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The treatment of hepatic encephalopathy

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Abstract

Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

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References

  • Als-Nielsen B, Gluud LL, Gluud C (2004a) Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomized trials. BMJ 328:1046–1051

    Article  PubMed  CAS  Google Scholar 

  • Als-Nielsen B, Gluud LL, Gluud C (2004b) Non-absorbable disaccharides for hepatic encephalopathy (Cochrane review). In: The Cochrane Library, Issue 2. Wiley, Chichester, UK

  • Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C (2004c) Branched-chain amino acids for hepatic encephalopathy (Cochrane review). In: The Cochrane Library, Issue 2. Wiley, Chichester, UK

  • Bass NM (2006) The current pharmacological therapies for hepatic encephalopathy. Aliment Pharmacol Ther 25(1):23–31

    Google Scholar 

  • Bircher J, Müller J, Guggenheim P, Hammerli UP (1966) Treatment of chronic portal systemic encephalopathy with lactulose. Lancet i:890–892

    Google Scholar 

  • Blanc P, Daures JP, Liautard J, Buttigieg R, Desprez D, Pageaux G et al (1994) Lactulose–neomycin combination versus placebo in the treatment of acute hepatic encephalopathy. Results of a randomized controlled trial. Gastroenterol Clin Biol 18:1063–1068

    PubMed  CAS  Google Scholar 

  • Blei AT (2004) Infection, inflammation and hepatic encephalopathy, synergism redefined. J Hepatol 40:327–330

    Article  PubMed  Google Scholar 

  • Canales JJ, Elayadi A, Errami M, Llansola M, Cauli O, Felipo V (2003) Chronic hyperammonemia alters motor and neurochemical responses to activation of group I metabotropic glutamate receptors in the nucleus accumbens in rats in vivo. Neurobiol Dis 14:380–390

    Article  PubMed  CAS  Google Scholar 

  • Chandra RK, McBean LD (1994) Zinc and immunity. Nutrition 10:79–80

    PubMed  CAS  Google Scholar 

  • Conn HO, Lieberthal MM (1979) The hepatic coma syndromes and lactulose. Williams and Wilkins, Baltimore

    Google Scholar 

  • Córdoba J, Mínguez B, Vergara M (2005) Treatment of hepatic encephalopathy. Lancet 365:1384–1385

    Article  PubMed  Google Scholar 

  • Dejong C, Deutz N, Soeters P (1993) Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat. J Clin Invest 92:2834–2840

    Article  PubMed  CAS  Google Scholar 

  • Dragon Y, Avraham Y, Ilan Y, Mechoulam R, Berry EM (2007) Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase. FASEB J (in press)

  • Erceg S, Monfort P, Hernandez-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005) Oral administration of sidenafil restore learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 41:299–306

    Article  PubMed  CAS  Google Scholar 

  • Fleig WE, Kircheis G, Spengler U, Zeuzem St, Görtelmeyer R, German–Austrian–Swiss Multicentre Study Group (1999) Placebo-controlled, double-blind evaluation of l-ornithine–l-aspartate (LOLA) granules in patients with cirrhosis and subclinical (SHE) or mild overt hepatic encephalopathy (HE). J Hepatol 30(1):65

    Article  Google Scholar 

  • Grüngreiff K, Presser HJ, Franke D, Lössner B, Abicht K, Kleine FD (1989) Correlations between zinc, amino acids and ammonia in liver cirrhosis. Z Gastroenterol 27:731–735

    PubMed  Google Scholar 

  • Grüngreiff K, Grüngreiff S, Reinhold D (2000) Zinc deficiency and hepatic encephalopathy. Results of a long-term zinc supplementation. Trace Elem Exp Med 13:21–31

    Article  Google Scholar 

  • Henglein-Ottermann D (1976) Der Einfluβ von Ornithin-Aspartat auf die Experimentell erzeugte Hyperammoniämie. Klinisch-experimentelle Studie. Therapie der Gegenwart 115:1504–1518

    PubMed  CAS  Google Scholar 

  • Ishiki Y, Ohnishi H, Muto Y, Matsumoto K, Nakamura T (1992) Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 16:1227–1235

    PubMed  CAS  Google Scholar 

  • Iwasa M, Matsumura K, Watanabe Y, Yamamoto M, Kaito M, Ikoma J et al (2003) Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis. Eur J Gastroenterol Hepatol 15:733–737

    Article  PubMed  CAS  Google Scholar 

  • Jalan R, Kapoor D (2004) Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid. Clin Sci 106:467–474

    Article  PubMed  CAS  Google Scholar 

  • Jalan R, Wright G, Davies NA, Hodges SJ (2007) L-ornithine-phenylacetate (OP): A novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses (in press)

  • Kale RA, Gupta RK, Saraswat VA, Hasan KM, Trivedi R, Mishra AM et al (2006) Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology 43:698–706

    Article  PubMed  Google Scholar 

  • Kalk H (1958) Die Klinik der akuten Leberinsuffizienz. Gastroenterologia 90:271–290

    Article  PubMed  CAS  Google Scholar 

  • Katayama K (2004) Ammonia metabolism and hepatic encephalopathy. Hepatol Res 30S:S71–S78

    Google Scholar 

  • Kircheis G, Metz M, Frey S, Seiller E (1996) Correlation between pharmacokinetic aspects and clinical efficacy of l-ornithine–l-aspartate (OA): results of randomized, controlled clinical trials. J Hepatol 25(1):131

    Google Scholar 

  • Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R et al (1997) Therapeutic efficacy of l-ornithine–l-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled double-blind study. Hepatology 25:1351–1360

    Article  PubMed  CAS  Google Scholar 

  • Kunin CM, Chalmers TC, Leevy CM, Sebastyen SC, Lieber CS, Finland M (1960) Absorption of orally administered neomycin and kanamycin with special reference to patients with severe hepatic and renal disease. N Engl J Med 262:380–385

    Article  PubMed  CAS  Google Scholar 

  • Lai D, Gorbach SL, Levitan R (1972) Intestinal microflora in patients with alcoholic cirrhosis: urea-splitting bacteria and neomycin resistance. Gastroenterology 62:275–279

    PubMed  CAS  Google Scholar 

  • Lanthier PL, Morgan MY, Ballantyne J (1984) Bromocriptine-associated ototoxicity. J Laryngol Otol 98:399–404

    PubMed  CAS  Google Scholar 

  • Leevy CB, Phillips JA (2007) Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 52:737–741

    Article  PubMed  CAS  Google Scholar 

  • Leonhardt H, Bungert HJ (1972) Therapie der schweren Hyperammoniämie. Med Klin 67:1052–1056

    PubMed  CAS  Google Scholar 

  • Lighthouse J, Naito Y, Helmy A, Hotten P, Fuji H, Min CH et al (2004) Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: A randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatol Res 28:155–160

    Article  PubMed  CAS  Google Scholar 

  • Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM (2004) Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 39:1441–1449

    Article  PubMed  Google Scholar 

  • Loguercio C, Abbiati R, Rinaldi M, Romano A, Del Vecchio Blanco C, Coltorti M (1995) Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1–2 hepatic encephalopathy. J Hepatol 23:39–46

    Article  Google Scholar 

  • Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C et al (2005) Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 39:540–543

    Article  Google Scholar 

  • Macbeth WA, Kass EH, McDermott WV Jr (1965) Treatment of hepatic encephalopathy by alteration of intestinal flora with Lactobacillus acidophilus. Lancet 191:399–403

    Article  Google Scholar 

  • Malaguarnera M, Pistone G, Elivra R, Leotta C, Scarpello L, Liborio R (2005) Effect of l-carnitine in patients with hepatic encephalopathy. World J Gastroenterol 11:7197–7202

    PubMed  CAS  Google Scholar 

  • Marchesini G, Fabr A, Bianchi G, Brizi M, Zoloi M (1996) Zinc supplementation and amino-acid nitrogen-metabolism in patients with advanced cirrhosis. Hepatology 23:1084–1092

    Article  PubMed  CAS  Google Scholar 

  • Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C et al (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792–1801

    Article  PubMed  CAS  Google Scholar 

  • Marshall AW, Jakobovits AW, Morgan MY (1982) Bromocriptine-associated hyponatraemia in cirrhosis. BMJ 285:1534–1535

    PubMed  CAS  Google Scholar 

  • Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V et al , Spanish Association for the Study of the Liver Hepatic Encephalopathy Cooperative Group (2003) Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: Results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 38:51–58

    Article  PubMed  CAS  Google Scholar 

  • Matsuda I, Ohtani Y, Ohyanagi K, Yamamoto S (1987) Hyperammonemia related to carnitine metabolism with particular emphasis on ornithine transcarbamylase deficiency. Enzyme 38:251–255

    PubMed  CAS  Google Scholar 

  • Morgan MY, Hawley KE (1987) Lactitol versus lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 7:1278–1284

    Article  PubMed  CAS  Google Scholar 

  • Morgan MY, Jakobovits AW, James IM, Sherlock S (1980) Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology 78:663–670

    PubMed  CAS  Google Scholar 

  • Morgan MY, Alonso M, Stanger LC (1989) Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients. J Hepatol 8:208–217

    Article  PubMed  CAS  Google Scholar 

  • Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A et al (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3:705–713

    Article  PubMed  CAS  Google Scholar 

  • Neff GW, Kemmer N, Zacharias VC, Kaiser T, Duncan C, McHenry R et al (2006) Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 38:3552–3555

    Article  PubMed  CAS  Google Scholar 

  • Olde Damink SW, Deutz N, Redhead D, Hayes P, Soeters P, Jalan R (2002) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171

    Article  PubMed  CAS  Google Scholar 

  • Olde Damink SW, Jalan R, Deutz NE, Redhead DN, Dejong CH, Hynd P et al (2003) The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 37:1277–1285

    Article  PubMed  Google Scholar 

  • Pedretti G, Calzetti C, Missale G, Fiaccadori F (1991) Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy in cirrhotics. A double-blind, randomized trial. Ital J Gastroenterol 23:175–178

    PubMed  CAS  Google Scholar 

  • Poo JL, Gongora J, Sanchez-Avila F, Aguilar-Castillo S, Garcia-Ramos G, Fernandez-Zertuche M et al (2006) Efficacy of oral l-ornithine–l-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study. Ann Hepatol 5:281–288

    PubMed  Google Scholar 

  • Prasad AS, Rabbani P, Abasi A, Bowersox E (1978) Experimental zinc deficiency. Ann Intern Med 89:483–490

    PubMed  CAS  Google Scholar 

  • Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007) Lactulose improves cognitive function and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 45:549–559

    Article  PubMed  Google Scholar 

  • Rabbani P, Prasad AS (1978) Plasma ammonia and liver ornithine carbamoyltransferase activity in zinc deficient rats. Am J Physiol 235:E203–E206

    PubMed  CAS  Google Scholar 

  • Raskind JY, El-Chaar GM (2000) The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 34:630–638

    Article  PubMed  CAS  Google Scholar 

  • Reding P, Duchateau J, Bataille C (1984) Oral zinc supplementation improves hepatic encephalopathy. Results of a randomized controlled trial. Lancet 2:493–494

    Article  PubMed  CAS  Google Scholar 

  • Rees CJ, Oppong K, Al Mardini H, Hudson M, Record CO (2000) Effect of l-ornithine–l-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial. Gut 47:571–574

    Article  PubMed  CAS  Google Scholar 

  • Riggio O, Ariosto F, Merli M, Caschera M, Zullo A, Balducci G et al (1991) Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Results of a double-blind crossover trial. Dig Dis Sci 36:1204–1208

    Article  PubMed  CAS  Google Scholar 

  • Riggio O, Merli M, Capocaccia L, Caschera M, Zullo A, Pinto G et al (1992) Zinc supplementation reduces blood ammonia and increases liver transcarbamylase activity in experimental cirrhosis. Hepatology 16:785–789

    Article  PubMed  CAS  Google Scholar 

  • Romero-Gómez M, Ramos-Guerrero R, Grande L, de Terán LC, Corpus R, Camacho I et al (2004) Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 41:49–54

    Article  PubMed  CAS  Google Scholar 

  • Rössle M, Nasari I, Ochs A, Haag K (1997) Effekt einer Zinksubstitution auf die Ammoniakkonzentration und die hepatische Enzephalopathie bei Patienten mit Zirrhose und Shunt. Z Gastroenterol 35(96):A155

    Google Scholar 

  • Schölmerich J (1987) Zinc and vitamin A in liver cirrhosis. In: Boyer JL, Bianchi L (eds) Liver cirrhosis. MTP, Lancaster, pp 421–432

    Google Scholar 

  • Shawcross D, Jalan R (2005) Dispelling myths in the treatment of hepatic encephalopathy. Lancet 365:431–433

    PubMed  Google Scholar 

  • Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonaemia in cirrhosis. J Hepatol 40:247–254

    Article  PubMed  CAS  Google Scholar 

  • Shawcross DL, Wright G, Olde Damink SWM, Jalan R (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Met Brain Dis 22:125–138

    Article  CAS  Google Scholar 

  • Staedt U, Leweling H, Gladisch R, Kortsik C, Hagmuller E, Holm E (1993) Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design. J Hepatol 19:424–430

    Article  PubMed  CAS  Google Scholar 

  • Stauch S, Kircheis G, Adler G, Beckh H, Ditschuneit H, Görtelmeyer R (1998) Oral l-ornithine–l-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol 28:856–864

    Article  PubMed  CAS  Google Scholar 

  • Strauss E, Tramote R, Silva EP, Caly WR, Honain NZ, Maffei RA et al (1992) Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 39:542–545

    PubMed  CAS  Google Scholar 

  • Sushma S, Dasarathy S, Tandon RK, Jain S, Gupta S, Bhist MS (1992) Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 16:138–144

    Article  PubMed  CAS  Google Scholar 

  • Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H, Tejima K et al (2002) Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem Biophys Res Commun 297:1108–1111

    Article  PubMed  CAS  Google Scholar 

  • Uribe M, Rampollo O, Vargas F, Ravelli GP, Mundo F, Zapata L et al (1987) Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind randomized clinical trial. Hepatology 7:639–643

    Article  PubMed  CAS  Google Scholar 

  • Van der Rijt C, Schalm SW, Han S, Foelen K, De Jong G (1991) Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 100:1114–1118

    PubMed  Google Scholar 

  • van Leeuwen PA, van Berlo CL, Soeters PB (1988) New mode of action for lactulose. Lancet i:55–56

    Article  Google Scholar 

  • Yamamoto M, Iwasa M, Matsumura K, Nakagawa Y, Fujita N, Kobayashi Y et al (2005) Improvement of regional cerebral blood flow after oral intake of branched-chain amino acids in patients with cirrhosis. World J Gastroenterol 11:6792–6799

    PubMed  CAS  Google Scholar 

  • Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura S, Watanabe A et al (2001) Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 55:349–355

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Centre for Hepatology, Division of Medicine, Royal Free Campus, Royal Free and University College Medical School, University College London, Rowland Hill St, London, NW3 2PF, Great Britain, UK

    Marsha Y. Morgan

  2. Northwestern University, Chicago, IL, USA

    A. Blei

  3. Hepatology Outpatient Practice, Magdeburg, Germany

    K. Grüngreiff

  4. Institute of Hepatology, Division of Medicine, Bloomsburg Campus, Royal Free and University College Medical School, University College London, London, Great Britain, UK

    R. Jalan

  5. Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany

    G. Kircheis

  6. Unit of Clinical Dietetics, Alma Mater Studiorum University, Bologna, Italy

    G. Marchesini

  7. Department of Clinical Medicine, Division of Gastroenterology, University of Rome La Sapienza, Rome, Italy

    O. Riggio

  8. Department of Neurology, Medical School Hannover, Hannover, Germany

    Karin Weissenborn

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  1. Marsha Y. Morgan
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  2. A. Blei
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Correspondence to Marsha Y. Morgan.

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Morgan, M.Y., Blei, A., Grüngreiff, K. et al. The treatment of hepatic encephalopathy. Metab Brain Dis 22, 389–405 (2007). https://doi.org/10.1007/s11011-007-9060-7

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