Branched-chain amino acids for people with cirrhosis and hepatic encephalopathy

RATIONALE: Hepatic encephalopathy is a brain dysfunction characterised by neurological and psychiatric changes due to liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. The previous version of this updated review meta-analysed data from 16 randomised clinical trials on branched-chain amino acids (BCAAs) versus control interventions, and found that BCAAs did not affect mortality but had a beneficial effect on hepatic encephalopathy. As data on critical outcomes were insufficient and new trials were published, we updated the review again.

OBJECTIVES: To assess the beneficial and harmful effects of BCAAs versus any control intervention for people with cirrhosis and 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, MEDLINE, Embase, Latin American and Caribbean Health Science Information database (LILACS), Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched other resources and contacted experts for additional published and unpublished trials. The latest search date was 12 December 2024.

ELIGIBILITY CRITERIA: We included randomised clinical trials, irrespective of bias control, language, outcomes reported, or publication status, that compared any form of branched-chain amino acid with no intervention, placebo, diets, non-absorbable disaccharides, antibiotics, or any other intervention with a potential effect on hepatic encephalopathy, in children and adults with overt or minimal hepatic encephalopathy associated with acute or chronic liver disease.

OUTCOMES: The critical outcomes were all-cause mortality, hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and serious adverse events (including nausea and diarrhoea). The important outcomes were quality of life and markers of nutritional status, including serum albumin and nitrogen balance. We evaluated outcomes at the longest available follow-up duration. The longest follow-up was also our primary time point for analysis.

RISK OF BIAS: We assessed the risk of bias (RoB) of the critical and important outcomes using the Cochrane RoB 2 tool.

SYNTHESIS METHODS: We used standard Cochrane methodology. We performed meta-analyses, based on intention-to-treat, with risk ratios (RRs) for dichotomous outcomes, standardised mean differences (SMDs) for continuous outcomes in trials using different scales, and mean differences (MDs) for continuous outcomes when trials used the same scales, all with 95% confidence intervals (CI). We conducted the main analysis using a random-effects model. We assessed the overall certainty of the evidence per outcome with the GRADE approach, with five components (risk of bias, indirectness, heterogeneity, imprecision using the minimally contextualised approach, and dissemination bias).

INCLUDED STUDIES: We added two new randomised clinical trials to this review update. Thus, the 18 trials, published between 1984 and 2023, included 934 adults (mean age 47 to 64 years). We found no trials in children. Participants had overt hepatic encephalopathy (13 trials) and covert hepatic encephalopathy (five trials). Ten trials assessed oral BCAA supplements and eight trials assessed intravenous BCAAs. The control groups received no intervention or placebo (two trials), diets (11 trials), lactulose (three trials), or neomycin (two trials). Most participants had cirrhosis (minimum 97%). One trial included participants with acute hepatitis. The follow-up periods were from four days to two years (104 weeks). Ten trials were conducted in Europe, four in Asia, two in the USA, and one each in Brazil and Australia. Three trials received support from for-profit organisations in the form of interventions.

SYNTHESIS OF RESULTS: BCAAs may have little to no effect on all-cause mortality compared with the control interventions, but the evidence is very uncertain (RR 0.89, 95% CI 0.71 to 1.12; 17 studies, 867 participants; very low-certainty evidence). We found no evidence of small-study effects. All trials reported the effect of BCAAs on hepatic encephalopathy. The evidence suggests that BCAAs reduce hepatic encephalopathy (RR 0.79, 95% CI 0.64 to 0.96; 18 studies, 934 participants; low-certainty evidence). The follow-up ranges for the two outcomes were four days to two years. Nausea and diarrhoea, considered as serious adverse events, occurred in 58 of 477 (12%) participants in the BCAAs group and 16 of 538 (3%) participants in the control intervention group (diets). The evidence is very uncertain about the effect of BCAAs on nausea and diarrhoea (RR 2.05, 95% CI 0.40 to 10.58; 6 studies, 1015 participants; very low-certainty evidence). Three trials provided data on quality of life, but we were unable to meta-analyse the data because of the methods used to register the scores. All participants in the three trials had cirrhosis, but some did not have hepatic encephalopathy at baseline. When the analyses were limited to people with hepatic encephalopathy, none of the trials found beneficial or harmful effects of BCAAs on the global 36-item Short Form Health Survey (SF-36) score or any of the subscales. BCAAs may have little to no effect on albumin concentration (range 12 to 56 weeks) (MD 0.60, 95% CI -0.90 to 2.09; I² = 0%; 3 studies, 176 participants; very low-certainty evidence), but the evidence is uncertain. The evidence is very uncertain about the effect of BCAAs on nitrogen balance (range four days to two years) (SMD 0.82, 95% CI -1.01 to 2.64; 3 studies, 108 participants; very low-certainty evidence). We downgraded the certainty of evidence for risk of bias, indirectness, and imprecision. Three trials are ongoing.

AUTHORS' CONCLUSIONS: We added two new trials to the analyses. The evidence suggests BCAAs reduce hepatic encephalopathy, but the certainty of evidence is low. We do not know if BCAAs, compared with controls, have any effect on all-cause mortality, nausea and diarrhoea, albumin, and nitrogen balance because of very low-certainty evidence. We could not meta-analyse the data on quality of life. Trials in children are lacking. We lack randomised clinical trials comparing BCAAs with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.

FUNDING: No funding REGISTRATION: Protocol (1997): Gluud C, Koretz RL. Branched-chain amino acids for hepatic encephalopathy (Protocol for a Cochrane Review). The Cochrane Library 1997, Issue 1. Original review (2003): doi.org/10.1002/14651858.CD001939 Review update (2015 Feb): doi.org/10.1002/14651858.CD001939.pub2 Review update (2015 Sep) doi.org/10.1002/14651858.CD001939.pub3 Review update (2017): doi.org/10.1002/14651858.CD001939.pub4.