Hepatocyte expression of minichromosome maintenance protein-2 predicts fibrosis progression after transplantation for chronic hepatitis C virus: a pilot study.
Although graft infection with hepatitis C virus (HCV) occurs in virtually all patients transplanted for HCV-related liver disease, the outcome ranges from minimal disease to the rapid development of cirrhosis. Induction of hepatocyte cell cycle entry followed by inhibition of cell cycle progression has been proposed as a potential mechanism whereby HCV may cause hepatocyte dysfunction and may promote fibrogenesis. The aim of this study was to assess whether early hepatocyte cell cycle entry might predict subsequent fibrosis progression in patients with graft HCV infection after liver transplantation. Liver biopsies from 21 liver transplant recipients diagnostic of graft HCV infection but before development of significant fibrosis were studied. Patients were classed as nonprogressors, intermediate progressors, or rapid progressors according to the rate of fibrosis progression calculated from the most recent biopsy. Minichromosome maintenance protein 2 (Mcm-2), a highly sensitive and specific marker of cell cycle entry, and cyclin-dependent kinase inhibitor p21 were detected by immunohistochemistry. Hepatocyte Mcm-2 expression increased significantly according to rate of fibrosis. For nonprogressors, the median percentage of positive hepatocytes was 5.3% (range, 0.92%-11.2%) compared with 20.7% (4.6%-43.7%) in intermediate progressors and 23.7% (11.6%-55.2%) in rapid progressors (P = 0.002). By contrast, there was no evidence of a difference in hepatocyte p21 expression. Median values and ranges were 3.4% (range, 1.1%-30%), 13.3% (range, 1.4%-42.3%), and 11.8% (range, 7.6%-52.3%) for nonprogressors, intermediate progressors, and rapid progressors, respectively (P = 0.11). In conclusion, hepatocyte cell cycle entry may be important in the pathogenesis of posttransplant HCV hepatitis. Early assessment of hepatocyte Mcm-2 expression could help identify patients at high risk for progressive fibrosis before it occurs.
Marshall
Aileen
A
University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Rushbrook
Simon
S
Morris
Lesley S
LS
Scott
Ian S
IS
Vowler
Sarah L
SL
Davies
Susan E
SE
Coleman
Nicholas
N
Alexander
Graeme
G
D000328:Adult; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018450:Disease Progression; D005260:Female; D019698:Hepatitis C, Chronic / Q000601:surgery*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010865:Pilot Projects
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2