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Ornithine Phenylacetate: A Novel Strategy for the Treatment of Hepatic Encephalopathy

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Hepatic Encephalopathy

Part of the book series: Clinical Gastroenterology ((CG))

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Abstract

Over the past 100 years a central role of ammonia in the pathogenesis of hepatic encephalopathy (HE) has been hypothesized. Treatment of hyperammonemia and HE are unmet clinical needs. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. Ammonia-mediated mechanisms include changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. Systemic hyperammonemia has been largely found in patients with HE with underlying cirrhosis and acute liver failure (ALF). The mechanism by which OP directly reduces ammonia levels in cirrhosis is by increasing muscle glutamine synthesis activity, subsequently trapping and increasing ammonia excretion as phenylacetylglutamine, with the concomitant normalization of gut glutaminase activity. The reduction of ammonia (by OP) leads to a reduction in intracranial hypertension in models of ALF and is associated with an improvement in inflammation and nitric oxide availability in the context of cirrhosis. Studies to date have indicated that it is safe and patient studies in minimal HE and overt HE are underway to establish OP as a treatment for this major complication of liver disease.

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References

  1. Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science. 1977;195:1356–8.

    Article  PubMed  CAS  Google Scholar 

  2. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis. 2003;23:271–82.

    Article  PubMed  Google Scholar 

  3. Neary JT, del Pilar Gutierrez M, Norenberg LO, Norenberg MD. Protein phosphorylation in primary astrocyte cultures treated with and without dibutyryl cyclic AMP. Brain Res. 1987;410:164–8.

    Article  PubMed  CAS  Google Scholar 

  4. Kato M, Hughes RD, Keays RT, Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology. 1992;15:1060–6.

    Article  PubMed  CAS  Google Scholar 

  5. Master S, Gottstein J, Blei AT. Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology. 1999;30:876–80.

    Article  PubMed  CAS  Google Scholar 

  6. Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, et al. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol. 2001;35:598–604.

    Article  PubMed  CAS  Google Scholar 

  7. Balata S, Olde Damink SW, Ferguson K, Marshall I, Hayes PC, Deutz NE, et al. Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Hepatology. 2003;37:931–9.

    Article  PubMed  CAS  Google Scholar 

  8. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology. 1999;29:648–53.

    Article  PubMed  CAS  Google Scholar 

  9. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004;127:1338–46.

    Article  PubMed  CAS  Google Scholar 

  10. Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut. 2006;55:98–104.

    Article  PubMed  CAS  Google Scholar 

  11. Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46:1844–52.

    Article  PubMed  CAS  Google Scholar 

  12. Rama Rao KV, Jayakumar AR, Tong X, Alvarez VM, Norenberg MD. Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes. J Neuroinflammation. 2010;7:66.

    Article  PubMed  Google Scholar 

  13. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247–54.

    Article  PubMed  CAS  Google Scholar 

  14. Wong D, Dorovini-Zis K, Vincent SR. Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp Neurol. 2004;190:446–55.

    Article  PubMed  CAS  Google Scholar 

  15. Wright G, Davies NA, Shawcross DL, Hodges SJ, Zwingmann C, Brooks HF, et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology. 2007;45:1517–26.

    Article  PubMed  CAS  Google Scholar 

  16. Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol. 2005;42(Suppl):S45–53.

    Article  PubMed  Google Scholar 

  17. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci. 2005;62:2295–304.

    Article  PubMed  CAS  Google Scholar 

  18. Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs. 2000;60:1353–70.

    Article  PubMed  CAS  Google Scholar 

  19. Blei AT. Diagnosis and treatment of hepatic encephalopathy. Baillieres Best Pract Res Clin Gastroenterol. 2000;14:959–74.

    Article  PubMed  CAS  Google Scholar 

  20. Wright G, Noiret L, Olde Damink SW, Jalan R. Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Liver Int. 2011;31(2):163–75.

    Article  PubMed  CAS  Google Scholar 

  21. Romero-Gomez M, Ramos-Guerrero R, Grande L, de Teran LC, Corpas R, Camacho I, et al. Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol. 2004;41:49–54.

    Article  PubMed  CAS  Google Scholar 

  22. Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, Soeters PB. Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology. 2002;36:1163–71.

    Article  PubMed  CAS  Google Scholar 

  23. Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology. 1999;30:636–40.

    Article  PubMed  CAS  Google Scholar 

  24. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004;328:1046.

    Article  PubMed  CAS  Google Scholar 

  25. Alba L, Hay J, Lee WM. Lactulose therapy in acute liver failure. J Hepatol. 2002;36:33A.

    Article  Google Scholar 

  26. Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology. 2008;47:1401–15.

    Article  PubMed  Google Scholar 

  27. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–81.

    Article  PubMed  CAS  Google Scholar 

  28. Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a doubleblind, randomized, placebo-controlled study. Gastroenterology. 2009;136(7):2159–68.

    Article  PubMed  CAS  Google Scholar 

  29. Jalan R, Wright G, Davies NA, Hodges SJ. L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses. 2007;69:1064–9.

    Article  PubMed  CAS  Google Scholar 

  30. Smith I. The treatment of inborn errors of the urea cycle. Nature. 1981;291:378–80.

    Article  PubMed  CAS  Google Scholar 

  31. Romero-Gomez M, Jover M, Diaz-Gomez D, de Teran LC, Rodrigo R, Camacho I, et al. Phosphate-activated glutaminase activity is enhanced in brain, intestine and kidneys of rats following portacaval anastomosis. World J Gastroenterol. 2006;12:2406–11.

    PubMed  CAS  Google Scholar 

  32. Romero-Gomez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galan JJ, et al. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med. 2010;153:281–8.

    PubMed  Google Scholar 

  33. Jover-Cobos M, Noiret L, Habtesion A, Balasubramaniyan V, Sharifi Y, Romero-Gómez M, et al. The mechanism behind synergistic action of L-ornithine and phenylacetate to reduce ammonia in Cirrhotic rats. Hepatology. 2010;52(Suppl):893A.

    Google Scholar 

  34. Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology. 2010;139:675–84.

    Article  PubMed  CAS  Google Scholar 

  35. Davies N, Wright G, Ytrebo LM, Stadlbauer V, Fuskevag O-M, Zwingmann C, et al. L-ornithine and phenylacetate synergistically produces sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology. 2009;50(1):155–64.

    Article  PubMed  CAS  Google Scholar 

  36. Ytrebo LM, Kristiansen RG, Maehre H, Fuskevag O-M, Kalstad T, Revhaug A, et al. L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology. 2009;50(1):165–74.

    Article  PubMed  Google Scholar 

  37. Oria M, Chatauret N, Chavarria L, Romero-Gimenez J, Palenzuela L, Pardo-Yules B, et al. Motor-evoked potentials in awake rats are a valid method of assessing hepatic encephalopathy and of studying its pathogenesis. Hepatology. 2010;52:2077–85.

    Article  PubMed  Google Scholar 

  38. Oria M, Romero-Giménez J, Arranz JA, Riudor E, Raguer N, Córdoba J. Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis. J Hepatol. 2012;56(1):109–14. Epub 2011 Aug 9.

    Google Scholar 

  39. Montoliu C, Piedrafita B, Serra MA, del Olmo JA, Urios A, Rodrigo JM, et al. IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol. 2009;43:272–9.

    Article  PubMed  CAS  Google Scholar 

  40. Montoliu C, Rodrigo R, Monfort P, Llansola M, Cauli O, Boix J, et al. Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications. Metab Brain Dis. 2010;25:39–48.

    Article  PubMed  CAS  Google Scholar 

  41. Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, et al. Infection and systemic inflammation, not ammonia, are associated with grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2010;54:640–9.

    Article  PubMed  Google Scholar 

  42. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725–34.

    Article  PubMed  CAS  Google Scholar 

  43. Balasubramaniyan V, Wright G, Sharma V, Davies NA, Sharifi Y, Habtesion A, Mookerjee RP, Jalan R. 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. 2012;302(1):G145–52.

    Article  Google Scholar 

  44. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007;13:198–203.

    Article  PubMed  CAS  Google Scholar 

  45. Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology. 2007;45:62–71.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. UCL Institute of Hepatology, Royal Free Hospital, University College of London, Upper Third UCL Medical School, Pond Street, London, NW3 2PF, UK

    Maria Jover-Cobos PhD, Nathan A. Davies PhD, BSc, Yalda Sharifi MD, BAO, BCh, LRCP, SI&MRCP (UK) & Rajiv Jalan MBBS, MD, PhD, FRCPE, FRCP

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  1. Maria Jover-Cobos PhD
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  2. Nathan A. Davies PhD, BSc
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  3. Yalda Sharifi MD, BAO, BCh, LRCP, SI&MRCP (UK)
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  4. Rajiv Jalan MBBS, MD, PhD, FRCPE, FRCP
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Corresponding author

Correspondence to Rajiv Jalan MBBS, MD, PhD, FRCPE, FRCP .

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Editors and Affiliations

  1. , Division of Gastroenterology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, 44145, USA

    Kevin D. Mullen

  2. , Division of Gastroenterology, MetroHealth Medical Center, 2500 MetroHealth Medical Center, Cleveland, 44145, USA

    Ravi K. Prakash

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Jover-Cobos, M., Davies, N.A., Sharifi, Y., Jalan, R. (2012). Ornithine Phenylacetate: A Novel Strategy for the Treatment of Hepatic Encephalopathy. In: Mullen, K., Prakash, R. (eds) Hepatic Encephalopathy. Clinical Gastroenterology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-836-8_13

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  • DOI: https://doi.org/10.1007/978-1-61779-836-8_13

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-835-1

  • Online ISBN: 978-1-61779-836-8

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