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Ammonia is a degradation product of nitrogen-containing compounds (mainly proteins and amino acids) and is generated by the metabolism in all living organisms. Dietary protein contains approximately 16% nitrogen, and the excess nitrogen from the amino acids that are not incorporated back into proteins is excreted in the urine as urea. Urea is produced in the liver by an enzymatic process that is dependent on an intact urea cycle. When the urea cycle malfunctions, urea is produced and nitrogen in the form of ammonia accumulates in blood and tissues.

The physiology of ammonia production and disposal is summarized in Figure 145-1. In humans and other mammals, most of the ammonia that circulates in the bloodstream originates in the intestine via two main mechanisms. The first is circulating glutamine, most of which is produced in the muscle, is taken up by the intestinal mucosa, where it is used as an energy source after deamination by glutaminase releasing free ammonia. The second mechanism for intestinal ammonia production involves the intestinal bacterial flora, which releases ammonia by splitting urea and by oxidizing amino acids. The ammonia produced in the intestine is absorbed into the portal circulation, where ammonia concentration is approximately 10 times higher than in the peripheral blood. More than 90% of portal ammonia is converted to urea in the liver by a series of enzymatic reactions that comprise the urea cycle, which is most active in periportal hepatocytes. The remaining ammonia that escapes the urea cycle is trapped in perivenous hepatocytes to produce glutamine. Ammonia is also produced from glutamine by glutaminase in the distal renal tubule as a mechanism of urine acidification, but this occurs only when the blood pH becomes abnormally acidic. Since ammonia is readily diffusible and extremely toxic to the brain (the only organ that displays toxicity from high ammonia levels), its level in the blood needs to be maintained at nontoxic, relatively low levels. The normal level of free ammonia in plasma of humans is usually less than 35 μmol/L. Levels less than 50 μmol/L are considered safe while levels above 100 μmol/L are frequently associated with a range of clinical symptoms, including lethargy, vomiting, and altered consciousness. The severity of symptoms usually correlates with the degree of hyperammonemia, but this correlation may vary in different patients—while some patients may show severe brain dysfunction at ammonia levels between 100 and 200 μmol/L, others may function normally at a similar degree of hyperammonemia. The reasons for this phenomenon are unknown.

Figure 145-1.

Human ammonia physiology. The complete urea cycle resides exclusively in the liver. The intestine is a source of ammonia and citrulline. Most of the ammonia that is absorbed from the intestine is converted to urea in the liver. Ammonia concentration in the portal blood is approximately 10 times higher than in systemic blood. The citrulline produced in the intestine bypasses the liver and is converted ...

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