Effects of liver failure on inter‐organ trafficking of ammonia: implications for the treatment of hepatic encephalopathy

  Hepatic encephalopathy due to acute or chronic liver failure is invariably associated with hyperammonemia. High ammonia concentrations have deleterious effects on brain function by both direct and indirect mechanisms. There is increasing evidence to suggest that hyperammonemia in liver failure results from altered inter‐organ ammonia trafficking. Under normal conditions the gut produces ammonia from glutamine and urea. During liver failure, the contribution of the gut to hyperammonemia is predominantly the consequence of a diminished hepatic elimination rather than increased intestinal production. Normally, the liver removes ammonia by two distinct pathways, namely urea and glutamine synthesis catalyzed by enzymes that are, respectively, localized in the periportal and perivenous hepatocytes. The skeletal muscle relies solely on glutamine synthesis to remove ammonia. During liver failure, muscle glutamine production increases and the muscle becomes the major route for ammonia detoxification. The kidney is capable of both producing and removing ammonia. Under normal conditions, the kidney produces ammonia from glutamine which is mainly excreted into the renal vein, the remainder being excreted into the urine. However, in liver failure the excretion of the ammonia produced by the kidney is increased. Like skeletal muscle the brain relies solely on glutamine synthesis to remove ammonia. But unlike muscle, glutamine synthetase in the brain operates at nearly maximal capacity in normal conditions, and its activity is reduced during chronic liver failure. A better understanding of the alterations of inter‐organ ammonia trafficking could give rise to combined therapies aimed at reducing ammonia production and increasing ammonia removal by target organs.