Arginine Treatment for Alcoholic Hepatitis

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DESCRIPTION (provided by applicant): Alcoholic hepatitis progresses to cirrhosis due to inflammatory damage of the liver that occurs as a result of intestinal endotoxin exposure and intrahepatic microcirculatory nitric oxide (NO) deficiency. Insufficient dietary arginine intake promotes bacterial translocation, endotoxin absorption and reduced intrahepatic NO generation. Dietary arginine is cytoprotective, reduces endotoxin absorption and will increase intrahepatic NO generation. Increase intrahepatic NO generation will reduce liver inflammation, intrahepatic vascular resistance and fibrosis. Evidence to support the role of additional arginine comes from three clinical trials that have both demonstrated improved liver function and survival with increased dietary protein and arginine intake. In the first study, enteral nutrition with additional arginine and BCAA added improved mortality in patients with active liver disease. The patients in the control arm consumed 44 vs. 71 grams of protein per day. In a second study, enteral nutrition was compared to steroid therapy for alcoholic hepatitis. Enteral nutrition (1 gm of protein/kg/day) improves follow-up survival compared to steroid treated patients. In a s third study of 245 patients with alcoholic hepatitis, 88% died at 6-months who had <34 grams of protein intake. In contrast, 100% of the patients who ingested approximately 95 grams of protein per day were alive at 6-months. The increased dietary protein also increased the dietary arginine intake. Additional arginine in the diet is known to reduce endotoxin damage of the liver, provide intestinal cytoprotection, reduced bacterial translocation and improved intestinal structure. This pilot project (R21) will test if additional protein (94 vs. 70 grams per day) and additional agrinine (24 additional grams per day or 6% of total calories) can improve liver histology, reduce endotoxin production and improve liver function in patients with alcoholic hepatitis.