Hyperammonemia in Hepatic Encephalopathy

Abstract

The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.

Keywords: AHE, Acute Hepatic Encephalopathy; ALF, Acute Liver Failure; CHE, Chronic Hepatic Encephalopathy; CNS, Central Nervous System; CSF, Cerebrospinal Fluid; ECs, Endothelial Cells; HE, Hepatic Encephalopathy; IL, Interleukin; LPS, Lipopolysaccharide; MAPKs, Mitogen-Activated Protein Kinases; NCX, Sodium-Calcium Exchanger; NF-κB, Nuclear Factor-kappaB; NHE, Sodium/Hydrogen Exchanger-1 or SLC9A1 (SoLute Carrier Family 9A1); SUR1, The Sulfonylurea Receptor 1; TDP-43 and tau proteinopathies; TDP-43, TAR DNA-Binding Protein, 43 kDa; TLR, Toll-like Receptor; TNF-α, Tumor Necrosis Factor-Alpha; TSP-1, Thrombospondin-1; ammonia; hepatic encephalopathy; inflammation; matricellular proteins.