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Hepatitis - Complete Clinical Overview

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Classification at a Glance

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Pathophysiology (General)

1. Viral entry into hepatocytes via specific surface receptors
2. Innate immune activation - interferon release, NK cell recruitment
3. Cytotoxic T lymphocyte (CTL) attack on infected hepatocytes - responsible for most of the liver damage (not the virus directly)
4. Hepatocyte necrosis and apoptosis - leads to elevated transaminases (AST, ALT)
5. Cholestasis - impaired bile flow causes jaundice, dark urine, pale stools
6. Resolution or chronicity - depends on the virus and host immune response

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Clinical Phases

• Fatigue, malaise, anorexia, nausea, vomiting, right upper quadrant (RUQ) pain
• Flu-like symptoms: fever, headache, myalgia
• Immune-complex-mediated: rash, urticaria, arthralgias (10-20% of cases)
• Leukopenia with relative lymphocytosis

• Jaundice, dark urine (bilirubinuria), acholic (pale) stools
• Pruritus (in cholestatic forms)
• Hepatomegaly, possible splenomegaly
• LFTs: ALT/AST often >10x upper limit of normal (frequently >1000 U/L)
• Elevated total and direct bilirubin

• Gradual normalization of LFTs and resolution of symptoms

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Hepatitis A (HAV)

• Relapsing cholestatic hepatitis occurs in 3-20% before full recovery
• HAV is the most common cause of relapsing cholestatic hepatitis
• No chronic form - always self-limited

• Acute infection: Anti-HAV IgM (peaks at ~2 months, clears by 4-12 months) - diagnostic
• Past immunity: Anti-HAV IgG (persists for decades/lifetime)
• HAV RNA detectable in stool 2 weeks before to 2 weeks after jaundice onset

• Inactivated vaccine (2 doses, 6-18 months apart) - ~94% protective efficacy, lifelong protection
• Live attenuated vaccine (single dose, used in China)
• Combination HAV+HBV and HAV+typhoid vaccines available
• Human immunoglobulin (IG): 80-90% effective if given within 14 days of exposure; protection lasts 1-5 months
• Improved sanitation and hand hygiene

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Hepatitis B (HBV)

• Neonatal/perinatal infection: 85-95% risk of chronicity
• Early childhood: ~30% chronicity
• Adult infection: 95-99% spontaneous resolution; fulminant hepatitis in ~0.1%
• In women HBeAg+ during pregnancy: ~90% vertical transmission without prophylaxis

• Acute HBV: Supportive - no antiviral therapy (self-resolves in 95-99% of adults)
• Chronic HBV: Antivirals - first-line agents include tenofovir (TDF or TAF) or entecavir; pegylated interferon-alpha is an alternative. Goal: suppress HBV DNA, prevent cirrhosis/HCC.
• In pregnancy: Tenofovir preferred (potent, safe, low resistance risk)
• Post-exposure prophylaxis (HCP): Hepatitis B immunoglobulin (HBIG) 0.06 mL/kg IM within 96h + start vaccine series (if unvaccinated)

• HBV vaccine (3 doses: 0, 1, 6 months) - safe, effective, >95% seroconversion
• Universal infant vaccination has dramatically reduced transmission
• Neonatal: HBIG + vaccine within 12 hours of birth if mother is HBsAg+
• The 2025 AGA guideline on HBV reactivation (PMID 39863345) also addresses prevention in immunosuppressed patients receiving biologics/chemotherapy

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Hepatitis C (HCV)

• Intravenous drug use (60-80% of new cases in developed countries)
• Unsafe medical/surgical procedures, blood transfusions (in developing countries)
• Nosocomial (contaminated equipment)
• Sexual transmission is less efficient than HBV; perinatal ~5-6%

• Acute HCV is often asymptomatic or mildly symptomatic - frequently goes undetected
• Chronic HCV: progressive liver fibrosis over decades, cirrhosis in ~20%, HCC

• Screening: Anti-HCV antibody (by ELISA/chemiluminescent assay)
• Confirmation: HCV RNA by PCR (detectable within weeks of infection)
• Genotyping guides treatment selection

• Acute HCV: Antiviral treatment indicated (because of 50-80% chronicity risk). Pegylated interferon ± ribavirin historically used; now direct-acting antivirals (DAAs) are preferred.
• Chronic HCV: DAA combinations achieve >95% sustained virological response (SVR/cure)
  • Pan-genotypic regimens: sofosbuvir/velpatasvir (12 weeks), glecaprevir/pibrentasvir (8-12 weeks)
  • SVR = undetectable HCV RNA 12 weeks after treatment = functional cure
• No vaccine available
• No role for post-exposure immunoglobulin
• Pregnancy: treatment not recommended during pregnancy; initiate post-delivery

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Hepatitis D (HDV) - Delta Hepatitis

1. Co-infection (HDV + HBV simultaneously): usually self-limited; higher risk of fulminant hepatitis
2. Superinfection (HDV in a chronic HBV carrier): often leads to chronic HDV infection, rapid progression to cirrhosis, worse prognosis

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Hepatitis E (HEV)

• Genotypes 1 & 2: Strictly human; fecal-oral, waterborne epidemics in Asia/Africa
• Genotypes 3 & 4: Zoonotic (pigs, wild boar, deer); sporadic cases in Europe, US, Japan
• Now considered the most common cause of acute viral hepatitis worldwide

• Incubation: 3-8 weeks
• Usually mild and self-limited in immunocompetent adults
• Severe disease in pregnant women - particularly genotypes 1 & 2: mortality up to 20-25% in the third trimester (fulminant hepatic failure)
• Chronic HEV in immunocompromised patients (transplant recipients, HIV) - especially genotype 3
• Neurological complications: Guillain-Barré syndrome association

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Diagnosis - Key Laboratory Approach

• AST, ALT: Often >10x ULN (frequently >1000 U/L)
• Bilirubin: Elevated total and direct
• ALP/GGT: Elevated in cholestatic forms
• PT/INR: Elevated in severe disease (reflects synthetic function)

Suspected acute hepatitis
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Anti-HAV IgM → HAV
HBsAg + Anti-HBc IgM → Acute HBV
Anti-HCV + HCV RNA → HCV
Anti-HDV (in HBsAg+ patient) → HDV
Anti-HEV IgM → HEV

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Non-Viral Causes of Hepatitis

• Alcoholic hepatitis: AST:ALT ratio >2:1; tender hepatomegaly, fever, jaundice
• Drug-induced liver injury (DILI): Paracetamol, INH, statins, herbal remedies
• Autoimmune hepatitis: Young women; ANA, anti-smooth muscle antibodies, elevated IgG; responds to steroids
• NAFLD/NASH: Metabolic syndrome association; now the most common cause of chronic liver disease in developed countries
• Other viruses: CMV (owl's eye inclusions), EBV, HSV (vesicular rash; acyclovir), VZV

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Complications

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Summary Table

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• Goldman-Cecil Medicine, Chapter 134 (Acute Viral Hepatitis)
• Park's Textbook of Preventive and Social Medicine, Viral Hepatitis chapter
• Frameworks for Internal Medicine, Infectious Causes of Hepatocellular Injury
• AGA 2025 Clinical Practice Guideline on HBV Reactivation (PMID 39863345)
• WHO Hepatitis B Fact Sheet 2024