Table 2.

Branched-chain supplementation in patients with hepatocellular carcinoma

Ref.	Type of study	Population	Intervention (BCAA amount, time of supplementation)	Outcomes
Tada et al[63], 2019	Clinical trial (78 patients)	BCAA group: 27 patients	5.712 g of L-leucine, 2.856 g of L-isoleucine, 3.432 g of L-valine. 18 mo	BCAA therapy was independently associated with good prognosis in patients with HCC (HR: 0.317, 95%CI = 0.123–0.813, P = 0.017). Multivariate analysis using competing risks methods indicated that BCAA therapy is independently associated with reduction of disease-specific mortality (HR: 0.216, 95%CI = 0.068–0.689, P = 0.001)
		Non-BCAA group: 51 Patients
Nojiri et al[64], 2016	Randomized clinical trial (51 patients)	Control: 26 patients. Diet: Energy: 30–35 kcal/kg; Protein: 1–1.3 g/kg per day	420 kcal. 26.6 g of protein. 4.074 g of L-leucine. 3.845 g of L-isoleucine. 3.204 g of L-valine. 3 mo	Event-free survival was significantly higher in the BCAA group, whereas the intrahepatic recurrence rate was significantly lower (P = 0.04 and 0.036, respectively). A significant improvement in the SF-8 mental component score was observed in the BCAA group only (P < 0.01)
		Intervention: 25 patients. Diet + Supplementation
Ichikawa et al[65], 2013	Randomized clinical trial (56 patients)	Control: 30 patients. Standard diet	1.144 g of L-isoleucine, 1.904 g of L-leucine, 0.952 g of L-valine. 2 wk before hepatic resection and 6 mo after.	There was no significant difference in the overall survival rate between the two patient groups. Recurrence rate at 30 mo after surgery was significantly better in the BCAA group in comparison to the control group. Tumor markers such as AFP and PIVKA-II, significantly decreased at 36 mo after liver resection in the BCAA group in comparison to the control group
		Intervention: 26 patients. Standard diet + BCAA
Saito et al[66], 2014	Prospective cohort study (40 patients)	Control: 13 patients. Standard diet	2.856 g of L-isoleucine, 5.712 g of L-leucine, 3.432 g of L-valine. > 3 mo	Supplementation with BCAA granules improves energy metabolism after RFA. BCAA granules improve the liver function after RFA. Improvements in the residual liver function may result in consistently adequate treatment for HCC recurrence after RFA
		Intervention: 27 patients. Standard diet + BCAA
Nishikawa et al[52], 2012	Retrospective cohort study (99 patients)	Control = 59 patients. Regular diet	2.856 g L-isoleucine, 5.712 g L-leucine, 3.432 g L-valine. > 3 mo	Serum albumin level and Child-Pugh score improved significantly in the BCAA group as compared with the control 3 and 6 mo after TACE (P < 0.05)
		Intervention: 40 patients. BCAA treatment
Hayaishi et al[67], 2011	Randomized clinical trial (211 patients)	Control: 155 patients. Standard diet	Intervention: 12 g/d BCAA (LIVACT Granules; Ajinomoto Co., Inc., Tokyo, Japan). > 6 mo	The incidence of HCC was significantly lower in the BCAA group than in the control group (HR: 0.416, 95%CI: 0.216–0.800, P = 0.0085). Oral BCAA supplementation also seems to be effective in the prevention of liver-related complications in patients with Child-Pugh A cirrhosis.
		Intervention: 56 patients. Standard diet + BCAA
Hachiya et al[68], 2020	Randomized clinical trial (156 patients)	Control: 81 patients. Standard diet	Intervention: 12 g/d BCAA (LIVACT Granules; Ajinomoto Co., Inc., Tokyo, Japan). 4 yr	BCAA supplementation may reduce tumor recurrence in low-risk patients. BCAA may not reduce the risk of tumor recurrence after hepatic resection in HCC in high-risk patients
		Intervention: 75 patients. Standard diet + BCAA

AFP: Alpha-fetoprotein; BCAA: Branched-chain amino acid; CI: Confidence interval; HCC: Carcinoma hepatocellular; HR: Hazard ratio; PIVKA-II; Protein induced by vitamin K absence-II; RFA: Radiofrequency ablation; SF-8: School Form 8 Learner’s Basic Health and Nutrition Report; TACE: Transcatheter arterial chemoembolization.