Hepatitis C pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Seyedmahdi Pahlavani, M.D. [2], Javaria Anwer M.D.[3]

Overview[edit | edit source]

In isolated acute HCV infection, the host immune system stimulates the secretion of interferon alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which cause hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

Transmission[edit | edit source]

The transmission of HCV can be defined as percutaneous, sexual, healthcare-associated, or maternal-infant in nature.

Percutaneous Transmission[edit | edit source]

• Blood and blood components transfusion
  • More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.^[1]
• Contaminated shared needles among intravenous drug users
  • Before 1992, at least two-thirds of new HCV infections in the United States were associated with illicit drug use; the number has since decreased significantly.^[2]
• Chronic hemodialysis
  • The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.^[3]

Sexual Transmission[edit | edit source]

• HCV RNA has been detected in semen and saliva.^[4] People with multiple sexual partners and commercial sex workers have a high HCV prevalence.^[5]

Health care Associated[edit | edit source]

• Nosocomial transmission has been observed under several different conditions (e.g. needle stick, organ transplant, during surgery); now, however, because of infection control protocols, nosocomial transmission of HCV is rare except in cases of breach of protocols.^[6][7]

Maternal Infant Transmission[edit | edit source]

• Perinatal transmission frequency ranges from 0% to 4% in larger studies.^[8][9]

HCV Clearance and Persistence[edit | edit source]

Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I interferon alpha (IFN-alpha) and activation of natural killer (NK) cells. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV replication.^[10][11][12]

HCV proteins play a crucial role in inhibiting IFN-alpha effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent protein kinase (PKR), and the JAK-STAT signaling pathway.^[13][14][15] More importantly, chronic carriage of HCV is associated with impaired activation of NK cells despite IFN-alpha secretion. It is believed that the cross-linking of CD81 and the envelope protein E2 of the virus is a key mechanism by which NK cells are inactivated and INF-gamma is not produced by these cells.^[16]

The activation of IFN-gamma is a prerequisite for the appropriate clearance of HCV. When activation occurs normally, antibodies start to form 7-31 weeks later.^{[17][18][19][20]} While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target for anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.^{[17][18][19][20]}

Similarly, the activation of the CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV.^[21] Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective dendritic cells, and/or failure of interleukin (IL) 12 activation.^{[21][22][23][24][25][26]}

Liver Injury and Cirrhosis, and Hepatocellular Carcinoma[edit | edit source]

HCV is directly associated with hepatic steatosis, which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection; it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol consumption or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.^{[27][28][29][30][31][32][33]}

In chronic hepatitis C infections, the local immune response leads to portal lymphoid infiltration and chronic inflammation, which give way to bridging necrosis and degenerative lobular lesions.^[16] Hepatic injury is directly associated with the degree of Th1 cytokine expression. The adaptive immune system, namely the cytotoxic T-cell response, injures infected cells as well as bystander cells. Nonetheless, it has not been confirmed whether the number of cytotoxic T cells is associated with the extent of liver injury.

Chronic inflammation ultimately leads to fibrogenesis due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.^[16]

Hepatocellular Carcinoma[edit | edit source]

Hepatocellular carcinoma (HCC) occurs following chronic HCV infection complicated by liver cirrhosis. The precise role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.^{[34][35][36][37][38]}

Histology[edit | edit source]

Click on the arrow to view the pathologic findings in viral hepatitis: {{#ev:youtube|_hXvbpSxFZw}}

Mechanisms involved in extra-hepatic manifestations[edit | edit source]

• Cryoglobulinemic vasculitis: Chronic antigen stimulation reduces the threshold for activation and proliferation of B-lymphocyte and induces Bcl-2 activation and t(14;18) translocation. It results in decreased apoptosis. As a result, CD21−CD27+ cells produce antibodies against the Fc portion of IgG, forming immune complexes that precipitate in small blood vessels.^[39]
• B-cell lymphoma: A continuous HCV antigen stimulation and permanent genetic damage caused by viral proteins cause clonal proliferation of CD21−CD27+. It also down-regulates tumor-suppressive signals (such as, microRNA-26b). Oncogenic signals are further enhanced and additional tumor suppressor genes such as Bcl-6, p53, and β-catenin undergo mutation. Hence, the reduced levels of caspase 3, 7, and 9 reduce their sensitivity to Fas-induced apoptosis.^[39]
• Cardiovascular disease: Local vascular damage is caused by an increased expression of adhesion molecules on endothelial surface. Smooth cells in the media proliferate and apoptosis is inhibited, with local macrophages producing proinflammatory cytokines and free radicals. These processes result in accelerated atherosclerosis, procoagulant effects, and lead to major cardiovascular events.^[39]
• Chronic kidney disease: Direct HCV cytopathic effect, chronic inflammation from atherosclerosis and insulin resistance, endothelial and mesangial inflammation, and podocyte and tubular injury caise CKD. Cryoprecipitates deposit at glomeruli also manifested as type I membranoproliferative glomerulonephritis.^[39]
• Type 2 diabetes: Caused by both hepatic and peripheral insulin resistance. In the liver, HCV leads to PI3K-AKT insulin-signaling pathway reduction via insulin receptor substrate 1 inhibition and impaired Glut2–mediated hepatic glucose intake. In the extrahepatic tissue, insulin resistance is a consequence of soluble endocrine mediators released by hepatocytes. Up-regulation of TNF, G6P, and resistin, with an imbalance in the adipocytokine profile, increases gluconeogenesis in these sites.^[39]

References[edit | edit source]