Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease.

Chronic alcoholism results in brain damage and dysfunction leading to a constellation of neuropsychiatric symptoms including cognitive dysfunction, the Wernicke-Korsakoff Syndrome, alcoholic cerebellar degeneration and alcoholic dementia. That these clinically-defined entities result from independent pathophysiologic mechanisms is unlikely. Alcohol and its metabolite acetaldehyde are directly neurotoxic. Alcoholics are thiamine deficient as a result of poor diet, gastrointestinal disorders and liver disease. In addition, both alcohol and acetaldehyde have direct toxic effects on thiamine-related enzymes in liver and brain. Alcoholics frequently develop severe liver disease and liver disease per se results in altered thiamine homeostasis, in cognitive dysfunction and in neuropathologic damage to astrocytes. The latter may result in the loss of neuron-astrocytic trafficking of neuroactive amino acids and thiamine esters, essential to CNS function. The present review article proposes mechanisms whereby the effects of alcohol, thiamine deficiency and liver disease combine synergistically to contribute to the phenomena of cognitive dysfunction and "alcoholic brain damage".