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01-12-2016 | Short Communication

Current state of knowledge of hepatic encephalopathy (part I): newer treatment strategies for hyperammonemia in liver failure

Author: Rune Gangsoy Kristiansen

Published in: Metabolic Brain Disease | Issue 6/2016

Abstract

Alterations in interorgan metabolism of ammonia play an important role in the onset of hyperammonemia in liver failure. Glutamine synthetase (GS) in muscle is an important target for ammonia removal strategies in hyperammonemia. Ornithine Phenylacetate (OP) is hypothesized to remove ammonia by providing glutamate as a substrate for increased GS activity and hence glutamine production. The newly generated glutamine conjugates with phenylacetate forming phenylacetylglutamine which can be excreted in the urine, providing an excretion pathway for ammonia. We have also shown that OP targets glycine metabolism, providing an additional ammonia reducing effect.

Balasubramaniyan V, Wright G, et al. (2012) Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 302(1):G145–G152CrossRefPubMed

Brusilow S, Tinker J, et al. (1980) Amino acid acylation: a mechanism of nitrogen excretion in inborn errors of urea synthesis. Science 207(4431):659–661CrossRefPubMed

Clemmesen JO, Kondrup J, et al. (2000) Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 118(6):1131–1139CrossRefPubMed

Dabos KJ, Whalen HR, et al. (2011) Impaired gluconeogenesis in a porcine model of paracetamol induced acute liver failure. World J Gastroenterol 17(11):1457–1461CrossRefPubMedPubMedCentral

Dadsetan S, Sorensen M, et al. (2013) Interorgan metabolism of ornithine phenylacetate (OP)--a novel strategy for treatment of hyperammonemia. Biochem Pharmacol 85(1):115–123CrossRefPubMed

Davies NA, Wright G, et al. (2009) L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology 50(1):155–164CrossRefPubMed

Jalan R, Wright G, et al. (2007) L-ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 69(5):1064–1069CrossRefPubMed

James MO, Smith RL, et al. (1972) The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species. Proc R Soc Lond B Biol Sci 182(66):25–35CrossRefPubMed

Jover-Cobos M, Khetan V, et al. (2014a) Treatment of hyperammonemia in liver failure. Curr Opin Clin Nutr Metab Care 17(1):105–110PubMed

Jover-Cobos M, Noiret L, et al. (2014b) Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats. J Hepatol 60(3):545–553CrossRefPubMed

Kristiansen RG, Rose CF, et al. (2014) L-Ornithine Phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway. Am J Physiol Gastrointest Liver Physiol: ajpgi 00244 02014s

Oria M, Romero-Gimenez J, et al. (2012) Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis. J Hepatol 56(1):109–114CrossRefPubMed

Rose CF (2012) Ammonia-lowering strategies for the treatment of hepatic encephalopathy. Clin Pharmacol Ther 92(3):321–331CrossRefPubMed

Rose C, Michalak A, et al. (1999) L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 30(3):636–640CrossRefPubMed

Rudman D, Galambos JT, et al. (1973) Comparison of the effect of various amino acids upon the blood ammonia concentration of patients with liver disease. Am J Clin Nutr 26(9):916–925PubMed

Sturgeon JP, Shawcross DL (2014) Recent insights into the pathogenesis of hepatic encephalopathy and treatments. Expert Rev Gastroenterol Hepatol 8(1):83–100CrossRefPubMed

Sushma S, Dasarathy S, et al. (1992) Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 16(1):138–144CrossRefPubMed

Tremblay GC, Qureshi IA (1993) The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen. Pharmacol Ther 60(1):63–90CrossRefPubMed

Ventura-Cots M, Arranz JA, et al. (2013) Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study. J Clin Gastroenterol 47(10):881–887CrossRefPubMed

Wright G, Vairappan B, et al. (2012) Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver Int 32(3):410–419PubMed

Ytrebo LM, Kristiansen RG, et al. (2009) L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology 50(1):165–174CrossRefPubMed

Title: Current state of knowledge of hepatic encephalopathy (part I): newer treatment strategies for hyperammonemia in liver failure
Author: Rune Gangsoy Kristiansen
Publication date: 01-12-2016
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 6/2016
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-016-9908-9

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