Translational Bioenergetics in Patients with Alcoholic Liver Disease

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 DESCRIPTION (provided by applicant): Alcoholic hepatitis is a syndrome characterized by rapid onset of jaundice, liver failure and the key features of a systemic inflammatory response syndrome. Patients with severe episodes of alcoholic hepatitis have a mortality rate as high as 40-50% 1 month after presentation. The treatment of acute alcoholic hepatitis is a clinical challenge because a) it is difficult to differentiate it from spontaneous decompensation of alcoholic cirrhosis and b) the limited treatment options have variable and unpredictable efficacy. Furthermore, currently- available treatments for alcoholic hepatitis patients with corticosteroids or pentoxifylline provide only about 50% survival benefit. Hence, there is an unmet need of a biomarker for diagnosis of alcoholic hepatitis and predicting its responsiveness to treatment with corticosteroids. Basic research into the pathogenesis of alcoholic liver disease using animal models has identified a number of contributory factors including inflammation, mitochondrial dysfunction and a severe oxidative/nitrative stress. An intrinsic characteristic of pathologies associated with inflammation and metabolic dysfunction is the suppression of the cellular bioenergetics to below the threshold that induces cell death. In this proposal, we will use a novel methodology to assess cellular bioenergetics in the leukocytes isolated from patient's blood and test the hypothesis that this can serve as a biomarker of the severity of alcoholic liver disease. This project builds on the expertise of the PIs in managing alcoholic liver disease patients, biostatistics and the evaluation of mitochondrial dysfunction in disease. We have found that a) bioenergetic health can be defined by an analysis of cellular bioenergetics in blood leukocytes that can be isolated from 20 ml of human blood, b) monocytes show a rapidly developing decrease in bioenergetic health in patients with alcoholic liver disease, and c) the oxidative burs in neutrophils and monocytes can be readily assessed in the same sample and is depressed in alcoholic patients. In this application we will test the hypothesis that alcoholic liver disease patients with severe cellular bioenergetic defects and low oxidative burst activity detectable in monocytes and neutrophils will progress more rapidly to liver failure and be unresponsive to corticosteroid treatment.