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Biomarkers used to predict recurrent disease in hepatitis C transplant patients
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Two new studies on Hepatitis C (HCV) patients who underwent liver transplants examined a potential biomarker that could be used to predict who might develop hepatic fibrosis, a formation of scar-like tissue that can lead to cirrhosis. The studies found that changes in a certain type of liver cell were useful in determining those who were at the greatest risk for developing this serious complication.
The results of these studies appear in the October 2005 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/livertransplantation.
Hepatitis C is the leading cause of liver transplants and recurrence of the disease following transplant is a serious problem. It is estimated that up to 20 percent of HCV patients will develop fibrosis or cirrhosis within two years of undergoing a transplant. Antiviral therapy is not highly effective in transplant patients and poses additional problems for these individuals, who may have difficulty tolerating the potent drugs it involves. However, antiviral therapy might be useful for those patients likely to develop fibrosis, if they could somehow be identified. Hepatic stellate cells (HSC) normally store vitamin A in the liver, but in HCV patients these cells produce collagen and other proteins that can lead to fibrosis. Researchers tried to determine if HSC activation could help predict which patients would later develop fibrosis by using laboratory analysis of alpha smooth muscle actin (alpha-SMA), a reliable marker for HSC activation.
In one study, led by Samer Gawrieh of the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, MN, 26 patients who underwent HCV-related liver transplants at the Mayo Clinic between April 1993 and July 1999 were included. Biopsies obtained 4 months and 1 year post-transplant were evaluated and given a score for alpha-SMA. The results showed that HSC activation of one particular type of cell (mesenchymal cells, which give rise to connective tissue) was highly reliable in predicting the development of fibrosis. "Staining early post-LT liver biopsies for alpha-SMA may help identify patients with hepatitis C at risk for severe recurrence who may benefit from early anti-HCV or anti-fibrotic therapy," the authors conclude.
In another study, led by Mark W. Russo, M.D., M.P.H. of the Division of Gastroenterology and Hepatology of the University of North Carolina in Chapel Hill, 46 patients who underwent HCV-related liver transplants at the University of Florida between 1997 and 2001 were included. Patients were divided into two groups: those who developed advanced fibrosis within 2 years of liver transplant and those who developed mild or no fibrosis in the same period. Biopsies from 4 months, 1 year and 2 years post-transplant were scored for alpha-SMA. The results showed that HSC activation was significantly higher in the 4 month biopsies for those who developed advanced fibrosis within 2 years. The authors note that alpha-SMA "is an attractive biomarker because it is determined from the organ of interest and there is biological plausibility for why increased stellate cell activity would lead to advanced fibrosis."
In an accompanying editorial by A.J Demetris and J.G. Lunz III of the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh Medical Center in Pittsburgh, the authors note that the ability of alpha-SMA to predict disease at 4 months after transplant suggests that something triggers a chain of events that begins with mesenchymal and/or HSC activation and leads to the development of fibrosis. They speculate as to what the trigger might be and how it might explain the mechanism of liver disease, examining risk factors for recurrent HCV that might offer clues, as well as substances such as viral proteins and proteins secreted by liver cells. In particular, they cite their research on p21, a protein made in the liver, which showed that progression of fibrosis was related to the effect of p21 on liver cell proliferation. "This model better fits observations about disease pathogenesis," they conclude. "It explains why any hepatocyte stressors, such as steatosis [accumulation of fat in the liver], iron, inflammation, HCV replication or spontaneously increased 21 expression, such as occurs with aging, can accelerate liver disease progression."
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Article: "Early Hepatic Stellate Cell Activation Predicts Severe Hepatitis C Recurrence After Liver Transplantation," Samer Gawrieh, Bettina G. Papouchado, Lawrence J. Burgart, Shogo Kobayashi, Michael R. Charlton, Gregory J. Gores, Liver Transplantation; October 2005 (DOI: 10.1002/lt.20455).
Article: "Early Hepatic Stellate Cell Activation is Associated with Advanced Fibrosis After Liver Transplantation in Recipients with Hepatitis C," Mark Russo, Roberto Firpi, David Nelson, Robert Schoonhoven, Roshan Shrestha, Michael Fried, Liver Transplantation; October 2005 (DOI: 10.1002/lt.20432).
Editorial: "Early HCV-Associated Stellate Cell Activation in Aggressive Recurrent HCV: What Can Liver Allografts Teach About HCV Pathogenesis?" A.J. Demetris, J.G. Lunz III, Liver Transplantation; October 2005 (DOI: 10.1002/lt.20506).
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