Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection

Background& Aims: An increased risk of hepatitis C virus (HCV)-related cirrhosis is associated with hepatic steatosis, older age, and high alcohol consumption, which could be explained by synergistic effects on cell proliferation. We aimed to investigate hepatocyte cell cycle state and phase distribution in chronic HCV infection. Methods: Liver biopsy specimens diagnostic for chronic HCV (70), liver regeneration following transplant-related ischemic-reperfusion injury (15), and normal liver adjacent to colorectal cancer metastasis (10) were studied. Immunohistochemistry was used to detect cell cycle phase markers cyclin D1 (maximal in G(1).), cyclin A (S), cyclin B1 (cytoplasmic during G(2)) and phosphorylated histone 3 protein (mitosis), mini-chromosome maintenance protein 2 (Mcm-2; present throughout the cell cycle), and cyclindependent kinase inhibitor p21, which inhibits G:L/S progression. Results: Hepatocyte Mcm-2 expression was elevated in chronic HCV and liver regeneration (13% vs 26.4%) but negligible in normal liver. In proportion to Mcm-2, there was no difference in cyclin 131 between chronic HCV infection and liver regeneration (51.6% of Mcm-2-positive hepatocytes vs 52.6%). In co.ntrast, there was a striking reduction in cyclin A (3% vs 16.3%), cyclin 1311 (.4% vs 2.3%), and phosphorylated histone 3 protein (0% vs 3.8%) in chronic HCV infection compared with liver regeneration. In chronic HCV infection, Mcm-2 and p21 expression were associated with fibrosis stage and positive serum HCV RNA. Conclusions: The data are consistent with hepatocyte G(1) arrest in chronic HCV infection. This could impair hepatocellular function and limit hepatic regeneration.