EFFECTS OF SAM IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

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DESCRIPTION (provided by applicant): Prior evidence from controlled animal studies has established the association of abnormal hepatic methionine metabolism and the development of alcoholic liver disease (ALD), and two clinical studies suggest that S-adenosylmethionine (SAM) may be efficacious in promoting anti-oxidant defense and survival in patients with moderately severe disease. Liver SAM is deficient in animal models of ALD, regulates several methionine cycle pathways, and up-regulates the synthesis of glutathione. The overall hypothesis of the proposed research is that the severity of ALD correlates with abnormal hepatic methionine metabolism and is improved by SAM intervention, and the overall objective is to define the metabolic rationale and short term efficacy of the clinical use of SAM in the treatment of ALD. Specific Aim I is to contrast the profiles of SAM, its product S-adenosylhomocysteine (SAH), and other methionine metabolites in liver biopsies and blood samples from 40 stable ALD patients contrasting with findings in 40 non-alcoholic non-liver disease patient controls and in blood samples from 20 healthy subjects. These data will be used to determine relationships between liver and blood SAM, SAH, and other metabolite levels and to define the effect of ALD and its severity on methionine metabolites. Specific Aim II is to demonstrate the metabolic and clinical efficacy of SAM treatment in the same 40 ALD patients who will be randomized to receive SAM or placebo in three daily doses over 6 mo. Blood samples at intervals will be used for measurements of SAM, SAH and other metabolites and markers of liver oxidative injury and function. Histopathology will be assessed by a computerized grading system in liver biopsies obtained before and after treatment. These data will be used to determine the effects of SAM intervention on methionine metabolism and to establish a rationale for its use according to quantitative changes in oxidative injury, liver function, and histopathology. By confirming the relationship of abnormal methionine metabolism to clinical, biochemical, and pathologic disease severity, the study will establish a metabolic basis for determining the efficacy of SAM intervention in ALD.