What is the pathophysiology of hepatitis C and its complications?

Pathophysiology of Hepatitis C and Its Complications

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

Viral Infection and Immune Response

Initial Infection

• HCV is a single-stranded RNA virus that primarily infects hepatocytes
• Transmission occurs primarily through blood exposure (unsafe injection practices, unsterile medical procedures, and blood transfusions before screening)
• After infection, the virus evades immune clearance in 55-85% of cases, establishing chronic infection 1

Immune Evasion Mechanisms

• High genetic variability of HCV enables escape from host immune response 2
• Viral proteins interfere with innate immune signaling pathways
• HCV can establish persistent infection despite presence of neutralizing antibodies

Inflammatory Response

• HCV is not directly cytopathic - liver damage is primarily immune-mediated 2
• Activation of innate immune system through pattern recognition receptors
• Recruitment of inflammatory cells (monocytes, T cells, NK cells) into the liver 1
• Predominant type 1 helper cell (Th1) immune response drives inflammation 2
• Inflammasome activation contributes to ongoing liver damage 3

Progression of Liver Disease

Chronic Inflammation

• Persistent inflammation leads to hepatocyte injury and death
• Hepatocyte apoptosis and necrosis trigger fibrogenic responses
• Elevated levels of cytokines and chemokines perpetuate inflammatory cascade 3

Fibrosis Development

• Hepatic stellate cells become activated by inflammatory mediators
• Activated stellate cells transform into myofibroblasts that produce collagen
• Progressive accumulation of extracellular matrix components
• Fibrosis progression is highly variable, with 10-20% developing cirrhosis over 20-30 years 1

Factors Accelerating Disease Progression

• Host factors: older age at infection, male gender, genetic factors
• Metabolic factors: obesity, insulin resistance, type 2 diabetes
• Environmental factors: alcohol consumption (>50g/day), tobacco smoking
• Coinfections: HIV, HBV 1
• Interestingly, coffee consumption appears protective, associated with less inflammation and fibrosis 1

Major Complications of Chronic HCV

Cirrhosis

• End-stage fibrosis with distortion of liver architecture
• Portal hypertension development
• Hepatic synthetic dysfunction
• Risk of decompensation (ascites, variceal bleeding, encephalopathy)
• Once cirrhosis develops, the risk of hepatocellular carcinoma is 1-5% per year 1

Hepatocellular Carcinoma (HCC)

• Primarily develops in patients with cirrhosis, though can occur without cirrhosis in 10-20% of cases 1
• Mechanisms include:
  • Integration of viral DNA into hepatocyte chromosomes causing insertional mutagenesis 1
  • Chromosomal instability and translocations
  • Chronic inflammation driving oncogenic mutations
  • HCV proteins (particularly HBx) promoting carcinogenesis 1
• 33% mortality in the first year after HCC diagnosis 1

Extrahepatic Manifestations

• Mixed cryoglobulinemia with vasculitis (skin manifestations, kidney damage) 1
• Metabolic disorders (insulin resistance, type 2 diabetes)
• Lymphoproliferative disorders
• Neurological manifestations
• Renal disease

Impact of Treatment on Disease Course

• Sustained virological response (SVR) corresponds to cure of HCV infection 1
• SVR is associated with:
  • Normalization of liver enzymes
  • Improvement or regression of liver inflammation and fibrosis
  • Improved liver function
  • Significantly reduced (but not eliminated) risk of HCC in cirrhotic patients
  • Reduced all-cause mortality
  • Reversal of most extrahepatic manifestations 1

Clinical Implications

• Early diagnosis and treatment are essential to prevent progression to advanced liver disease
• Even after viral clearance, patients with cirrhosis require continued surveillance for HCC
• Management of cofactors (alcohol abstinence, weight management, diabetes control) is crucial
• Modern direct-acting antiviral regimens can achieve >90% cure rates 1

The pathophysiology of HCV infection involves complex interactions between viral factors and host immune responses, leading to progressive liver damage and multiple complications. Understanding these mechanisms is essential for appropriate management and prevention of long-term sequelae.