Role of circulating neurotoxins in the pathogenesis of hepatic encephalopathy: potential for improvement following their removal by liver assist devices

Both acute and chronic liver failure result in impaired cerebral function known as hepatic encephalopathy (HE). Evidence suggests that HE is the consequence of the accumulation in brain of neurotoxic and/or neuroactive substance including ammonia, manganese, aromatic amino acids, mercaptans, phenols, short-chain fatty acids, bilirubin and a variety of neuroactive medications prescribed as sedatives to patients with liver failure. Brain ammonia concentrations may attain levels in excess of 2 mM, concentrations which are known to adversely affect both excitatory and inhibitory neurotransmission as well as brain energy metabolism. Manganese exerts toxic effects on dopaminergic neurones. Prevention and treatment of HE continues to rely heavily on the reduction of circulation ammonia either by reduction of gut production using lactulose or antibiotics or by increasing its metabolism using L-ornithine-L-aspartate. No specific therapies have so far been designed to reduce circulation concentrations of other toxins. Liver assist devices offer a potential new approach to the reduction of circulating neurotoxins generated in liver failure. In this regard, the Molecular Absorbents Recirculating System (MARS) appears to offer distinct advantages over hepatocyte-based systems.