Ammonia metabolism in normal and portacaval-shunted rats

Ammonia is generated from a large number of metabolically important reactions. Despite its central importance in whole body nitrogen homeostasis excess ammonia is neurotoxic and its concentration must be kept low. Ammonia generated in most extrahepatic tissues is detoxified by incorporation into glutamine (amide). This glutamine may be used in a number of biosynthetic reactions (e.g. in pyrimidine synthesis). Alternatively, as a means of maintaining nitrogen balance, glutamine may be released to the blood. Resting skeletal muscle is particularly important 1) as a "sink" for removal of blood ammonia, and 2) as a major source of circulating glutamine. However, during vigorous exercise skeletal muscle may become a net contributor of ammonia to the blood. A few tissues and cell types (e.g. lymphocytes, macrophages, enterocytes, colonocytes, thymocytes, fibroblasts, bone) and tumors exhibit marked rates of glutamine utilization. In the kidney, glutamine is an important source of urinary ammonia. Ammonia generated from 1) the breakdown of nitrogenous substances in the gut, and 2) from the use of glutamine as a metabolic fuel in the small intestine, is taken up by the liver wherein it is detoxified by conversion to urea and to a lesser extent, glutamine. Some portal vein glutamine acts as a source of urea nitrogen. Ultimately, however, most excess ammonia nitrogen is detoxified indirectly (via glutamine (blood)----glutamine (small intestine)----ammonia (portal vein) or directly in the liver as urea. Portal-systemic shunting of blood, as occurs in chronic cirrhosis of the liver or following the surgical construction of a portacaval shunt results in portal blood bypassing the normal ammonia detoxification machinery of the liver. Under this condition blood ammonia levels rise markedly, increasing the burden on extrahepatic tissues, such as skeletal muscle, brain, and kidney, in maintaining ammonia homeostasis. The most commonly employed animal model of human liver disease is the rat in which an end-to-side portacaval shunt (PCS) has been surgically constructed. Brain glutamine synthetase activity is not increased in PCS rats and in some areas of the brain there may even be a decrease in activity. The brain glutamine synthetase appears to be working at near maximal capacity. Thus, the PCS rats exhibit profound neurological dysfunction when administered ammonium salts in amounts easily tolerated by normal animals. Because of the limited capacity of brain to remove excess ammonia, a rational approach to the treatment of patients with liver disease should include a regimen directed toward lowering the associated hyperammonemia.