Semin Liver Dis 2007; 27: 010-017
DOI: 10.1055/s-2007-984574
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Treatment Options for Hepatic Encephalopathy: A Review

Peter Ferenci1
  • 1Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Publikationsverlauf

Publikationsdatum:
14. August 2007 (online)

ABSTRACT

Hepatic encephalopathy (HE) encompasses a broad spectrum of neuropsychiatric manifestations that affect individuals with cirrhosis and end-stage liver disease. Although the pathogenesis of HE remains unclear, experimental and clinical data support a central role for ammonia as a key pathogenetic factor. Initial evaluation of the patient who has overt HE should include careful identification and resolution of predisposing factors and other etiologies of neurologic abnormalities. The rationale for treatment of HE is predicated on current knowledge of pathogenesis and empirical clinical experience. Despite limited evidence of efficacy from clinical studies, the nonabsorbable disaccharides, particularly lactulose, have been the mainstay of treatment. Alternative treatments, which are usually employed as second-line options in patients who do not respond to lactulose, include nonabsorbable antibiotics (neomycin), l-ornithine-l-aspartate, sodium benzoate, and probiotics. Modification of dietary protein and supplementation with thiamine and zinc have also been reported to have beneficial effects. This review discusses the rationale, advantages, and limitations of conventional treatment options that are commonly employed in the management of HE.

REFERENCES

  • 1 Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.  Cell Mol Life Sci. 2005;  62 2295-2304
  • 2 Shawcross D L, Wright G, Olde Damink S W, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy.  Metab Brain Dis. 2007;  22 125-138
  • 3 Weissenborn K, Ennen J C, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy.  J Hepatol. 2001;  34 768-773
  • 4 Conn H, Lieberthal M M. Hepatic Coma Syndromes and Lactulose. Baltimore; Lippincott Williams & Wilkins 1979
  • 5 Ferenci P, Muller C H. Hepatic encephalopathy: treatment. In: Burroughs AK, Feagan B, McDonald JE Evidence Based Gastroenterology. London; BMJ 1999: 443
  • 6 Fessel J M, Conn H O. An analysis of the causes and prevention of hepatic coma.  Gastroenterology. 1972;  62 191 (Abstract)
  • 7 Uribe M, Campollo O, Vargas F et al.. Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial.  Hepatology. 1987;  7 639-643
  • 8 Plauth M, Merli M, Kondrup J, Weimann A, Ferenci P, Muller M J. ESPEN guidelines for nutrition in liver disease and transplantation.  Clin Nutr. 1997;  16 43-55
  • 9 Riggio O, Varriale M, Testore G P et al.. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients.  J Clin Gastroenterol. 1990;  12 433-436
  • 10 Mortensen P B. The effect of oral-administered lactulose on colonic nitrogen metabolism and excretion.  Hepatology. 1992;  16 1350-1356
  • 11 Mortensen P B, Holtug K, Bonnen H, Clausen M R. The degradation of amino acids, proteins, and blood to short-chain fatty acids in colon is prevented by lactulose.  Gastroenterology. 1990;  98 353-360
  • 12 Conn H O, Leevy C M, Vlahcevic Z R et al.. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double blind controlled trial.  Gastroenterology. 1977;  72 573-583
  • 13 Als-Nielsen B, Gluud L L, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.  BMJ. 2004;  328 1046
  • 14 Morgan M Y, Hawley K E. Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial.  Hepatology. 1987;  7 1278-1284
  • 15 Blanc P, Daures J P, Rouillon J M et al.. Lactitol or lactulose in the treatment of chronic hepatic encephalopathy: results of a meta-analysis.  Hepatology. 1992;  15 222-228
  • 16 Camma C, Fiorello F, Tine F, Marchesini G, Fabbri A, Pagliaro L. Lactitol in treatment of chronic hepatic encephalopathy: a meta-analysis.  Dig Dis Sci. 1993;  38 916-922
  • 17 Uribe-Esquivel M, Moran S, Poo J L, Munoz R M. In vitro and in vivo lactose and lactulose effects on colonic fermentation and portal-systemic encephalopathy parameters.  Scand J Gastroenterol Suppl. 1997;  222 49-52
  • 18 Strauss E, Tramote R, Silva E P et al.. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy.  Hepatogastroenterology. 1992;  39 542-545
  • 19 Tarao K, Ikeda T, Hayashi K et al.. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy.  Gut. 1990;  31 702-706
  • 20 Paik Y H, Lee K S, Han K H et al.. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study.  Yonsei Med J. 2005;  46 399-407
  • 21 Williams R, James O F, Warnes T W, Morgan M Y. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study.  Eur J Gastroenterol Hepatol. 2000;  12 203-208
  • 22 Zeneroli M L, Avallone R, Corsi L, Venturini I, Baraldi C, Baraldi M. Management of hepatic encephalopathy: role of rifaximin.  Chemotherapy. 2005;  51(suppl 1) 90-95
  • 23 Festi D, Vestito A, Mazzella G, Roda E, Colecchia A. Management of hepatic encephalopathy: focus on antibiotic therapy.  Digestion. 2006;  73(suppl 1) 94-101
  • 24 Bass N M. Review article: the current pharmacological therapies for hepatic encephalopathy.  Aliment Pharmacol Ther. 2007;  25(suppl 1) 23-31
  • 25 Staedt U, Leweling H, Gladisch R, Kortsik C, Hagmuller E, Holm E. 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. 1993;  19 424-430
  • 26 Kircheis G, Nilius R, Held C et al.. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study.  Hepatology. 1997;  25 1351-1360
  • 27 Stauch S, Kircheis G, Adler G et al.. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study.  J Hepatol. 1998;  28 856-864
  • 28 Fleig W E, Kircheis G, Spengler U et al.. Placebo-controlled, double-blind evaluation of L-ornithine-L-aspartate (LOLA) granules in patients with cirrhosis and subclinical (SHE) or mild or overt hepatic encephalopathy [abstract].  J Hepatol. 1999;  31(suppl 2) WP3/1
  • 29 Sushma S, Dasarathy S, Tandon R K, Jain S, Gupta S, Bhist M S. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial.  Hepatology. 1992;  16 138-144
  • 30 Efrati C, Masini A, Merli M, Valeriano V, Riggio O. Effect of sodium benzoate on blood ammonia response to oral glutamine challenge in cirrhotic patients: a note of caution.  Am J Gastroenterol. 2000;  95 3574-3578
  • 31 Cordoba J, Lopez-Hellin J, Planas M et al.. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.  J Hepatol. 2004;  41 38-43
  • 32 Nielsen K, Kondrup J, Martinsen L, Stilling B, Wikman B. Nutritional assessment and adequacy of dietary intake in hospitalized patients with alcoholic liver cirrhosis.  Br J Nutr. 1993;  69 665-679
  • 33 Bianchi G P, Marchesini G, Fabbri A et al.. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy: a randomized cross-over comparison.  J Intern Med. 1993;  233 385-392
  • 34 Ferenci P. Critical evaluation of the role of branched chain amino acids in liver disease. In: Thomas HC, Jones EA Recent Advances in Hepatology. Vol. 2. New York; Churchill Livingstone 1986: 137
  • 35 Naylor C D, O'Rourke K, Detsky A S, Baker J P. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: a meta-analysis.  Gastroenterology. 1989;  97 1033-1042
  • 36 Als-Nielsen B, Koretz R L, Kjaergard L L, Gluud C. Branched-chain amino acids for hepatic encephalopathy.  Cochrane Database Syst Rev. 2003;  (2) CD001939
  • 37 Marchesini G, Dioguardi F S, Bianchi G P et al.. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy: a randomized double-blind casein-controlled trial. The Italian Multicenter Study Group.  J Hepatol. 1990;  11 92-101
  • 38 Horst D, Grace N D, Conn H O et al.. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial.  Hepatology. 1984;  4 279-287
  • 39 Basile A S, Hughes R D, Harrison P M et al.. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure.  N Engl J Med. 1991;  325 473-478
  • 40 Barbaro G, Di Lorenzo G, Soldini M et al.. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study.  Hepatology. 1998;  28 374-378
  • 41 Cadranel J F, el Younsi M, Pidoux B et al.. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study.  Eur J Gastroenterol Hepatol. 1995;  7 325-329
  • 42 Gyr K, Meier R, Haussler J et al.. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.  Gut. 1996;  39 319-324
  • 43 Pomier-Layrargues G, Giguere J F, Lavoie J et al.. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial.  Hepatology. 1994;  19 32-37
  • 44 Van der Rijt C C, Schalm S W, Meulstee J, Stijnen T. Flumazenil therapy for hepatic encephalopathy: a double-blind cross over study.  Gastroenterol Clin Biol. 1995;  19 572-580
  • 45 Als-Nielsen B, Kjaergard L L, Gluud C. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy.  Cochrane Database Syst Rev. 2001;  (2) CD002798
  • 46 Goulenok C, Bernard B, Cadranel J F et al.. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis.  Aliment Pharmacol Ther. 2002;  16 361-372
  • 47 Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis.  Hepatology. 1996;  23 1084-1092
  • 48 Van der Rijt C C, Schalm S W, Schat H, Foeken K, De Jong G. Overt hepatic encephalopathy precipitated by zinc deficiency.  Gastroenterology. 1991;  100 1114-1118
  • 49 Riggio O, Ariosto F, Merli M et al.. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy: results of a double-blind crossover trial.  Dig Dis Sci. 1991;  36 1204-1208
  • 50 Blanc P, Daures J P, Liautard J et al.. [Lactulose-neomycin combination versus placebo in the treatment of acute hepatic encephalopathy: results of a randomized controlled trial].  Gastroenterol Clin Biol. 1994;  18 1063-1068
  • 51 Wahren J, Denis J, Desurmont P et al.. Is intravenous administration of branched chain amino acids effective in the treatment of hepatic encephalopathy? A multicenter study.  Hepatology. 1983;  3 475-480
  • 52 Michel H, Pomier-Layrargues G, Aubin J P et al.. Treatment of hepatic encephalopathy by infusion of a modified amino acid solution: results of a study in 47 cirrhotic patients. In: Capocaccia L, Fischer J, Rossi-Fanelli F Hepatic Encephalopathy in Chronic Liver Failure. New York; Plenum Press 1984: 301-310
  • 53 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A T. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.  Hepatology. 2002;  35 716-721

Peter FerenciM.D. 

Department of Internal Medicine III, Gastroenterology and Hepatology, University of Vienna

Wahringer Gurtel 18-20, Vienna 1090, Austria

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