title: Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives.
abstract: There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.
authors.affiliation: Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Simkova 870, 500 38, Hradec Kralove, Czech Republic, holecek@lfhk.cuni.cz.
authors.forename: Milan
authors.initials: M
authors.lastname: Holecek
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism / Q000627:therapeutic use; D000641:Ammonia / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016638:Critical Illness; D004347:Drug Interactions; D020895:Enterocytes / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005972:Glutaminase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D007656:Ketoglutaric Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D064307:Microbiota; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity; D010654:Phenylbutyrates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000597:Amino Acids, Branched-Chain; D007656:Ketoglutaric Acids; D010654:Phenylbutyrates; D005973:Glutamine; D018698:Glutamic Acid; D000641:Ammonia; D005972:Glutaminase