Biomarkers as Predictors of Rapidity of Fibrosis in the Liver Allograft of Hepatitis C Patients
Z Meriden, T Pasha, R Wells, R Reddy, G Makar, EE Furth. University of Pennsylvania, Philadelphia, PA
Background: Recurrent hepatitis C with subsequent highly variable rates of fibrosis post liver transplantation is the leading cause of allograft loss. We hypothesized that early increased collagen synthesis, bile duct proliferation, epithelial to mesynchemal transition, and other features may predict the rapidity of subsequent liver fibrosis.
Design: For 476 hepatitis C liver transplant (1999-2007) patients, the stage of fibrosis (METAVIR 0-4) from each post-transplant liver biopsy was recorded with respect to time post-transplantation. Rapid (52 patients) and slow (61 patients) fibrosis were defined as having at stage 3 (bridging) by 24 months, and stage 0 or 1 at 24 months or later, respectively. The stage 0 biopsy was 1. scored for hepatitis activity and number of apoptotic hepatocytes 2. immunostained and scored (0-3) for Hsp47 (a collagen chaperone protein), CK19 (expressed in bile ducts), and vimentin (a marker of epithelial to mesynchemal transition). The area under the Receiver Operator Characteristic curve (AUC), a measure of test diagnostic utility (1= perfect test, 0.5=no utility), was calculated for all immunostains with the exception of vimentin which was scored on a binary scale and analyzed by Chi Square. The number of rejection episodes was determined.
Results: By year 8, 61% of our entire transplant population had cirrhosis; 78% of rapid fibrosers (RF) had cirrhosis by year 2, while only 4% of slow fibrosers (SF) had fibrosis by year 8. Hsp47 was not different in RF vs. SF (AUC= 0.61; P=0.13). However, CK19 was predictive of rapid fibrosis (AUC = 0.71; P=0.003), as was vimentin staining (81% RF vs. 52% SF, P=0.022). Stage 0 biopsies of RF had more hepatocyte apoptosis than SF (mean apoptotic cells/hpf SD = 0.30 0.37 vs. 0.08 0.15; P = 0.001) with no difference in hepatic activity. RF had more numbers of acute rejection episodes than SF (number of patients with 1 or more acute rejection episodes = 65% vs. 18%, P <0.0001). The rate of fibrosis over time was constant for each group.
Conclusions: CK19 and vimentin are good markers predictive of rapidity of liver allograft fibrosis in patients transplanted for hepatitis C, implicating the bile ductular reaction and epithelial to mesynchemal transition as critical early processes. While the inflammatory hepatic activity is not predictive of the rate of fibrosis, the level of hepatocellular apoptosis is. Importantly, the rate of fibrosis is established early in the post-transplant period, as this initial rate dictates long-term outcome.
Category: Liver & Pancreas
Monday, March 9, 2009 1:00 PM
Platform Session: Section E, Monday Afternoon