Central Aminergic Function and its Disturbance by Hepatic Disease: The Current Status of L-valine Pharmacotherapy in Metabolic Coma

Abstract

Animal experiments and human post mortem brain analyses led to the assumption that hepatic encephalopathy may be more associated with disturbances of serotonin (5-HT) metabolism than with disorders of catecholaminergic functions. Tryptophan (TRP), 5-HT, and 5-hydroxy indole acetic acid (5-HIAA) have been found to be substantially above normal values, especially in brain stem areas. These disturbances in hepatic coma are associated with high concentrations of ammonia and glutamate. Both the high neuronal activity of 5-HT and the high concentrations of the neurotoxic ammonia may, therefore, contribute to the state of hepatic coma. However, neuronal uptake of 5-HT is decreased and 5-HT receptors appear to change their Bmax and KD values with depth of coma. Reduced activity of TRP-2,3-dioxygenase may be involved in stimulation of 5-HT synthesis. Therefore, therapeutic strategies which reduce both TRP and ammonia concentrations should be employed. One possibility is the parenteral administration of L-valine (VAL), a branched chain amino acid. Its administration to patients with liver cirrhosis reduced plasma ammonia which subsequently increased after VAL withdrawal. Patients with higher baseline levels of ammonia responded better than those with lower baseline ammonia. Such treatment has been shown to decrease TRP, 5-HT, 5-HIAA and ammonia levels in human brain tissue. Although the mechanism by which VAL exerts its action is still unknown, experimental evidence provides the following possible explanations: 1. VAL competes with TRP at the blood brain-barrier; 2. VAL seems to generally decrease ammonia by inhibition of a) ammonia induced reduction of protein-synthesis or b) protein breakdown Utilization of VAL in the presence of high ammonia concentrations is, therefore, enhanced and induces lower plasma levels of branched chain amino acids but higher levels of aromatic amino acids. 3. Catabolism of VAL to products involved in energy metabolism.