An Algorithm for the Management of Hepatic Encephalopathy

ABSTRACT

Hepatic encephalopathy (HE) is a serious and progressive, but potentially reversible, neuropsychiatric complication associated with both acute liver failure and advanced chronic liver disease. Currently, no gold standard exists for the diagnosis and treatment of HE, particularly its mildest form, minimal HE. Recently, a panel of international hepatologists met to develop practical recommendations for the diagnosis and treatment of HE. Their recommendations were based on current understanding of the pathogenesis of HE, the availability of practical diagnostic methods, and the efficacy, safety, and cost of available therapies. The panel recommendations include screening all patients with cirrhosis for minimal HE using psychometric testing, because of the association of this disorder with variable degrees of impaired functional status and decreased health-related quality of life. Pharmacologic therapy is recommended for patients diagnosed with minimal HE. If psychometric testing is unavailable, a trial of therapy is recommended when patient history suggests the presence of minimal HE. Initial management of overt HE involves detection and treatment of precipitating causes, followed by measures to lower the blood ammonia concentration. The recommendations to restrict driving privileges in patients with overt HE should be individualized. Although well-performed, placebo-controlled studies of lactulose therapy are lacking, clinical experience with the disaccharides supports their use in the management of HE. The safety profile and efficacy of the oral nonabsorbable antibiotic rifaximin make it a viable alternative therapy for HE. Ongoing studies will better define the role rifaximin and other potentially useful pharmacotherapies under study including acarbose, l-ornithine-l-aspartate, levocarnitine, and probiotics.

KEYWORDS

Hepatic encephalopathy - treatment guidelines - diagnosis - pharmacotherapy

REFERENCES

• 1 Ferenci P, Lockwood A, Mullen K et al.. 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
• 2 Prasad S, Dhiman R K, Duseja A et al.. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.  Hepatology. 2007;  45 549-559
• 3 Groeneweg M, Quero J C, De Bruijn I et al.. Subclinical hepatic encephalopathy impairs daily functioning.  Hepatology. 1998;  28 45-49
• 4 Bajaj J S, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: an AASLD survey.  Hepatology. 2007;  45 833-834
• 5 Zeneroli M L, Cioni G, Vezzelli C et al.. Prevalence of brain atrophy in liver cirrhosis patients with chronic persistent encephalopathy: evaluation by computed tomography.  J Hepatol. 1987;  4 283-292
• 6 Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.  Cell Mol Life Sci. 2005;  62 2295-2304
• 7 Shawcross D L, Damink S W, Butterworth R F, Jalan R. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.  Metab Brain Dis. 2005;  20 169-179
• 8 Wright G, Jalan R. Management of hepatic encephalopathy in patients with cirrhosis.  Best Pract Res Clin Gastroenterol. 2007;  21 95-110
• 9 Keiding S, Sorensen M, Bender D et al.. Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography.  Hepatology. 2006;  43 42-50
• 10 Lockwood A H. Positron emission tomography in the study of hepatic encephalopathy.  Metab Brain Dis. 1998;  13 303-309
• 11 Bhatia V, Singh R, Acharya S K. Predictive value of arterial ammonia for complications and outcome in acute liver failure.  Gut. 2006;  55 98-104
• 12 Clemmesen J O, Larsen F S, Kondrup J et al.. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.  Hepatology. 1999;  29 648-653
• 13 Kundra A, Jain A, Banga A et al.. Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension.  Clin Biochem. 2005;  38 696-699
• 14 Shawcross D L, Davies N A, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.  J Hepatol. 2004;  40 247-254
• 15 Mullen K D. Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy.  Aliment Pharmacol Ther. 2007;  25(suppl 1) 11-16
• 16 Amodio P, Montagnese S, Gatta A, Morgan M Y. Characteristics of minimal hepatic encephalopathy.  Metab Brain Dis. 2004;  19 253-267
• 17 Mattarozzi K, Campi C, Guarino M, Stracciari A. Distinguishing between clinical and minimal hepatic encephalopathy on the basis of specific cognitive impairment.  Metab Brain Dis. 2005;  20 243-249
• 18 Weissenborn K, Giewekemeyer K, Heidenreich S et al.. Attention, memory, and cognitive function in hepatic encephalopathy.  Metab Brain Dis. 2005;  20 359-367
• 19 Romero-Gomez M, Boza F, Garcia-Valdecasas M S et al.. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy.  Am J Gastroenterol. 2001;  96 2718-2723
• 20 Hartmann I J, Groeneweg M, Quero J C et al.. The prognostic significance of subclinical hepatic encephalopathy.  Am J Gastroenterol. 2000;  95 2029-2034
• 21 Das A, Dhiman R K, Saraswat V A et al.. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis.  J Gastroenterol Hepatol. 2001;  16 531-535
• 22 Saxena N, Bhatia M, Joshi Y K et al.. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy.  Liver. 2002;  22 190-197
• 23 Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy.  Metab Brain Dis. 2001;  16 37-41
• 24 Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.  J Hepatol. 2005;  42(suppl) S45-S53
• 25 Amodio P, Del Piccolo F, Marchetti P et al.. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests.  Hepatology. 1999;  29 1662-1667
• 26 Howanitz J H, Howanitz P J, Skrodzki C A, Iwanski J A. Influences of specimen processing and storage conditions on results for plasma ammonia.  Clin Chem. 1984;  30 906-908
• 27 Barsotti R J. Measurement of ammonia in blood.  J Pediatr. 2001;  138 S11-S19
• 28 Weissenborn K, Ennen J C, Schomerus H et al.. Neuropsychological characterization of hepatic encephalopathy.  J Hepatol. 2001;  34 768-773
• 29 Weissenborn K, Heidenreich S, Ennen J et al.. Attention deficits in minimal hepatic encephalopathy.  Metab Brain Dis. 2001;  16 13-19
• 30 Conn H O. Trailmaking and number-connection tests in the assessment of mental state in portal systemic encephalopathy.  Am J Dig Dis. 1977;  22 541-550
• 31 Vergara-Gomez M, Flavia-Olivella M, Gil-Prades M et al.. [Diagnosis and treatment of hepatic encephalopathy in Spain: results of a survey of hepatologists].  Gastroenterol Hepatol. 2006;  29 1-6
• 32 Amodio P, Marchetti P, Del Piccolo F et al.. Spectral versus visual EEG analysis in mild hepatic encephalopathy.  Clin Neurophysiol. 1999;  110 1334-1344
• 33 Butterworth R F. Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies.  J Hepatol. 2003;  39 278-285
• 34 Kullmann F, Hollerbach S, Holstege A, Scholmerich J. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials.  J Hepatol. 1995;  22 101-110
• 35 Stewart C A, Reivich M, Lucey M R, Gores G J. Neuroimaging in hepatic encephalopathy.  Clin Gastroenterol Hepatol. 2005;  3 197-207
• 36 Yang S S, Wu C H, Chiang T R, Chen D S. Somatosensory evoked potentials in subclinical portosystemic encephalopathy: a comparison with psychometric tests.  Hepatology. 1998;  27 357-361
• 37 Romero-Gomez M, Cordoba J, Jover R et al.. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy.  Hepatology. 2007;  45 879-885
• 38 Kircheis G, Wettstein M, Timmermann L et al.. Critical flicker frequency for quantification of low-grade hepatic encephalopathy.  Hepatology. 2002;  35 357-366
• 39 Montagnese S, Gordon H M, Jackson C et al.. Disruption of smooth pursuit eye movements in cirrhosis: relationship to hepatic encephalopathy and its treatment.  Hepatology. 2005;  42 772-781
• 40 Bajaj J S, Saeian K, Verber M D et al.. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy.  Am J Gastroenterol. 2007;  102 754-760
• 41 Atterbury C E, Maddrey W C, Conn H O. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy: a controlled, double-blind clinical trial.  Am J Dig Dis. 1978;  23 398-406
• 42 Conn H, Lieberthal M M. Hepatic Coma Syndromes and Lactulose. Baltimore; Lippincott Williams & Wilkins 1979
• 43 Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale.  Lancet. 1974;  2 81-84
• 44 Amodio P, Pellegrini A, Ubiali E et al.. The EEG assessment of low-grade hepatic encephalopathy: comparison of an artificial neural network-expert system (ANNES) based evaluation with visual EEG readings and EEG spectral analysis.  Clin Neurophysiol. 2006;  117 2243-2251
• 45 Pellegrini A, Ubiali E, Orsato R et al.. Electroencephalographic staging of hepatic encephalopathy by an artificial neural network and an expert system.  Neurophysiol Clin. 2005;  35 162-167
• 46 Blei A T. Treatment of hepatic encephalopathy.  Lancet. 2005;  365 1383-1384
• 47 Arria A M, Tarter R E, Starzl T E, Van Thiel D H. Improvement in cognitive functioning of alcoholics following orthotopic liver transplantation.  Alcohol Clin Exp Res. 1991;  15 956-962
• 48 Mattarozzi K, Stracciari A, Vignatelli L et al.. Minimal hepatic encephalopathy: longitudinal effects of liver transplantation.  Arch Neurol. 2004;  61 242-247
• 49 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
• 50 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
• 51 Camma C, Fiorello F, Tine F et al.. Lactitol in treatment of chronic hepatic encephalopathy: a meta-analysis.  Dig Dis Sci. 1993;  38 916-922
• 52 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
• 53 Uribe M, Marquez M A, Garcia-Ramos G et al.. Treatment of chronic portal-systemic encephalopathy with lactose in lactase-deficient patients.  Dig Dis Sci. 1980;  25 924-928
• 54 Als-Nielsen B, Gluud L L, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy.  Cochrane Database Syst Rev. 2004;  (2) CD003044
• 55 Orlandi F, Freddara U, Candelaresi M T et al.. Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy: a randomized clinical study.  Dig Dis Sci. 1981;  26 498-506
• 56 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
• 57 Tromm A, Griga T, Greving I et al.. Orthograde whole gut irrigation with mannite versus paromomycine + lactulose as prophylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial.  Hepatogastroenterology. 2000;  47 473-477
• 58 Morgan M H, Read A E, Speller D C. Treatment of hepatic encephalopathy with metronidazole.  Gut. 1982;  23 1-7
• 59 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
• 60 Bucci L, Palmieri G C. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.  Curr Med Res Opin. 1993;  13 109-118
• 61 Mas A, Rodes J, Sunyer L et al.. 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. 2003;  38 51-58
• 62 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
• 63 Di Piazza S, Gabriella F M, Valenza L M et al.. Rifaximine versus neomycin in the treatment of portosystemic encephalopathy.  Ital J Gastroenterol. 1991;  23 403-407
• 64 Pedretti G, Calzetti C, Missale G, Fiaccadori F. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics: a double-blind, randomized trial.  Ital J Gastroenterol. 1991;  23 175-178
• 65 Leevy C B, Phillips J A. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy.  Dig Dis Sci. 2007;  52 737-741
• 66 Neff G W, Kemmer N, Zacharias V C et al.. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy.  Transplant Proc. 2006;  38 3552-3555
• 67 Spiegel B, Huang E, Esrailian E. Is rifaximin cost-effective in the management of hepatic encephalopathy?.  Gastroenterology. 2006;  130 A-806 Abstract M1031
• 68 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
• 69 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
• 70 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
• 71 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
• 72 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
• 73 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
• 74 Ferenci P, Grimm G, Meryn S, Gangl A. Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil.  Gastroenterology. 1989;  96 240-243
• 75 Gentile S, Guarino G, Romano M et al.. A randomized controlled trial of acarbose in hepatic encephalopathy.  Clin Gastroenterol Hepatol. 2005;  3 184-191
• 76 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
• 77 Staedt U, Leweling H, Gladisch R et al.. 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
• 78 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
• 79 Poo J L, Gongora J, Sanchez-Avila F et al.. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy: results of a randomized, lactulose-controlled study.  Ann Hepatol. 2006;  5 281-288
• 80 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
• 81 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
• 82 Bass N M. Review article: the current pharmacological therapies for hepatic encephalopathy.  Aliment Pharmacol Ther. 2007;  25(suppl 1) 23-31
• 83 Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease.  J Nutr. 2006;  136 295S-298S
• 84 Khanna S, Gopalan S. Role of branched-chain amino acids in liver disease: the evidence for and against.  Curr Opin Clin Nutr Metab Care. 2007;  10 297-303
• 85 Therrien G, Rose C, Butterworth J, Butterworth R F. Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat.  Hepatology. 1997;  25 551-556
• 86 Malaguarnera M, Pistone G, Elvira R et al.. Effects of L-carnitine in patients with hepatic encephalopathy.  World J Gastroenterol. 2005;  11 7197-7202
• 87 Malaguarnera M, Pistone G, Astuto M et al.. Effects of L-acetylcarnitine on cirrhotic patients with hepatic coma: randomized double-blind, placebo-controlled trial.  Dig Dis Sci. 2006;  51 2242-2247
• 88 Siciliano M, Annicchiarico B E, Lucchese F, Bombardieri G. Effects of a single, short intravenous dose of acetyl-L-carnitine on pattern-reversal visual-evoked potentials in cirrhotic patients with hepatic encephalopathy.  Clin Exp Pharmacol Physiol. 2006;  33 76-80
• 89 Vogels B A, Maas M A, Daalhuisen J et al.. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats.  Hepatology. 1997;  25 820-827
• 90 Yurdaydin C, Herneth A M, Puspok A et al.. Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists.  Eur J Gastroenterol Hepatol. 1996;  8 667-671
• 91 Blei A T, Cordoba J. Hepatic encephalopathy.  Am J Gastroenterol. 2001;  96 1968-1976
• 92 Arguedas M R, DeLawrence T G, McGuire B M. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.  Dig Dis Sci. 2003;  48 1622-1626
• 93 Harcourt Test Services .PSE syndrome test. Available at: http://www.harcourt.de/front_content.php?idcat=18&idart=63 Accessed April 19, 2007
• 94 Harcourt Assessment .Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). Available at: http://harcourtassessment.com/HAIWEB/Cultures/en-us/Productdetail.htm?Pid=015-8980-727&Mode=summary Accessed April 19, 2007
• 95 Duphalac. Number connection A test. Available at: http://www.duphalac.com/professionals/portosystemicencephalopathy/psetest/0,10319-2-0,00.htm Accessed April 19, 2007
• 96 Bajaj J S, Hafeezullah M. Minimal hepatic encephalopathy, a vehicle for accidents and violations: the reality beyond the driving test.  Hepatology. 2006;  44 233A (abstract 120)
• 97 Wein C, Koch H, Popp B et al. Minimal hepatic encephalopathy impairs fitness to drive.  Hepatology. 2004;  39 739-745