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Meta-Analysis
. 2017 May 18;5(5):CD001939.
doi: 10.1002/14651858.CD001939.pub4.

Branched-chain amino acids for people with hepatic encephalopathy

Lise Lotte Gluud  1 , Gitte Dam  2 , Iñigo Les  3 , Giulio Marchesini  4 , Mette Borre  2 , Niels Kristian Aagaard  2 , Hendrik Vilstrup  5
Affiliations
Meta-Analysis

Branched-chain amino acids for people with hepatic encephalopathy

Lise Lotte Gluud et al. Cochrane Database Syst Rev. .

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.

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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
1.1. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 2 Mortality: mode of administration.
1.3
1.3. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 3 Mortality: type of hepatic encephalopathy.
1.4
1.4. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 4 Mortality: type of control.
1.5
1.5. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 5 Mortality: type of data.
1.6
1.6. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 6 Mortality: bias control.
1.7
1.7. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 7 Hepatic encephalopathy.
1.8
1.8. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 8 Hepatic encephalopathy: mode of administration.
1.9
1.9. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 9 Overt or minimal hepatic encephalopathy.
1.10
1.10. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 10 Hepatic encephalopathy: type of control.
1.11
1.11. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 11 Hepatic encephalopathy: type of data.
1.12
1.12. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 12 Hepatic encephalopathy: publication status.
1.13
1.13. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 13 Hepatic encephalopathy: bias control.
1.14
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
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
1.16. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 16 Hepatic encephalopathy: trials with lactulose or neomycin control.
1.17
1.17. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 17 Nausea and diarrhoea.
1.18
1.18. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 18 Albumin.
1.19
1.19. Analysis
Comparison 1 Branched‐chain amino acids (BCAA) versus control, Outcome 19 Nitrogen balance.
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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Eriksson 1982 {published data only}
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References to other published versions of this review

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