Cerebral consequences of alcoholic liver disease

Abstract

Alcoholic Liver Disease (ALD) and its consequences play an important role in the pathogenesis of cerebral dysfunction in chronic alcoholism. There is convincing evidence that Portal-Systemic Encephalopathy (PSE), the predominant neuropsychiatric abnormality resulting from ALD, is caused by the accumulation of neurotoxins such as ammonia and manganese in brain. Both toxins are normally eliminated almost exclusively by the liver. Ammonia exerts its deleterious effects on cerebral function by an array of direct and indirect mechanisms including effects of the ammonium ion (NH +4 ) on inhibitory and excitatory neurotransmission as well as effects on cerebral energy metabolism. Existing treatment of PSE relies on ammonia-lowering strategies including reduction of dietary protein and the use of lactulose, neomycin and, and more recently, L-ornithine-aspartate. Proton Magnetic Resonance Spectroscopy reveals increased brain concentrations of the ammonia detoxification product glutamine in patients with PSE. Magnetic Resonance Imaging, on the other hand, shows bilateral signal hyperintensity in globus pallidus in a large majority of patients with ALD. Neurochemical and neuropathological examination of pallidal tissue from these patients reveals several-fold increases of manganese and the appearance of Alzheimer-type II astrocytes, the cardinal neuropathological feature of PSE. Neurochemical studies of postmortem brain tissue from patients with ALD who died in hepatic coma demonstrate modifications of glutamate and serotonin synthesis and metabolism as well as increased expression of “peripheral-type” benzodiazepine receptors (PTBRs). Studies in experimental animal models of PSE reveal alterations in expression of PTBRs and of neuronal nitric oxide synthase. Further elucidation of these neurotransmitter changes could provide potential targets for pharmacological manipulation and thus afford new approaches to the prevention and treatment of PSE in patients with ALD.