What is the pathogenesis of acute and chronic Hepatitis C (HCV)?

Pathogenesis of Acute and Chronic Hepatitis C

Hepatitis C virus (HCV) infection causes progressive liver damage through multiple mechanisms, including direct viral effects, immune-mediated inflammation, and metabolic alterations, ultimately leading to fibrosis, cirrhosis, and potentially hepatocellular carcinoma in untreated patients. 1

Acute HCV Infection

Initial Infection and Clinical Presentation

• HCV is a single-stranded RNA virus that primarily infects hepatocytes, with transmission occurring primarily through blood exposure 1
• Acute HCV infection is typically asymptomatic (60-70%) or presents with mild clinical illness; only 20-30% develop jaundice 2
• Incubation period averages 6-7 weeks from exposure to symptom onset, while seroconversion takes 8-9 weeks 2
• Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in ≥90% within 5 months, and in ≥97% by 6 months 2

Immunological Response in Acute Infection

• Upon infection, HCV triggers activation of the innate immune system through pattern recognition receptors 1
• The virus is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors, initiating antiviral cytokine production including interferons 3
• Neutralizing antibodies develop but are often thwarted by the high mutation rate of HCV, which generates a highly variable quasispecies 4
• Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells mediate cytolysis of infected hepatocytes through perforin and granzyme B, while non-cytolytic clearance occurs via interferon-gamma 3

Outcome of Acute Infection

• 15-25% of infected individuals spontaneously clear the virus with normalization of ALT levels 2
• 75-85% develop chronic infection, with the host-virus interaction determining whether resolution occurs or viral persistence develops 2, 3
• No clinical or epidemiologic features during acute infection reliably predict either persistent infection or chronic liver disease 2

Chronic HCV Infection

Mechanisms of Viral Persistence

• HCV evades host immune responses through:
  1. High mutation rate creating a quasispecies that continuously evolves in infected individuals 4
  2. Interference with innate immune signaling pathways 3
  3. Exhaustion of HCV-specific T cells 3
  4. Escape from neutralizing antibodies 5

Liver Damage Pathogenesis

• Two primary mechanisms contribute to liver damage 4:

  1. Direct cytopathic effects: HCV proteins directly damage hepatocytes
  2. Immune-mediated damage: Host immune responses against infected cells

• Chronic inflammation leads to activation of hepatic stellate cells, which transform into myofibroblasts that produce collagen, resulting in progressive fibrosis 1

• Predominant type 1 helper cell (Th1) immune response drives ongoing inflammation 1

Disease Progression Factors

• Host factors influencing progression include:

  • Age at infection (>40 years accelerates progression) 2
  • Male gender 1
  • Genetic predisposition 1

• Environmental factors include:

  • Alcohol consumption (>50g/day significantly increases fibrosis progression) 2
  • Coinfection with HBV, HDV, or HIV 2
  • Metabolic factors (obesity, insulin resistance, diabetes) 1

Rate of Disease Progression

• Fibrosis progression is variable with median time from infection to cirrhosis of approximately 30 years (range 13-42 years) 2
• 10-20% of chronically infected individuals develop cirrhosis over 20-30 years 2
• Once cirrhosis is established, 5-year survival is over 90% and 10-year survival is 80% 2
• After decompensation occurs, prognosis worsens with only 50% survival at 5 years 2

Extrahepatic Manifestations

HCV infection is associated with numerous extrahepatic manifestations through complex pathogenic mechanisms:

Immunological Disorders

• Mixed cryoglobulinemia: Results from prolonged B-cell stimulation by HCV, leading to immune complex formation 2
• The pathogenesis involves:
  • HCV E2 protein binding to CD81 on B cells, lowering activation threshold
  • Direct B-cell infection by HCV
  • Overexpression of anti-apoptotic protein Bcl-2 due to t(14;18) translocation
  • Cytokine effects, particularly B-cell Activating Factor (BAFF) 2

Metabolic Disorders

• Insulin resistance and type 2 diabetes: HCV directly affects beta-cell function 2
• Abnormal lipid metabolism 2

Neurological Manifestations

• Peripheral neuropathies through direct viral neuroinvasion or immune-mediated injury 2
• Central nervous system manifestations including encephalopathy and cerebrovascular events 2

Complications of Chronic HCV

Cirrhosis and Hepatic Decompensation

• End-stage fibrosis leads to portal hypertension and hepatic synthetic dysfunction 1
• Risk of decompensation increases with disease progression 2

Hepatocellular Carcinoma (HCC)

• 1-5% of patients with chronic HCV develop HCC 2
• HCC risk is 1.4% per year in patients with compensated cirrhosis 2
• Mechanisms include:
  • Integration of viral DNA into hepatocyte chromosomes
  • Chromosomal instability
  • Chronic inflammation driving oncogenic mutations 1

Clinical Implications

Early diagnosis and treatment are essential to prevent progression to advanced liver disease. Modern direct-acting antiviral regimens achieve >90% cure rates, with sustained virological response associated with normalization of liver enzymes, improvement of inflammation and fibrosis, and significantly reduced risk of HCC in cirrhotic patients 1.

Even after viral clearance, patients with cirrhosis require continued surveillance for HCC, as the risk is reduced but not eliminated 1.