Viral Hepatitis - Short Answer (Pathology)

Definition

Comparative Table of Hepatitis Viruses

Hepatitis A Virus (HAV)

• Accounts for ~25% of acute hepatitis worldwide
• Endemic in countries with poor hygiene/sanitation
• Spread by fecal-oral route - contaminated water, food (raw shellfish), close personal contact
• Shed in stool 2-3 weeks before and 1 week after jaundice onset
• Sexual transmission may occur; maternal-fetal transmission does NOT occur
• Viremia is transient - blood not screened; bloodborne transmission rare

• Incubation period: 2-6 weeks
• Self-limiting; does NOT cause chronic hepatitis or carrier state
• Symptoms: fatigue, loss of appetite, jaundice; most recover within 3 months
• Fulminant hepatitis in 0.1-0.3% (especially those with underlying chronic liver disease)
• Extrahepatic manifestations: rash, arthralgia, leukocytoclastic vasculitis, glomerulonephritis, cryoglobulinemia
• Rare complications: prolonged cholestasis, relapse within 6 months

• IgM anti-HAV: appears at onset of symptoms; persists 3-6 months; marker of acute infection
• IgG anti-HAV: appears during recovery; persists for years; confers lifelong immunity
• Vaccine available since 1995; has reduced HAV rates by >95%

Hepatitis B Virus (HBV)

1. HBsAg - three related envelope glycoproteins (large, middle, small). Large HBsAg is associated with complete virions; small HBsAg is released in large quantities (non-infectious, tubular/spherical 22 nm particles)
2. HBcAg - nucleocapsid protein. Pre-core region encodes HBeAg (secreted; marker of active replication and high infectivity)
3. HBV DNA polymerase - reverse transcriptase activity (replication proceeds via RNA intermediate)
4. HBx protein - transcriptional transactivator; plays role in HCC development

• 254 million people with chronic HBV infection worldwide (WHO 2022); 1.2 million new infections/year; 1.1 million deaths/year
• Highest prevalence (>8%) in Africa, Asia, Western Pacific rim
• Transmission: parenteral (IV drug use, blood transfusion), sexual contact, perinatal (vertical - accounts for 90% of cases in high-prevalence regions)
• Transfusion-related transmission curtailed by screening for HBsAg

1. Acute hepatitis with recovery and viral clearance
2. Nonprogressive chronic hepatitis
3. Progressive chronic disease → cirrhosis
4. Fulminant hepatitis with massive liver necrosis
5. Asymptomatic "healthy" carrier state

• Neonatal infection → >90% chronic infection
• Adult infection → >90% recover; <10% chronic

• HBV is NOT directly cytopathic
• Liver damage is immune-mediated by HBV-specific CD8+ CTLs
• In immunotolerant state (especially neonates): high viral replication, minimal immune attack → healthy carrier state
• HBV DNA can integrate into host genome → oncogenic role (HCC via HBx protein, chromosomal instability)

1. Immune tolerant phase: HBeAg+, high HBV DNA, normal ALT, minimal liver injury
2. Immune active phase (immune clearance): HBeAg+, high HBV DNA, elevated ALT, active hepatitis
3. Inactive carrier phase: HBeAg- (seroconverted), low/undetectable HBV DNA, normal ALT
4. HBeAg-negative chronic hepatitis: anti-HBe+, fluctuating HBV DNA, elevated ALT (due to pre-core mutations)

Hepatitis C Virus (HCV)

• ~70 million people infected worldwide; ~1.5 million new infections/year
• Highest prevalence in Egypt (genotype 4), East Asia (genotypes 1b, 2), USA predominantly genotype 1a/1b
• Transmission: primarily parenteral (IV drug use - most common route in high-income countries; needle sharing); intranasal cocaine use is a risk factor; blood transfusion (before 1992 screening); sexual transmission (low risk, 1-3% per year in stable couples); perinatal transmission (5%)
• NOT efficiently spread by fecal-oral route

• Viral hypervariability allows escape from host immune response
• HCV actively suppresses innate immunity (NS3/4A cleaves MAVS, blocks interferon signaling)
• Defective CD8+ T cell response in most patients

• Incubation: 4-26 weeks (mean 9 weeks)
• Acute infection: usually subclinical (80% asymptomatic); jaundice in <20%
• Chronic hepatitis: >80% develop chronic infection
• Of chronic HCV: ~20-30% develop cirrhosis over 20-30 years; cirrhosis is a major risk factor for HCC
• Extrahepatic manifestations: cryoglobulinemia (most common), membranoproliferative glomerulonephritis, porphyria cutanea tarda, Sjogren syndrome, non-Hodgkin lymphoma

• Lymphoid follicles/aggregates in portal tracts (characteristic)
• Fatty change (steatosis) - more common with genotype 3
• Bile duct damage
• Mild lobular inflammation

• Anti-HCV (ELISA): appears 8-12 weeks after exposure; does NOT confer immunity
• HCV RNA (PCR): most sensitive; detectable within days of infection; used to confirm active infection and monitor treatment

Hepatitis D Virus (HDV)

• Family: Deltaviridae
• Contains: delta antigen (HDAg) + HDV RNA wrapped in HBsAg coat

1. Co-infection (simultaneous HBV + HDV):
   • Clinically similar to acute hepatitis B
   • Usually self-limiting; both viruses cleared together
   • Higher rate of fulminant hepatic failure (especially in IV drug users)
   • Chronic HDV infection in only ~10%
2. Superinfection (HDV in a chronic HBV carrier):
   • Disease appears 30-50 days after HDV inoculation
   • Presents as severe acute hepatitis in previously asymptomatic HBV carrier, OR as exacerbation of chronic HBV
   • Chronic HDV infection in >80-90% of superinfections
   • Accelerates progression to cirrhosis and HCC

• HDV RNA detectable at onset of symptomatic disease
• IgM anti-HDV: recent exposure marker (short-lived)
• IgG anti-HDV: persists in chronic superinfection
• In acute co-infection: IgM anti-HDAg + IgM anti-HBcAg (new HBV infection)

Hepatitis E Virus (HEV)

• Zoonotic disease - animal reservoirs include pigs, monkeys, cats, dogs
• Epidemics: Asia, Indian subcontinent, sub-Saharan Africa, Mexico
• Sporadic cases: USA, Canada, Europe (especially where pig farming is common)
• In India: accounts for 30-60% of sporadic acute hepatitis, exceeding HAV
• Transmission: fecal-oral, waterborne

• Self-limiting disease in immunocompetent hosts
• Usually infects young to middle-aged adults
• Incubation: 4-5 weeks
• No chronic carrier state or chronic liver disease in immunocompetent hosts
• High mortality in pregnant women - up to 20% (especially in 3rd trimester) - characteristic feature
• In immunocompromised patients (e.g., organ transplant recipients): HEV can cause chronic infection

Morphology of Viral Hepatitis (Histopathology)

Acute Hepatitis

1. Hepatocyte injury:
   • Hepatocyte swelling (ballooning degeneration): Most characteristic feature. Hepatocytes enlarge, cytoplasm becomes pale/rarefied due to cytoskeletal disruption (loss of intermediate filaments).
   • Acidophilic (Councilman/apoptotic) bodies: Shrunken, intensely eosinophilic hepatocytes with pyknotic nuclei undergoing apoptosis. Engulfed by adjacent hepatocytes or Kupffer cells.
   • Feathery degeneration: In cholestatic hepatitis (bile accumulation).
2. Inflammation:
   • Portal tract inflammation: lymphocytes, plasma cells, macrophages, occasional eosinophils/neutrophils
   • Lobular disarray: Disruption of normal cord pattern
   • Kupffer cell hypertrophy/hyperplasia
   • Spotty (focal) necrosis: Individual hepatocyte death scattered throughout lobule
   • Inflammation spills into limiting plate - interface hepatitis (piecemeal necrosis)
3. Regeneration:
   • Hepatocyte mitoses
   • Binucleate hepatocytes
   • Thickened hepatocyte cords
4. Cholestasis: Bile plugs in canaliculi and hepatocytes (in cholestatic variants)

Severe Acute Hepatitis - Patterns of Necrosis

• Gross: shrunken liver, wrinkled capsule, bile-stained, soft texture
• Micro: massive loss of hepatocytes; collapsed reticulin framework; congested sinusoids; residual portal tracts with bile ductule proliferation

Chronic Hepatitis

1. Portal tract inflammation with lymphocytes and plasma cells
2. Interface hepatitis (piecemeal necrosis): Inflammatory infiltrate at portal-parenchyma interface with hepatocyte destruction - hallmark of chronic hepatitis activity
3. Lobular hepatitis: Scattered inflammatory cells in lobule
4. Fibrosis: Portal fibrosis → periportal fibrosis → bridging fibrosis → cirrhosis (progression over years)
5. Ground-glass hepatocytes (in chronic HBV): Smooth, pale eosinophilic cytoplasm due to HBsAg accumulation in ER - confirmed by orcein stain or immunohistochemistry
6. Lymphoid follicles in portal tracts (characteristic of HCV)

• Grade: Degree of necro-inflammatory activity (portal, periportal, lobular)
• Stage: Degree of fibrosis (F0 = no fibrosis → F4 = cirrhosis)
• Systems used: Metavir, Knodell, Ishak scoring

Clinicopathologic Syndromes

1. Acute Asymptomatic Infection with Recovery

• Minimally elevated transaminases or antibodies detected incidentally
• Common with HAV, HBV

2. Acute Symptomatic Infection with Recovery

1. Incubation period (varies by virus)
2. Preicteric (prodromal) phase: Malaise, fatigue, nausea, vomiting, anorexia, RUQ discomfort, low-grade fever; peak infectivity; constitutional symptoms
3. Icteric (jaundice) phase: Dark urine, clay-colored stools, tender hepatomegaly, jaundice; ALT/AST peak and begin to fall
4. Convalescence (recovery) phase: Symptoms resolve; liver enzymes normalize

• Markedly elevated ALT, AST (>10× normal; ALT > AST)
• Elevated bilirubin (conjugated + unconjugated)
• Elevated ALP (mild-moderate)
• Prolonged PT in severe disease
• Elevated ESR

3. Acute Liver Failure (Fulminant Hepatitis)

• Viral hepatitis accounts for ~10% of acute liver failure
• Defined as liver failure within 8 weeks of onset of illness in a patient without pre-existing liver disease
• Clinical: encephalopathy, coagulopathy, jaundice, elevated PT/INR
• Causes: HBV (most common viral cause), coinfection HBV+HDV, HCV (rarely), HEV (in pregnancy)
• Gross: shrunken, bile-stained liver; micro: massive hepatic necrosis

4. Chronic Hepatitis

• Defined as hepatic inflammation lasting >6 months
• HBV: 5-10% of adults; >90% of neonates
• HCV: >80% of infected individuals
• Risks: cirrhosis, hepatocellular carcinoma
• Symptoms: fatigue, RUQ discomfort, anorexia; may be asymptomatic for years
• Labs: persistently or fluctuating elevated ALT/AST; HBsAg/HCV RNA positive

5. Healthy Carrier State

• Defined as HBsAg+ for >6 months with no evidence of liver disease
• HBV: two types:
  • Inactive HBsAg carrier: HBeAg negative, anti-HBe positive, low/undetectable HBV DNA, normal liver histology
  • Immunotolerant carrier (in perinatally infected): HBeAg positive, very high HBV DNA, normal ALT, minimal liver damage

Hepatocellular Carcinoma (HCC) - Association

• HBV: Major risk worldwide (especially in Asia/Africa). HBV DNA integrates into host genome; HBx protein acts as transcriptional transactivator promoting malignant transformation. HCC can develop even without cirrhosis.
• HCV: HCC develops almost exclusively in the setting of cirrhosis. No direct mutagenic integration; carcinogenesis via chronic inflammation and regeneration.
• HDV co-/super-infection with HBV: Further increases HCC risk.

Summary Points for Short Answer

1. HAV and HEV - fecal-oral; self-limiting; no chronicity (except HEV in immunocompromised); HEV has high mortality in pregnancy
2. HBV, HCV, HDV - parenteral; can cause chronic disease
3. HCV has highest rate of chronicity (>80%)
4. HBV diagnosis - HBsAg is the first and most important antigen; IgM anti-HBc indicates acute infection; window period = only anti-HBc positive
5. Morphologic hallmarks: Ballooning degeneration + acidophilic bodies (acute); interface hepatitis + fibrosis (chronic); ground-glass hepatocytes (HBV)
6. Ground-glass hepatocytes in HBV - due to HBsAg accumulation; stain positive with orcein, Victoria blue, shikata orcein; seen in chronic HBV
7. HDV is a defective virus requiring HBV HBsAg for its envelope - prevented by HBV vaccination
8. HCV - lymphoid aggregates in portal tracts + steatosis are characteristic histologic features
9. Fulminant hepatitis = massive/submassive hepatic necrosis
10. Chronic hepatitis graded (activity) and staged (fibrosis) on biopsy