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Viral Hepatitis A, B, C, D, E

Sources: Jawetz, Melnick & Adelberg's Medical Microbiology 28e; Sherris & Ryan's Medical Microbiology 8e

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Comparison at a Glance

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HEPATITIS A

Causative Agent

Morphology

• Family: Picornaviridae, genus Hepatovirus
• Size: 27-32 nm spherical particle
• Symmetry: Cubic (icosahedral)
• Genome: Linear single-stranded RNA, 7.5 kb, positive-sense
• Non-enveloped (naked capsid)
• Only one serotype known; 7 genotypes based on 1D/2A gene junction
• No antigenic cross-reactivity with other hepatitis viruses
• Stability: Resistant to ether (20%), acid (pH 1.0 for 2h), heat (60°C/1h); destroyed by autoclaving (121°C/20 min), boiling 5 min, UV irradiation, formalin, chlorine (10-15 ppm/30 min)

Mode of Transmission (MOT)

• Primary: Fecal-oral route (+++), contaminated food and water
• Outbreaks linked to contaminated shellfish, water supplies, day-care centres
• Sexual contact: uncommon (+)
• Parenteral: extremely rare (-)
• Person-to-person spread during incubation period (virus shed in feces before jaundice appears)

Incubation Period (IP)

• 15-45 days (mean ~25 days; some sources state 2-4 weeks to 6 weeks)

Clinical Features

• Onset: Usually sudden (abrupt)
• Age preference: Older children and young adults
• Prodromal/Pre-icteric phase:
  • Fever, malaise, anorexia, nausea, vomiting, abdominal discomfort, dark urine
• Icteric phase:
  • Jaundice (hyperbilirubinemia), hepatomegaly, right upper quadrant tenderness
  • Elevated liver enzymes (ALT/AST)
• Course: Self-limiting; complete recovery in most
• Fulminant hepatitis: Rare (<1%)
• Chronicity: None - does NOT progress to chronic liver disease
• Carrier state: None
• HAV may cause transient viremia during acute phase; virus appears in feces 2 weeks before and 1 week after onset of jaundice

Lab Diagnosis

• Serology (gold standard):
  • IgM anti-HAV: Diagnostic marker of acute infection; appears at onset of illness, persists 3-6 months
  • IgG anti-HAV: Appears during convalescence; persists lifelong; indicates past infection/immunity
• PCR: HAV RNA detectable in stool and serum (used in research/outbreak investigation)
• Stool electron microscopy: Historically used (immune electron microscopy)
• Elevated serum ALT/AST, bilirubin (direct + indirect), alkaline phosphatase
• No antigen test routinely used clinically

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HEPATITIS B

Causative Agent

Morphology

• Family: Hepadnaviridae
• Three distinct particles in infected serum:
  1. Dane particle (complete virion): 42 nm, double-shelled, infectious
  2. Spherical particles: 22 nm diameter, HBsAg only, non-infectious
  3. Filamentous/tubular particles: 22 nm wide, variable length, HBsAg only, non-infectious
• Genome: Partially double-stranded circular DNA (~3.2 kb), smallest DNA virus to infect humans
• Enveloped - outer envelope contains HBsAg (surface antigen)
• Inner nucleocapsid (core) contains HBcAg and HBeAg (soluble form)
• Contains HBV DNA polymerase with reverse transcriptase activity (replicates via RNA intermediate)
• 8 genotypes (A-H); genotype influences disease progression and treatment response
• Extremely stable: survives on environmental surfaces for >7 days

Mode of Transmission (MOT)

• Parenteral (+++): most efficient route
  • Blood transfusion, needle-sharing (IV drug users), needlestick injuries in healthcare workers
  • Blood products, organ transplantation
• Sexual contact (++): Especially men who have sex with men; heterosexual transmission
• Vertical (perinatal/mother to child): Major route in endemic areas; occurs during delivery (not transplacental usually); 90% of perinatally infected infants become chronic carriers
• Fecal-oral: rare (±)
• Virus present in: blood, saliva, semen, vaginal secretions, breast milk, wound exudates

Incubation Period (IP)

• 60-150 days (mean ~90 days / 1-6 months)

Clinical Features

• Onset: Usually slow/insidious
• Age: All ages; neonates at highest risk for chronicity
• Pre-icteric phase: Fever (low grade), malaise, anorexia, nausea, arthralgia, urticaria (serum sickness-like - due to immune complex deposition)
• Icteric phase: Jaundice, hepatomegaly, right upper quadrant pain, elevated liver enzymes
• Outcomes:
  • Acute self-limiting hepatitis: majority of adults
  • Fulminant hepatitis: ~1%
  • Chronic hepatitis: ~10% adults; up to 90% if acquired perinatally
  • Chronic carriers may develop cirrhosis and hepatocellular carcinoma (HCC)
• Extrahepatic manifestations: Polyarteritis nodosa, membranous glomerulonephritis, cryoglobulinemia (via immune complex deposition)

Lab Diagnosis

• HBsAg (+), Anti-HBs (-), Anti-HBc (-) = Early acute HBV
• HBsAg (+), Anti-HBc (+) = Acute or chronic (differentiate with IgM anti-HBc)
• HBsAg (-), Anti-HBs (+), Anti-HBc (+) = Past infection, immunity
• HBsAg (-), Anti-HBs (-), Anti-HBc (+) = "Window period" or remote past infection
• HBsAg (-), Anti-HBs (+), Anti-HBc (-) = Successful vaccination

• ALT/AST elevated (may fluctuate in chronic disease)
• Liver biopsy for grading/staging in chronic hepatitis

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HEPATITIS C

Causative Agent

Morphology

• Family: Flaviviridae, genus Hepacivirus
• Size: ~55-65 nm
• Genome: Positive-sense single-stranded RNA, ~9.6 kb
• Enveloped with icosahedral capsid (core protein C)
• Envelope glycoproteins: E1 and E2 (E2 contains hypervariable region HVR1 - basis for immune evasion)
• Non-structural proteins: NS2-NS3 (protease), NS5A (phosphoprotein), NS5B (RNA-dependent RNA polymerase) - antiviral drug targets
• 6 major genotypes (1-6); genotype 1 most common and most resistant to treatment
• High mutation rate due to error-prone RNA polymerase - leads to quasispecies, immune evasion, persistence

Mode of Transmission (MOT)

• Parenteral (+++): Injection drug use (most common in developed countries), blood/blood products transfusion (before 1992 screening), needlestick injuries, organ transplantation
• Sexual contact (+): Less efficient than HBV
• Vertical (mother to child): ~5% risk
• Fecal-oral: Not transmitted (-)
• HCV is the leading indication for liver transplant in the developed world

Incubation Period (IP)

• 2-26 weeks (mean 6-12 weeks; some references: 14-182 days, mean 14-84 days)

Clinical Features

• Onset: Insidious (most infections subclinical initially)
• Acute phase: ~75% asymptomatic; 25% have fever, fatigue, abdominal pain, poor appetite, arthralgia, jaundice
• Chronic infection in 80-85% of infected individuals (most important feature)
  • Chronic hepatitis waxes and wanes, often asymptomatic
  • May have elevated or normal ALT
  • Progresses over 10-18 years to cirrhosis and HCC
• Fulminant hepatitis: Rare
• Extrahepatic manifestations: Vasculitis, arthritis, glomerulonephritis, cryoglobulinemia, porphyria cutanea tarda, lichen planus (via immune complex deposition)
• No carrier state per se - chronically infected = carrier

Lab Diagnosis

• Anti-HCV antibody (ELISA/EIA): Screening test; appears 8-12 weeks after infection; does NOT distinguish acute, chronic, or resolved infection
• HCV RNA by RT-PCR:
  • Qualitative: confirms active infection (appears 1-2 weeks after exposure, before antibody)
  • Quantitative (viral load): treatment monitoring
• HCV genotyping: Guides treatment duration and drug choice
• Anti-HCV + HCV RNA (+): Active infection
• Anti-HCV (+) + HCV RNA (-): Past resolved infection
• HCV Core Antigen test: Alternative to RNA in resource-limited settings
• ALT may be normal even with active infection
• Liver biopsy/elastography (FibroScan): staging fibrosis

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HEPATITIS D (DELTA HEPATITIS)

Causative Agent

Morphology

• Family: Deltaviridae (previously unclassified)
• Size: 35-37 nm
• Genome: Negative-sense single-stranded circular RNA, ~1.7 kb (smallest RNA virus of humans)
• Enveloped - outer coat is HBsAg (borrowed from HBV)
• Contains: HDAg (Hepatitis D antigen) - the only protein encoded by HDV
  • Small HDAg (p24): promotes viral replication
  • Large HDAg (p27): inhibits replication; required for virion assembly
• Depends entirely on HBV for its outer coat - cannot infect HBV-negative individuals

Mode of Transmission (MOT)

• Same routes as HBV:
  • Parenteral (++): IV drug users (major route), blood products
  • Sexual contact (++)
  • Vertical: Less common than HBV
• Fecal-oral: rare (±)
• Two patterns:
  • Co-infection: HDV + HBV simultaneously; usually self-limited; risk of fulminant hepatitis
  • Superinfection: HDV in chronic HBV carrier; more severe; higher chronicity (50-80%)

Incubation Period (IP)

• 21-49 days (similar to HBV for co-infection)

Clinical Features

• Co-infection (HDV + HBV simultaneously):
  • Biphasic ALT elevation (two peaks)
  • Usually self-limited
  • Risk of fulminant hepatitis increased compared to HBV alone
  • Chronicity low (~5%)
• Superinfection (HDV in chronic HBV carrier):
  • Acute exacerbation of previously stable hepatitis B
  • High risk of fulminant hepatitis
  • Chronicity 50-80% with rapid progression to cirrhosis
• Severity: HDV co-/superinfection produces more severe liver disease than HBV alone
• Can only persist as long as HBsAg is present

Lab Diagnosis

• IgM Anti-HDV: Acute infection marker
• IgG Anti-HDV: Past or chronic infection
• HDAg: Detectable early in acute infection (briefly); detected in liver biopsy by immunofluorescence/immunohistochemistry
• HDV RNA by RT-PCR: Most sensitive marker; confirms active replication
• Must always check HBV markers simultaneously (HBsAg required)
• In co-infection: IgM anti-HBc positive; In superinfection: IgG anti-HBc positive, HBsAg positive

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HEPATITIS E

Causative Agent

Morphology

• Family: Hepeviridae, genus Orthohepevirus
• Size: 27-34 nm (some references: 32-34 nm)
• Genome: Positive-sense single-stranded RNA, ~7.2 kb
• Non-enveloped (naked capsid), icosahedral symmetry
• Single capsid protein (ORF2); ORF3 encodes viroporin
• 4 major genotypes:
  • Genotypes 1 & 2: human-only; endemic in Asia, Africa, Mexico (waterborne epidemics)
  • Genotypes 3 & 4: zoonotic (pigs, deer, rabbits); sporadic cases in developed countries

Mode of Transmission (MOT)

• Primary: Fecal-oral route (+++), contaminated water (major epidemics)
• Waterborne outbreaks in developing countries (India, Southeast Asia, Central America, Africa)
• Zoonotic: genotype 3/4 from pigs/wild boar (undercooked meat) in developed countries
• Vertical transmission (mother to neonate): severe disease
• Fecal-oral: main; sexual transmission uncommon

Incubation Period (IP)

• 15-60 days (mean ~40 days; some: 3-8 weeks)

Clinical Features

• Onset: Similar to HAV (acute, self-limiting in most)
• Age preference: Young adults (20-40 years)
• Usually self-limiting acute hepatitis (like HAV)
• Hallmark: Very high mortality in pregnant women - 15-25% (especially third trimester); fulminant hepatitis
• Clinical: fever, jaundice, hepatomegaly, elevated liver enzymes, dark urine, clay-coloured stools
• No chronicity in immunocompetent (rare chronic cases in organ transplant/immunocompromised patients with genotype 3)
• No carrier state (in immunocompetent hosts)
• Rarely: cholestatic hepatitis, neurological manifestations (Guillain-Barre syndrome, neuralgic amyotrophy)

Lab Diagnosis

• IgM Anti-HEV: Marker of acute infection; appears at onset of symptoms
• IgG Anti-HEV: Past infection / immunity; persists 1-4 years
• HEV RNA by RT-PCR: Detectable in stool and serum during acute phase; confirmatory test
• HEV antigen assay: available in some labs
• Diagnosis often by exclusion of HAV, HBV, HCV in returning travelers from endemic areas
• Elevated ALT/AST, bilirubin

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Key Memory Hooks

• Jawetz, Melnick & Adelberg's Medical Microbiology, 28e, Chapter 35
• Sherris & Ryan's Medical Microbiology, 8e, Chapter 13