Gastroenterology
Volume 136, Issue 7 , Pages 2048-2051 , June 2009

Treatment of Hyperammonemia in Liver Failure: A Tale of Two Enzymes

  • Rajiv Jalan

      Affiliations

    • Institute of Hepatology, University College Medical School, London, United Kingdom
    • ,
  • William M. Lee

      Affiliations

    • Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
    • Corresponding Author InformationReprint requests Address requests for reprints to: William M. Lee, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas

References 

  1. O'Grady J, Alexander G, Hayllar K, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439–445
  2. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis. 2003;23:271–282
  3. Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science. 1977;195:1356–1358
  4. Clemmesen JO, Larsen FS, Kondrup J, et al. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology. 1999;29:648–653
  5. Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut. 2006;55:98–104
  6. Jalan R, Olde Damink SW, Hayes PC, et al. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia, cerebral blood flow. J Hepatol. 2004;41:613–620
  7. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46:1844–1852
  8. Häussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?. J Hepatol. 2000;32:1035–1038
  9. Wright G, Davies NA, Shawcross , et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology. 2007;45:1517–1526
  10. Pedersen HR, Ring-Larsen H, Olsen NV, et al. Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital. J Hepatol. 2007;47:245–252
  11. Acharya SK, Bhatia V, Sreenivas V, et al. Efficacy of l-ornithine l-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology. 2009;136:2159–2168
  12. Olde Damink SW, Jalan R, Redhead DN, et al. Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology. 2002;36:1163–1171
  13. Romero-Gómez M, Ramos-Guerrero R, Grande L, et al. Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol. 2004;41:49–54
  14. Rose C, Michalak A, Rao KV, et al. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain oedema in rats with acute liver failure. Hepatology. 1999;30:636–640
  15. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247–254
  16. Lee WM. Acute liver failure in the United States. Semin in Liver Dis. 2003;23:217–226
  17. Polson J, Lee WM. AASLD position paper: the management of acute liver failure (American Association for the Study of Liver Disease). Hepatology. 2005;41:1179–1197
  18. Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl. 2005;11:1581–1589
  19. Shawcross D, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005;365:431–433
  20. Jalan R, Wright G, Davies NA, et al. L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses. 2007;69:1064–1069
  21. Davies NA, Wright G, Ytrebø LM, et al. L-ornithine and phenylacetate synergistically produces sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology. 2009;in press
  22. Ytrebø LM, Kristiansen RG, Mæhre H, et al. l-Ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology. 2009;in press
  23. Lee WN, Hynan LS, Rossaro L, et al. ALFSG Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;in press

 Conflicts of interest The authors disclose the following: Professor Rajiv Jalan (University College London) has filed for patents surrounding the use of l-ornithine phenylacetate for the treatment of hepatic encephalopathy. The technology has been licensed to Ocera Therapeutics. William M. Lee discloses no conflicts.

PII: S0016-5085(09)00561-7

doi: 10.1053/j.gastro.2009.04.016

Gastroenterology
Volume 136, Issue 7 , Pages 2048-2051 , June 2009

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