Alcohol and the liver: Metabolism of alcohol and its role in hepatic and extrahepatic diseases

Dr. Charles S. Lieber has conducted clinical and experimental studies for m ore than four decades (three at Mount Sinai and the Bronx VA Medical Center s) with emphasis on liver, nutrition and GI pathophysiology. His major cont ributions include elucidation of the pathogenesis of alcoholic liver diseas e, by demonstrating the toxic role of alcohol and describing associated met abolic disorders. This was achieved through judicious clinical studies and newly developed rodent and primate models with the administration of ethano l in liquid diets. The mechanisms of various pathological and metabolic eff ects of ethanol were clarified, including hyperlipemia (with the rise in HD L), hyperuricemia, the role of acetaldehyde toxicity and alcohol-induced ox idative stress. The latter including glutathione depletion, was corrected b y S-adenosyl-1-methionine given to alcohol-fed baboons; the compound is now being used successfully for the treatment of patients with alcoholic liver disease in Europe. Alcoholic cirrhosis was produced for the first time in nonhuman primates and shown to be fully prevented by polyenylphosphatidylch oline, which is now being tested in a multicenter clinical trial. Lieber al so discovered a new (microsomal) pathway of ethanol metabolism, responsible for the tolerance to ethanol and for several clinically important toxic in teractions with other drugs (e.g., acetaminophen), anesthetics, industrial solvents, carcinogens, as well as retinol and beta-carotene, with narrowing of their therapeutic window. His work defined the role of the stomach in e thanol metabolism, description of corresponding gender differences, cloning (for the first time) of the gene for sigma ADH (a newly recognized gastric alcohol dehydrogenase isozyme) with its chromosomal localization, and the discovery of the effects of commonly used medications (e.g., Hz blockers an d aspirin) on the activities of the enzyme and on blood alcohol levels in s ocial drinkers. Lieber was among the first to use antibiotics for the elimi nation of gastric bacterial urease and its ammonia production in man, there by alleviating chronic gastritis and hypoacidity with attenuation of hepati c encephalopathy in cirrhotics. He promoted early detection and treatment o f heavy drinkers before their social or medical disintegration, by defining precirrhotic lesions and markers of alcohol consumption. Conclusions: The research of Dr. Lieber and his group has yielded a better understanding of the pathogenesis of common hepatic, gastric and nutritiona l disorders, with elucidation and prevention of serious toxic alcohol-drug interactions and the development of methods for early recognition and more effective approaches to prevent and treat Liver and gastrointestinal diseas es.