Two different approaches to biomarker discovery have identified genetic and protein markers that could help predict which hepatitis C patients undergoing liver transplantation are most likely to develop severe fibrosis and potentially liver failure.

The two sets of research have been carried out by scientists working in the laboratory of Dr. Michael Katze, M.D., at the University of Washington, and are both reported in Hepatology.

Liver failure from chronic hepatitis C infection is the most common reason for liver transplantation worldwide, and invariably the virus will infect the transplanted organ. About a third of HCV patients who receive a liver transplant will progress to severe fibrosis and end-stage liver disease. As there isn’t currently any reliable way of clinically predicting which patients will be affected, transplant recipients have to regularly undergo invasive core-needle biopsies to check the status of the organ, and antiviral drugs are used to try and stem hepatitis C-related liver damage, resulting in drug-related toxicity.

The two University of Washington teams therefore used different discovery techniques to try and identify molecular markers of impending liver transplant fibrosis and liver failure. Angela L. Rasmussen, Ph.D., and colleagues analyzed the transcriptomes of 111 liver biopsy specimens taken from 57 HCV-infected patients who had undergone a liver transplant. They identified a molecular signature of altered gene expression in patients at risk of developing severe fibrosis that could be detected before histological evidence of liver disease progression manifested. Moreover, the results pointed to a single precursor state, or set of conditions that predicted the development of liver damage, which was common for different, severe clincial outcomes.

Deborah L. Diamond, Ph.D., and colleagues carried out global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV+ liver transplant recipients at six and/or 12 months posttransplantation, and analyzed serum metabolites from another 60 liver transplant patients using computational methods to analyze their data and identify potential key regulatory proteins of liver fibrogenesis. The results highlighted 250 proteins that were highly differentially regulated in patients with rapidly progressive fibrosis, including those associated with various immune, hepatoprotective, and fibrogenic processes.

The findings also suggested that patients who develop significant liver injury experience higher oxidative stresses. This notion was supported by a separate study demonstrating that these patients exhibit changes in oxidative stress-associated serum metabolites. Moreover, further computational analyses indicated that liver fibrogenesis occurs in part due to a link between HCV-associated oxidative stress and epigenetic regulatory mechanisms. 

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