CHRONIC HEPATITIS C: MOLECULAR & CELLULAR MARKERS
Principal Investigator: Geoff C Farrell
Abstract: Only a minority of HCV-infected individuals have progressive forms of chronic hepatitis that will result in cirrhosis in 20 to 30 years. This project is concerned with the biological basis of disease progression in chronic hepatitis C. We have noted that, to date, viral factors and the systemic immune response to HCV are poorly correlated with disease progression. The key pathobiological process that determines progression of liver disease in chronic hepatitis C is fibrogenesis, with hepatocyte cell death and proliferation playing lesser roles. In the present proposal, these processes are conceptualized as responses to hepatic inflammation and oxidative stress causing activation of hepatic stellate cells and liver cell injury. Thus our overall objective is to characterize how interactions between HCV, the hepatic inflammatory response and liver cells promote fibrogenesis and disease progression in chronic hepatitis C. In particular, we will test the hypothesis that, in the early stages of chronic HCV infection, an intrahepatic "molecular map" can be created to identify subsets of individuals who will develop progression of liver disease. We will then seek to identify patterns of hepatic gene expression that correlate with the pathogenesis of fibrosis, hepatocyte death and proliferation. A particular focus will be on the identification of genes not previously known to be associated with individual susceptibility to HCV. A unique feature of these studies is that they will be performed on serial liver biopsy samples obtained at 3 to 5 year intervals from 200 patients with mild to moderate chronic hepatitis C who will be followed prospectively and monitored by quantitative liver functional assessments. The Specific Aims are: 1) To establish the relationship between cytokine mediators of the hepatic inflammatory response, macrophage activation and the presence of oxidative stress in the liver, and to compare these with characteristics of the HCV infection in hepatocytes and other cell types; 2) To determine whether expression of these cytokines and/or oxidative stress correlate with the activity of hepatic fibrogenesis, using both cross-sectional and prospective longitudinal approaches. 3) To identify hepatic genes previously not known to be associated with a progressive course for hepatitis C. The findings may allow those individuals most at risk of progressive liver disease from HCV to be identified at a time when they are most likely to respond to antiviral therapy. It will also allow the design of adjunctive treatments more appropriately targeted towards the key pathogenic processes that determine disease progression.
Funding Period: 1999-09-30 - 2004-08-31
more information: NIH RePORT
- Antioxidant levels in peripheral blood, disease activity and fibrotic stage in chronic hepatitis CPriyanka Bandara
Storr Liver Unit, Westmead Millennium Institute, Sydney, Australia
Liver Int 25:518-26. 2005..We then determined whether regular antioxidant supplementation influenced these antioxidant levels or disease severity...
- Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis CDinesh Kumar
Storr Liver Unit, Westmead Millennium Institute, Westmead, New South Wales, Australia
J Gastroenterol Hepatol 20:1395-400. 2005..Obesity associated hepatic steatosis has been suggested to have a premalignant potential. We determined whether hepatic steatosis predisposes to liver cancer in persons with chronic hepatitis C virus (HCV) infection...
- Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosisElisabetta Bugianesi
Gastroenterology Department, University of Turin, Italy
Hepatology 44:1648-55. 2006..Virus-induced hepatic steatosis as seen in CHC-3 does not contribute significantly to liver fibrosis...
- Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosisXiao X Huang
A W Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, NSW, Australia
Liver Int 27:960-8. 2007..Cirrhosis can lead to hepatocellular carcinoma (HCC). Non-diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared...
- Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3Hossein Poustchi
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, NSW, Australia
J Hepatol 48:28-34. 2008..The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection...