Nutrition 23 (2007) 113120

www.elsevier.com/locate/nut

Applied nutritional investigation

BCAA-enriched snack improves nutritional state of cirrhosis

Yutaka Nakaya, M.D.a,*, Kiwamu Okita, M.D.b, Kazuyuki Suzuki, M.D.c,
Hisataka Moriwaki, M.D.d, Akinobu Kato, M.D.c, Yoshiyuki Miwa, M.D.d,
Koichi Shiraishi, M.D.e, Hiroaki Okuda, M.D.f, Morikazu Onji, M.D.g,
Hidenori Kanazawa, M.D.h, Hirohito Tsubouchi, M.D.i, Shinzo Kato, M.D.j,
Masahiko Kaito, M.D.k, Akiharu Watanabe, M.D.l, Daiki Habu, M.D.m, Susumu Ito, M.D.a,
Tomohisa Ishikawa, M.D.n, Naohiro Kawamura, M.D.o, and Yasuyuki Arakawa, M.D.p, for
the Hepatic Nutritional Therapy (HNT) Study Group
a

University of Tokushima Graduate School, Tokushima, Japan

b
Yamaguchi University School of Medicine, Ube, Japan
c
Iwate Medical University, School of Medicine, Morioka, Japan
d
Gifu University School of Medicine, Gifu, Japan
e
Tokai University School of Medicine, Hachioji Hospital, Hachioji, Japan
f
Tokyo Womens Medical University, Tokyo, Japan
g
Ehime University School of Medicine, Toon, Japan
h
Nippon Medical School, Tokyo, Japan
i
University of Miyazaki, Tokyo, Japan
j
School of Medicine, Keio University, Tokyo, Japan
k
Mie University Graduate School of Medicine, Tsu, Japan
l
Toyama Medical and Pharmaceutical University, Toyama, Japan
m
Osaka City University Graduate School of Medicine, Osaka, Japan
n
Jikei University School of Medicine, Tokyo, Japan
o
Kyorin University School of Medicine, Mitaka, Japan
p
Nihon University School of Medicine, Tokyo, Japan
Manuscript received May 17, 2006; accepted October 26, 2006.

Abstract

Objective: A late evening snack improves the catabolic state in patients with advanced liver cirrhosis.
We tested whether long-term (3 mo) late evening snacking that included a branched-chain amino acid
(BCAA) enriched nutrient mixture produces a better nutritional state and better quality of life than
ordinary food in patients with hepatitis C viruspositive liver cirrhosis.
Methods: In a multicenter, randomized study, 48 patients with liver cirrhosis received late-evening
supplementation with the BCAA-enriched nutrient mixture or ordinary food, such as a rice ball or bread,
for 3 mo. During the study period, each patient was instructed on energy and protein intake. Blood
biochemical data, nitrogen balance, respiratory quotient, and health-related quality of life (Short Form 36
questionnaire) were evaluated at baseline and at the end of the study.
Results: Total and late-evening energy intakes were similar in the two groups at 3 mo. Serum
albumin level, nitrogen balance, and respiratory quotient were significantly improved by the BCAA
mixture but not by ordinary food. The parameters of the Short Form 36 did not statistically
significantly improve over 3 mo in either group.
Conclusion: Long-term oral supplementation with a BCAA mixture is better than ordinary food in
a late evening snack at improving the serum albumin level and the energy metabolism in patients
with cirrhosis. 2007 Elsevier Inc. All rights reserved.

Keywords:

Liver cirrhosis; Late evening snack; Branched-chain amino acid; Nutritional therapy

* Corresponding author. Tel.: 81-88-633-7090; fax: 81-88-633-7113.

E-mail address: nakaya@nutr.med.tokushima-u.ac.jp (Y. Nakaya).
0899-9007/07/$ see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2006.10.008

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Y. Nakaya et al. / Nutrition 23 (2007) 113120

Introduction
The liver plays an important role in energy metabolism.
Patients with cirrhosis lack adequate glycogen stores because of liver atrophy and therefore develop a severe catabolic state after fasting. Owen et al. [1] reported that, after
an overnight fast, patients with cirrhosis have a marked
decrease in glucose oxidation, with enhanced fat and protein
catabolism similar to that observed in healthy subjects after
2 to 3 d of starvation. To avoid such nocturnal starvation,
energy supplements have been developed [25] and are
recommended as late evening snacks (LESs) in current
American Society for Parenteral and Enterel Nutrition [6]
and European Society for Clinical Nutrition and Metabolism [7] guidelines. Carbohydrate-rich snacks have been
used previously in LESs, but some recent studies have
indicated that a LES with a branched-chain amino acid
(BCAA) enriched nutrient mixture (BCAA mixture) can
also improve the oxidation of aberrant substrates in the early
morning in patients with cirrhosis [8,9]. However, these
studies have focused solely on the short-term effect of LESs
on energy metabolism, and there have been no studies on
the long-term outcome of LESs. Another important question
that has not been answered is whether or not LESs should
accompany BCAA supplementation.
Supplementation with BCAAs has mainly been attempted as a nutritional intervention for decompensated
liver cirrhosis. Clinical evidence about the efficacy of this
therapy has accumulated particularly in the past 3 y [10 13]
and indicates that BCAA supplementation raises the serum
albumin level and improves the quality of life (QOL) and
survival of patients with decompensated liver cirrhosis. A
laboratory study also supports the view that BCAA regulates albumin synthesis at a subcellular level [14]. However,
there are also many criticisms against BCAA administration
in cirrhosis [15]. To confirm its efficacy, if any, supplementation conditions, including dose, time, and use of energy,
might be further optimized. In this context, it is relevant that
BCAA supplementation at night improved the nitrogen balance compared with daytime administration [16].
Therefore, we investigated which would be better to
improve energy malnutrition, an ordinary LES or a BCAAenriched LES.

ria were 1) positive test results for the hepatitis C virus

antibody and 2) a serum albumin level 3.5 g/dL. Exclusion criteria were the presence of overt hepatic encephalopathy, uncontrolled esophageal varices, refractory ascites,
reduced renal function, or previous poor compliance with
pharmacologic treatment or nutritional counseling. Those
who used antidiabetic drugs or intravenous albumin regularly were also excluded. Those who had been treated for
hepatocellular carcinoma were included in this study if
ultrasound had not detected current local lesions and the
-fetoprotein levels were not elevated.
After dynamic balancing of the treatment groups for age,
Child-Pugh score, and serum albumin level, patients were
randomly assigned to one of two groups: LESs with BCAA
mixture (Aminoleban EN, Otsuka Pharmaceutical Co. Ltd.,
Tokyo, Japan; BCAA group, n 25) and LESs with ordinary food (snack group, n 23).
Study protocol
The intervention schedule is presented in Figure 1. After
randomization, patients had a standard diet for 2 wk and had
LESs for the next 3 mo. During the standard diet period,
patients were instructed to maintain a diet containing 30 35
kcal and 1.21.3 g of protein per kilogram of ideal body
weight per day. In the LES period, the patients were educated to adjust their total energy intake by subtracting 210
kcal from the standard meals. As a LES food, the BCAA
mixture contained 210 kcal of energy, 13.5 g of protein,
3.5 g of fat, and trace minerals and vitamins [17]. The
control snack provided 210 kcal of energy with 9 g of
protein and 5 g of fat. Dietitians showed examples of ordinary LESs, such as rice balls, bread, and cookies.
Nutritional education was presented to all patients once
every month during the study period by dietitians. The
patients were told to completely record food intake for a
72-h period at home. Food consumption was calculated
from these records at baseline and at the end of the study.
Standard therapies such as diuretics were allowed but dos-

Materials and methods

Patients
Forty-eight patients with liver cirrhosis were recruited
from 16 centers between April 2003 and June 2004. The
study protocol was approved by the ethics committee of
each hospital, and informed consent was obtained from each
subject. Liver cirrhosis was diagnosed by documented laboratory data and/or histology. The patients were graded
according to the Child-Pugh classification. Eligibility crite-

Fig. 1. Study protocol. After randomization, the patients spent 2 wk on a

standard diet and the next 3 mo with late evening snack supplementation.
For detailed contents of the standard diet and late evening snack, see STUDY
PROTOCOL. QOL, quality of life measured by the Short Form 36 questionnaire and subjective symptoms.

Y. Nakaya et al. / Nutrition 23 (2007) 113120

ages were fixed during the study. Compliance with treatment was assessed at each outpatient visit by interview.
Nutritional parameters
The baseline assessment included routine physical and
laboratory examinations, anthropometric measurements,
and self-administered questionnaires to evaluate dietary intake, subjective symptoms, and health-related QOL.
Laboratory tests were performed in individual centers
according to standard techniques. The BCAA-to-tyrosine
ratio (BTR) was measured to assess the intake of BCAAs.
The BTR was measured by an enzymatic method (Ono
Pharmaceutical Co. Ltd., Osaka, Japan). The clinical significance of the results obtained corresponds to Fischers ratio
(molar ratio of BCAAs and aromatic amino acids) [18]. At
baseline, when patients were in the hospital and after 3 mo
of the study, urine was collected and the nitrogen balance
and urinary excretion of 3-methylhistidine normalized by
creatinine were measured. The nitrogen balance was calculated from the intake of dietary protein and excreted urinary
nitrogen using the following equation:
nitrogen balance g

protein intake g
6.25
urinary urea nitrogen g 4

The anthropometric measurements included the midarm circumference and triceps skinfold thickness. The
midarm muscle circumference and midarm fat area were
calculated subsequently.
At baseline and at 3 mo, indirect calorimetry was performed to measure oxygen and carbon dioxide consumption
per unit time after overnight fasting, and the non-protein
respiratory quotient (npRQ) was estimated. The equipment
for measurement of respiratory parameters differed in each
institution, i.e., Deltatrac II respiratory gas analyzer (Datex
Ohmeda Inc., Helsinki, Finland), Calorie Scale (Cest MI,
Tokyo, Japan), and Aeromonitor AE-300S (Minato Medical
Science, Osaka, Japan), although each patient was measured
with the same equipment both times.

115

Outcome markers
The main outcome markers were serum albumin level,
nitrogen balance, and QOL measurements. The npRQ
served as an intermediate biomarker to evaluate directly the
effect of late evening energy supplementation and BTR to
evaluate BCAA supplementation.
Statistical analysis
Data analysis was performed using JMP 5.1J (SAS Institute Japan Ltd., Chuo-ku, Tokyo, Japan). The differences
between groups in baseline characteristics were analyzed by
chi-square test or Students t test. The effects of LESs were
analyzed by repeated measures analysis of variance between
groups and by the Wilcoxon signed-rank test within each
group. The subjective symptoms were analyzed by chisquare test between groups and by McNemars test within
each group. All data in the text and tables are presented as
mean SD.

Results
Clinical course
Forty-eight patients were initially enrolled and randomized (Fig. 2). However, one patient in the BCAA group
opted for other treatments and declined. Therefore, the supplementation was initiated in 24 patients in the BCAA
group and 23 patients in the snack group. During the study
period of 3 mo, five patients in the BCAA group and four in

Total number of patients assigned

(intention to reatITT)
N=48
BCAA:
Snack:

25
23

Patients subjected to safety analysis

N=47
BCAA:
Snack:

24
23

Patients who were not given assigned therapy

during the trial
N=1
BCAA:
Snack:

1
0

QOL questionnaire
Health-related QOL was measured using the Short Form
36 (SF-36) questionnaire [19 21]. The SF-36 contains 36
questions that provide a quantitative evaluation on each of
eight subscales: physical function, mental health, role physical, role emotional, bodily pain, general health, vitality, and
social function. Subjective symptoms possibly related to
liver cirrhosis, such as weakness, easy fatigability, pruritus,
muscle cramp, bleeding, and abdominal fullness, were also
surveyed with yes/no questions.

Full analysis setFAS

Withdrawn or lost to
follow-up N=9

N=38
BCAA:
Snack:

19
19

BCAA:
Snack:

5
4

Fig. 2. Details of analysis. The BCAA group consumed a late evening

snack with a BCAA-enriched nutrient mixture, and the snack group consumed a late evening snack with ordinary food. BCAA, branched-chain
amino acid; ITT, intention to treat.

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Y. Nakaya et al. / Nutrition 23 (2007) 113120

Table 1
Baseline characteristics of study patients*
BCAA group
(n 19)
Age (y)
Male/female
Severity of cirrhosis
Child-Pugh group (A/B/C)
Child-Pugh score
History of HCC
Presence of ascites
Albumin (g/dL)
Hemoglobin (g/dL)
Total bilirubin (mg/dL)
Platelet count (104/L)
Cholinesterase (IU/L)
Aspartate aminotransferase (IU/L)
Alanine aminotransferase (IU/L)
Height (m)
Body weight (kg)
Body mass index (kg/m2)

67 9
13/6
6/11/2
7 (610)
8
3
3.0 0.4
11.5 1.5
1.2 0.8
8.4 3.8
204 247
68 24
56 29
1.60 0.09
58.6 9.0
22.9 3.1

Baseline characteristics
Snack group
(n 19)
67 8
7/12
10/9/0
7 (59)
6
4
3.0 0.3
11.8 1.3
1.4 0.7
8.1 4.6
238 351
72 41
57 35
1.56 0.09
56.6 7.7
23.3 2.6

BCAA, late evening snack with branched-chain amino acids; HCC,

hepatocellular carcinoma; Snack, late evening snack with ordinary food
* Data are presented as number of patients, median (range), or mean
SD. There was no significant difference between groups.

the snack group were lost to follow-up. One patient in the

BCAA group died from a cause unrelated to liver disease
(cerebral bleeding). Two patients in the BCAA group and
one in the snack group were withdrawn from the study due
to aggravation of liver failure (severe ascites and hepatic
encephalopathy). One patient in the BCAA group and three
in the snack group failed to make a routine visit. One patient
in the BCAA group withdrew consent because of the bad
taste of the mixture. Thus, 19 patients in the BCAA group
and 19 in the snack group were subjected to full analysis
(Fig. 2).
As to the possible adverse effects of the LES, one patient
in the snack group complained of nausea and one in the
BCAA group developed a high fever. However, they recovered spontaneously without any treatment and were able to
complete the study. The 19 patients in the BCAA group
tolerated the taste of the mixture well.

Baseline demographic and clinical characteristics are

listed in Table 1. There was no significant difference between the two groups in the distribution of randomization
parameters of age, Child-Pugh score, and serum albumin.
Although the snack group seemed to have more female
patients, the difference did not reach statistical significance.
Dietary intake
Total energy intake and that from the LESs were not
significantly different between the two groups throughout
the study period (Table 2). Protein intake was significantly
greater and fat intake was less at the end of the study than
at baseline in the BCAA group but not in the snack group.
Nutritional parameters
Anthropometry. Body weight was slightly but significantly increased in the BCAA group (58.6 9.0 to 59.4
9.6 kg, P 0.008), but not in the snack group. No
significant improvement was shown in other anthropometric parameters in either group (data not shown). The
change in nitrogen balance significantly correlated with
that of the midarm muscle circumference (r 0.545, P
0.01), but not with the change in triceps skinfold thickness (r 0.031, P NS).
Blood biochemistry. The LES with the BCAA mixture had
significantly increased the BTR, as expected, by the end of
the study, but the ordinary food did not (Table 3). Serum
albumin, total protein, and red blood cell count significantly
increased in the BCAA group but not in the snack group.
The serum blood urea nitrogen level significantly rose in
the BCAA group between baseline and the end of the study
(Table 3), probably due to the increased nitrogen intake
(Table 2). Fasting plasma glucose levels were not significantly different between the groups at baseline, and LESs
did not affect them significantly in either group (Table 3).

Table 2
Total and LES energy intakes*
BCAA group

Snack group

Statistical analysis

Baseline

3 mo

Baseline

3 mo

Total energy (kcal/d)

Protein (g/d)
Carbohydrate (g/d)
Fat (g/d)

1829 274
67.2 14.5
274.9 45.5
48.1 14.5
1 mo

1848 181
75.8 8.4
286.2 39.2
41.6 9.9
3 mo

1714 330
66.5 15.8
268.7 63.6
40.0 10.0
1 mo

1714 358
68.1 17.4
266.5 66.7
39.6 9.6
3 mo

NS

NS

LES energy (kcal/d)

212.7 7.8

204.0 32.0

198.2 65.0

207.1 73.8

NS

BCAA, late evening snack with branched-chain amino acids; LES, late evening snack; Snack, late evening snack with ordinary food
* Data are presented as mean SD.

P 0.05, baseline versus 3 mo in BCAA group.

Y. Nakaya et al. / Nutrition 23 (2007) 113120

117

Table 3
Changes in laboratory parameters*
BCAA group

BTR
Albumin (g/dL)
Total protein (g/dL)
RBC count (104/uL)
AST (IU/L)
Total bilirubin (mg/dL)
BUN (mg/dL)
FPG (mg/dL)
IRI (U/mL)

Snack group

Statistical analysis

Baseline

3 mo

Baseline

3 mo

2.95 0.92
3.0 0.4
6.9 0.6
355 48
68 24
1.2 0.8
14.4 4.0
107 23
16.2 6.8

3.61 1.07
3.2 0.4
7.3 0.7
374 40
71 27
1.4 1.0
16.8 4.7
118 39
32.9 34.5

2.99 1.17
3.0 0.3
6.9 0.8
353 46
72 41
1.4 0.7
14.3 4.6
99 26
21.3 19.5

2.89 1.13
3.0 0.4
7.0 0.9
355 44
87 48
1.5 0.7
14.2 4.7
95 10
20.9 14.4

NS

NS
NS

AST, aspartate aminotransferase; BCAA, late evening snack with branched-chain amino acids; BTR, molar ratio of branched-chain amino acid to tyrosine;
BUN, serum urea nitrogen; FPG, fasting plasma glucose; IRI, immunoreactive insulin; RBC, red blood cell; Snack, late evening snack with ordinary food
* Data are presented as mean SD.

P 0.05, difference between groups for change over 3 mo.

P 0.05, baseline versus 3 mo in BCAA group.

P 0.05, baseline versus 3 mo in snack group.

Urine analysis. The nitrogen balance had significantly increased in the BCAA group by the end of the study, but not
in the snack group (Table 4). Neither LES type showed an
effect on the urinary excretion of 3-methylhistidine normalized by creatinine (Table 4).

groups for the change of npRQ over 3 mo was significant by

repeated measures analysis of variance (P 0.05).

Health-related QOL

This study was performed to test the feasibility of the

BCAA mixture, in comparison with ordinary food, as a LES
in patients with cirrhosis. The results indicate that the LES
with the BCAA mixture, but not with ordinary food, significantly improved nutritional parameters. The BCAA mixture improved the catabolic state (low npRQ), as expected
(Table 5). Further, the BCAA mixture raised the nitrogen
balance (Table 4) and serum albumin level (Table 3) in
patients with cirrhosis when compared with an equicaloric
food. However, in each group the patients did not report any
improvement in their QOL.
Patients with cirrhosis develop a catabolic state more
rapidly than do normal subjects. Such a catabolic state
brings about worse survival of patients with cirrhosis
[22,23]. Chang et al. [2] reported that carbohydrate-rich
supplementation taken before bedtime can shorten nocturnal
fasting and effectively diminish fat and protein oxidation in
patients with cirrhosis. An improvement in the nitrogen

Neither the BCAA LES nor the ordinary snack improved

the SF-36 scores within 3 mo (data not shown). Concerning
other subjective symptoms for liver cirrhosis, both types of
LES improved weakness (Fig. 3). Easy fatigability was
improved significantly by the BCAA mixture but not by the
ordinary food (Fig. 3).
Energy metabolism
Table 5 lists the changes in resting energy expenditure
and npRQ at baseline and at the end of the study. Resting
energy expenditure was not different within or between
groups at baseline, and the npRQ was not different at baseline between groups. However, npRQ was significantly
higher at the end of the study with the BCAA mixture than
with the ordinary food. The difference between the two

Discussion

Table 4
Nitrogen balance and 3-methylhistidine excretion*
BCAA group

Nitrogen balance (g/24h)

3-methylhistidine/creatinine ratio
(mol/g creatine per day)

Snack group

Statistical analysis

Baseline

3 mo

Baseline

3 mo

0.02 2.83
172.4 71.4

1.54 1.92
196.9 142.2

0.04 3.86
172.6 62.1

0.00 2.86
154.6 40.6

BCAA, late evening snack with branched-chain amino acids; Snack, late evening snack with ordinary food
* Data are presented as mean SD.

P 0.05, baseline versus 3 mo in BCAA group.

NS

118

Y. Nakaya et al. / Nutrition 23 (2007) 113120

Fig. 3. Effects of a late evening snack on the incidence of subjective

weakness (left) and easy fatigability (right) in patients with cirrhosis. The
incidence of each symptom was compared between groups by chi-square
test and within each group by McNemars test. *P 0.05 versus S group;

P 0.05 versus baseline incidence in B group. B, late evening snack with

a branched-chain amino acid enriched nutrient mixture; S, late evening
snack with ordinary food.

balance, as a result of a LES, has also been reported in other

studies [5]. In addition, carbohydrate-rich LESs correct increased protein metabolism and decrease ketone body levels
in patients with liver cirrhosis [24]. Therefore, nocturnal
energy supplementation may prevent the progression of
malnutrition that costs body fat and protein. However, all
these effects were observed within a couple of weeks of
LES consumption, and long-term evaluation of LES has not
been done. The present study elucidated the effects of LESs
as described above in a 3-mo observation period.
Various nutrients have been used in LESs to improve the
catabolic state in liver cirrhosis, such as a carbohydrate-rich
snack [25] and commercially available liquid nutrients [8].
Nakaya et al. [9] reported that the improvement of the RQ
with a BCAA mixture was similar to that with ordinary food
with equal energy. An oral BCAA mixture contains not only
BCAAs but alo glucose, lipids, and other nutrients, which
by themselves are insufficient in liver cirrhosis. Therefore,
the BCAA mixture seems to be a more favorable food for
LESs, but there has been limited evidence on the benefits of
the use of a BCAA mixture as compared with ordinary food.
Our study indicated beneficial effects of BCAA on energy
and nitrogen metabolism.
There are various opinions about the mechanism of the
decreased levels of BCAA in cirrhosis. Hyperinsulinemia
increases the uptake of BCAAs by skeletal muscle [24,25]

and BCAAs are increasingly utilized as energy substrates

[26]. In addition, BCAAs are used for ammonia degradation
in skeletal muscles of cirrhotic patients. A low BCAA level
impairs synthesis of proteins such as albumin [14] and
destroys muscle proteins [27]. However, the benefits of oral
BCAA supplements in cirrhosis have been controversial
[10,11,13,17]. This might be due to differences in study
design, study duration, and outcome markers. The most
recent large-scale, multicenter, long-term trials have shown
the effects of BCAAs on nutrition, survival, and QOL of
patients with cirrhosis [11,13] by using granulated BCAAs
over the course of 1 to 2 y.
The timing of administration of BCAA seems to be
important. Fukushima et al. [16] reported that, when cirrhotic patients were given BCAA granules after each meal
(12 g/d), their Fischers ratio remained low. However, when
they were given 8 g of BCAAs at bedtime and 4 g after
breakfast, an increased Fischers ratio, a significant recovery of the nitrogen balance and a significant improvement in
the serum albumin levels were observed [16]. Nocturnal
BCAA administration maintains Fischers ratio high during
the night-time and may then stimulate hepatic albumin synthesis [16]. When administered during the daytime to patients with cirrhosis, most BCAAs are oxidized for energy
generation but not directed to protein synthesis [28]. In the
present study, the patients in the BCAA group received
supplemental 6.075 g of BCAAs (isoleucine 2.04 g, leucine
2.25 g, and valine 1.785 g/210 kcal) before bedtime. However, this small addition of BCAAs might have influenced
not only serum BTR but also albumin (Table 3) and other
nutritional parameters over 3 mo, thus supporting the importance of timing of BCAA supplementation.
Total energy intake and that by LES were not different
between groups at the beginning of our study (Table 2).
However, the BCAA group showed a greater consumption
of food at the end of the study than did the snack group,
although the difference was not significant (Table 2). Dietary instructions were given regularly and similarly to both
groups by dietitians. These results suggest that BCAA supplementation improves anorexia, although we did not ask
directly about anorexia. Similar effects were also reported in
another liver cirrhosis survey [29] and in subjects with
cancer-related anorexia [30]. The group receiving BCAAs,

Table 5
REE and npRQ*
BCAA group

REE
npRQ

Snack group

Statistical analysis

Baseline

3 mo

Baseline

3 mo

1192 154
0.82 0.04

1232 181
0.85 0.05

1187 179
0.84 0.11

1220 220
0.81 0.07

N.S.

BCAA, late evening snack with branched-chain amino acids; npRQ, non-protein respiratory quotient; REE, resting energy expenditure; Snack, late
evening snack with ordinary food
* Data are presented as mean SD.

P 0.05, difference between groups for change over 3 mo.

P 0.05, baseline versus 3 mo in BCAA group.

Y. Nakaya et al. / Nutrition 23 (2007) 113120

however, may have actively eaten more because they were

receiving a specific nutritional treatment. Therefore, we
cannot exclude the possibility that improved nutrition and
serum albumin may stem also from a larger energy and
protein intake, which might be an indirect effect of BCAAs.
We found no significant improvement in the SF-36
scores. The lack of such an effect might be due to the 3-mo
duration of the study, because a significant improvement in
QOL required 12 y in granulated-BCAA studies [11,13].
Moreover, the studys sample was too small to show significant differences. In this study we measured RQ in the
hospital, which made it difficult to recruit patients. In addition, the SF-36 is a scale that evaluates health-related
QOL comprehensively, but does not specifically reflect
symptoms of a certain condition. Therefore, improved
weakness in both LES groups and easy fatigability in the
BCAA-LES group might show significant usefulness of
LESs and BCAAs regarding QOL.
There are some limitations to this study: 1) we could not
avoid observer bias in treatment of BCAAs because neither
the patients nor investigators were blinded to the treatment
allocation; 2) although we found significant improvement in
serum albumin, its change was small, and a longer study
period is required to confirm this change; 3) the sample was
not large enough to show significant differences in some
indices; and 4) the sex distribution between the two groups
was unbalanced, with more men in the BCAA group, although this was not statistically significant. The sex of the
patient may play a role in the effects on nitrogen balance.
Alberino et al. [31] found that women with cirrhosis are
better able to retain body muscle stores than are men, but
men are better able to retain fat stores, suggesting that men
might respond more to provision of an evening meal.
No serious adverse effects were found. Non-compliance
or withdrawals of consent in previous BCAA studies were
mainly due to the bad taste of the supplements [11,32].
Some patients complained of poor palatability of the formula in the present study, and one withdrew. Recently, a
new, more palatable BCAA formula has been developed
[33]. Thus, the problem concerning palatability of the
BCAA mixture can be overcome at least to some extent.

Conclusions
A BCAA mixture as a LES is a favorable nutritional
intervention for liver cirrhosis to repair hypercatabolism and
improve nutritional states, such as nitrogen balance and
serum albumin. Symptoms and QOL could have recovered,
but this effect requires confirmation by future studies.

Acknowledgment
In addition to the authors, the investigators in the Hepatic
Nutrition Therapy Study Group included: Isao Sakaida,

119

Katsuko Tasaka, Yamaguchi University School of Medicine; Takako Konno, Iwate Medical University, School of
Medicine; Hideki Fukushima, Makoto Shiraki, Gifu University School of Medicine; Shohei Matsuzaki, Honami
Fujii, Tokai University School of Medicine, Hachioji Hospital; Keiko Shiratori, Eiji Tatematsu, Tokyo Womens
Medical University; Michitaka Kojiro, Ikuko Ookubo,
Ehime University School of Medicine; Shushi Kondo, Tamaki Katakura, Nippon Medical School; Yasushi Imamura,
Sachiko Aburada, Kagoshima Kouseiren Hospital; Fuminori Katsukawa, Kazuko Suzuki, School of Medicine, Keio
University; Motoh Iwasa, Kazuko Iwata, Mie University
Graduate School of Medicine; Yoshinari Atarashi, Keiko
Yago, Toyama Medical and Pharmaceutical University;
Shuhei Nishiguchi, Masayoshi Fujiwara, Osaka City University Graduate School of Medicine; Hirohito Honda, Yasuko Takahashi, School of Medicine, University of Tokushima; Mikio Zeniya, Asako Fukushi, Jikei University
School of Medicine; Shin-ichi Takahashi, Kokoro Kameyama, Kyorin University School of Medicine; and Chikako
Matsuoka, Nihon University School of Medicine.

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