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Contents lists available at ScienceDirect

Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Liver, Pancreas and Biliary Tract

Sarcopenia is a risk factor for elevated aminotransferase in men

independently of body mass index, dietary habits, and physical
activity
Ki Deok Yoo, Dae Won Jun , Kang Nyeong Lee, Hang Lak Lee, Oh Young Lee,
Byung Chul Yoon, Ho Soon Choi
Department of Internal Medicine, Hanyang University, College of Medicine, Seoul, Republic of Korea

a r t i c l e

i n f o

Article history:
Received 19 August 2014
Accepted 24 December 2014
Available online xxx
Keywords:
Alanine aminotransferase
Aspartate aminotransferase
Muscle mass
Sarcopenia
Skeletal muscle index

a b s t r a c t
Background: Aminotransferase activity is a surrogate marker of liver injury showing strong correlations
with obesity and metabolic syndrome. However, elevated aminotransferase activity is not uncommon in
non-obese and non-alcoholic patients in clinical practice.
Aim: To examine the relationship between sarcopenia and aminotransferase activity in a large populationbased cohort.
Methods: Data from the Korean National Health and Nutrition Examinations were used. A total of 13,431
subjects were included. A whole-body dual X-ray absorptiometry scan was performed on each patient to
measure total and regional muscle mass. Appendicular skeletal muscle mass indices were also obtained.
Results: The prevalence of sarcopenia was signicantly higher in the group with elevated aminotransferase levels than in the normal liver enzyme group (males: 26.5% vs. 16.9%; females: 38.3% vs. 22.1%,
p < 0.05). The skeletal muscle index was negatively correlated with most cardiometabolic risk factors,
including fasting glucose and cholesterol levels. The frequency of elevated aminotransferase increased
in male patients with sarcopenia after adjusting for potential confounding factors including age, body
mass index, fasting glucose level, dietary, and exercise habits. However, the correlation was no longer
observed in women after adjusting for body mass index.
Conclusion: Sarcopenia is a risk factor for elevated aminotransferase in men, independently of body mass
index, dietary habits, and physical activity.
2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) are two well-known serologic markers of liver injury. Viral
hepatitis, heavy alcohol use, hepatotoxic drug use, and obesity
are common risk factors for abnormal aminotransferase levels [1]. However, it is not uncommon for patients who show
elevated liver enzymes to lack the traditional risk factors for
metabolic disease, including obesity, herbal medication use, viral
hepatitis, or signicant alcohol consumption. Non-obese patients
who present metabolic diseases, including diabetes, hypertension,
and metabolic syndrome, are also common. Despite using strict,

Corresponding author at: Department of Internal Medicine, Hanyang University,

College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-792, Republic of
Korea. Tel.: +82 2 2290 8338; fax: +82 2 972 0068.
E-mail address: noshin@hanyang.ac.kr (D.W. Jun).

ethnicity-specic criteria, many Asian-Pacic subjects having

diabetes or hypertension are also non-obese [1,2]. Genetic background, fat distribution, unhealthy dietary habits, and lifestyles
have all been suggested as risk factors for the development of
metabolic disease in non-obese subjects [35].
Recently, several studies have addressed metabolic diseases
in non-obese patients [2,3,6]. Some researchers have reported
the impact of muscle mass on metabolic disease incidence [69].
Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength [10]. Several
research groups have found that sarcopenia is associated with
insulin resistance, type 2 diabetes, dyslipidemia, and hypertension
[8,9,11]. Sarcopenia often occurs in elderly people with normal
body mass index (BMI) [12]. However, the relationship between
sarcopenia and liver enzymes or fatty liver disease has been rarely
studied. Hong et al. showed that the skeletal muscle index (SMI) is
negatively associated with intrahepatic fat accumulation [13]. This
provided a novel insight into the mechanism linking sarcopenia

http://dx.doi.org/10.1016/j.dld.2014.12.014
1590-8658/ 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Yoo KD, et al. Sarcopenia is a risk factor for elevated aminotransferase in men independently of body
mass index, dietary habits, and physical activity. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2014.12.014

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and non-alcoholic fatty liver disease (NAFLD) [13]. However, it

is still unclear whether an elevated aminotransferase activity is
associated with sarcopenia in non-obese subjects or in the general
population with few or no risk factors for liver disease.
The effects of muscle mass on aminotransferase activity may
provide clinicians a better understanding of the elevated liver
enzymes in non-obese patients who show no risk factors upon
evaluation in outpatient clinics, and could also suggest therapeutic
approaches for lean NAFLD patients. The purpose of this study was
to identify a correlation between sarcopenia and aminotransferase
activity, independently of BMI, body fat percentage, dietary habits,
and amount of exercise.
2. Methods
2.1. Subjects
This study used source data from the Fourth and Fifth Korea
National Health and Nutrition Examination Surveys (KNHANES V1) (20092010, Korea Centers for Disease Control and Prevention);
the KNHANES includes every household and individual in its latest
Population and Housing Census. With regard to region and housing
type, the nation was divided into 29 strata, and 200 administrative districts were extracted by applying a proportional allocation
method to match the sample component ratios for each stratum
with the population stratication variable. Enumeration districts
were extracted to reect the house characteristics in the selected
region. Groups of 2030 houses, which made up the third sampling unit, were extracted from the enumeration districts selected
as samples in systematic sampling.
The KNHANES survey was subdivided into a health interview
survey, a nutrition survey, and a health examination. The health
interview survey was carried out face-to-face by a trained interviewer in order to identify individuals diagnosed with diabetes,
hypertension, hepatitis C, liver cirrhosis, liver cancer, or various
other diseases, as well as to identify the subjects taking medicines
and, in this latter case, the type of medicines being taken. Alcohol intake was calculated by multiplying the frequency of alcohol
use by the amount of alcohol consumption. The nutrition survey
measured nutrient intake levels using the one-day 24-hour recall
method, as determined in the one-on-one conversations with a
trained interviewer.
2.2. Selection of the subject group
A total of 15,119 subjects older than 19 years of age who
underwent a blood test, dietary survey, and dual-energy X-ray
absorptiometry (DXA) were initially selected. Of these, we excluded
472 individuals who tested positive for hepatitis B antigen, 1197
males and females who drank more than 210 and 140 g of alcohol
a week, respectively, and 19 subjects with a history of hepatitis C,
liver cirrhosis, or liver cancer. Patients who did not receive a blood
test or for whom there was insufcient data on nutrient intake
were also excluded. Finally, 14,628 individuals were included in
the study (Supplementary Figure S1).
2.3. Terminology
Appendicular skeletal muscle mass (ASM) was measured by
whole-body DXA using a fan beam densitometer (Hologic Inc., MA,
USA) to measure total and regional lean mass (kg), total bone mineral contents (kg), BMD (kg/m2 ), total body fat mass (kg), and total
body fat percentage. Two X-ray beams with different energy levels
targeted the subjects bones. The BMD could then be calculated by
subtracting the soft tissue absorption. The ASM was calculated as
follows: starting from the total lean mass, the total body fat mass

and bone mineral contents were subtracted, supposing that the tissue without bone and fat is skeletal muscle. The SMI was calculated
by dividing the ASM by weight according to the method used in
previous studies [SMI (%) = total skeletal muscle mass (kg)/weight
(kg) 100] [9,10,13]. Sarcopenia was dened if the result was as at
least one standard deviation (SD) below the muscle mass of young
subjects (1939 years) [9,10,13]. Abnormal ALT was dened as ALT
higher than 30 U/L for males, and higher than 19 U/L for females
[14].
2.4. Blood chemistry
Blood tests, which were performed on all subjects after a 12hour fast, were conducted for hepatitis B antigen, AST, ALT, total
cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides. Blood samples were centrifuged, then
immediately refrigerated and sent in iceboxes to a single central
lab on the same day of blood collection. Routine biochemical tests
for total cholesterol, triglycerides, glucose, HDL cholesterol, LDL
cholesterol, ALT, and AST were performed with an ADIVIA 1650
analyser (Siemens, Deereld, IL, USA). HBsAg was measured with an
electrochemiluminescence immunoassay method using an E-170
automated analyser (Roche, Penzberg, Germany).
2.5. Statistical analysis
The Students t-test was used to compare the patients clinical characteristics, and partial Pearsons correlations were used
to examine the relationships between skeletal muscle mass and
other factors associated with metabolic syndrome. Skeletal muscle
mass was divided into four levels for the analysis. To determine if sarcopenia was a risk factor independent of BMI, dietary
habits, and exercise, a logistic regression analysis was performed.
A p < 0.05 was considered statistically signicant. SPSS 17.0 (SPSS
Inc., Chicago, IL) for Windows was used for all statistical analyses.
3. Results
3.1. Liver enzymes and metabolic parameters in sarcopenic
subjects
The frequency of elevated aminotransferase activity was higher
both in males and females with sarcopenia than in the control
group (males: 26.5% vs. 16.3%, p < 0.001; females: 38.3% vs. 16.3%,
p < 0.001). Although male and female subjects with sarcopenia
showed lower total calorie intake, they showed higher fasting
blood glucose, insulin, triglyceride, cholesterol, and aminotransferase activity levels (Table 1). Weekly exercise hours and bone
mineral density were lower in the sarcopenic group than normal
controls. In the sarcopenic group we found more subjects that were
obese, older, more sedentary, and had lower calorie intake compared to the control group, and this was true for both genders.
When skeletal muscle mass was classied into quartiles, the
frequencies of abnormal ALT, fasting blood glucose, and triglyceride levels were negatively correlated with muscle mass. Namely,
as the amount of skeletal muscle mass decreased, the frequencies of abnormal LFT, fasting blood glucose, and triglyceride levels
increased (Fig. 1).
3.2. Correlations between skeletal muscle mass and liver enzyme
levels in both genders after adjusting for body mass index and age
When we examined the correlations between skeletal muscle
mass, liver enzymes, and metabolic parameters using Pearsons correlation coefcients, ASM was found to be negatively correlated
with ALT levels for both genders (r = 0.222 for males and r = 3.17

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Table 1
Comparison of clinical and metabolic parameters according to skeletal muscle index.
Males

Females

Normal SMI
N = 4064
Age (years)
BMI (kg/m2 )
Glucose (mg/dl)
Insulin (U/ml)
Total cholesterol (mg/dl)
HDL cholesterol (mg/dl)
Triglycerides (mg/dl)
LDL cholesterol (mg/dl)
AST (U/L)
ALT (U/L)
Vitamin D (ng/ml)
Total BMD
Exercise (min/week)
Protein intake (g)
Calorie intake (Cal)

43.3
22.9
96.4
9.87
180.5
45.7
136
110.2
22.9
23.4
19.3
1.01
7.5
83.3
2223

19.0
3.1
20.3
5.1
35
9.9
110
31
11.6
16.6
6.6
0.1
11.7
43.1
826

Sarcopenia
N = 960
48.1
25.4
105.0
13.4
187.1
42.4
164
115.8
25.2
29.1
18.5
0.98
6.1
77.1
2019

22.4
3.3
30.4
8.3
37
9.0
116
32
12.1
23.8
6.1
0.1
9.1
44.6
780

<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.005
<0.001
<0.001
<0.001
<0.001
0.030
<0.001
<0.001

Normal SMI
N = 5315
43.2
22.5
93.5
10.0
181.6
50.4
102.9
107.0
19.3
15.8
17.1
0.88
7.9
59.8
1705

18.2
3.0
19.0
4.7
34
10.5
68
29
7.1
10.6
6.3
0.1
12.4
29.6
661

Sarcopenia
N = 1901
53.6
25.6
99.6
11.7
198.0
47.7
134.2
122.1
21.4
19.6
16.3
0.87
8.0
54.4
1564

16.5
3.5
23.3
8.4
36
9.9
80
31
8.1
12.5
6.1
0.1
12.3
27.5
601

<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.005
0.790
<0.001
<0.001

SMI, skeletal muscle index; BMI, body mass index; HDL, high density lipoprotein; LDL low density lipoprotein, AST, aspartate transaminase; ALT, alanine transaminase, BMD,
bone mineral density.
*
p < 0.05 by Students t-test.

for females, p < 0.001). As skeletal muscle mass increased, glucose,

insulin, triglyceride, and cholesterol levels decreased for both males
and females. However, after controlling for age and BMI, skeletal muscle mass was no longer correlated with ALT or metabolic
parameters in females; nevertheless, in males, most metabolic
parameters, including ALT activity, still showed a negative correlation with muscle mass (Table 2).

We then divided the subjects into quartiles based on

SMI and BMI. The frequency of abnormal ALT levels clearly
increased in men when SMI was decreased and BMI was
increased. The decreased amount of muscle mass was a risk
factor for elevated aminotransferase levels in men, independently of BMI. However, this correlation was not observed in
women (Fig. 2).

Fig. 1. Prevalence of abnormal liver enzyme level, serum fating glucose level and triglyceride level according to skeletal muscle index. Skeletal muscle index was divided
into quartiles. As skeletal muscle index decreased, prevalence of abnormal liver enzyme level and abnormal metabolic parameters were increased. LFT, liver function test;
abnormal LFT1, ALT>40 U/L in men and women; abnormal LFT2, ALT >30 U/L in men, and >19 U/L in women; ALT, alanine aminotransferase.

Please cite this article in press as: Yoo KD, et al. Sarcopenia is a risk factor for elevated aminotransferase in men independently of body
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Table 2
Partial correlations of skeletal muscle index and clinical parameters.
Partial correlation (I) Age
Male

ALT (U/L)
Glucose (mg/dl)
Insulin (U/ml)
HOMA
Cholesterol (mg/dl)
HDL-Cholesterol (mg/dl)
Triglycerides (mg/dl)
LDL-cholesterol (mg/dl)
Calorie intake (Cal)
Vitamin D (ng/ml)
Lumbar BMD
Total body BMD
Exercise (hour/week)

Partial correlation (II) Age, BMI

Female

0.284
0.179
0.324
0.337
0.137
0.255
0.194
0.152
0.097
0.102
0.072
0.072
0.114

<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.011
0.007
0.060
0.061
0.003

Male

0.099
0.063
0.255
0.233
0.164
0.172
0.203
0.188
0.110
0.050
0.059
0.018
0.027

0.008
0.092
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.003
0.185
0.116
0.636
0.473

Female

0.113
0.127
0.140
0.161
0.035
0.126
0.109
0.034
0.152
0.111
0.151
0.304
0.094

0.003
0.001
<0.001
<0.001
0.365
0.001
0.004
0.378
<0.001
0.004
<0.001
<0.001
0.014

0.031
0.021
0.067
0.039
0.124
0.037
0.133
0.100
0.096
0.062
0.041
0.205
0.015

0.401
0.570
0.073
0.292
0.001
0.321
<0.001
0.008
0.010
0.097
0.278
<0.001
0.681

BMI, body mass index; HOMA-IR, homeostasis model of assessment-insulin resistance; HDL, high density lipoprotein; LDL low density lipoprotein, AST, aspartate transaminase; ALT, alanine transaminase, BMD, bone mineral density.
*
p < 0.05 obtained by partial Pearsons correlation.

Fig. 2. Frequency of abnormal aminotransferase level in men (A and C) and women (B and D) within quartiles of skeletal muscle index and body mass index. The frequency
of abnormal alanine aminotransferase level was increased when skeletal muscle index was decreased and body mass index was increased in men. However, this correlation
was not observed in women. ALT, alanine aminotransferase; BMI, body mass index; prevalence of abnormal ALT, ALT >40 U/L in men and women; prevalence of abnormal
ALT, ALT >30 U/L in men, and >19 U/L in women.

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3.3. Multivariate analysis of the effect of skeletal muscle mass on

the frequencies of elevated liver enzymes and fatty liver disease
Multiple logistic regression analysis with abnormal liver
enzyme as the dependent variable was performed and showed
an increased frequency of elevated aminotransferase levels in sarcopenic male patients after controlling for age, BMI, smoking status,
glucose level, insulin level, as well as dietary and exercise habits
(Supplementary Table S1). However, this correlation was no longer
observed in women after controlling for BMI.

4. Discussion
BMI, dietary habits, and physical exercise have been correlated
with aminotransferase activity. Our results show that the skeletal
muscle mass was correlated with aminotransferase activity after
controlling for BMI, dietary habits, and amount of exercise only
in males. Sarcopenic subjects were older, more sedentary, and
showed greater central obesity compared with controls, despite
presenting a lower total calorie intake.
Several studies have investigated the impact of sarcopenia on
metabolic syndrome [9,11,15]. The pathophysiology of NAFLD is
similar to that of metabolic syndrome, but few studies have investigated the effect of muscle mass on the incidence of NAFLD. Recently,
Hong and Moon used abdominal computed tomography (CT) scan,
DXA, and body impedance assay (BIA) to show that skeletal muscle mass was associated with the incidence of NAFLD [13,16]. Hong
et al. showed that SMI is negatively associated with intrahepatic
fat accumulation [13]. This provided a novel insight into the mechanism linking sarcopenia and NAFLD. Although more than 450
subjects were enrolled in their study, a selection bias may limit the
generalization of their results. We used data from the KNHANES,
which includes the most relevant and representative data.
An emerging issue regarding sarcopenia is whether muscle mass
is a risk factor for NAFLD and metabolic disease independently of
body shape or BMI. Therefore, when analysing the impact of sarcopenia on fatty liver and metabolic diseases, it is important to
adjust for fat mass and BMI. In Moons study, the denition of
sarcopenia followed the Janssens method [17]. However, the simple ratio between body weight and muscle mass may be greatly
affected by the amount of total fat. Likewise, Hong et al did not
adjust for BMI [13]. In the present study, we adjusted for body fat
mass, as well as total body fat, when analysing the effects of muscle mass on metabolic disease and fatty liver. We found that the
impact of sarcopenia on liver enzymes was gender-dependent: the
effects of muscle mass on liver enzymes were no longer signicant
for women after controlling for BMI. The absolute volume of skeletal muscle differs between genders, and sex hormones are known
to play an essential role in muscle growth and development [18].
To better understand the reasons for these differences between
men and women, we compared 4020 premenopausal women
and 2893 postmenopausal women. However, multivariate analysis showed that the effects of ASM on liver enzymes and fatty liver
disease did not differ between pre- or post-menopausal women
(Supplementary Table S2). Thus, it seems likely that the genderdependent effect of sarcopenia on both ALT and incidence of fatty
liver is not due to female sex hormones, but rather results from the
fact that women have less muscles than men, resulting in a greater
impact of body fat mass rather than muscle mass.
Other major risk factors of abnormal liver enzyme levels are
dietary habits, physical activity, and age. This study clearly showed
a relationship between liver enzymes and peripheral ASM, independently of BMI, dietary habits, and physical activity. Despite the
much lower total calorie intake of the sarcopenic group compared
with the control group, BMI and body weight of the sarcopenic

subjects were higher than those of the controls (Table 1). Another
interesting nding is that low protein intake, and not high fat
intake, was correlated with sarcopenia and elevated liver enzymes.
Sarcopenic subjects were also characterised by lower serum vitamin D levels and less physical activity. The clinical characteristics of
sarcopenic obesity were sedentary lifestyle and low protein intake
rather than high calorie intake or high fat diet. This suggests that
increased physical activity and protein intake should be recommended as lifestyle modications rather than calorie or fat intake
restriction. Another strong point of this study is that it included
a large cohort of 14,628 subjects representative of the Korean
population and based on the KNHANES data. This allowed us to
evaluate the impact of sarcopenia on abnormal aminotransferase
level incidence after correcting for BMI, dietary habits, and amount
of exercise.
In our study, we used the SMI, which is dened as total skeletal
muscle mass (kg)/weight (kg) 100, as an indicator of sarcopenia.
Other indicators of sarcopenia were also present. The ASM divided
by the squared height (ASM/height2 ) is also often used as an indicator of sarcopenia. Sarcopenia can also be dened as two SDs
below the mean ASM/height2 . As the height increases, ASM can
be increased. The indicator ASM/height2 could adjust the inuence
of height; however, this indicator could be inuenced by obesity. In
overweight subjects the prevalence of sarcopenia was 8.9%, while
being 0% in obese people. Therefore, this indicator seems not to
be appropriate for obese people in the diagnosis of sarcopenia [19],
and thus was not used in our study. Another indicator is the genderspecic lowest 20th percentile of ASM.
In this study, we dened sarcopenia as a value at least 1 SD below
the muscle mass of young subjects. The European Working Group
on Sarcopenia in Older People (EWGSOP) developed a practical definition for sarcopenia [10]: in their report, they used SDs to dene
sarcopenia, measured in terms of SMI. Class-I sarcopenia was considered present in subjects whose SMI was between one and two
SDs below the mean values for young adults [9,10,13,17,20].
In clinical practice, there are several aetiologies that could cause
abnormal LFT. In almost all cases of patients with abnormal LFT, a
careful history and physical examination with a simple blood test
and radiologic test can reveal the aetiology of abnormal LFT. However, in some cases, the aetiology is unclear after both serologic and
radiologic evaluation. Our current study suggests that sarcopenia
can explain several abnormal LFT of unclear aetiology. Also, sarcopenia could be an aetiologic clue for non-obese patients with
unexplained elevation of serum aminotransferase, a condition that
is not rare in the Asian population.
This study had some limitations. First, the KNHANES surveyed
dietary habits using the one-day 24-hour recall method. Thus,
this method does not allow an easy quantication of the longterm dietary habits, since it relies on the subjects memory. All
data were collected by well-trained investigators; despite the
investigators were not physicians, they received regular and specic education for this large-scale survey providing them a good
ability to perform a survey. In our study, 19 among the 15,000
patients (0.13%) had liver cirrhosis. Previous studies conducted
in France and UK reported a prevalence of liver cirrhosis ranging between 0.076% and 0.3% [21,22]. Thus, we believe that our
reports are comparable with the results of the previous studies.
Second, although we excluded HBsAg-positive subjects, signicant
alcohol users, and subjects with a history of liver disease, we did
not perform further analysis to help revealing the aetiology of the
chronic liver disease (e.g. HCV-RNA, PCR test, and autoantibodies).
Despite the large part of the data used in our study was obtained
from KNHANES, platelet counts, abdominal ultrasonography, liver
biopsy, and liver stiffness test were not performed within this same
survey. Third, studies analysing large amounts of data generally
tend to have low p-values. Although several metabolic parameters

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showed correlations with sarcopenia in our study, the presence of

a statistical signicance is not always indicative of clinical signicance.
In conclusion, sarcopenia is a risk factor for elevated aminotransferase levels in men, independently of BMI, dietary habits, and
physical activity. Sarcopenic subjects with abnormal aminotransferase levels showed different clinical characteristics compared
with non-sarcopenic subjects. We believe that not all patients with
abnormal liver function test require further examination of muscle mass. However, subjects who have abnormal aminotransferase
activity with uncertain aetiology, and especially those with a normal BMI, need to undergo an estimation of muscle mass.
Conict of interest
None declared.
Funding
This study was supported by a grant from the Korea Healthcare
Technology R&D Project, Ministry of Health & Welfare, Republic
of Korea (A121185). The funding source had no role in the study
design or conduct; in data collection, analysis, or interpretation; or
in manuscript preparation, review, or approval.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.dld.2014.12.014.
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Please cite this article in press as: Yoo KD, et al. Sarcopenia is a risk factor for elevated aminotransferase in men independently of body
mass index, dietary habits, and physical activity. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2014.12.014