Liver Fibrosis, Inflammation & Oxidative Stress Markers

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DESCRIPTION (provided by applicant): Liver cirrhosis is a major cause of mortality in alcoholics. Recent experimental pathophysiotogic studies suggest several therapeutic approaches but their clinical verification is hampered by the requirement of liver biopsies to establish the stage of the disease, the therapeutic indications and documentation of outcome. Various circulating markers have been proposed as substitute for biopsies. The specific aim of the present study is to validate these markers, taking advantage of over 2,000 sequential liver biopsies and corresponding blood samples collected in 789 alcoholics studied for up to 6 years in VA Cooperative Study 391, including monthly measurements of carbohydrate deficient transferrin to substantiate the self-reported alcohol consumption. This recently conducted trial assessed the effects of polyunsaturated phosphatidylcholine (PPC), a soybean extract, on alcoholic liver disease, with superimposed hepatitis C in 1/3 of the patients. The liver pathology varied from fatty liver to perivenular and septal fibrosis and cirrhosis, with variable degrees of inflammation. Correlation of these lesions with the following proposed circulating markers of fibrosis will be determined: laminin, tenascin, procollagen type tll and collagen IV and VI. The activity of enzymes that degrade fibrotic tissue, such as metalloproteinases and their inhibitors, will also be measured. In addition, hepatic parameters with the potential to prognosticate progression of liver disorders, such as cytokeratins, will be assessed. Cytokines that affect fibrogenesis as well as inflammation, e.g. TNFalpha and TGF-beta will also be evaluated. One major pathogenic factor is oxidative stress resulting from free radicals generated by alcohol-induced cytochrome P450 (CYP2E1). Accordingly, the correlation of markers of oxidative stress (4-hydroxynonenal, F2-isoprostanes and malondialdehyde) with the degree of CYP2E1 induction in the liver will be evaluated. Once validated, these markers could serve in future studies to detect subjects vulnerable to drugs activated to toxins by CYP2E1. As controls for the markers of a specific lesion (such as cirrhosis), we will use the values of the same markers in patients without the specific liver disease. In conclusion, an available bank of sequential liver biopsies and monthly blood samples, collected in association with detailed clinical information, offers a unique opportunity to establish which circulating markers can serve as partial substitute for liver biopsies, thereby optimizing the diagnosis, prevention and treatment of alcoholic liver injury.