What is the role of ammonia metabolism in the pathogenesis of hepatic encephalopathy (HE)?

Updated: May 18, 2020
  • Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: BS Anand, MD  more...
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Ammonia is produced in the gastrointestinal tract by the bacterial degradation of amines, amino acids, purines, and urea. Enterocytes also convert glutamine to glutamate and ammonia by the activity of glutaminase. [17]

Normally, ammonia is detoxified in the liver by conversion to urea by the Krebs-Henseleit cycle. Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase. Two factors contribute to the hyperammonemia that is seen in cirrhosis. First, there is a decrease in the mass of functioning hepatocytes, resulting in fewer opportunities for ammonia to be detoxified by the above processes. Secondly, portosystemic shunting may divert ammonia-containing blood away from the liver to the systemic circulation.

Normal skeletal muscle cells do not possess the enzymatic machinery of the urea cycle but do contain glutamine synthetase. Glutamine synthetase activity in muscle actually increases in the setting of cirrhosis and portosystemic shunting. Thus, the skeletal muscle is an important site for ammonia metabolism in cirrhosis. However, the muscle wasting that is observed in patients with advanced cirrhosis may potentiate hyperammonemia.

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