Oral Branched-Chain Amino Acids in Patients with Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: a Meta-Analysis

Abstract

Background: Hepatocellular carcinoma (HCC) patients experience systemic catabolism, muscle protein depletion and reduced oxidation of branched-chain amino acids (BCAA), leading to protein-energy malnutrition (PEM). Transarterial chemoembolization (TACE), a loco-regional therapy for unresectable HCC may further worsen PEM and underlying cirrhosis. Oral BCAA (valine, leucine and isoleucine) stimulate protein synthesis, inhibit proteolysis and promote glutamine synthesis. We aimed to summarize the efficacy of oral BCAA supplementation compared to standard diet among unresectable HCC patients undergoing TACE, in terms of reduction of mortality and morbidity, and improvement of liver synthetic function. Methods: We searched the Cochrane Library, PUBMED, EMBASE and Google Scholar databases for any randomized controlled trials (RCTs) published until December 2012, comparing oral BCAA supplementation versus standard diet in any dose and form, in terms of mortality, morbidity and liver synthetic function (albumin, aminotransferase, protime, total bilirubin). Search terms were “hepatocellular carcinoma,” “liver cancer,” “hepatoma,” “unresectable HCC,” “chemoembolization,” “TACE,” “aminoleban” and “branched chain amino acids.”We also performed cross-reference and hand search of abstract books from major international gastroenterology and hepatology conferences. Two independent reviewers obtained 13 articles from the search strategy. Out of the six articles deemed eligible by the reviewers, only three were subsequently included in this meta-analysis. A third reviewer served as the arbiter. The reviewers assessed the methodological quality of each study separately using these domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other sources of bias. Results: We pooled the results of 163 participants from three RCTs. Participants were randomized into two groups: oral BCAA group (n = 82) and control group (n = 81). Oral BCAA reduced mortality (RR 0.89, 95% CI: 0.73 to 1.08, i2= 0%) and morbidity (RR 0.49, 95% CI: 0.23 to 1.03, i2= 0%) but results were not statistically significant (p value >0.05). The improvement in the liver synthetic function of the oral BCAA group did not significantly differ from that of the control group. The change in serum albumin was not significantly different between the two groups (mean difference -0.15, 95% CI: -0.37 to 0.07, p = 0.19, i2= 73%). Likewise, the change in serum ALT from baseline to post-intervention was not significantly different between the two groups (mean difference 13.66, 95% CI: -4.10 to 31.43, p value 0.13, i2= 0%). Protime results could not be combined because of different reporting methods. The change in total bilirubin from the baseline to post-intervention did not differ significantly between the two groups (mean difference -0.05, 95% CI: -0.21 to 0.11, i2= 0%, p = 0.54). There were no reported adverse drug effects of oral BCAA in the three studies. Conclusion: Oral BCAA supplementation did not significantly improve mortality, morbidity and liver synthetic function of patients with unresectable HCC undergoing TACE. More RCTs with larger sample size and high methodological quality are needed in the future.