Until two decades ago, dietary deficiencies were considered to be the major reason why alcoholics developed
liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary
malnutrition. Direct hepatotoxic effects of
ethanol were also established, some of which were linked to redox changes produced by reduced
nicotinamide adenine dinucleotide (
NADH) generated via the
alcohol dehydrogenase (ADH) pathway. It was also determined that
ethanol can be oxidized by a
microsomal ethanol oxidizing system (
MEOS) involving
cytochrome P-450: the newly discovered
ethanol-inducible
cytochrome P-450 (P-450IIE1) contributes to
ethanol metabolism, tolerance, energy wastage (with associated
weight loss), and the selective hepatic perivenular toxicity of various
xenobiotics. P-450 induction also explains depletion (and enhanced toxicity) of nutritional factors such as
vitamin A. Even at the early
fatty-liver stage, alcoholics commonly have a very low hepatic concentration of
vitamin A.
Ethanol administration in animals was found to depress hepatic levels of
vitamin A, even when administered with diets containing large amounts of the
vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of
retinol metabolism, inducible by either
ethanol or
drug administration. The hepatic depletion of
vitamin A was strikingly exacerbated when
ethanol and other drugs were given together, mimicking a common clinical occurrence. Hepatic
retinoid depletion was found to be associated with lysosomal lesions and decreased detoxification of chemical
carcinogens. To alleviate these adverse effects, as well as to correct problems of
night blindness and sexual inadequacies, the alcoholic patient should be provided with
vitamin A supplementation. Such
therapy, however, is complicated by the fact that in excessive amounts
vitamin A is hepatotoxic, an effect exacerbated by long-term
ethanol consumption. This results in striking morphologic and functional alterations of the mitochondria with leakage of mitochondrial
enzymes, hepatic
necrosis, and
fibrosis. Thus, treatment with
vitamin A and other nutritional factors (such as
proteins) is beneficial but must take into account a narrowed therapeutic window in alcoholics who have increased needs for such nutrients, but also display an enhanced susceptibility to their adverse effects. Massive doses of
choline also exerted some toxic effects and failed to prevent the development of
alcoholic cirrhosis.
Acetaldehyde (the metabolite produced from
ethanol by either ADH or
MEOS) impairs hepatic
oxygen utilization and forms
protein adducts, resulting in antibody production,
enzyme inactivation, and decreased DNA repair. It also enhances
pyridoxine and perhaps
folate degradation and stimulates
collagen production by the
vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)