Treatment of Hyperammonemia in Liver Failure: A Tale of Two Enzymes

In patients with liver failure, hyperammonemia results from a lack of urea synthetic capacity resulting in increasing quantities of circulating ammonia. The main mechanisms controlling ammonia levels in this situation are the enzymes regulating glutamine, namely, glutamine synthetase and glutaminase, setting up a “futile” cycle. In liver failure, LOLA is thought to act through the conversion of l-ornithine to glutamine in the muscle thereby detoxifying 1 molecule of ammonia. The lack of effectiveness of LOLA in the study by Acharya et al may be explained by the fact that the detoxification of ammonia into glutamine is a transient phenomenon as nitrogen is not actually eliminated from the system. Glutamine essentially acts as a “Trojan horse” for circulation of ammonia and can be readily converted back into glutamate and ammonia by glutaminase present in the gut.