Fig. 1. Multiorgan ammonia pathways with specific ammonia-lowering medications used in cirrhosis.

Circulating concentrations of ammonia (NH₃) are shown with multiorgan involvement in the production of NH₃, ultimately resulting in NH₃ crossing the blood–brain barrier, contributing to astrocyte swelling and hepatic encephalopathy, as decreased urea cycle capability and reduced liver glutamine synthetase activity is present in cirrhosis. The alternative pathway is also shown at the top, where NH₃ binds with glutamate (GLU) forming glutamine (GLN) after enzymatic processing using glutamine synthetase (GS). Both ornithine phenylacetate (OP) and glycerol phenylbutyrate (GPB) are ammonia-lowering medications; they combine GLN and phenylacetate (PAA) to form phenylacetylglutamine (PAGN), which is excreted in the urine. AST-120 is a carbon microsphere adsorbent that binds NH₃ in the gut, thus lowering circulating ammonia levels. Polyethylene glycol (PEG) is a cathartic, which causes rapid clearance of gut bacterial synthesizing ammonia to be excreted into the feces. About one-quarter of urea-derived byproducts from the urea cycle is shunted to the colon (not shown; remaining three-fourths of urea excreted in the kidneys), where urease-producing bacterial organisms produce ammonia that enters the portal circulation. Skeletal muscle also contributes to the regulation of NH₃ as depicted. Not shown in the figure is the presence of GS and glutaminase in each organ, contributing to NH₃ homeostasis. Adapted from publication by Thieme publications.76

Abbreviation: PBA, Phenylbutyric acid.