Epidemiology

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Etiology

• Parenteral
  • Needle sharing among individuals who use injection drugs
  • Needlestick injury (e.g., health care workers)
  • Blood transfusion
  • Dialysis
• Organ transplantation
• Sexual: rare (in contrast to HBV and HIV)

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Pathophysiology

Pathogen

• The risk of chronic infection is multifactorial and depends on the host’s ability to clear the pathogen through activation of multiple innate immunity pathways against the viral envelope.
  • Flawed proofreading capability of RNA-dependent RNA polymerase (no 3′– 5′ exonuclease activity) introduces mutations into genes encoding viral glycoprotein envelope and enabling novel antigen production.
  • Rapid replication rate produces many antigenically unique viral envelopes.
  • Infection persists because the production rate of new mutant virions exceeds the production rate of host antibodies.

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Clinical features

Mnemonic

HAV only has acute phase, HCV mostly has chronic phase (and is curable)

Incubation period

• 2 weeks to 6 months

Acute course (< 6 months)

• Asymptomatic in 80% of cases

Chronic course (> 6 months)

• Seen especially in asymptomatic individuals (up to 85%), as the disease may go undiagnosed and treatment may be delayed or never initiated (carrier state).
• Findings often mild, nonspecific (e.g., fatigue)
• Liver cirrhosis (up to 25% of cases) within 20 years of infection
• Extrahepatic features of HCV (common)
  • Hematological
    • Mixed cryoglobulinemia
    • Lymphoma (especially B-cell non-Hodgkin lymphoma)
    • ITP
    • Autoimmune hemolytic anemia
    • Monoclonal gammopathies
  • Renal
    • Membranoproliferative glomerulonephritis (more common)
    • Membranous glomerulonephritis
  • Dermatological
    • Porphyria cutanea tarda
    • Lichen planus
  • Endocrine
    • Diabetes mellitus
    • Autoimmune thyroiditis (may lead to hypothyroidism)
  • Vascular: leukocytoclastic vasculitis

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Diagnostics

Pathology

• Acute Phase
  • Focal areas of macrovesicular steatosis
  • Bile duct injury
  • Sinusoidal inflammation of hepatic cells
  • Lobular involvement in the form of eosinophilic single-cell necrosis
• Chronic phase
  • Lymphoid follicles in portal triad
  • Necroinflammation of periportal liver cells
  • Variable degree of fibrosis
  • Severe hepatocyte injury
• Without treatment, the disease will ultimately progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma.

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Treatment

Antiviral therapy

• Direct-acting antivirals (DAAs)
  • DAAs target specific enzymes in the HCV life cycle to inhibit viral replication and assembly
  • Example regimens
    • Glecaprevir PLUS pibrentasvir (all 6 genotypes)
    • Sofosbuvir PLUS velpatasvir (all 6 genotypes)
    • Ledipasvir PLUS sofosbuvir (genotypes 1, 4, 5, and 6)
• Interferon PLUS ribavirin
  • Was the preferred treatment before the development of DAAs
  • Associated with severe adverse effects (e.g., arthralgias, thrombocytopenia, leukopenia, depression, anemia) and teratogenicity
  • Contraindicated in patients with decompensated cirrhosis (high risk of worsening cirrhosis decompensation)
  • Ribavirin
    • Mechanism of action
      • Guanosine analogue (nucleoside inhibitor)
      • Competitive inhibition of IMP dehydrogenase → prevention of guanine nucleosides synthesis
    • Adverse effects
      • Hemolytic anemia
      • Highly teratogenic

Tip

DAAs have superior efficacy and safety profiles compared with interferon or ribavirin-based regimens and are thus preferred.

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