Branched-chain amino acids for people with hepatic encephalopathy

Lise Lotte Gluud, Gitte Dam, Iñigo Les, Giulio Marchesini, Mette Borre, Niels Kristian Aagaard, Hendrik Vilstrup, Lise Lotte Gluud, Gitte Dam, Iñigo Les, Giulio Marchesini, Mette Borre, Niels Kristian Aagaard, Hendrik Vilstrup

Abstract

Background: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy.

Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy.

Search methods: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, and LILACS (May 2017).

Selection criteria: We included randomised clinical trials, irrespective of the bias control, language, or publication status.

Data collection and analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach.

Main results: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30).

Authors' conclusions: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.

Conflict of interest statement

None of the authors have any financial interests that may conflict with this review.

Lise Lotte Gluud had previously conducted Cochrane systematic reviews on the treatment of hepatic encephalopathy. As explained in the Cochrane Hepato‐Biliary Group module (Gluud 2017), this entails a risk of academic bias. Lise Lotte Gluud participated in scientific meetings in Denmark sponsored by Norgine. Giulio Marchesini, Iñigo Les, and Hendrik Vilstrup had previously conducted clinical trials on BCAA, which also entails a risk of academic bias. Niels Kristian Aagaard, Gitte Dam, and Mette Borre have no conflicts of interest.

Post‐publication declaration of interest

Clarification statement added from the CHBG Co‐ordinating Editor on 04.03.2020: This review was found by the Cochrane Funding Arbiters, post‐publication, to be noncompliant with theCochrane conflict of interest policy, which includes the relevant parts of theCochrane Commercial Sponsorship Policy. It will be updated by 04.03.2021. The update will have a majority of authors and lead author free of conflicts.

Figures

1
1
Study flow diagram. BCAA: branched‐chain amino acids.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study. CHBG: Cochrane Hepato‐Biliary Group.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. CHBG: Cochrane Hepato‐Biliary Group.
4
4
Trial sequential analysis of branched‐chain amino acids (BCAA) versus control interventions (placebo, no intervention, neomycin, or lactulose) for mortality in people with hepatic encephalopathy. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The vertical green line represents the 5% level of significance. The monitoring boundary (and futility) was ignored because the number of events and participants included in the analysis was insufficient. In the sequential analysis, we set alpha to 5%, power to 80%, control group incidence to 25%, relative risk reduction to 5%, and heterogeneity correction to 17%. The estimated information size was 23,485 participants. In total, the number of participants randomised was 367 in the BCAA group and 393 in the control groups.
5
5
Trial sequential analysis of branched‐chain amino acids (BCAA) versus control interventions (placebo, no intervention, neomycin, or lactulose) for hepatic encephalopathy. The blue line (Z‐curve) shows the cumulative meta‐analysis adding the results of individual trials based on the year of publication. The vertical line represents the 5% level of significance. The monitoring boundary (inward sloping red line) shows the significance level after adjusting for the cumulative analysis. The horizontal green line shows the required information size (the number of participants needed to determine if firm evidence was established). We conducted the trial sequential analysis with alpha set to 5%, power to 80%, control group event rate to 63%, relative risk reduction to 45%, and heterogeneity correction to 47%. The estimated required information size was 186 participants (diversity adjusted). In total, the cumulative meta‐analysis included 402 participants in the BCAA group and 425 in the control groups.
1.1. Analysis
1.1. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 1 Mortality.
1.2. Analysis
1.2. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 2 Mortality: mode of administration.
1.3. Analysis
1.3. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 3 Mortality: type of hepatic encephalopathy.
1.4. Analysis
1.4. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 4 Mortality: type of control.
1.5. Analysis
1.5. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 5 Mortality: type of data.
1.6. Analysis
1.6. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 6 Mortality: bias control.
1.7. Analysis
1.7. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 7 Hepatic encephalopathy.
1.8. Analysis
1.8. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 8 Hepatic encephalopathy: mode of administration.
1.9. Analysis
1.9. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 9 Overt or minimal hepatic encephalopathy.
1.10. Analysis
1.10. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 10 Hepatic encephalopathy: type of control.
1.11. Analysis
1.11. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 11 Hepatic encephalopathy: type of data.
1.12. Analysis
1.12. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 12 Hepatic encephalopathy: publication status.
1.13. Analysis
1.13. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 13 Hepatic encephalopathy: bias control.
1.14. Analysis
1.14. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 14 Hepatic encephalopathy: excluding 1 trial on people with or without cirrhosis.
1.15. Analysis
1.15. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 15 Hepatic encephalopathy: excluding trials with lactulose or neomycin controls.
1.16. Analysis
1.16. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 16 Hepatic encephalopathy: trials with lactulose or neomycin control.
1.17. Analysis
1.17. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 17 Nausea and diarrhoea.
1.18. Analysis
1.18. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 18 Albumin.
1.19. Analysis
1.19. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 19 Nitrogen balance.

References

References to studies included in this review Calvey 1985 {published data only}

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Cerra 1985 {published and unpublished data}
    1. Cerra FB. Disease‐specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double‐blind, controlled trial [personal communication]. Correspondence with authors September 2002.
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    1. Cerra FB, Cheung NK, Fischer JE, Kaplowitz N, Schiff ER, Dienstag JL, et al. A multicenter trial of branched chain enriched amino acid infusion (F080) in hepatic encephalopathy (HE). Hepatology (Baltimore, Md.) 1982;2:699.
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Egberts 1985 {published data only}
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Fiaccadori 1984 {published and unpublished data}
    1. Fiaccadori F. Branched chain amino acid enriched solutions in the treatment of hepatic encephalopathy: a controlled trial. Italian Journal of Gastroenterology (additional information from author November 2012).
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Hayashi 1991 {published data only}
    1. Hayashi S, Aoyagi Y, Fujiwara K, Oka H, Oda T. A randomized controlled trial of branched‐chain amino acid (BCAA)‐enriched elemental diet (ED‐H) for hepatic encephalopathy. Journal of Gastroenterology and Hepatology 1991;6:191.
Horst 1984 {published data only}
    1. Horst D, Grace N, Conn HO, Schiff E, Schenker S, Viteri A, et al. A double‐blind randomized comparison of dietary protein and an oral branched chain amino acid (BCAA) solution in cirrhotic patients with chronic portal‐systemic encephalopathy (PSE) [IASL abstract]. Hepatology (Baltimore, Md.) 1982;2:184.
    1. Horst D, Grace ND, Conn HO, Schiff E, Schenker S, Viteri A, 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 (Baltimore, Md.) 1984;4:279‐87.
Hwang 1988 {published data only}
    1. Hwang SJ, Chan CY, Wu JC, Lee SD, Huan YS, Tsai YT, et al. A randomized controlled trial for the evaluation of the efficacy of branched chain amino acid‐enriched amino acid solution in the treatment of patients with hepatic encephalopathy. Chinese Journal of Gastroenterology 1988;5:185‐92.
Les 2011 {published data only}
    1. Les I, Doval E, Garcia‐Martinez R, Planas M, Cardenas G, Gomez P, et al. Effects of branched‐chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. American Journal of Gastroenterology 2011;106:1081‐8.
Marchesini 1990 {published data only}
    1. Bianchi GP, Marchesini G, Zoli M, Abbiati R, Ferrario E, Fabbri A, et al. Oral BCAA supplementation in cirrhosis with chronic encephalopathy: effects on prolactin and estradiol levels. Hepato‐gastroenterology 1992;39:443‐6.
    1. Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched‐chain amino acids in advanced cirrhosis: a double‐blind, randomized trial. Gastroenterology 2003;124:1792‐801.
    1. Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, 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. Journal of Hepatology 1990;11:92‐101.
Marchesini 2003 {published and unpublished data}
    1. Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched‐chain amino acids in advanced cirrhosis: a double‐blind, randomized trial. Gastroenterology 2003;124:1980‐2.
Michel 1985 {published data only}
    1. Michel H, Bories P, Aubin JP, Pomier‐Layrargues G, Bauret P, Bellet‐Herman H. Treatment of acute hepatic encephalopathy in cirrhotics with a branched‐chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver 1985;5:282‐9.
    1. Michel H, Pomier‐Layrargues G, Aubin JP, Bories P, Mirouze D, Bellet‐Herman H. Treatment of hepatic encephalopathy by infusion of a modified amino acid solution: results of a controlled study in 47 cirrhotic patients. In: Capocaccia L, Fischer JE, Rossi‐Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:301‐10.
    1. Michel H, Pomier‐Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet‐Hermann H. Intravenous infusion of ordinary and modified amino‐acid solutions in the management of hepatic encephalopathy (controlled study, 30 patients). Gastroenterology 1980;79:1038.
    1. Pomier‐Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet H, Michel H. Intravenous infusion of ordinary and modified amino‐acid solutions in the management of hepatic encephalopathy. Liver 1981;1:140.
Muto 2005 {published and unpublished data}
    1. Horie‐Takashi I. Effects of oral branched‐chain amino acid granules on event‐free survival in patients with liver cirrhosis. Clinical Gastroenterology and Hepatology 2005; Vol. 3:705‐13 (additional information and data received November 2011).
    1. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Effects of oral branched‐chain amino acid granules on event‐free survival in patients with liver cirrhosis. Clinical Gastroenterology and Hepatology 2005;3:705‐13.
    1. Sato S, Watanabe A, Muto Y, Suzuki K, Kato A, Moriwaki H, et al. Clinical comparison of branched‐chain amino acid (l‐Leucine, l‐Isoleucine, l‐Valine) granules and oral nutrition for hepatic insufficiency in patients with decompensated liver cirrhosis (LIV‐EN study). Hepatology Research 2005;31:232‐40.
Plauth 1993 {published data only}
    1. Plauth M, Egberts E‐H, Hamster W, Török M, Müller P, Brand O, et al. Long‐term treatment with branched‐chain amino acids (BCA) improves the portosystemic encephalopathy (PSE) in ambulant patients. Results of a double blind, placebo controlled crossover study. Klinische Wochenschrift 1992;69:126.
    1. Plauth M, Egberts EH, Hamster W, Török M, Müller PH, Brand O, et al. Long‐term treatment of latent portosystemic encephalopathy with branched‐chain amino acids. A double‐blind placebo‐crossover study. Journal of Hepatology 1993;17:308‐14.
Rossi‐Fanelli 1986 {published data only}
    1. Riggio O, Cangiano C, Cascino A, Merli M, Stortoni M, Rossi‐Fanelli F, et al. Long term dietary supplement with branched chain amino acids: a new approach in the prevention of hepatic encephalopathy: results of a controlled study in cirrhotics with porto‐caval anastomosis. In: Associazione Italiana per Lo Studio del Fegato. Congress, editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:183‐92.
    1. Rossi‐Fanelli F, Cangiano C, Capocaccia L, Cascino A, Ceci F, Muscaritoli M, et al. Use of branched chain amino acids for treating hepatic encephalopathy: clinical experiences. Gut 1986;27:111‐5.
    1. Rossi‐Fanelli F, Cangiano C, Cascino A, Merli M, Riggio O, Stortoni M, et al. Branched‐chain amino acids in the treatment of severe hepatic encephalopathy. In: Capocaccia L, Fischer JE, Rossi‐Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:335‐44.
    1. Rossi‐Fanelli F, Riggio O, Cangiano C, Cascino A, Conciliis D, Merli M, et al. Branched‐chain amino acids vs lactulose in the treatment of hepatic coma: a controlled study. Digestive Diseases and Sciences 1982;27:929‐35.
Strauss 1986 {published and unpublished data}
    1. Strauss E, Cartapatti Da Silva E, Lacet CM, Capacci MLL, Bernardini AP. Treatment of hepatic encephalopathy: a randomized clinical trial comparing a branched chain enriched amino acid solution to oral neomycin. Nutritional Support Services 1986;6:18‐21.
    1. Strauss E, Santos WR, Silva EC, Lacet CM, Capacci LL, Bernardini AP. A randomized controlled clinical trial for the evaluation of the efficacy of an enriched branched‐chain amino‐acid solution compared to neomycin in hepatic encephalopathy. Hepatology (Baltimore, Md.) 1983;3:862.
Vilstrup 1990 {published data only}
    1. Gluud C, Dejgaard A, Hardt F, Kristensen M, Køhler O, Melgaard B, et al. Preliminary treatment results with balanced amino acid infusion to patients with hepatic encephalopathy. Scandinavian Journal of Gastroenterology 1983;18:19.
    1. Vilstrup H, Gluud C, Hardt F, Kristensen M, Køhler O, Melgaard B, et al. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double‐blind study of 65 patients with cirrhosis. Hepatology (Baltimore, Md.) 1990;10:291‐6.
    1. Vilstrup H, Gluud C, Hardt F, Kristensen M, Melgaard B, Køhler O, et al. Branched chain enriched amino acid nutrition does not change the outcome of hepatic coma in patients with cirrhosis of the liver. Journal of Hepatology 1985;1:S347.
References to studies excluded from this review Eriksson 1982 {published data only}
    1. Eriksson LS, Persson A, Wahren J. Branched‐chain amino acids in the treatment of chronic hepatic encephalopathy. Gut 1982;23:801‐6.
Hayashi 2007 {published data only}
    1. Hayashi M, Ikezawa K, Ono A, Okabayashi S, Hayashi Y, Shimizu S, et al. Evaluation of the effects of combination therapy with branched‐chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatology Research 2007;37:615‐19.
Malaguarnera 2009 {published data only}
    1. Malaguarnera M, Risino C, Cammalleri L, Malaguarnera L, Astuto M, Vecchio I, et al. Branched chain amino acids supplemented with L‐acetylcarnitine versus BCAA treatment in hepatic coma: a randomized and controlled double blind study. European Journal of Gastroenterology & Hepatology 2009;21:762‐70.
O'Keefe 1987 {published data only}
    1. O'Keefe SJ, Ogden J, Dicker J. Enteral and parenteral branched chain amino acid‐supplemented nutritional support in patients with encephalopathy due to alcoholic liver disease. JPEN. Journal of Parenteral and Enteral Nutrition 1987;11:447‐53.
Wahren 1983 {published data only}
    1. Wahren J, Denis J, Desurmont P, Eriksson LS, Escoffier JM, Gauthier AP, et al. Is intravenous administration of branched chain amino acids effective in the treatment of hepatic encephalopathy? A multicenter study. Hepatology (Baltimore, Md.) 1983;3:475‐80.
Walker 1982 {published data only}
    1. Walker S, Gotz R, Czygan P, Stiehl A, Lanzinger G, Sieg A, et al. Oral keto analogs of branched‐chain amino acids in hyperammonemia in patients with cirrhosis of the liver. A double‐blind crossover study. Digestion 1982;24:105‐11.
References to ongoing studies ACTRN12610001021066 {unpublished data only}
    1. The effects of supplementation with synbiotics, branched chain amino acids on levels of hepatic encephalopathy in patients with cirrhosis. (accessed 10 May 2017).
Additional references AASLD and EASL guideline 2014a
    1. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology (Baltimore, Md.) 2014;60:715‐35.
AASLD and EASL guideline 2014b
    1. American Association for the Study of Liver Diseases, European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. Journal of Hepatology 2014;61:642‐59.
Amodio 2008
    1. Amodio P, Campagna F, Olianas S, Iannizzi P, Mapelli D, Penzo M, et al. Detection of minimal hepatic encephalopathy: normalization and optimization of the Psychometric Hepatic Encephalopathy Score. A neuropsychological and quantified EEG study. Journal of Hepatology 2008;49(3):346‐53. [PUBMED: 18602716]
Amodio 2014
    1. Amodio P, Canesso F, Montagnese S. Dietary management of hepatic encephalopathy revisited. Current Opinion in Clinical Nutrition and Metabolic Care 2014;17(5):448‐52. [PUBMED: 25025262]
Bajaj 2008
    1. Bajaj JS. Minimal encephalopathy matters in daily life. World Journal of Gastroenterology 2008;14(23):3609‐15.
Bajaj 2010
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Bajaj 2011
    1. Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, et al. Review article: the design of clinical trials in hepatic encephalopathy ‐ an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Alimentary Pharmacology & Therapeutics 2011;33(7):739‐47. [PUBMED: 21306407]
Bak 2006
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Blei 2001
    1. Blei AT, Córdoba J, Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. American Journal of Gastroenterology 2001;96:1986‐76.
Córdoba 2004
    1. Córdoba J, López‐Hellín J, Planas M, Sabín P, Sanpedro F, Castro F, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. Journal of Hepatology 2004;41:38‐43.
Dam 2011
    1. Dam G, Keiding S, Munk OL, Ott P, Buhl M, Vilstrup H, et al. Branched‐chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. American Journal of Physiology. Gastrointestinal and Liver Physiology 2011;301(2):G269‐77. [PUBMED: 21636533]
Egger 1997
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Ferenci 2002
    1. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy ‐ definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology (Baltimore, Md.) 2002;35(3):716‐21. [PUBMED: 11870389]
Fichet 2009
    1. Fichet J, Mercier E, Genée O, Garot D, Legras A, Dequin PF, et al. Prognosis and 1‐year mortality of intensive care unit patients with severe hepatic encephalopathy. Journal of Critical Care 2009;24:364‐70.
Garcia‐Martinez 2011
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Gluud 1991
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Gluud 2010
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Gluud 2013a
    1. Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, et al. Oral branched‐chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta‐analyses of randomized controlled trials. Journal of Nutrition 2013;143:1263‐8. [PUBMED: 23739310]
Gluud 2013b
    1. Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, et al. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?. Metabolic Brain Disease 2013;28(2):221‐5. [PUBMED: 23275147]
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