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

A Marshall, S Rushbrook, SE Davies, LS Morris… - Gastroenterology, 2005 - Elsevier
A Marshall, S Rushbrook, SE Davies, LS Morris, IS Scott, SL Vowler, N Coleman…
Gastroenterology, 2005Elsevier
Backgrounds & 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 …
Backgrounds & 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 G1), cyclin A (S), cyclin B1 (cytoplasmic during G2) and phosphorylated histone 3 protein (mitosis), mini-chromosome maintenance protein 2 (Mcm-2; present throughout the cell cycle), and cyclin-dependent kinase inhibitor p21, which inhibits G1/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 D1 between chronic HCV infection and liver regeneration (51.6% of Mcm-2-positive hepatocytes vs 52.6%). In contrast, there was a striking reduction in cyclin A (3% vs 16.3%), cyclin B1 (.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 G1 arrest in chronic HCV infection. This could impair hepatocellular function and limit hepatic regeneration.
Elsevier