Acute Viral Hepatitis

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1. DEFINITION AND OVERVIEW

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2. VIROLOGY AND ETIOLOGY

Hepatitis A (HAV)

• 27-nm, nonenveloped, heat/acid/ether-resistant picornavirus
• Single serotype (despite 6 genotypes; 3 affect humans)
• Inactivated by boiling for 1 min, formaldehyde, chlorine, UV irradiation
• Replication limited to the liver; shed in bile/feces during late incubation and pre-icteric phase
• Infectivity diminishes rapidly once jaundice appears

Hepatitis B (HBV)

• 42-nm (Dane particle) hepadnavirus with partial dsDNA genome
• Key antigens and their antibodies (diagnostically critical):
  • HBsAg: surface antigen - first marker to appear; indicates active infection
  • HBcAg: core antigen - not detected in serum, only in liver tissue
  • HBeAg: e-antigen - indicates active viral replication, high infectivity
  • Anti-HBs: protective neutralizing antibody; appears after recovery or vaccination
  • Anti-HBc IgM: marker of acute or recent infection (also reappears during reactivation)
  • Anti-HBc IgG: past infection (persists lifelong)
  • Anti-HBe: low replication state, lower infectivity
• Precore mutants: produce HBcAg but not HBeAg; associated with severe/fulminant disease

Hepatitis C (HCV)

• Flavivirus, 6 major genotypes; genotype 1 most common globally
• Extremely high mutation rate leading to quasispecies formation - facilitates immune escape
• No vaccine available
• Spontaneous clearance occurs in only ~15-20% of acute infections

Hepatitis D (HDV)

• Defective viroid; requires HBV co-infection to provide its envelope (HBsAg)
• Two presentations:
  • Coinfection: simultaneous HDV + HBV acute infection; usually self-limited
  • Superinfection: HDV in a chronic HBV carrier; more severe, often leads to chronic HDV + progressive disease

Hepatitis E (HEV)

• 4 genotypes: genotypes 1 and 2 - waterborne outbreaks in endemic areas; genotypes 3 and 4 - zoonotic (swine reservoir), sporadic in developed countries
• Most common cause of acute viral hepatitis worldwide (~20 million infections/year)
• Particularly severe in pregnant women (mortality up to 10-25% in 3rd trimester)

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3. EPIDEMIOLOGY AND TRANSMISSION

• HBV: 3-5% global prevalence; up to 10% in East Asia/sub-Saharan Africa
• HBV transmission risk from screened blood transfusion: ~1 in 360,000
• Universal HBV screening (all adults ≥18 years) recommended by CDC since 2023

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4. PATHOGENESIS

General Mechanism

• CD8+ cytotoxic T lymphocytes (CTL) sensitized to viral antigens (especially nucleocapsid proteins HBcAg/HBeAg expressed on hepatocyte membranes) destroy infected cells
• Pro-inflammatory cytokines, NK cells, and antibody-dependent cellular cytotoxicity (ADCC) also contribute
• Successful immune response → viral clearance ± jaundice → recovery
• Inadequate immune response → viral persistence → chronic hepatitis

HBV-Specific Immunopathogenesis

• Innate immune response (NK cells) dominates early: eliminates >90% of HBV DNA before T-cell infiltration
• NK cells paradoxically suppress helper CD4+ T cells → reduced CD8+ T cells → T-cell exhaustion
• Differences in robustness and polyclonality of CD8+ CTL response determine outcome:
  • Strong, broad CTL response → recovery
  • Weak/exhausted CTL response → chronicity
• HDV co-infection: has additional direct cytopathic effect in addition to immune-mediated injury

Fulminant Hepatitis

• Occurs when immune reaction is so potent that massive hepatocyte necrosis overwhelms liver regeneration
• More common with: HBV + HDV coinfection, precore mutants, HBV superinfection, HAV/HEV in pregnancy

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5. INCUBATION PERIODS

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6. CLINICAL FEATURES

Phases of Illness

• Constitutional symptoms: anorexia, nausea, vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia
• Characteristic distaste for cigarettes in smokers
• Alterations in olfaction and taste
• Low-grade fever (38-39°C) - more common in HAV/HEV; uncommon in serum hepatitis (HBV)
• Serum sickness-like syndrome in HBV: arthritis, urticaria, angioedema (due to immune complex deposition)
• Dark urine, pale stools, pruritus appear just before jaundice

• Constitutional symptoms often diminish with onset of jaundice
• Mild weight loss (2.5-5 kg) common
• Hepatomegaly with right upper quadrant tenderness
• Splenomegaly and cervical lymphadenopathy in 10-20%
• Rarely: spider angiomas (disappear in convalescence)
• Many patients do not become jaundiced (anicteric hepatitis) - more common in HCV than HBV

• Symptoms resolve; liver may remain enlarged with abnormal labs
• Duration: 2-12 weeks
• Complete recovery expected:
  • HAV and HEV: 1-2 months
  • HBV (healthy adults): 3-4 months; self-limited in 95-99%
  • HCV: only ~15-20% self-limited

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7. LABORATORY FEATURES

Aminotransferases (ALT/AST)

• Rise during the prodromal phase, before bilirubin rises (key exam point)
• Peak typically 400-4000 IU/L in acute viral hepatitis
• Level does not correlate well with degree of liver damage
• ALT > AST (unlike alcoholic hepatitis where AST:ALT > 2:1)

Other Labs

• Bilirubin: rises after aminotransferases; both conjugated and unconjugated elevated
• Alkaline phosphatase: usually only mildly elevated (unless cholestatic presentation)
• Prothrombin time: most sensitive indicator of severe hepatic dysfunction; prolonged PT signals risk of fulminant hepatic failure
• WBC: often normal to low (leukopenia) during prodrome; relative lymphocytosis; occasionally atypical lymphocytes
• Serum albumin: usually normal in acute hepatitis; hypoalbuminemia suggests chronicity or fulminant failure
• Urine urobilinogen: elevated early
• Hypoglycemia: may occur in fulminant hepatic failure

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8. SEROLOGIC DIAGNOSIS

HAV

HBV (Critical for exams - Table 350-5 from Harrison's)

HCV

• No IgM anti-HCV of clinical utility exists
• Anti-HCV positivity alone cannot distinguish acute from chronic or recovered infection - need HCV RNA

HDV

HEV

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9. COMPLICATIONS

Fulminant Hepatic Failure (FHF)

• Definition: severe acute hepatic insufficiency with encephalopathy within 8 weeks of onset in a person with no prior liver disease
• Incidence: <1% for HAV; ~1% for HBV (higher with HDV coinfection); rare for HCV; up to 1-2% for HEV
• Highest risk with HEV in pregnancy (up to 10-25% mortality in 3rd trimester)
• Features: encephalopathy, coagulopathy (markedly prolonged PT), cerebral edema, renal failure (hepatorenal syndrome), hypoglycemia
• Mortality without transplantation: 70-80%

Cholestatic Hepatitis

• Prolonged jaundice (weeks to months) with markedly elevated bilirubin and alkaline phosphatase
• Can mimic extrahepatic biliary obstruction
• More common with HAV; generally self-limited

Relapsing Hepatitis

• Occurs in 10-20% of HAV cases
• One or more relapses of aminotransferase elevation after apparent recovery
• Still self-limited; full recovery expected

Chronicity

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10. SPECIAL POPULATIONS

Pregnancy and HEV

• Genotype 1 HEV has disproportionately high mortality in pregnancy (3rd trimester)
• HEV-related FHF: may be related to impaired cell-mediated immunity in pregnancy

Perinatal HBV Transmission

• Risk: 70-90% when mother is HBeAg-positive
• Leads to immune tolerant chronic infection in >90% of perinatally infected children
• Prevention: HBV vaccine + HBIG within 12 hours of birth

Immunocompromised Hosts

• Nonhepatotropic viruses (CMV, EBV, HSV) more commonly cause severe hepatitis
• HEV genotype 3/4 can cause chronic hepatitis in immunocompromised (transplant recipients)

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11. MANAGEMENT

General Supportive Care

• Most patients do NOT require hospitalization
• Forced bed rest is not essential; restrict physical activity as symptoms dictate
• High-calorie diet preferred; major caloric intake in the morning (nausea worse in evenings)
• IV fluids if persistent vomiting prevents oral intake
• Avoid hepatotoxic drugs and drugs metabolized by the liver
• Cholestyramine for severe pruritus
• Glucocorticoids have no role in acute viral hepatitis and may increase risk of chronicity

Specific Antiviral Therapy

• Most adults (~99%) recover spontaneously; antiviral therapy NOT routinely required
• Indications for nucleoside analogue therapy (entecavir or tenofovir - most potent, least resistance-prone):
  • Fulminant hepatic failure (with referral to transplant center)
  • Prolonged course of acute hepatitis B (>4 weeks with severe disease)
• Treatment continued until: 3 months after HBsAg seroconversion OR 6 months after HBeAg seroconversion

• Spontaneous recovery: only ~15-20%
• Recommendation (current era of DAAs): early treatment with standard 8-12 week oral DAA regimen (same as chronic HCV first-line)
• No longer appropriate to wait 3-6 months for spontaneous resolution (was done in interferon era)
• Key populations to treat early:
  • Health care workers after needlestick (3% develop acute HCV)
  • Persons who inject drugs (rising incidence with opioid epidemic)

Hospitalization Criteria

• Encephalopathy (sign of fulminant failure)
• Coagulopathy (significantly prolonged PT)
• Persistent vomiting with inability to maintain oral intake
• Hypoglycemia
• Clinical deterioration

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12. PREVENTION AND VACCINATION

HAV Vaccine

• Inactivated virus vaccine; 2-dose schedule
• Indications: travelers, MSM, IVDU, chronic liver disease, food handlers
• Post-exposure prophylaxis: HAV vaccine (preferred) or immune globulin (within 2 weeks)

HBV Vaccine

• Recombinant HBsAg; 3-dose series (0, 1, 6 months); or 2-dose (Heplisav-B)
• Universal childhood vaccination recommended since 1991 in US (resulted in ~90% decline in new infections and ~85% reduction in HBsAg seropositivity in children)
• Universal adult screening ≥18 years (CDC, 2023)
• Post-exposure prophylaxis: HBV vaccine + HBIG (within 24 hours for high-risk exposures)

HEV Vaccine

• HEV 239 (Hecolin) - approved in China; not globally available

Passive Immunoprophylaxis

• HAV: immune globulin (ISG) within 2 weeks of exposure
• HBV: HBIG for unvaccinated/non-immune contacts; combined with vaccine for perinatal exposure

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13. KEY EXAM MNEMONICS & HIGH-YIELD POINTS

• Only IgM anti-HBc positive in window period of HBV
• HAV: relapsing course possible, no chronicity
• HBV + HDV coinfection: usually self-limited; HDV superinfection = worse prognosis
• ALT rises BEFORE bilirubin; PT prolongation = most sensitive marker of severe disease
• Glucocorticoids are CONTRAINDICATED in acute viral hepatitis
• HCV acute infection: treat early with DAAs (do not wait)
• HEV in pregnancy: highest mortality of all acute viral hepatitides
• Aminotransferase level does NOT correlate with histologic severity
• Anti-HCV does not protect against reinfection (unlike anti-HAV and anti-HBs)
• Neonatal HBV: >90% progress to chronic infection (vs. ~5% in adults)

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