Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years

Lieber CS

Abstract 

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a  mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of -carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or -carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC’s main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.

Key words: 	alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), cytochrome P450 (CYP2E1), S-adenosylmethionine (SAMe), polyenylphosphatidylcholine (PPC).