Hepatitis B and C

Mechanism of acquisition — percutaneous/parenteral

• Injection drug use with shared equipment: the dominant route for HCV in the US and a major route for HBV; even a single sharing event transmits because HCV RNA persists in residual blood in syringes and cookers.
• Contaminated blood products or procedures: transfusion or organ transplant before routine anti-HCV screening of the blood supply (early 1990s), unregulated tattooing/piercing, and reuse of vials or hemodialysis equipment. Chronic hemodialysis remains a recognized risk factor.
• Occupational needlestick: HBV is by far the most transmissible per percutaneous exposure, HCV intermediate, HIV lowest — the ordering, not the exact percentage, is what stems test. HBV also survives on environmental surfaces for days, which HCV does not.

Mechanism — sexual and vertical

• Sexual transmission: efficient for HBV (multiple partners, MSM, other STIs); inefficient for HCV except with HIV coinfection, MSM sexual networks, or mucosal trauma.
• Perinatal transmission: the leading global route for HBV and the reason for near-universal chronicity — neonatal infection becomes chronic in the great majority because of immature immune clearance, whereas adult infection usually resolves. CDC and ACOG mandate HBsAg screening in every pregnancy.

• HBV viral replication and integration: HBV is a partially double-stranded DNA virus that replicates in hepatocytes via reverse transcriptase; the viral genome can integrate into host DNA, perpetuating chronic infection in ~90% of infected adults (higher in neonates). Integration and viral proteins (particularly HBsAg and HBeAg) trigger immune-mediated hepatocellular injury and inflammation.

• HCV direct cytotoxic and immune mechanisms: HCV is a positive-sense single-stranded RNA virus with high mutation rates; it causes hepatic inflammation through both direct viral cytopathicity and vigorous CD8+ T-cell responses. Unlike HBV, HCV rarely integrates into host DNA, yet still establishes persistent infection in ~80% of acutely infected individuals through immune evasion and viral diversity.

• Progression to cirrhosis: Both viruses cause chronic inflammation leading to hepatic stellate cell activation, excessive collagen deposition, and progressive fibrosis. This process typically occurs over 10–30 years but is accelerated by coinfection (HBV/HCV or HIV), alcohol use, hepatic steatosis, and older age at infection. Cirrhosis itself promotes portal hypertension, esophageal varices, ascites, and HCC development.

• Hepatocellular carcinoma (HCC) pathogenesis: Both viruses increase HCC risk through chronic inflammation, cirrhosis-induced genomic instability, and viral oncoproteins; HBV-encoded X protein (HBx) and HCV-encoded NS5A protein promote cellular proliferation and apoptosis evasion. HCC risk persists even after viral suppression, particularly in cirrhotic patients.

• Acute hepatitis (both HBV and HCV): Patients present with malaise, anorexia, jaundice, dark urine, and abdominal discomfort; fever and arthralgia are more common in acute HBV. Most adults with acute HBV clear infection spontaneously (~90%), while acute HCV is usually asymptomatic (70% of cases), delaying diagnosis.

• Chronic hepatitis (asymptomatic phase): The majority of chronically infected patients are asymptomatic for years or decades, with elevation of liver transaminases (ALT > AST in early HCV; AST > ALT suggests cirrhosis) discovered incidentally on laboratory screening. This silent progression underscores the importance of universal screening and risk-based surveillance.

• Advanced liver disease (cirrhosis and decompensation): Patients develop ascites, hepatic encephalopathy, variceal bleeding, jaundice, and coagulopathy. Portal hypertension complications (splenomegaly, thrombocytopenia) are common. Clinical decompensation signals need for urgent specialist evaluation and possible transplant consideration.

• Extrahepatic manifestations: HBV may present with serum sickness-like syndrome (arthralgia, urticaria) during acute infection or with polyarteritis nodosa and glomerulonephritis in chronic disease. HCV is associated with cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, and B-cell lymphomas.

• Fulminant hepatic failure: Rare but life-threatening; occurs in <1% of acute HBV infections (more common with HDV superinfection) and <1% of acute HCV but can appear with massive hepatic necrosis, coagulopathy, and encephalopathy requiring urgent transplant evaluation.

• Hepatitis B serology and interpretation: HBsAg (hepatitis B surface antigen) is the first marker of infection and indicates active or chronic infection; anti-HBs indicates immunity (from vaccination or resolved infection). HBeAg and HBeAb reflect viral replication status. Anti-HBc IgM indicates acute infection, while anti-HBc IgG (with HBsAg) indicates chronic infection. HBV DNA quantification by PCR assesses viral load and guides treatment decisions; >2×10⁵ IU/mL or >10⁴ copies/mL typically indicates high replication and treatment eligibility.

• Hepatitis C serology and RNA testing: Anti-HCV antibodies (by ELISA or rapid test) indicate exposure but do not distinguish acute, chronic, or resolved infection; antibodies can persist after viral clearance. HCV RNA by PCR is the gold standard for confirming active infection and is required before initiating treatment. Genotyping (6 major genotypes) guides duration of direct-acting antiviral (DAA) therapy; genotype 1 and 3 are most prevalent in North America.

• Additional diagnostic workup: Transaminases (ALT/AST), alkaline phosphatase, bilirubin, albumin, PT/INR, and platelet count assess hepatic synthetic function and degree of inflammation. Ultrasound or CT evaluates for cirrhosis signs (echogenicity, splenomegaly, ascites) and HCC surveillance. Liver biopsy or non-invasive fibrosis markers (FIB-4 score, transient elastography/FibroScan) stage fibrosis; biopsy is now rarely needed given availability of non-invasive methods.

• Important diagnostic pearls: HBsAg positivity >6 months defines chronic HBV. Anti-HCV with detectable HCV RNA indicates chronic or acute HCV requiring treatment. Occult HBV (HBsAg-negative, anti-HBc and/or HBV DNA positive) can reactivate with immunosuppression; screen high-risk patients undergoing immunotherapy. HBV/HCV coinfection accelerates cirrhosis and requires coordinated treatment.

• Hepatitis B antiviral therapy: Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are first-line agents; tenofovir alafenamide (TAF) and entecavir are preferred due to high efficacy and low resistance rates. Dosing: entecavir 0.5 mg daily (1 mg daily if lamivudine-resistant), tenofovir alafenamide 25 mg daily. Treatment indications include HBeAg-positive with ALT >5× upper limit normal (ULN) or HBV DNA >10⁷ IU/mL, or HBeAg-negative with ALT >2× ULN or HBV DNA >10⁶ IU/mL, or evidence of cirrhosis regardless of HBeAg/DNA status. Interferon-alpha is rarely used as first-line due to side effects but may achieve HBsAg clearance in select patients.

• Hepatitis C cure with direct-acting antivirals (DAAs): Sofosbuvir-based regimens (e.g., sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir) are pangenotypic and represent the standard of care. Typical treatment duration is 12 weeks (or 8 weeks for certain genotype/cirrhosis combinations); genotype-specific regimens may be shorter (e.g., glecaprevir/pibrentasvir for 8 weeks across all genotypes). DAA therapy achieves >95% cure rates (sustained virologic response at 12 weeks post-treatment, SVR12) even in cirrhotic patients; treatment is now recommended for all HCV-infected patients, including those with mild fibrosis or decompensated cirrhosis.

• Special populations and situations:
• HBV-infected pregnant women with high viral load (typically HBeA

Complications of the disease

• Cirrhosis and portal hypertension: stellate-cell–driven fibrosis raises sinusoidal resistance; signaled by thrombocytopenia, low albumin, rising INR, and a reversed AST/ALT ratio.
• Variceal hemorrhage — emergency: portosystemic collaterals rupture; hematemesis with hemodynamic collapse. Requires resuscitation, octreotide, prophylactic antibiotics (ceftriaxone), and urgent endoscopy per AASLD portal hypertension guidance.
• Spontaneous bacterial peritonitis — emergency: translocation of enteric flora into ascites; diagnostic paracentesis showing ascitic PMN ≥250/mm³ mandates cefotaxime plus albumin.
• Hepatic encephalopathy and hepatorenal syndrome — emergencies when acute; ammonia-driven cerebral edema and splanchnic vasodilation with renal hypoperfusion, respectively.
• Hepatocellular carcinoma: HBV can cause HCC without cirrhosis because integrated HBx drives oncogenesis directly; HCV-related HCC almost always arises in a cirrhotic liver. AASLD recommends ultrasound ± AFP every 6 months in cirrhosis and in at-risk HBV carriers. Risk persists after HCV cure.
• Acute liver failure — emergency: coagulopathy plus encephalopathy; transfer to a transplant center. Consider HDV superinfection in an HBsAg carrier with an abrupt flare.
• Immune-complex disease: HBV-associated polyarteritis nodosa; HCV-associated mixed cryoglobulinemia with palpable purpura, low C4, and membranoproliferative GN, which can be rapidly progressive.

Complications of treatment

• HBV reactivation — emergency: withdrawing a nucleos(t)ide analogue, or giving rituximab/anthracyclines/high-dose steroids to an HBsAg- or anti-HBc–positive patient, precipitates a severe hepatitis flare. AASLD advises prophylactic entecavir or tenofovir; FDA warns that reactivation can also occur during DAA therapy for HCV, so screen for HBV before starting DAAs.
• Tenofovir disoproxil fumarate: proximal tubulopathy (Fanconi syndrome) and bone density loss; tenofovir alafenamide mitigates this.
• Interferon: cytopenias, depression, autoimmune thyroiditis; contraindicated in decompensated cirrhosis.
• DAAs: protease-inhibitor–containing regimens are contraindicated in Child-Pugh B/C; sofosbuvir with amiodarone causes symptomatic bradycardia; ribavirin causes hemolytic anemia and is teratogenic.

• Window period: HBsAg has cleared but anti-HBs has not yet appeared — anti-HBc IgM is the only positive marker. Isolated anti-HBs = vaccination; anti-HBs plus anti-HBc IgG = resolved natural infection. HBsAg persisting beyond 6 months = chronic HBV.
• Single best next step after a positive anti-HCV: HCV RNA by PCR. Antibody alone cannot distinguish active from cleared infection, and anti-HCV is not protective — reinfection after cure is possible and there is no HCV vaccine.
• The association examiners love: HBV causes HCC even without cirrhosis (viral DNA integration, HBx oncoprotein); HCV essentially requires cirrhosis first. AASLD surveillance is ultrasound every 6 months, and it continues after DAA-induced SVR in anyone with established cirrhosis.
• Before any immunosuppression or DAA course, screen for HBV. A patient given rituximab without checking anti-HBc who then develops jaundice and a soaring HBV DNA is a reactivation vignette; prophylaxis is entecavir or tenofovir.
• HDV needs HBsAg to exist. Coinfection usually resolves with the HBV; superinfection of a chronic carrier produces a fulminant flare and high chronicity.
• Perinatal HBV: infant of an HBsAg-positive mother gets HBIG plus hepatitis B vaccine within 12 hours of birth; maternal antiviral therapy in the third trimester when viral load is high. Cesarean delivery is not routinely indicated and breastfeeding is not contraindicated.
• Buzzwords: ground-glass hepatocytes on biopsy = chronic HBV; palpable purpura + arthralgia + low C4 + RF positivity = HCV cryoglobulinemia; porphyria cutanea tarda (blistering dorsal-hand lesions) should prompt HCV testing.
• Common distractor: after a needlestick, HBV has post-exposure prophylaxis (HBIG ± vaccine per CDC) but HCV does not — the correct answer is serial HCV RNA testing and treatment if infection is confirmed, not immunoglobulin.