Figure 1 presents a flowchart of study selection. We excluded duplications twice and excluded unrelated citations through the screening of titles and abstracts. Furthermore, after screening the full texts of retrieved records, we excluded studies that were duplicates, consisting patients that failed to meet the study criteria, having irrelevant interventions or outcomes and the studies that were non-RCTs. Finally, 11 RCTs were included in the meta-analysis [10–20].
The characteristics of all the included RCTs are presented in Table 1. The studies were published between 1997 and 2020, with sample sizes ranging from 24 to 154. The liver disease status of patients in most of the included studies was evaluated according to the Child–Pugh classification and albumin level. The liver treatments included hepatectomy [10, 12, 13, 15–17, 19, 20], liver transplantation [18], transcatheter arterial chemoembolization (TACE) [11], and RFA [14]. All studies include two supplements: LIVACT® [10, 12, 17, 20] and Aminoleban EN® [11, 13, 14, 15, 16, 18, 19]. Two supplementations both contain three main BCAAs: isoleucine, leucine and valine. The details of BCAA supplementation are provided in Table 1.
Table 1
Characteristics of selected randomized controlled trials
Study | Selection criteria | No. of patients (% male) | Age, year, mean ± SD | Child–Pugh class A/B/C, % | Albumin, g/dL (mean ± SD) | Treatment procedure | Intervention |
Hepatectomy |
Beppu et al. [2015] | History of PVE; Child–Pugh class A or B | B: 13 (69) C: 15 (67) | B: 64 (47–83)† C: 72 (56–78)† | NA | NA | B: RH 89%, LH 0%, LH + S 0%, S 11% C: RH 58%, LH 8%, LH + S 8%, S 25% | B: Livact 4.15 g BID, post-op PVE 6 m C: Conventional diet |
Hachiya et al. [2020] | Curative hepatic resection for HCC | B: 74 (80) C: 80 (82) | B: 69 (47–85)† C: 70 (47–85)† | B: 82/18/0 C: 80/20/0 | B: 3.7 (2.1–4.9) C: 3.6 (1.5–4.6† | B: AR 74%, NAR 26% C: AR 68%, NAR 32% | B: Livact 4 g TID, 4 y C: Surgery only |
Ichikawa et al. [2013] | First hepatic resection for solitary HCC | B: 26 (69) C: 30 (67) | B: 64.7 ± 9.8 C: 64.5 ± 11.4 | B: 81/19/0 C: 83/17/0 | B: 0.6 ± 0.3 C: 0.8 ± 0.4 | B: 2 Seg or extended: 10, Seg: 16 C: 2 Seg or extended: 14, Seg: 16 | B: Livact 4.74 g TID, pre-op 2 w and post-op 6 m C: Conventional diet |
Ishikawa et al. [2010] | Surgery for liver neoplasm | B: 11 (55) C: 13 (62) | B: 63.1 ± 12.5 C: 61.3 ± 11.3 | B: 91/9/0 C: 92/8/0 | NA | B: 3–4 Seg: 3, 1–2 Seg: 8 C: 3–4 Seg: 2, 1–2 Seg: 11 | B: Aminoleban EN + usual diet pre-op 2 w and post-op 7 d C: Usual diet |
Kikuchi et al. [2016] | Liver resection for HCC | B: 39 (79) C: 38 (76) | B: 69.4 ± 7.5 C: 71.9 ± 7.4 | B: 100/0/0 C: 100/0/0 | NA | B: Partial 33%, Seg 0%, 2 Seg/Seg 33%, bisections or more 33% C: Partial 32%, Seg 16%, 2 Seg/Seg 26%, bisections or more 26% | B: Livact 4.74 g TID, pre-op 1 m and post-op 1 y C: Post-op BCAA 1 y |
Meng et al. [1999] | Curative hepatic resection for HCC | B: 21 (90) C: 23 (78) | B: 51.5 ± 10.8 C: 53.3 ± 12.8 | B: 81/19/0 C: 87/13/0 | B: 3.4 ± 0.5 C: 3.3 ± 0.5 | B: Major: 13, Minor: 8; C: Major: 18, Minor: 5 | B: Aminoleban EN 50 g TID plus protein 40 g/day, 12 w C: Normal diet (protein 80 g/day) |
Okabayashi et al. [2011] | Hepatectomy for HCC | B: 40 (73) C: 36 (69) | B: 68.7 ± 7.6 C: 65.1 ± 11.3 | B: 70/30/0 C: 71/29/0 | B: 3.7 ± 0.5 C: 3.7 ± 0.5 | B: Hemi: 10, Seg: 30, Limited: 60 C: Hemi: 11, Seg: 28, Limited: 61 | P: Aminoleban EN 50 g BID pre-op 2 w and post-op 6 m C: Conventional diet |
San-in group [1997] | Curative hepatic resection for HCC | B: 67 (81) C: 65 (85) | B: <50: 5 50–70: 55 >70: 7 C: <50: 7 50–70: 45 >70: 13 | B: 79/19/1 C: 77/22/2 | B: 3.5 ± 0.5 C: 3.5 ± 0.4 | B: 1 Seg or more: 19, limited: 48 C: 1 Seg or more: 26, limited: 39 | B: Aminoleban EN 50 g BID, post-op 1 y C: Usual diet |
Liver transplantation |
Yoshida et al. [2012] | Elective LDLT | B: 12 (58) C: 12 (33) | B: 52.6 ± 10.2 C: 48.5 ± 4.4 | B: 10.8 ± 2.1 C: 10.0 ± 2.4 | NA | LDLT | B: Aminoleban EN 1 pack BID, 1–7 d before LDLT, 3 d to 4 w after LDLT C: Ordinary diet |
RFA or TACE |
Nojiri et al. [2017] | ≤ 3 tumors; size ≤ 3 cm for TACE or RFA | B: 25 (60) C: 26 (58) | B: 69.7 ± 9 C: 69.1 ± 11 | B: 84/16/0 C: 88/12/0 | B: 3.72 ± 0.5 C: 3.71 ± 0.4 | TACE or RFA | B: Aminoleban EN 1 pack BID, 2 w before and to 5 y C: Usual diet |
Poon et al. [2004] | TACE for unresectable HCC | B: 41 (95) C: 43 (91) | B: 59 (24–84)† C: 59 (27–80)† | NA | B: 3.5 (2.5–4.8) C: 3.6 (2.4–4.6)† | TACE | B: Aminoleban EN 50 g BID plus usual diet, 1 w before first TACE, continued 1 y C: Usual diet |
†median (range); ‡patient numbers from different age ranges. |
BCAA: branched-chain amino acid; B: BCAA group; C: control group; NA: not available; y: year; m: month; w: week; d: day; BID: twice per day; TID: thrice per day; PVE: portal vein embolization; HCC: hepatocellular carcinoma; LDLT: living donor liver transplantation; TACE: transcatheter arterial chemoembolization; RFA: radiofrequency ablation; RH: right hemihepatectomy; LH: left hemihepatectomy; S: sectionectomy; Hemi: hemihepatectomy; Seg: segmentectomy; AR: anatomical resection; NAR: nonanatomical resection; SD: standard deviation; op: operation. |
The methodological quality of included trials is summarized in Supplemental Table 1. In total, 11 trials reported acceptable randomization methods, and 5 trials did not describe allocation concealment [12–14, 16, 19]. All trials used the intention-to-treat analysis. One trial did not describe participant blinding [17]. A high loss to follow-up was reported in three trials [13, 17, 19], and outcome measurement in one study might have caused potential bias [19].
Tumor recurrence and overall survival
Six RCTs compared the overall survival between the BCAA groups and control groups that take conventional diet without supplementation for liver disease [10–12, 14–16]. Five of them showed that BCAA supplementation did not improve overall survival compared with conventional diet [10, 12, 14–16]. However, Nojiri et al. demonstrated that BCAA supplementation achieved the overall survival rate benefit in patients who underwent TACE or RFA during the median follow-up of 3.9 years [11].
Five studies reported the recurrence rate of HCC after intervention [10–12, 15, 16]. Three of them showed no significant difference in recurrence rates between the BCAA and control groups of patients undergoing hepatic resection [10, 15, 16]. The subgroup analysis by Hachiya et al. revealed recurrence-free survival benefit in patients < 72 years old with a HBA1c level of < 6.4% [10]. Ichikawa et al. demonstrated that the recurrence rate at 30 months was significantly lower in the BCAA group than in the control group in patients who underwent hepatic resection for HCC [12]. Furthermore, Nojiri et al. showed that the BCAA group achieved a lower tumor recurrence rate than did the control group among patients undergoing TACE or RFA [11].
Posttreatment complication
Eight trials reported post-hepatic-intervention complications, including encephalopathy, edema, ascites, post-operation infection, bleeding, effusion, and liver abscess [10, 11, 12, 14, 15, 16, 18, 20]. Three trials reported that encephalopathy incidence at a 12-month follow-up showed no significant difference between the BCAA and control groups (RR: 0.48, 95% CI: 0.12–1.83; Fig. 2) [11, 14, 16]. The pooled estimate of two trials revealed significant differences in the incidence of edema at 3 and 12 months [14, 16]. Six trials reported ascites, with two trials [12, 16] showing no significant difference at 6 months (RR: 0.83, 95% CI: 0.25–2.75), and the pooled estimate of four trials [11, 14, 16, 20] showed that the BCAA group exhibited a significantly reduced incidence of ascites at 12 months compared with the control group (RR: 0.39, 95% CI: 0.21–0.71; Fig. 3).
Regeneration
Beppu et al. used the single-photon emission computed tomography (SPECT/CT) system to assess liver volume and function in patients with HCC undergoing portal vein embolization and subsequent hepatectomy. They found that the BCAA group had a significantly higher percentage of liver volume and functional liver volume than did the control group at 6 months after hepatectomy [17]. Yoshida et al. compared BCAA supplementation with ordinary diet in patients undergoing living donor liver transplantation (LDLT). The ordinary diet was based on European Society for Parental and Enteral Nutrition (ESPEN) guidelines. The liver regeneration rate was calculated using a formula consisting of the measurements of liver graft weight obtained from CT and actual graft weight. However, no significant difference was observed between the BCAA and control groups at 4 weeks after LDLT [18].
Postintervention liver function
Six RCTs reported the serum albumin level postintervention [11, 12, 14–16, 19]. The pooled analysis showed a significantly higher serum albumin level in the BCAA group than in the control group at 6 months postintervention (MD: 0.11 g/dL, 95% CI: 0.02–0.20). No significant differences were observed in the serum albumin level at 2 (MD: 0.09, 95% CI: −0.11 to 0.29), 4 (MD: 0.11, 95% CI: −0.07 to 0.30), and 12 (MD: 0.14, 95% CI: −0.03 to 0.32) months postintervention (Fig. 4).
Serum cholinesterase levels were similar in two trials [12, 19]. The pooled estimate showed no significant difference at 2 (MD: −3.41 U/L, 95% CI: −25.31 to 18.49), 4 (MD: 6.10, 95% CI: −16.39 to 28.59), and 6 (MD: 21.69, 95% CI: −4.99 to 48.38) months postintervention between the BCAA and control groups. However, one trial reported that the BCAA group expressed a significantly higher cholinesterase level than did the control group 12 months after the intervention (MD: 50.00, 95% CI: 21.08–78.92; Fig. 5) [19].
Three RCTs reported AST and ALT serum levels [11, 14, 16]. The pooled estimate showed no significant differences between the BCAA and control groups in terms of AST (MD: 3.42 IU/L, 95% CI: −20.99 to 27.82) and ALT (MD: −3.56, 95% CI: −15.18 to 8.06) levels at 12 months postintervention (Fig. 6).
Hospitalization duration
In total, four trials compared the hospitalization duration between the BCAA and control groups [12, 15, 18, 20]. The pooled results showed that the BCAA group had a non-significant shorter hospitalization length (MD: −2.36 days, 95% CI: −4.78 to 0.07) than did the control group (Supplemental Fig. 1).
Body weight and arm circumference
In total, three trials investigated the body weight between the BCAA and control groups [12, 14, 19]. Poon et al. [14] measured the aforementioned parameters at 3, 6, 9, and 12 months post-treatment, whereas Ichikawa et al. [12] recorded the parameters at 2, 4, and 6 months. The pooled result showed that the BCAA group had significantly more weight gain that did the control group in 12 months (MD: 3.29 kg, 95% CI: 1.07 to 5.50; Supplemental Fig. 2). The trial that used percentage changes for comparison demonstrated that body weight was greater in the treatment group than in the control group at all time points in the first year [19].
Four trials compared the arm circumference between the BCAA and control groups. Among them, three clearly described statistical data included for the analysis [12, 14, 19]. The arm circumference was higher in the BCAA group than in the control group at both 6 and 12 months, with an average increase of 0.84 and 3.29 cm, respectively. However, only the increase in arm circumference at 12 months was statistically significant (MD: 3.29, 95% CI: 1.07–5.50; Supplemental Fig. 3). In the trial that did not report statistical data, arm circumference was not significantly different between the groups [15].
Adverse effect of BCAA
Only one trial reported the adverse effect of BCAA on patients undergoing hepatectomy. Among the 67 patients in the BCAA group, seven patients experienced adverse reactions, namely four had nausea and vomiting, one had diarrhea, one had abdominal distension, and one had hypertension [16].