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.
KEYWORDS
Hepatic encephalopathy - lactulose - neomycin -
l-ornithine-l-aspartate - branched-chain amino acids
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
