Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties

Table 1 Selected published studies on beneficial effects of branched chain amino acids in liver cirrhosis

Ref.	Study design	Participants	Intervention	Route	Treatment duration	Associated treatments	Outcomes	Results
Horst et al[16], 1984	Multicentric RCT	37 cirrhotic patients with OHE	BCAAs (20 g/d increased to 80 g/d) vs isonitrogenous diet (placebo)	Oral	4 wk	No	Mortality and hepatic encephalopathy assessed after 4 wk	HE recurrence (decreased). No differences in nitrogen balance
Muto et al[17], 2005	Multicentric RCT	646 patients with decompensated cirrhosis	BCAAs (12 g/d) vs standard diet (1.0-1.4 protein kg/d	Oral	2 yr	No	Mortality, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival)	EFS (increased), health-related quality of life, mortality (decreased). No differences in improvement of HE
Les et al[18], 2011	Double-blind multicentric RCT	40 cirrhotic patients with previous episodes of minimal hepatic encephalopathy	BCAAs (30 g/d) vs isocaloric placebo (maltodextrin)	Oral	56 wk	No	Mortality and hepatic encephalopathy assessed after 56 wk	Improvement in MHE symptoms and muscle mass. No reduction of HE recurrence
Gluud et al[19], 2017	Meta-analysis of RCT	11 RCT; 14 RCT	BCAAs vs diets, antibiotics (neomycin) and non-absorbable disaccharides	Oral and IV	Variable	No	Effect on HE manifestations and prevention of HE episodes	Oral BCAAs improve HE manifestations and prevention of HE episodes. No effects for IV BCAA
Gluud et al[20], 2013	Systematic review with meta-analysis	8 RCT: 382 cirrhotic patients with recurrent MHE or OHE	BCAAs (0.25 g/kg body weight/day) vs no intervention/placebo/control supplements	Oral	Variable	No	Effect on HE manifestations, mortality, nutritionalstatus, and adverse events in patients with recurrent HE	Improvement in the recurrent HE manifestation (more evident in OHE than MHE). No differences in survival
Gluud et al[19], 2017	Cochrane systematic review	16 RCT: 827 cirrhotic patients with OHE or MHE	BCAAs vs placebo/no intervention/other (diet, lactulose, neomycicn)	Oral and IV	Variable	No	Beneficial or harmful effects of BCAA versus any control intervention in HE	Oral BCAAs improve HE manifestation (no effect vs lactulose or neomycicn). No effect on mortality
Park et al[21], 2017	Multicentric retrospective cohort study	307 cirrhotic patients with CTP 8-10	BCAAs (4.15 g/d or 8.3 g/d or 12.45 g/d) vs normal diet	Oral	24 wk	No	Changes in MELD score, CP score, incidence of cirrhosis-related complications and event-free survival over 2 yr	Improvement in MELD score, serum bilirubin and CTP score in 12.45/d BCAAs. No differences in HE manifestation
Tajiri et al[23], 2018	Retrospective observational study	53 cirrhotic patients with OHE	IV BCAAs and conventional therapies vs IV BCAAs and conventional therapies + IV L-carnitine	IV	Median 5 d (range 2-20 d)	L-carnitine conventional therapies (non-absorbable disaccharides and non-absorbable antibiotics)	Effect on HE manifestation, recurrence-free-survival and overall-survival	L-carnitine + BCAAS improve HE manifestation and reduce HE recurrence

BCAAs: Branched chain amino acids; RCT: Randomized control trial; OHE: Overt hepatic encephalopathy; HE: Hepatic encephalopathy; EFS: Early feeding skill; MELD: Model for end stage liver disease; CP: Child-pugh score; CTP: Child-Turcotte-Pugh score.