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.

Sarcopenia from mechanism to diagnosis and treatment in liver disease

“…However, glutamine disposal will then become limiting and strategies for long-term ammonia disposal to protect the skeletal muscle are necessary. Isoleucine and valine as anaplerotic substrates have been suggested because they can remove one mole of ammonia per mole of amino acid but the molecular and functional responses to these interventions have not been evaluated in preclinical or clinical studies to lower muscle ammonia or reverse sarcopenia[82, 83]. …”

A genetic variant in the promoter of phosphate‐activated glutaminase is associated with hepatic encephalopathy

“…Conversely, a reduced plasma level of ammonia was observed after administration of the ammonia-lowering agent ornithine phenylacetate, which specifically blocks GLS activity in the intestine [43]. Emerging therapeutic options for HE have recently been reviewed by Holecek [44]; one exciting novel area is that of probiotic administration for the prevention of HE [45].…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…Ammonia is generated through both gut bacteria and enterocytes and is subsequently metabolized by the liver into urea after its passage through the portal tract [16,17]. Urea, unlike ammonia, can be excreted from the body via the kidney.…”