Gastrointestinal · PANCE / PANRE

Viral Hepatitis (A, B, C)

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

Acute and chronic hepatocellular inflammation from hepatotropic viruses; transmission, course, and treatment differ by type.

Also known as: viral hepatitis, hepatitis A, hepatitis B, hepatitis C, HAV, HBV, HCV

Overview

Hepatocellular inflammation caused by hepatotropic viruses. Hepatitis A (HAV — picornavirus, fecal-oral, acute only); Hepatitis B (HBV — hepadnavirus, parenteral/sexual/perinatal, acute and chronic, DNA virus with reverse transcriptase); Hepatitis C (HCV — flavivirus, parenteral/sexual, predominantly chronic, RNA virus).

Epidemiology

HAV: outbreaks in food/water-contaminated settings; 6,500 cases/yr US (peaks with outbreaks). HBV: 1.5 million chronic carriers in US, 296 million worldwide. HCV: 2.4 million chronic infections in US; rising due to opioid epidemic and injection drug use; baby boomers (1945-1965) carry disproportionate burden.

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Question 1GastrointestinalMedium
A patient's hepatitis serology shows: HBsAg negative, anti-HBs positive, anti-HBc IgG positive, anti-HBc IgM negative, HBeAg negative. Which interpretation is correct?
  • AAcute hepatitis B in window period
  • BChronic hepatitis B with high infectivity
  • CPast hepatitis B with resolved immunity
  • DVaccination without prior infection
Reveal answer & full explanation
Correct answer: C — Past hepatitis B with resolved immunity
  • AAcute hepatitis B in window period
  • BChronic hepatitis B with high infectivity
  • CPast hepatitis B with resolved immunity✓
  • DVaccination without prior infection

Why past hepatitis B with resolved immunity is correct

  • Pattern: HBsAg(−), anti-HBs(+), anti-HBc IgG(+), anti-HBc IgM(−) = recovered past infection with immunity
  • Anti-HBc IgG indicates past or ongoing infection and is NOT produced by vaccination

Why the others are wrong

  • A) Acute hepatitis B in window period — Window period pattern: HBsAg(−), anti-HBs(−), anti-HBc IgM(+); this patient's anti-HBc is IgG (not IgM) and anti-HBs is positive
  • B) Chronic hepatitis B with high infectivity — Chronic hepatitis B virus (HBV) infection requires HBsAg(+) for >6 months; HBeAg indicates high infectivity; both are absent here
  • D) Vaccination without prior infection — Vaccination produces ONLY anti-HBs(+); anti-HBc IgG is absent after vaccination and its presence here indicates true prior infection

Additional high-yield points

  • HBsAg = active infection (acute or chronic)
  • Anti-HBs = immunity (vaccination or recovery)
  • Anti-HBc IgM = acute/recent infection
  • HBeAg = high infectivity
Question 2GastrointestinalMedium
A 48-year-old man with a remote history of injection drug use is found to have a hepatitis C RNA level of 2 million IU/mL that has persisted for 8 months, along with mildly elevated aminotransferases. Genotype 1a infection is confirmed and liver stiffness suggests early fibrosis. He is started on a fixed-dose combination regimen for chronic hepatitis C. Which of the following describes the mechanism of action of the sofosbuvir component of his regimen?
  • AInhibits the NS5B viral polymerase
  • BInhibits the NS3/4A serine protease
  • CInhibits the NS5A complex protein
  • DDepletes GTP via IMP dehydrogenase
Reveal answer & full explanation
Correct answer: A — Inhibits the NS5B viral polymerase
  • AInhibits the NS5B viral polymerase✓
  • BInhibits the NS3/4A serine protease
  • CInhibits the NS5A complex protein
  • DDepletes GTP via IMP dehydrogenase

Why Inhibits the NS5B viral polymerase is correct

  • This patient has chronic hepatitis C, acquired through injection drug use, the leading bloodborne transmission route in the U.S.; persistence beyond 6 months defines chronic infection, which develops in most untreated patients and drives cirrhosis and hepatocellular carcinoma.
  • Modern therapy uses direct-acting antivirals that target specific nonstructural (NS) proteins of the HCV replication machinery.
  • Sofosbuvir is a nucleotide analog that is incorporated into the growing viral RNA strand and inhibits the NS5B RNA-dependent RNA polymerase, terminating replication, so that is the correct mechanism.

Why the others are wrong

  • Inhibits the NS3/4A serine protease — this is the mechanism of the '-previr' agents (e.g., glecaprevir, grazoprevir), a different DAA class than sofosbuvir.
  • Inhibits the NS5A complex protein — this describes the '-asvir' agents (e.g., ledipasvir, velpatasvir), which are often co-formulated with sofosbuvir but act on a distinct target.
  • Depletes GTP via IMP dehydrogenase — this is the mechanism of ribavirin, an older adjunctive antiviral, not sofosbuvir.

Recognizing sofosbuvir as the NS5B polymerase inhibitor is the key pharmacologic point.

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Risk factors

  • HAV: fecal-oral; travel to endemic areas, contaminated food/water (raw shellfish), MSM, homelessness, IV drug use, daycare outbreaks
  • HBV: parenteral (IV drug use, needlestick, transfusion before 1992), sexual contact, perinatal (vertical transmission — most important worldwide), MSM, dialysis, multiple partners
  • HCV: parenteral (IV/intranasal drug use — leading risk factor; transfusion before 1992; tattooing with unsterile equipment), perinatal (~5%), sexual (less efficient; higher in MSM/HIV), needlestick, dialysis
  • Birth cohort: HCV — born 1945-1965 (USPSTF universal screening)

Pathophysiology

HAV: cytopathic and immune-mediated; no chronic state. HBV: non-cytopathic; hepatocyte injury immune-mediated (CD8 T cells targeting infected hepatocytes); cccDNA in nucleus drives chronicity; viral DNA can integrate into host genome (HCC risk even without cirrhosis). HCV: high mutation rate (lacks proofreading) drives quasispecies and immune evasion; chronicity in 75-85%; cirrhosis develops over 20-30 yr.

Clinical presentation

Symptoms

  • Acute hepatitis (any type): malaise, fatigue, anorexia, nausea, vomiting, RUQ pain, low-grade fever, arthralgias, jaundice, dark urine, pale stools
  • Prodromal flu-like symptoms 1-2 weeks before jaundice
  • Asymptomatic in most acute HBV/HCV cases
  • Chronic infection: often asymptomatic; fatigue, intermittent RUQ discomfort; complications of cirrhosis (ascites, variceal bleed, encephalopathy)
  • Fulminant hepatic failure (<1% acute HAV/HBV): encephalopathy, coagulopathy, cerebral edema

Signs / physical exam

  • Jaundice, scleral icterus
  • Tender hepatomegaly
  • Splenomegaly possible
  • Stigmata of chronic liver disease (in chronic infection with cirrhosis): spider angiomata, palmar erythema, gynecomastia, caput medusae, ascites, asterixis
  • Extrahepatic manifestations of chronic HBV: polyarteritis nodosa, membranous nephropathy
  • Extrahepatic manifestations of chronic HCV: cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, B-cell lymphoma

Classic findings

HAV: traveler to endemic area, raw shellfish, daycare exposure; acute illness, full recovery. HBV: 'serologic chase' (HBsAg, anti-HBs, anti-HBc IgM/IgG, HBeAg, anti-HBe). HCV: incidental detection of elevated ALT or positive antibody; new injection drug use.

Differential diagnosis

  • Alcoholic hepatitis — AST:ALT ratio >2:1, both <500; alcohol history; macrocytosis, GGT elevation
  • Autoimmune hepatitis — Female, elevated IgG, ANA/anti-smooth muscle (type 1) or anti-LKM1 (type 2); responds to steroids
  • Drug-induced liver injury (acetaminophen, INH, statins, amiodarone, methotrexate) — Medication exposure; RUCAM score; resolves with discontinuation
  • Hemochromatosis — Elevated ferritin and transferrin saturation; HFE mutation; arthropathy, bronze diabetes
  • Wilson disease — Young patient, neuropsychiatric symptoms, Kayser-Fleischer rings, low ceruloplasmin, elevated urinary copper
  • Alpha-1 antitrypsin deficiency — Low serum A1AT, MZ/ZZ phenotype, COPD in younger patients
  • Non-alcoholic steatohepatitis (MASH) — Metabolic syndrome features; ALT > AST; biopsy or imaging
  • Ischemic hepatitis ('shock liver') — ALT/AST in thousands rapidly after hypotensive event; resolves quickly
  • Hepatitis D, E, EBV, CMV, HSV — Specific serologies; HDV requires HBV co-infection
  • Biliary obstruction — Cholestatic LFT pattern; dilated ducts on imaging

Diagnostic workup

Diagnostic criteria

HAV: anti-HAV IgM positive. HBV acute: HBsAg + anti-HBc IgM. HBV chronic: HBsAg positive >6 months. HBV cleared: anti-HBs + anti-HBc IgG, HBsAg negative. HBV vaccine response: isolated anti-HBs (no anti-HBc). HCV active: anti-HCV + HCV RNA detectable.

Labs

  • ALT, AST — often in 1000s in acute viral hepatitis; AST < ALT typically
  • Bilirubin (total and direct), alk phos, GGT
  • INR, albumin (synthetic function — prognostic)
  • CBC (thrombocytopenia in chronic disease/cirrhosis)
  • Serologic panel based on clinical context:
  • HAV: anti-HAV IgM (acute), anti-HAV IgG (immunity)
  • HBV: HBsAg (active infection), anti-HBs (immunity from vaccine or recovery), anti-HBc IgM (acute), anti-HBc IgG (current or past), HBeAg (high infectivity), anti-HBe, HBV DNA (viral load)
  • HCV: anti-HCV antibody (screening); if positive → HCV RNA (confirms active infection); HCV genotype (less critical with pan-genotypic DAAs)
  • HIV testing in all suspected viral hepatitis
  • Hepatitis D antibody if HBsAg positive
  • Alpha-fetoprotein (chronic HBV/HCV — HCC surveillance)
  • Iron studies, ceruloplasmin, A1AT, autoimmune workup as indicated to exclude other causes

Imaging

  • Abdominal ultrasound — assess for cirrhosis, splenomegaly, ascites, HCC; first-line
  • Transient elastography (FibroScan) or MR elastography — non-invasive fibrosis assessment
  • FIB-4 and APRI scores — calculated from labs, useful for fibrosis staging
  • Liver biopsy rarely required for fibrosis staging in HBV/HCV with current non-invasive options
  • CT/MRI for evaluation of suspicious hepatic lesions

Diagnostic algorithm

HBV Serologic PatternHBsAgAnti-HBsAnti-HBc IgMAnti-HBc IgGInterpretation
Acute infection+-++/-Active acute hepatitis B
Window period--++/-Acute, between HBsAg loss and anti-HBs
Chronic infection+ (>6 mo)--+Chronic hepatitis B
Resolved infection-+-+Recovered, immune
Vaccine immunity-+--Vaccine response (no anti-HBc)
Isolated anti-HBc---+Resolved, false positive, or occult HBV — check HBV DNA
Hepatitis B serologic interpretation chart.

Treatment

First-line

  • Supportive care for acute hepatitis A — most resolve spontaneously
  • Acute HBV — supportive care; antivirals (entecavir, tenofovir) only for fulminant or severe acute hepatitis
  • Chronic HBV — see by_subtype for treatment indications
  • Chronic HCV — direct-acting antiviral (DAA) therapy — see by_subtype
  • Universal precautions; partner testing and vaccination
  • Avoid alcohol, hepatotoxic medications, weight management
  • HCC surveillance with US ± AFP every 6 months in cirrhotic patients and high-risk HBV carriers

Hepatitis A — prevention and post-exposure

  • Vaccination: 2-dose series; recommended for travelers, MSM, IV drug users, chronic liver disease, occupational exposure, homeless persons, post-exposure prophylaxis within 2 weeks
  • Post-exposure prophylaxis: HAV vaccine for healthy persons 12 months-40 yr; immune globulin for <12 months, >40 yr, immunocompromised, or chronic liver disease
  • No specific antiviral therapy; supportive care

Chronic Hepatitis B — treatment indications (AASLD 2018)

  • Treat: immune-active phase (HBeAg+ with HBV DNA >20,000 and elevated ALT, or HBeAg- with HBV DNA >2,000 and elevated ALT) OR cirrhosis with any detectable HBV DNA
  • Preferred first-line: entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) — high barrier to resistance
  • Pegylated interferon — alternative; finite duration; selected patients (young, no cirrhosis, high ALT, low HBV DNA, HBeAg+ genotype A or B)
  • Vaccinate household contacts and sexual partners (3-dose hepatitis B vaccine)
  • Post-exposure prophylaxis: HBIG + vaccine within 24 h for unvaccinated exposed individuals
  • Pregnancy: tenofovir for HBV DNA >200,000 IU/mL in 3rd trimester to prevent vertical transmission; HBIG + vaccine for infant at birth

Chronic Hepatitis C — direct-acting antivirals (AASLD 2023)

  • Universal treatment recommended — all patients with chronic HCV regardless of fibrosis stage
  • Pan-genotypic DAA regimens: sofosbuvir/velpatasvir (Epclusa) × 12 weeks OR glecaprevir/pibrentasvir (Mavyret) × 8 weeks (treatment-naive without cirrhosis)
  • Decompensated cirrhosis: sofosbuvir/velpatasvir + ribavirin × 12 weeks
  • Retreatment after DAA failure: sofosbuvir/velpatasvir/voxilaprevir (Vosevi)
  • Cure (SVR12) achieved in >95% of patients
  • HCC surveillance continues in cirrhotic patients despite SVR

Second-line / adjunct

  • Liver transplantation for fulminant hepatic failure or decompensated cirrhosis
  • Manage cirrhosis complications: ascites (sodium restriction, diuretics, paracentesis, TIPS), varices (beta-blockers, EVL), encephalopathy (lactulose, rifaximin), HCC (LI-RADS surveillance, locoregional or systemic therapy)
  • Treat extrahepatic manifestations: cryoglobulinemic vasculitis with rituximab + DAAs; HCV-associated MPGN responds to viral eradication

Complications

  • Acute: fulminant hepatic failure (<1% HAV/HBV; rare HCV); cholestatic hepatitis; relapsing hepatitis A
  • Chronic: cirrhosis, portal hypertension, ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome
  • Hepatocellular carcinoma (HBV and HCV — even without cirrhosis in HBV; surveillance recommended)
  • Cryoglobulinemia, glomerulonephritis (HCV > HBV)
  • Polyarteritis nodosa (HBV)
  • Lymphoproliferative disorders (HCV)
  • Reactivation: HBV reactivation with immunosuppression (chemotherapy, anti-CD20, anti-TNF) — screen all patients receiving immunosuppression

PANCE pearls

  • HCV screening: USPSTF (2020) recommends one-time universal screening for all adults age 18-79 and repeat screening in those with ongoing risk (injection drug use, hemodialysis).
  • Universal HCV treatment with DAAs — all infected patients regardless of fibrosis stage. >95% cure with 8-12 week oral regimens.
  • HBV reactivation: screen ALL patients before immunosuppression (chemotherapy, rituximab, anti-TNF, transplant) — HBsAg, anti-HBc, anti-HBs. Prophylax with entecavir or tenofovir during and 6-12 months after immunosuppression.
  • Hepatitis B vaccine: 3-dose series; universal infant immunization since 1991; adults now universally recommended (ACIP 2022) for ages 19-59 and ≥60 with risk factors.
  • Hepatitis A vaccine: 2-dose series; consider for ALL patients with chronic liver disease, MSM, IV drug users, travelers, homeless.
  • AASLD HCC surveillance: every 6 months with ultrasound ± AFP in all cirrhotic patients and high-risk HBV carriers (Asian male >40, Asian female >50, African >20, family history HCC, cirrhotic).
  • HBeAg-negative chronic HBV is now the predominant form globally — precore mutations; HBV DNA is the key marker, not HBeAg.
  • Fulminant hepatic failure: INR ≥1.5 + encephalopathy in patient without prior liver disease — refer immediately to transplant center.
  • Avoid acetaminophen >2 g/day in chronic liver disease; AVOID NSAIDs in cirrhosis (renal failure, GI bleed risk).
  • Vaccinate HBV and HAV in patients with chronic HCV or chronic liver disease of any cause.

References

  • AASLD HBV 2018 — Terrault NA et al. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology 2018;67:1560-1599
  • AASLD/IDSA HCV — AASLD-IDSA HCV Guidance Panel. Recommendations for Testing, Managing, and Treating Hepatitis C. hcvguidelines.org (2023 update)
  • USPSTF HCV 2020 — US Preventive Services Task Force. Screening for Hepatitis C Virus Infection in Adolescents and Adults. JAMA 2020;323:970-975
  • ACIP HBV 2022 — Weng MK et al. Universal Hepatitis B Vaccination in Adults Aged 19-59 Years: Updated ACIP Recommendations. MMWR 2022;71:477-483

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Differentials & related conditions

Wilson Disease

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