reduced bile salt pool or excess cholesterol secretion
  2. Accelerated cholesterol nucleation - mucin glycoproteins promote crystallization
  3. Gallbladder hypomotility - stasis allows crystal aggregation and stone growth
• Bile composition: Normal bile keeps cholesterol soluble as mixed micelles with bile salts and phospholipids; any imbalance tips to precipitation

B. Pigment Stones (~20-25%)

• Composition: Calcium bilirubinate (polymerized bilirubin); calcium phosphate, calcium carbonate
• Risk factors: Chronic hemolytic anemia (hereditary spherocytosis, sickle cell disease, thalassemia), ineffective erythropoiesis, cirrhosis
• Mechanism: Excess unconjugated bilirubin from hemolysis exceeds bile's capacity to keep it in solution; precipitates as calcium bilirubinate
• Gross: Small, irregular, jet-black; multiple; may be spiculated; crumble easily
• Radiopacity: 50-75% are radiopaque (calcium content)
• Location: Gallbladder

• Composition: Calcium bilirubinate + calcium soaps of fatty acids (calcium palmitate, stearate)
• Risk factors: Biliary infection (E. coli, Ascaris lumbricoides, Clonorchis sinensis); bile stasis
• Mechanism: Bacterial beta-glucuronidase deconjugates bilirubin glucuronide to free bilirubin + glucuronic acid; free bilirubin precipitates with calcium; bacterial phospholipase generates free fatty acids from lecithin
• Gross: Soft, earthy, brownish-tan; easily crushable; laminated cross-section
• Location: Bile ducts (intrahepatic or extrahepatic ducts) - key distinguishing feature from black stones

Clinical Consequences

• Biliary colic: Stone impacted in cystic duct; severe RUQ/epigastric pain radiating to right shoulder
• Acute cholecystitis: Obstruction of cystic duct with secondary infection
• Choledocholithiasis: Stone in common bile duct - jaundice, cholangitis, pancreatitis
• Gallstone ileus: Rare; fistula between gallbladder and bowel; stone obstructs terminal ileum
• Carcinoma: Long-standing gallstones associated with carcinoma of gallbladder

4. Pathophysiology of Jaundice

Bilirubin Metabolism - Normal

1. Hemoglobin from senescent RBC breakdown --> heme --> biliverdin (by heme oxygenase) --> unconjugated bilirubin (UCB)
2. UCB is water-insoluble, tightly bound to albumin in plasma; cannot be excreted in urine
3. In hepatocytes: UCB taken up by OATP transporters --> conjugated with glucuronic acid by UGT1A1 --> conjugated bilirubin (CB) = bilirubin diglucuronide
4. CB is water-soluble, excreted into bile canaliculi via MRP2 (ABCC2) transporter
5. In intestine: CB converted by bacteria --> urobilinogen --> stercobilin (feces - brown color); some urobilinogen reabsorbed enterohepatic circulation --> excreted in urine

Definition

Classification and Mechanisms

1. Pre-hepatic (Unconjugated Hyperbilirubinemia)

• Hemolytic anaemias (hereditary spherocytosis, sickle cell disease, G6PD deficiency, autoimmune hemolysis)
• Ineffective erythropoiesis (thalassemia, megaloblastic anemia)
• Resorption of large hematomas

• Elevated UCB (indirect bilirubin); CB normal or mildly elevated
• Urine: no bilirubin (UCB not filtered by glomerulus - albumin bound)
• Urine urobilinogen: increased
• Feces: dark (excess stercobilin)
• Serum: indirect > direct bilirubin

2. Hepatic (Mixed Hyperbilirubinemia - both UCB and CB elevated)

• Hepatocellular disease: Viral hepatitis, alcoholic hepatitis, drug-induced liver injury, cirrhosis, sepsis
• Hereditary defects:
  • Gilbert syndrome: Mild UGT1A1 promoter polymorphism; mild UCB elevation (especially with fasting); benign
  • Crigler-Najjar syndrome type I: Absent UGT1A1; severe UCB; kernicterus; fatal without phototherapy/transplant
  • Crigler-Najjar syndrome type II: Reduced UGT1A1; less severe
  • Dubin-Johnson syndrome: Defective MRP2 (CB excretion); CB elevation; black pigment in hepatocytes; benign
  • Rotor syndrome: Impaired hepatic storage of CB

• Mixed hyperbilirubinemia
• Urine: bilirubin present (CB is water-soluble, filtered by kidney)
• Urine urobilinogen: variable
• ALT/AST markedly elevated in hepatocellular disease

3. Post-hepatic (Obstructive/Cholestatic Jaundice - Conjugated Hyperbilirubinemia)

• Intrahepatic cholestasis: Primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, drug-induced cholestasis
• Extrahepatic obstruction: Choledocholithiasis, carcinoma of head of pancreas, cholangiocarcinoma, carcinoma of ampulla of Vater, biliary strictures

• Elevated CB (direct bilirubin)
• Urine: bilirubin present (dark/tea-colored urine) - key sign
• Urine urobilinogen: absent/reduced (no intestinal conversion)
• Feces: pale/clay-colored (no stercobilin reaches gut)
• Serum: ALP, GGT markedly elevated; pruritus (bile salt retention)
• Elevated cholesterol (impaired bile excretion)

Special - Neonatal Jaundice

• Immature hepatic conjugation machinery (UGT1A1) matures only at ~2 weeks
• Breastfeeding exacerbates (breast milk contains bilirubin-deconjugating enzymes)
• If unconjugated bilirubin rises sharply (especially in hemolytic disease of newborn), it can cross the blood-brain barrier in infants --> kernicterus (bilirubin encephalopathy, brain damage)
• Treatment: phototherapy (converts bilirubin to soluble isomers excreted in urine)

5. Haemochromatosis

Definition

Classification

• Most common: HFE gene mutation (chromosome 6p; autosomal recessive)
  • Most common mutation: C282Y (Cys282Tyr); found in ~85% of hereditary cases in Northern European populations
  • Second mutation: H63D (compound heterozygotes C282Y/H63D)
• Less common hereditary forms: mutations in hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2), ferroportin (SLC40A1)
• More common in males (menstruation in females is protective)

• Chronic hemolytic anemias (thalassemia, sickle cell disease, myelodysplastic syndrome) - due to repeated transfusions + ineffective erythropoiesis
• Dietary iron overload (rare)
• Alcoholic cirrhosis (secondary iron accumulation due to reduced hepcidin)

Pathogenesis

• Hepcidin (produced by liver) is the central regulator of iron absorption - it inhibits ferroportin, blocking iron release from enterocytes and macrophages
• In hereditary haemochromatosis (especially HFE mutations): hepcidin production is inappropriately low despite iron overload
• Result: ferroportin activity is unchecked --> excess iron absorption from duodenum --> iron accumulates in tissues
• Iron toxicity: excess iron in hepatocytes and other cells causes lipid peroxidation of cell membranes, stimulation of hepatic stellate cell fibrosis, DNA damage (via Fenton reaction producing hydroxyl radicals)

Morphology

• Hemosiderin deposition (blue granules on Prussian blue stain) - first in periportal hepatocytes, then progressive centripetal spread
• Periportal fibrosis progressing to micronodular cirrhosis ("bronze liver")
• Liver is enlarged, rusty-brown colored

• Pancreas: Interstitial fibrosis + hemosiderin in acinar and islet cells --> "bronze diabetes"
• Heart: Hemosiderin in myocardial cells --> dilated cardiomyopathy, arrhythmias
• Skin: Increased melanin + hemosiderin in dermis --> bronze discoloration
• Joints: Calcium pyrophosphate crystals (pseudogout), iron deposits in synovium
• Pituitary/gonads: Hemosiderin deposition --> hypogonadism

Clinical Features

1. Cirrhosis with hepatomegaly
2. Abnormal skin pigmentation (bronze)
3. Diabetes mellitus ("bronze diabetes")
4. Cardiac dysfunction (dilated cardiomyopathy, arrhythmias)

• Hypogonadism (amenorrhea in females; impotence, loss of libido in males)
• Atypical arthritis (pseudogout pattern)
• Rarely presents before age 40; more common in males

Laboratory Findings

• Serum iron: elevated
• Serum ferritin: elevated (>200 mcg/L in women, >300 mcg/L in men)
• Transferrin saturation: elevated (>45%; most sensitive screening test)
• HFE genetic testing: confirms diagnosis
• Liver biopsy: Prussian blue stain quantifies iron; assesses fibrosis (but not always needed with genetic testing + imaging)

Complications

• Cirrhosis (with risk of portal hypertension, liver failure)
• Hepatocellular carcinoma: 200-fold greater risk than general population; this risk is NOT fully removed by iron depletion therapy
• Cardiac failure
• Diabetes mellitus
• Death: from cirrhosis, cardiac disease, or HCC

Treatment

• Phlebotomy (venesection): 450-500 mL blood removed weekly; each session removes ~250 mg iron; treatment continued until serum ferritin <50 ng/mL; remarkably simple and effective
• With early treatment: normal life expectancy
• Chelation therapy (desferrioxamine): for patients who cannot tolerate phlebotomy
• Screening first-degree relatives: essential (C282Y genetic testing)

6. Histological Spectrum of Hepatocellular Carcinoma (HCC)

Background

• HCC is the most common primary hepatic malignant neoplasm
• Globally, the third most common cause of cancer death
• Occurs predominantly in cirrhotic livers (chronic HBV, HCV, alcoholic/MASLD, haemochromatosis)
• In sub-Saharan Africa and East Asia: HBV + aflatoxin B1 co-exposure is major risk factor

Gross Pathology

1. Unifocal (massive): Single large mass, usually right lobe; may or may not have satellite nodules
2. Multifocal: Multiple nodules of varying sizes scattered throughout - difficult to distinguish metastasis from multicentric origin
3. Diffuse infiltrative: Permeates portal veins diffusely; may be hard to detect by imaging; associated with portal vein thrombosis

• Cut surface: pale to bile-stained; soft; areas of necrosis and hemorrhage
• Portal vein invasion: characteristic; causes portal hypertension and tumor spread
• Bile production visible on gross section (pathognomonic)

Microscopic (Histological) Spectrum

Well-Differentiated HCC

• Tumor cells closely resemble normal hepatocytes
• Arranged in thick trabeculae (>3 cell layers - "trabecular pattern") or acinar/pseudoglandular structures
• Cells have abundant granular eosinophilic cytoplasm, prominent nucleoli
• Bile production/bile canaliculi may be identifiable
• Unpaired arteries (no portal tracts) within tumor - key distinguishing feature from normal liver
• Intracytoplasmic inclusions: Mallory-Denk bodies, pale bodies, fat, glycogen
• May be difficult to distinguish from hepatocellular adenoma; requires immunohistochemistry

Moderately-Differentiated HCC

• More recognizable as carcinoma
• Trabecular pattern prominent
• Nuclear pleomorphism, prominent nucleoli
• Increased mitotic activity
• Intracanalicular bile plugs may be seen

Poorly Differentiated (Anaplastic) HCC

• Marked nuclear pleomorphism
• Bizarre giant cells (multinucleated tumor giant cells)
• Small undifferentiated cells
• Sarcomatoid change (spindle cells) may occur
• Limited resemblance to hepatocytes; immunohistochemistry needed (HepPar-1, Arginase-1, AFP, glypican-3)

Histological Growth Patterns

1. Trabecular pattern (most common): Tumor cells arranged in trabeculae of varying thickness separated by sinusoid-like spaces lined by endothelium
2. Pseudoglandular (acinar) pattern: Formation of gland-like structures or rosettes; may contain bile
3. Compact (solid) pattern: Densely packed cells with minimal stroma; usually in poorly differentiated tumors
4. Scirrhous pattern: Abundant fibrous stroma; can mimic cholangiocarcinoma; less common

Special Variant - Fibrolamellar HCC

• Distinct clinically: Occurs in young adults without cirrhosis (age 20-40), no gender predilection
• Genetics: Characteristic DNAJB1-PRKACA gene fusion (almost pathognomonic)
• Morphology: Large polygonal cells with abundant deeply eosinophilic granular cytoplasm (oncocytic), prominent nucleoli, arranged in nests and cords separated by parallel lamellae of dense fibrous bands (the "fibrolamellar" pattern)
• Central scar may be present (similar to FNH)
• Immunostaining: CD68+, CK7+; AFP usually negative
• Prognosis: Better than conventional HCC due to resectability; but recurrence is common

Immunohistochemical Profile of HCC

• HepPar-1 (Hepatocyte Paraffin 1): Positive in well/moderately differentiated; mitochondrial antigen
• Arginase-1: Most sensitive hepatocellular marker; positive in HCC including poorly differentiated
• Glypican-3: Positive in malignant hepatocytes; helpful in distinguishing HCC from dysplastic nodules and adenoma
• AFP (alpha-fetoprotein): Positive in ~50% of HCC (serum AFP elevated in 70-80%)
• CK8/CK18: Cytokeratins expressed in hepatocytes and HCC
• CD34: Diffuse sinusoidal staining in HCC (vs. periportal only in normal liver) - reflects aberrant vascularity

Molecular Classification (Brief)

• Multiple molecular subclasses based on CTNNB1 (beta-catenin), TP53, AXIN1, TERT promoter, ARID1A, and other mutations
• TERT promoter mutations: most frequent, found in >60% of HCC

Prognosis

• Generally poor; 5-year survival <20% overall
• Resectable HCC (single, no vascular invasion): better prognosis
• Fibrolamellar HCC has relatively better prognosis
• AFP levels correlate with tumor burden and recurrence
• Sorafenib, lenvatinib (systemic therapy); atezolizumab + bevacizumab (first-line immunotherapy)