PRACTICE POINT

www.nature.com/clinicalpractice/gasthep

Branched-chain amino-acid granules:

can they improve survival in patients
with liver cirrhosis?
Original article Muto Y et al. (2005) Effects of branched-

chain amino acid granules on event-free survival in patients

with liver cirrhosis. Clin J Gastroenterol 3: 705713

every 3 months in the first year and every

6 months in the second year.
OUTCOME MEASURES

SYNOPSIS
KEYWORDS branched-chain amino acid,
decompensated cirrhosis, nutrition, survival

BACKGROUND

Nutrition has been shown to influence the

survival of patients with decompensated
cirrhosis, but the impact of branched-chain
amino-acid (BCAA) supplementation on survival
has not been assessed.
OBJECTIVES

To evaluate BCAA supplementation for

improving the survival of patients with
decompensated cirrhosis.
DESIGN AND INTERVENTION

Patients with decompensated cirrhosis and,

or with a history of, ascites, peripheral edema,
a serum albumin concentration 3.5 g/dl or
hepatic encephalopathy were included in this
multicenter, prospective, randomized trial.
Exclusion criteria included prolonged serum
albumin concentration 2.5 g/dl, albumin
infusion more than once a week for at least
1 month, history of receiving BCAA granules
for 5 months or more, serum total bilirubin
3.0 g/ dl, dietary protein restriction, complicated hepatic encephalopathy (grade III or
higher), complicated liver cancer or complicated
esophageal varices. Patients were assigned to
a regimen of BCAA supplementation (1 sachet
of 12 g/day [Livact Granules, Ajinomoto Co,
Tokyo, Japan]) or a diet therapy (1.01.4 g
protein/kg/day and 2535 kcal/ kg/ day)
for 2 years. Routine laboratory tests and physical examination were performed on admission
to the trial and at every follow-up visit, which
occurred every 3 months for the duration of
the trial. Patients underwent ultrasonography
at follow-up for the detection of hepatocellular
carcinoma. Diet was assessed by questionnaire

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2006 Nature Publishing Group

The primary endpoint was time to the aggravation of hepatic failure (including ascites, peripheral edema and jaundice), the rupture of gastric
or esophageal varices, or the development of
liver cancer or death. Secondary endpoints
included improvement in quality of life.
RESULTS

A total of 646 patients were included in the trial of

whom 622 were included in the final analysis: 314
patients received BCAA supplementation and
308 patients received diet therapy. The median
observation period for all patients was 445 days.
Twelve patients died. Aggravation of hepatic
failure was significantly lower in the BCAA group
compared with the diet-therapy group (12 [4%]
versus 24 [8%], P = 0.04). The total number of
events related to the primary endpoint were
significantly fewer in the BCAA group than in the
diet-therapy group (66 [21%] versus 88 [29%],
P = 0.03). The survival rate in the BCAA group
was significantly higher compared with the diettherapy group (hazard ratio 0.67 [95% CI 0.49
0.93], P = 0.015). Levels of serum albumin were
significantly higher in the BCAA group compared
with the diet-therapy group (P = 0.018). Quality
of life was significantly improved in the BCAA
group compared with the diet-therapy group
(P = 0.03). Minor adverse events occurred in 38
(12%) patients in the BCAA group and included
abdominal distension, gastrointestinal problems,
constipation and diarrhea. One patient had
a serious adverse event relating to increased
serum alanine aminotransferase and aspartate
aminotransferase.
CONCLUSION

BCAA supplementation improves survival,

serum albumin concentrations and quality of
life in patients with decompensated cirrhosis
and an adequate daily food intake.

FEBRUARY 2006 VOL 3 NO 2

PRACTICE POINT
www.nature.com/clinicalpractice/gasthep

C O M M E N TA RY
Michael Charlton
BCAA-enriched nutritional supplements are,
theoretically, an appealing approach to the prevention of complications in patients with cirrhosis.
This is especially true in the case of portosystemic
encephalopathy, for which the relatively low
ammoniagenic properties of BCAA-enriched
supplements make obvious physiological sense.
Indeed, there have been several reports of beneficial effects of BCAA supplementation, including
protein sparing and normalization of respiratory
quotients,1,2 as well as clinical improvement of
hepatic encephalopathy.25 Demonstrating an irrefutable clinical benefit of BCAA supplementation
has, however, proven a Sisyphean task.
This study by Muto et al. was preceded by
a large Italian trial6 comparing outcomes in
patients with cirrhosis following a year of
BCAA-enriched nutritional support versus
lactalbumin or maltodextrin dietary supplementation. The primary outcome (a composite
of death, frequency of hospital admission and
duration of hospital stay) was significantly
lower in the BCAA arm than in the lactalbumin
arm. In retrospect, the failure to identify a
single complication (as opposed to a composite
endpoint) lessened the impact of this study. The
withdrawal of patients receiving BCAAs from the
study, owing to poor palatability of the BCAA
supplement, was a key factor in the study losing
power to detect significance in the frequency of
individual outcomes.
The Muto et al. study was different in two
critical aspects. Firstly, BCAA supplements were
formulated into granules, which meant that the
surface area over which BCAAs were able to come
into contact with taste buds was reduced; the
superior palatability of the granules was reflected
in the low dropout rate. Secondly, a much larger
number of patients were included in this study;
the total number exceeded that in all previously
reported BCAA supplement trials combined.
Many clinicians will have read the paper hoping
to see a significant benefit to BCAA supplementation in terms of a clear-cut endpoint; then came
the results. The outcomes that clinicians and
patients care about the mostdeath, encephalopathy, variceal bleeding and the development
of hepatocellular carcinomawere similar
between study groups. There were, however,

FEBRUARY 2006 VOL 3 NO 2

positive findings: the total number of events

and the frequency of composite events were
significantly reduced among patients receiving
BCAAs. Composite endpoints, however, are difficult to sell to clinicians and third-party payers
particularly when the treatment is expensive,
unpalatable and of indefinite duration.
Does a BCAA-enriched diet improve outcomes
in patients with cirrhosis? I think so. Do I prescribe
it? Only in the setting of chronic encephalopathy
in patients who are intolerant of a standard diet
and unresponsive to or intolerant of lactulose. In
conclusion, BCAA supplementation is still hard
to swallow, even as granules. Ajinomoto Co.,
the sponsors of this study, deserve much credit
for supporting it and their BCAA preparation
seems to be a step forward. Owing to the aforementioned concerns, however, not to mention a
lack of prescription coverage for what is viewed
as a nutritional supplement, the study will not
in all likelihood lead to a notable change in the
frequency of prescriptions for BCAA-enriched
supplementation. Unfortunately, this study might
become a lighthouse to other potential investigators warning of the perils of BCAA-enriched
trials. A definitive study would be prohibitively
expensive unless a more targeted approach to
BCAA-enriched supplementation is developed,
and perhaps that should be the immediate goal.
References
1 Nakaya Y et al. (2002) Severe catabolic state after
prolonged fasting in cirrhotic patients: effect of
oral branched-chain amino-acid-enriched nutrient
mixture.[comment]. J Gastroenterol 37: 531536
2 Watanabe A et al. (1983) Effect of a branched chain
amino acid-enriched nutritional product on the
pathophysiology of the liver and nutritional state of
patients with liver cirrhosis. Acta Med Okayama 37:
321333
3 Plauth M et al. (1993) Long-term treatment of latent
portosystemic encephalopathy with branched-chain
amino acids. A double-blind placebo-controlled
crossover study. J Hepatol 17: 308314
4 Marchesini G et al. (1990) Long-term oral branchedchain amino acid treatment in chronic hepatic
encephalopathy. A randomized double-blind caseincontrolled trial. The Italian Multicenter Study Group.
J Hepatol 11: 92101
5 Egberts EH et al. (1985) Branched chain amino acids in
the treatment of latent portosystemic encephalopathy.
A double-blind placebo-controlled crossover study.
Gastroenterology 88: 887895
6 Marchesini G et al. (2003) Nutritional supplementation
with branched-chain amino acids in advanced
cirrhosis: a double-blind, randomized trial.[see
comment]. Gastroenterology 124: 17921801

M Charlton is Associate Professor of Medicine

at the Mayo Clinic and Foundation, Rochester,
MN, USA.

Acknowledgments
The synopsis was written
by Rachel Jones,
Associate Editor,
Nature Clinical Practice.

Competing interests
The author declared he has
no competing interests.

Correspondence
Division of Gastroenterology
and Hepatology
Mayo Clinic and Foundation
200 First St S.W.
Rochester
MN 55905
USA
charlton.michael@mayo.edu
Received 10 October 2005
Accepted 18 November 2005
www.nature.com/clinicalpractice
doi:10.1038/ncpgasthep0392

PRACTICE POINT
Branched-chain
amino-acid granules
are useful for the
treatment of cirrhosis
and chronic hepatic
encephalopathy
in patients who
are intolerant to a
standard diet and
unresponsive or
intolerant of lactulose

NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 73

2006 Nature Publishing Group