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Viral Hepatitis: Approach and Management

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Overview

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PART 1 - VIROLOGY AND ETIOLOGY

Hepatitis A (HAV)

• Nonenveloped 27-nm, heat-, acid-, and ether-resistant, single-stranded positive-sense RNA virus
• Genus Hepatovirus, family Picornaviridae
• Six genotypes (three affect humans), all belong to one serotype - immunologically indistinguishable
• Incubation period: ~3-4 weeks
• Replication limited to the liver; shed in feces during late incubation and preicteric phase
• Infectivity diminishes rapidly once jaundice appears
• No carrier state exists

Hepatitis B (HBV)

• 42-nm hepadnavirus with a double-stranded DNA genome
• Replicates through an RNA intermediate via reverse transcription (retrovirus-like)
• HBsAg (surface antigen) - the major outer envelope protein; presence indicates active infection
• HBcAg (core antigen) - not detectable in serum; only HBsAb from past infection
• HBeAg - marker of active replication and high infectivity
• Incubation: 1-6 months
• Transmission: parenteral (blood, IV drug use), sexual, perinatal

Hepatitis C (HCV)

• Single-stranded RNA flavivirus; 6 major genotypes (genotype 1 most common worldwide)
• Incubation: 7-8 weeks (range 2-26 weeks)
• Most commonly transmitted parenterally; high risk in IV drug users
• Spontaneous clearance occurs in only ~15-20% of cases - majority progress to chronic hepatitis

Hepatitis D (HDV) - Delta Virus

• Defective RNA virus that requires HBV for assembly and expression (needs HBsAg as its envelope)
• Can present as co-infection (simultaneous HBV + HDV) or superinfection (HDV in a chronic HBV carrier)
• Superinfection carries worse prognosis - higher rate of chronic hepatitis and cirrhosis

Hepatitis E (HEV)

• Nonenveloped, single-stranded RNA calicivirus
• Fecal-oral transmission (similar to HAV); waterborne outbreaks common in developing countries
• Particularly severe in pregnancy - case fatality rate up to 10-20% in pregnant women
• Generally self-limited; rare chronic infection in immunocompromised hosts (post-transplant patients)

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PART 2 - CLINICAL FEATURES AND APPROACH

Phases of Acute Viral Hepatitis

• Constitutional symptoms: malaise, fatigue, anorexia, nausea, vomiting
• Right upper quadrant discomfort
• Low-grade fever (especially in HAV)
• Arthralgias, myalgias (especially in HBV - serum sickness-like)
• Smokers often lose taste for cigarettes - a classic early clue

• Jaundice appears as prodromal symptoms subside
• Dark urine, light-colored stools, pruritus
• Hepatomegaly, splenomegaly (~20%)
• Symptoms improve as jaundice peaks

• Gradual resolution of symptoms and laboratory abnormalities

Laboratory Findings

• ALT and AST: Markedly elevated (often >10x ULN); ALT > AST typically
• Bilirubin: Elevated (direct + indirect) during icteric phase
• Alkaline phosphatase: Mildly elevated
• PT/INR: Prolonged in severe disease - best indicator of hepatic synthetic function
• CBC: Mild leukopenia, relative lymphocytosis; atypical lymphocytes may be seen

Serologic Markers - Summary

Extrahepatic Manifestations

• Serum sickness-like syndrome in HBV: urticaria, arthralgias, arthritis (immune complex deposition)
• Polyarteritis nodosa - associated with chronic HBV
• Cryoglobulinemia - strongly associated with chronic HCV
• Membranoproliferative glomerulonephritis - HCV
• Porphyria cutanea tarda - HCV

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PART 3 - MANAGEMENT

Acute Viral Hepatitis - General Measures

• Hospitalization: Required only for clinically severe illness; most patients managed as outpatients
• Rest: Bed rest is not essential; restrict activity as the patient feels necessary
• Diet: High-calorie diet preferred; major caloric intake in the morning (patients often nauseated in evenings)
• IV fluids: If persistent vomiting prevents oral intake
• Avoid: Hepatotoxic drugs and drugs metabolized by the liver
• Pruritus: Cholestyramine (bile salt-sequestering resin)
• Glucocorticoids: Contraindicated - no value even in severe cases; may increase risk of chronicity (especially in HBV)
• Alcohol: Avoid completely
• Isolation: Standard precautions; contact precautions for HAV and HEV in healthcare settings

Specific Treatment - Acute Hepatitis B

• Typical acute HBV in healthy adults: No antiviral therapy needed - recovery rate ~99%
• Severe acute hepatitis B (fulminant liver failure or prolonged course >4 weeks): Treat with oral nucleoside analogue - entecavir or tenofovir (most potent, least resistance-prone)
• Continue until 3 months after HBsAg seroconversion or 6 months after HBeAg seroconversion

Specific Treatment - Acute Hepatitis C

• Spontaneous recovery rate: only ~15-20%
• In the era of direct-acting antivirals (DAAs), waiting for spontaneous recovery is no longer advised
• Early treatment with a standard 8-12 week course of first-line DAA combination is recommended
• High-risk groups to treat: healthcare workers with needle stick injuries (~3% develop acute HCV), IV drug users

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PART 4 - CHRONIC HEPATITIS: CLASSIFICATION

Classification by Cause

• Chronic viral hepatitis (HBV, HCV, HDV)
• Drug/toxin-induced
• Alcohol-associated
• Metabolic (MASLD - metabolic dysfunction-associated steatotic liver disease)
• Autoimmune hepatitis

Classification by Grade (Histologic Activity)

• Periportal necrosis / interface hepatitis (piecemeal necrosis)
• Bridging necrosis (portal-portal or portal-central bridges)
• Focal hepatocyte degeneration and necrosis

Classification by Stage (Fibrosis)

• METAVIR F0-F4 scale; F4 = cirrhosis
• Non-invasive alternatives: FibroScan (transient elastography), FIB-4 score, APRI

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PART 5 - MANAGEMENT OF CHRONIC HEPATITIS

Chronic Hepatitis B - Management

• HBV DNA >2,000 IU/mL with elevated ALT or significant fibrosis
• All patients with cirrhosis regardless of HBV DNA level
• HBeAg-positive chronic hepatitis with high viral load

• HBeAg-positive disease: HBeAg seroconversion to anti-HBe, then continue 1 year; HBsAg loss is ideal endpoint
• HBeAg-negative disease: Long-term, often indefinite therapy required
• Cirrhosis: Indefinite therapy; HBsAg loss is the only endpoint allowing cessation

Chronic Hepatitis C - Management

• Cirrhosis: May require extended 16-24 week courses or addition of ribavirin
• Prior treatment failure: Choice based on resistance-associated substitutions (RAS) testing
• Renal impairment: Glecaprevir/pibrentasvir preferred (no renal dose adjustment needed)
• Drug interactions: Check for interactions with all DAAs (especially NS3/4A inhibitors)

Chronic Hepatitis D - Management

• Nucleoside analogues for HBV do not work for HDV (HDV replicates using host RNA polymerase)
• Treat underlying HBV if HBV DNA >2×10³ IU/mL
• PEG IFN-α (high dose) for 48 weeks remains the primary option:
  • ~25-50% achieve undetectable HDV RNA at 24 weeks post-treatment
  • Long-term durable suppression in only ~12%
  • Extending therapy to 2 years provides no additional benefit
• Bulevirtide (entry inhibitor blocking NTCP receptor - prevents HBV and HDV hepatocyte entry):
  • Conditionally authorized by European Medicines Agency (EMA) since 2020
  • Phase 3 data: 45-48% had ≥2 log reduction or undetectable HDV RNA at 48 weeks; maintained through 96 weeks
  • ALT normalization in 51-56% of patients
• Lonafarnib/ritonavir (prenylation inhibitor): Phase 2 studies show significant on-treatment reductions; still experimental
• Liver transplantation for end-stage liver disease (HDV recurrence prevented by anti-HBs immunoglobulin + nucleoside analogues post-transplant)

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PART 6 - PREVENTION

Hepatitis A

• Vaccine: Highly effective, two-dose inactivated vaccine (Havrix, Vaqta); recommended for all children at age 1, travelers to endemic areas, MSM, IV drug users, chronic liver disease patients
• Post-exposure prophylaxis: Single-antigen HAV vaccine or immune globulin (0.1 mL/kg IM) within 2 weeks of exposure
• Sanitation and safe water/food practices

Hepatitis B

• Vaccine: Recombinant HBsAg vaccine (three-dose series at 0, 1, 6 months); highly effective
• Universal vaccination for all infants; catch-up vaccination for unvaccinated adolescents and adults
• Post-exposure prophylaxis: HBIG (0.06 mL/kg IM) + HBV vaccine within 24 hours (e.g., needle sticks, neonates born to HBsAg-positive mothers)
• Safe injection practices, screening of blood products

Hepatitis C

• No vaccine available
• Prevention through harm reduction (needle exchange programs, safe sex)
• Universal screening recommended (anti-HCV testing for all adults 18-79 in the US)
• Post-exposure: No effective prophylaxis; monitor for acute HCV and treat early with DAAs

Hepatitis D

• Prevention through HBV vaccination (preventing HBV also prevents HDV)
• HDV-specific vaccine under development

Hepatitis E

• No licensed vaccine in Western countries (recombinant HEV vaccine licensed in China)
• Safe water and sanitation
• Pregnant women should avoid travel to hyperendemic areas
• Ribavirin used for chronic HEV in immunosuppressed patients (off-label)

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PART 7 - COMPLICATIONS AND PROGNOSIS

Fulminant Hepatic Failure (FHF)

• Defined as coagulopathy (INR >1.5) with encephalopathy within 26 weeks of illness onset
• Most common with HBV (especially with HDV superinfection), rare with HCV
• Mortality without transplantation: >80%
• Management: ICU care, lactulose, early transplant evaluation
• Risk factors: Older age, jaundice-to-encephalopathy interval >7 days, bilirubin >300 μmol/L

Chronic Complications

• Cirrhosis: HBV (~20% at 20 years), HCV (~20-30% at 20 years)
• Hepatocellular carcinoma (HCC): Major long-term complication of HBV and HCV cirrhosis; HCC can also develop in non-cirrhotic HBV patients
• HCC surveillance: Ultrasound + AFP every 6 months in all patients with cirrhosis and in HBV patients with family history or high viral load

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