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.

Fig. 1

The role of GLN in ammonia detoxification in physiological state. The most of endogenous GLN is synthesized from glutamate and ammonia in the brain, skeletal muscle, and likely the lungs. GLN released to the circulation is catabolized in enterocytes, kidneys, and liver to ammonia, and this is detoxified to urea in the liver or excreted together with urea in the urine

Fig. 2

The role of GLN in ammonia detoxification in liver failure. In liver failure, ammonia escapes the urea cycle and is detoxified to GLN in the brain, skeletal muscle, and lungs. Enhanced GLN availability leads to enhanced GLN catabolism to ammonia in enterocytes and the kidneys. Thus GLN-ammonia cycling among tissues is activated. PSS Portal-systemic shunts

Fig. 3

Supposed vicious cycle in GLN synthesis and breakdown in pathogenesis of hyperammonemia in liver injury. Enhanced ammonia concentration due to impaired detoxification to urea in the liver activates GLN synthesis in skeletal muscle and in the brain leading to enhanced GLN catabolism to ammonia in enterocytes and the kidneys, and to subsequent increase in ammonia levels in the blood

Fig. 4

Effects of hyperammonemia on GLN metabolism in the brain. Enhanced GLN synthesis may cause edema in astrocytes, alterations in availability of excitatory neurotransmitter glutamate, and amino acid imbalance in the brain. AA Amino acids; GA Glutaminase; GLN Glutamine; Glu Glutamate; GS Glutamine synthetase

Fig. 5

Effects of hyperammonemia on GLN and BCAA metabolism in skeletal muscle (Holecek et al. 2011). Hyperammonemia enhances GLN synthesis that may enhance the consumption of BCAA, resulting in their deficiency in extracellular fluid. BCAA deficiency may participate in the pathogenesis of muscle wasting and HE. 1 branched-chain aminotransferase; 2 branched-chain α-ketoacid dehydrogenase; 3 GLN synthetase. ECF The extracellular fluid; BCAA Branched-chain amino acids; BCKA Branched-chain keto acids; BCA-CoA Branched-chain acyl-CoA; αnKG α-ketoglutarate; Glu Glutamate; Ala Alanine