The clinical spectrum of chronic hepatitis C is variable and the factors responsible for these divergent outcomes remain unknown. Alcohol consumption has been identified as a co-factor in accelerating the progression of liver disease in patients with chronic hepatitis C. Studies of this issue are difficult because there is no animal model of hepatitis C-induced fibrosis. We propose to prospectively study a cohort of patients infected with hepatitis C who also consume alcohol to define the effects of alcohol consumption on hepatic fibrogenesis, oxidant stress, and expression of mediators of inflammation and fibrogenesis in liver tissue and peripheral blood mononuclear cells. The hypothesis to be tested is that alcohol consumption will increase markers of hepatic inflammation, fibrogenesis and oxidant stress, and ultimately reflect an increase in the progression of liver disease. Subjects with concurrent hepatitis C infection on ongoing alcohol use/abuse will undergo a detailed clinical evaluation, including liver biopsy and blood sampling. A control group of non-drinking subjects with chronic hepatitis C will be matched for gender, estimated duration of HCV infection, and mode of HCV acquisition. We will study the effects of alcohol use on hepatic fibrogenesis using standard histologic techniques and novel immunohistochemical markers of stellate cell activation (alpha-smooth muscle actin, collagen II propeptide) in liver biopsy specimens from alcohol consuming and non-drinking patients with chronic hepatitis C. We will also evaluate lipid peroxidation production products using immunohistochemical techniques with antibodies to 4-nonalal and malondealdehyde. In addition, using specimens obtained from these two cohorts, we will identify mRNAs in liver tissue and peripheral blood mononuclear cells encoding host mediators of inflammation and fibrogenesis that are up-regulated in patients with hepatitis C who consume alcohol. This information will provide key information for developing additional hypotheses to be tested in a larger clinical trial.
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