Key messages:
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BCAAs may have little to no effect on the number of people with hepatic encephalopathy who die, compared to other treatments or no treatment, but we are very uncertain about the results.
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BCAAs may reduce the number of people who develop hepatic encephalopathy.
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We need more high-quality studies that give participants BCAAs combined with other medicines used in practice, such as antibiotics.
What are cirrhosis and hepatic encephalopathy?
Cirrhosis is a condition in which healthy liver tissue is gradually replaced by scar tissue. This damage reduces the liver’s ability to work properly and is the main cause of hepatic encephalopathy, a condition that affects brain function.
Symptoms can range from mild to severe. Mild symptoms include small, almost unnoticeable, changes in thinking, such as problems with attention, memory, or problem-solving abilities. In more severe stages of the condition, symptoms are clearly noticeable. These may include obvious confusion or disorientation, changes in behaviour or personality, or reduced alertness. In very severe cases, people may lose consciousness or enter a coma.
How is hepatic encephalopathy treated?
Most treatments for hepatic encephalopathy aim to lower toxins in the blood, especially ammonia, and to manage the underlying liver disease. Doctors often use medicines that reduce the amount of toxins produced in the gut or stop them from being absorbed into the bloodstream.
Branched-chain amino acids (BCAAs) may also be used as part of treatment, but they work in a different way. People with cirrhosis often have low levels of BCAAs. Taking BCAA supplements can help correct this imbalance and support muscles in removing ammonia from the blood, which may help improve brain function.
BCAAs are amino acids with a specific chemical structure and are important for maintaining muscle mass and supporting normal brain signalling. Because of these roles, BCAA supplementation may help people with hepatic encephalopathy.
What did we want to find out?
We wanted to know if BCAAs are an effective and safe treatment for people with hepatic encephalopathy and cirrhosis. We were interested to know if they made any difference to these outcomes: death, development or progression of hepatic encephalopathy, serious unwanted or harmful events (also known as 'adverse events'), quality of life, and markers of nutritional status.
What did we do?
We searched for studies that compared BCAAs to another treatment, including placebo (an inactive or 'dummy' medication), no intervention, diets, lactulose (a liquid sugar often used to treat constipation), or neomycin (an antibiotic) in people with hepatic encephalopathy and cirrhosis.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and size.
What did we find?
We found 18 studies involving 934 adults. The participants had cirrhosis, often due to alcoholic liver disease or viral hepatitis (liver infection due to a virus). Participants' average age ranged from 47 to 64 years. The proportion of men in the studies ranged from 47% to 90%. The studies' follow-up durations ranged from four days to two years. Ten trials were conducted in Europe, four in Asia, two in the USA, and one each in Brazil and Australia. We found no studies involving children.
Main results
Our analyses demonstrated that BCAAs:
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may make little to no difference to the number of people who die, but the evidence is very uncertain;
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may reduce the number of people who develop hepatic encephalopathy or whose condition worsens;
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may increase the risk of nausea and diarrhoea, but the evidence is very uncertain.
The evidence regarding the effect of BCAAs on markers of nutritional status is very uncertain. We were unable to analyse evidence on people's quality of life due to the way studies assessed this outcome, and because some studies included participants without hepatic encephalopathy.
What are the limitations of the evidence?
We are not confident in the evidence because many studies did not provide sufficient information to adequately assess how well they were designed or conducted. We also had concerns about the possibility of selective reporting, which is when a study shares only some of its results, which can give a misleading picture of the true effect of treatment. In addition, most studies were small.
How current is this evidence?
This review updates our previous review from 2017. The evidence is current to 12 December 2024.
Read the full abstract
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 assess the beneficial and harmful effects of BCAAs versus any control intervention for people with cirrhosis and hepatic encephalopathy.
Search strategy
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.
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
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
