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

Dr. Charles S. Lieber conducted clinical and experimental studies for more than four decades (three at Mount Sinai and the Bronx VA Medical Centers) with emphasis on liver, nutrition and GI pathophysiology. His major contributions include elucidation of the pathogenesis of alcoholic liver disease, by demonstrating the toxic role of alcohol and describing associated metabolic disorders. This was achieved through judicious clinical studies and newly-developed rodent and primate models with the administration of ethanol in liquid diets. The mechanisms of various pathological and metabolic effects of ethanol were clarified, including hyperlipemia (with the rise in HDL), hyperuricemia, the role of acetaldehyde toxicity and alcohol-induced oxidative stress. The latter, including glutathione depletion, was corrected by 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 polyenylphosphatidylcholine, which is now being tested in a multicenter clinical trial. Lieber also discovered a new (microsomal) pathway of ethanol metabolism, responsible for the tolerance to ethanol and for several clinically important toxic interactions with other drugs (e.g., acetaminophen), anesthetics, industrial solvents, carcinogens, as well as retinol and b-carotene, with narrowing of their therapeutic window. His work defined the role of the stomach in ethanol 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., H2 blockers and aspirin) on the activities of the enzyme and on blood alcohol levels in social drinkers. Lieber was among the first to use antibiotics for the elimination of gastric bacterial urease and its ammonia production in man, thereby alleviating chronic gastritis and hypoacidity, with attenuation of hepatic encephalopathy in cirrhotics. He promoted early detection and treatment of heavy drinkers before their social or medical disintegration, by defining precirrhotic lesions and markers of alcohol consumption.The research of Dr. Lieber and his group yielded a better understanding of the pathogenesis of common hepatic, gastric and nutritional 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 diseases.