Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease.

Abstract

Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk of atherosclerosis and alanine aminotransferase (ALT) is associated with insulin resistance independently of metabolic factors. The aim of the present study was to investigate whether NAFLD patients with ALT elevation had a higher risk of carotid atherosclerosis.
A total of 190 individuals were enrolled from the health management center. Among them, 20 subjects were excluded due to the presence of hepatitis B surface antigen (HbsAg), anti-hepatitis C virus (HCV) and cardiovascular disease. NAFLD was diagnosed by ultrasound examination. Carotid ultrasonography was used to measure maximal intima-media thickness (IMT) of the common carotid artery (CCA) and IMT (mean) > 1.0 mm was defined as the presence of carotid atherosclerosis.
NAFLD patients with ALT elevation had increased risk of carotid atherosclerosis than those with normal ALT by Fisher's exact test (P < 0.05). Multivariate analyses showed that serum ALT levels were positively associated with carotid atherosclerosis after adjustment for age, sex, number of metabolic syndrome components or status of metabolic syndrome (OR, 1.44; 95% CI 1.09-1.89; OR, 1.45; 95% CI 1.11-1.91). In addition, the higher the serum ALT levels with every 10 IU/L increment, the greater the risk of carotid atherosclerosis.
Serum ALT levels are positively associated with the risk of carotid atherosclerosis in patients with NAFLD, suggesting that serum ALT levels could serve as a surrogate marker of cardiovascular risk in this special clinical setting.

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HEPATOLOGY
Elevation of serum aminotransferase activity increases risk
of carotid atherosclerosis in patients with non-alcoholic
fatty liver disease
Chia-Chi Wang,* Shinn-Kuang Lin,†Yuan-Fu Tseng,†Ching-Sheng Hsu,* Tai-Chung Tseng,*
Hans Hsienhong Lin,* Li-Yu Wang‡and Jia-Horng Kao§
jgh_58721411..1416
Departments of *Hepatology,†Neurology, Buddhist Tzu Chi General Hospital, Taipei Branch,‡Graduate Institute of Aboriginal Health, Tzu Chi
University, Hualien and§Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine
and Hospital, Taiwan
Abstract
Background and Aim: Patients with non-alcoholic fatty liver disease (NAFLD) have an
increased risk of atherosclerosis and alanine aminotransferase (ALT) is associated with
insulin resistance independently of metabolic factors. The aim of the present study was to
investigate whether NAFLD patients with ALT elevation had a higher risk of carotid
atherosclerosis.
Methods: A total of 190 individuals were enrolled from the health management center.
Among them, 20 subjects were excluded due to the presence of hepatitis B surface antigen
(HbsAg), anti-hepatitis C virus (HCV) and cardiovascular disease. NAFLD was diagnosed
by ultrasound examination. Carotid ultrasonography was used to measure maximal intima-
media thickness (IMT) of the common carotid artery (CCA) and IMT (mean) > 1.0 mm
was defined as the presence of carotid atherosclerosis.
Results: NAFLD patients withALT elevation had increased risk of carotid atherosclerosis
than those with normalALTby Fisher’s exact test (P < 0.05). Multivariate analyses showed
that serum ALT levels were positively associated with carotid atherosclerosis after adjust-
ment for age, sex, number of metabolic syndrome components or status of metabolic
syndrome (OR, 1.44; 95% CI 1.09–1.89; OR, 1.45; 95% CI 1.11–1.91). In addition, the
higher the serum ALT levels with every 10 IU/L increment, the greater the risk of carotid
atherosclerosis.
Conclusions: Serum ALT levels are positively associated with the risk of carotid athero-
sclerosis in patients with NAFLD, suggesting that serum ALT levels could serve as a
surrogate marker of cardiovascular risk in this special clinical setting.
Key words
alanine aminotransferase, atherosclerosis,
carotid ultrasonography, intima-media
thickness, non-alcoholic fatty liver disease.
Accepted for publication 20 March 2009.
Correspondence
Professor Jia-Horng Kao, Hepatitis Research
Center, National Taiwan University Hospital,
1 Chang-Te St, Taipei 10002, Taiwan. Email:
kaojh@ntu.edu.tw
Introduction
Non-alcoholic fatty liver disease (NAFLD) is the most common
liver disease in the USA, and its prevalence can be expected to
increase in parallel with national epidemics of obesity and type 2
diabetes mellitus.1The spectrum of NAFLD in histology ranges
from simple steatosis to non-alcoholic steatohepatitis (NASH),
which is hepatic steatosis with a necroinflammatory component or
fibrosis.2Up to 20% of patients with NASH may progress to
cirrhosis, and NASH is now recognized as the leading cause of
cryptogenic cirrhosis worldwide.3In addition, patients with
NAFLD have high prevalence rates of metabolic syndrome,4,5
which is considered a predictor of future cardiovascular disease.6–9
Therefore,NAFLDisemergingasanimportantglobalhealthissue.
NAFLD has been reported to increase overall mortality and risk
of cardiovascular events.10–13Previous studies showed that patients
with NAFLD had an increased risk of carotid atherosclerosis
compared to matched controls in the general population and diet-
controlled type 2 diabetic patients.14,15In addition, recent studies
indicated that serum alanine aminotransferase (ALT) level was
positively associated with severity of insulin resistance and
atherosclerosis.16,17However, whetherALT elevation could further
increase the risk of carotid atherosclerosis in patients with NAFLD
remains unknown and deserves further study.
Methods
Patients
A total of 190 subjects were enrolled from the health examination
center of Buddhist Tzu Chi General Hospital between November
doi:10.1111/j.1440-1746.2009.05872.x
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2006 and July 2007. To investigate the association of fatty liver
with carotid atherosclerosis, we randomly collected subjects with
ultrasonic findings of fatty liver and those without in a 2 : 1 ratio.
Demographic, anthropometric, clinical and laboratory data were
obtained from each subject. Among them, 14 subjects positive for
hepatitis B surface antigen, five positive for antibody against hepa-
titis C virus and one with a past history of cardiovascular disease
were excluded. Therefore, 170 subjects were included for final
analysis. NAFLD was diagnosed on the basis of ultrasonic find-
ings with exclusion of known hepatic disorders, drug or alcohol
use (> 140 g/week).18Elevation of serumALT was defined asALT
level > 40 IU/L. Central obesity was defined as waist circumfer-
ence > 90 cm in men and > 80 cm in women according to the
guidelines of metabolic syndrome modified by the Department of
Health, Taiwan.
Ultrasound examination of the liver
The GE LOGIQ 5 PRO ultrasound system (GE Medical Systems,
Seoul, Korea) with a 4 MHz electronic probe was used for ultra-
sound examinations. Fatty liver was confirmed if at least two of the
following three findings were present: increased liver echogenicity
with evident contrast between liver and kidney; the blurring of
vessels; and deep attenuation of the ultrasound signal.19
Ultrasound measurements of the carotid artery
The GE LOGIQ 5 PRO ultrasound system (GE Medical Systems)
with a 7 MHz electronic probe was used for carotid ultrasonogra-
phy. All subjects received the carotid ultrasonography by one
ultrasonographer who was blinded to the clinical data of partici-
pants. Three measurements of IMT were obtained from the right
and left common carotid artery (CCA) proximal to the bifurcation
with a 1-cm interval. Right or left IMT were the largest values
among the three measurements of each side. IMT (mean) was the
mean of right and left IMT.
Ethical considerations
The present study was carried out in accordance with the prin-
ciples of the 1975 Declaration of Helsinki and approved by the
Ethical Committee of Buddhist Tzu-Chi General Hospital. Serum
samples were obtained from each participant after receiving
written informed consent.
Statistical analysis
Chi-squared and Student’s t-tests were used to compare whether
there was significant difference in the frequency distributions and
the means between participants with normal or elevatedALTlevels
or between those with or without ultrasonographic fatty liver.
Univariate and multivariate logistic regression analyses were used
to measure the strength of association between each component of
metabolic syndrome and NAFLD, signified as OR. Statistical
analyses were carried out using SAS 9.1 (SAS Institute Inc., Cary,
NC, USA). A P value of < 0.05 was considered statistically
significant.
Results
Study population and demographic data
A total of 170 subjects including 81 men and 89 women with a
mean age of 52.8 years were enrolled for final analysis.There were
101 (59.4%) subjects with NAFLD and 30 (17.7%) with elevated
serum ALT levels. Twenty-nine subjects (28.7%) with NAFLD
had abnormal serum ALT levels. Subjects with ALT elevation had
higher body height (BH), bodyweight (BW), body mass index
(BMI), waist circumference (WC), systolic blood pressure (SBP),
diastolic blood pressure (DBP), triglyceride, aspartate amino-
transferase (AST), uric acid levels, and higher frequencies of male
gender, metabolic syndrome components, and metabolic syn-
drome, as well as the presence of atherosclerosis, but lower high-
density lipoprotein–cholesterol (HDL-C) compared to those with
normal ALT. These two groups were comparable in age, fasting
plasma glucose (FPG), glycated hemoglobin (HbA1C), choles-
terol, low-density lipoprotein–cholesterol (LDL-C) levels, alkaline
phosphatase (ALP) and in the percentages of those with plaques
and who smoked cigarettes (Tables 1,2). By using univariate
analysis, IMT (mean) for subjects withALT elevation tended to be
higher than for those with normal ALT (1.00 ? 0.23 mm vs
0.91 ? 0.26 mm, P = 0.076).
Comparison of variables among NAFLD
patients and controls
Subjects with NAFLD were divided into two groups by serum
ALT levels: NAFLD with ALT elevation in 29 and without ALT
elevation in 72. The control group included 68 subjects with
normal ALT levels and without fatty liver. One subject without
fatty liver but with ALT elevation was excluded for further analy-
ses. Significant differences were found among these three groups
in terms of gender, types of obesity, blood pressure, HDL-C,
fasting glucose, triglyceride, number of metabolic syndrome com-
ponents and status of metabolic syndrome (Table 3).
Association of ALT elevation with carotid
atherosclerosis
NAFLD patients with ALT elevation had a higher frequency of
carotid atherosclerosis than those with normal ALT by Fisher’s
exact test (P value = 0.018). Further multivariate analyses after
adjustment for age, sex, number of metabolic syndrome compo-
nents or status of metabolic syndrome showed that serum ALT
levels were positively associated with carotid atherosclerosis (OR,
1.44; 95% CI 1.09–1.89; OR, 1.45; 95% CI 1.11–1.91) (Table 4).
In addition, the higher the serum ALT levels by each 10-IU/L
increment, the greater the risk of carotid atherosclerosis.
Discussion
A previous case–control study found that patients with NAFLD
had a higher prevalence of plaque and increased IMT than con-
trols, and the presence of NAFLD was an independent predictor of
increased IMT.14Another study proved the association of liver
histology with carotid atherosclerosis in NAFLD patients, regard-
less of classical risk factors such as insulin resistance and the
ALT and carotid atherosclerosis in NAFLD
C-C Wang et al.
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presence of metabolic syndrome.20In addition, the degree of ath-
erosclerotic change was proportional to the severity of histological
findings according to the categories of steatosis, necroinflamma-
tion or fibrosis.Taken together, NAFLD may be associated with an
increased risk of carotid atherosclerosis, independent of metabolic
syndrome. However, whether serum ALT levels are associated
with increased risk of cardiovascular disease in patients of
NAFLD remains unknown. SerumALT level, a serological marker
of liver inflammation or injury, could predict coronary heart
disease events in a 10-year follow-up study.21A recent study also
indicated the association of serum aminotransferase activity with
the severity of insulin resistance and atherosclerosis in patients
Table 1
Comparison of continuous variables between subjects with and without ALT elevation
ALT ? 40 IU/L (n = 140)ALT > 40 IU/L (n = 30)P value
Mean SDMean SD
Age (years)
Body height (m)
Bodyweight (kg)
BMI (kg/m2)
WC (cm)
SBP (mmHg)
DBP (mmHg)
FPG (mg/dL)
HbA1C (%)
AST (IU/L)
Cholesterol (mg/dL)
Triglyceride (mg/dL)
HDL (mg/dL)
LDL (mg/dL)
ALP (IU/mL)
Uric acid (mg/dL)
IMT (Right; mm)
IMT (Left; mm)
IMT (Mean; mm)
53.1
1.61
60.4
23.3
76.1
124.1
77.7
95.8
5.94
21.6
190.1
107.8
58.7
123.6
69.5
5.53
0.90
0.92
0.91
10.5
0.07
11.0
3.4
8.8
15.6
11.4
26.4
1.08
6.3
37.6
56.6
16.4
35.9
19.9
1.40
0.30
0.29
0.26
51.7
1.66
73.5
26.7
86.9
132.3
82.4
106.3
6.16
38.3
198.0
185.4
46.0
132.0
74.8
6.92
0.96
1.04
1.00
9.4
0.08
11.5
3.1
7.5
13.1
10.7
40.1
1.05
12.2
42.8
105.6
11.0
41.3
19.3
1.85
0.26
0.27
0.23
0.50
0.001
< 0.001
< 0.001
< 0.001
0.009
0.039
0.18
0.31
< 0.001
0.31
< 0.001
< 0.001
0.26
0.19
< 0.001
0.25
0.047
0.076
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure;
FPG, fasting plasma glucose; HbA1C, glycated hemoglobin; HDL, high-density lipoprotein; IMT, intima media thickness; LDL, low-density lipoprotein;
SBP, systolic blood pressure; WC, waist circumference.
Table 2
Comparison of variables between subjects with and without ALT elevation
ALT ? 40 (n = 140)ALT > 40 (n = 30)P value
n%n%
Male
Cigarette smoking
Central obesity
High blood pressure
Decreased HDL-C
Increased fasting glucose
Increased triglyceride
No. metabolic syndrome components
0
1
2
3
4
5
Status of metabolic syndrome
Atherosclerosis
Plaque
60
17
23
59
27
27
24
42.9
12.1
16.4
42.1
19.3
19.3
17.1
21
3
16
21
13
11
15
70.0
10.0
53.3
70.0
43.3
36.7
50.0
0.007
0.74
< 0.001
0.006
0.005
0.038
< 0.001
< 0.001
54
40
27
12
5
2
19
24
115
38.6
28.6
19.3
8.6
3.6
1.4
13.6
17.1
82.1
2
5
7
8
7
1
6.7
16.7
23.3
26.7
23.3
3.3
53.3
40.0
83.3
16
12
25
< 0.001
0.005
0.88
Atherosclerosis is defined as intima media thickness ? 1 mm.
ALT, alanine aminotransferase; HDL-C, high-density lipoprotein–cholesterol.
C-C Wang et al.
ALT and carotid atherosclerosis in NAFLD
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with rheumatoid arthritis.16In the present study, we found that
serum ALT levels were positively associated with carotid athero-
sclerosis in NAFLD patients by multivariate analyses after adjust-
ment for several demographic, anthropometric and metabolic
variables, suggesting that serumALT levels may be independently
associated with an increased risk of arteriosclerosis in NAFLD
patients. A systemic review has already confirmed the association
of NAFLD with carotid atherosclerosis.22Nevertheless, this is the
first report that serum ALT levels could serve as a useful tool for
the evaluation of cardiovascular risk in these patients. Therefore,
NAFLD patients with increased ALT activity deserve aggressive
treatment of coexisting metabolic disorders and strict lifestyle
modification to improve insulin sensitivity and reduce the risk of
cardiovascular disease.
Serum ALT levels were initially found to be associated with
insulin resistance in obese subjects and patients with HIV
lipodystrophy.23–25Two recent studies found an early association of
serum ALT levels with insulin resistance in women.26,27In addi-
tion, the Insulin Resistance Atherosclerosis Study confirmed the
association of serum ALT levels with directly measured insulin
sensitivity,28and concluded that addition of serum ALT level is an
inexpensive way to identify subjects with insulin resistance. Fur-
thermore, pioglitazone, an insulin sensitizer, could normalize
serum ALT level and improve histological findings in NASH
patients.29Taking these lines of evidence together, serum ALT
level is strongly associated with the development of insulin resis-
tance, which is an established cardiovascular risk factor. The find-
ings of the present study showed an association of serum ALT
levels with carotid atherosclerosis in patients with NAFLD.There-
fore, serum ALT could serve as a predictor for insulin resistance
and the risk of cardiovascular disease, which could be classified as
extrahepatic complications of NAFLD. As we know, NAFLD
refers to a spectrum of disorders from simple steatosis to a more
aggressive form known as non-alcoholic steatohepatitis (NASH),
by which patients are at greater risk for progression to cirrhosis,
end-stage liver disease and even hepatocellular carcinoma. In addi-
tion, patients with NAFLD appear to have higher all-cause mor-
tality in addition to liver-related causes of death. Although liver
biopsy is the gold standard to identify patients who are at greatest
risk of these hepatic complications, it is invasive and not free of
Table 3
Comparison of variables among NAFLD patients and controls
Controls (n = 68)†
NAFLDP-value of
chi-squared
test‡
ALT ? 40 (n = 72)ALT > 40 (n = 29)
n%n%n%
Male
Cigarette smoking
Central obesity
High blood pressure
Decreased HDL-C
Increased fasting glucose
Increased triglyceride
No. metabolic syndrome components
0
1
2
3
4
5
Status of metabolic syndrome§
Atherosclerosis
Plaque
28
7
2
21
10
9
4
41.2
10.3
2.9
30.9
14.7
13.2
5.9
32
10
21
38
17
18
20
44.4
13.9
29.2
52.8
23.6
25.0
27.8
20
3
16
20
13
11
14
69.0
10.3
55.2
69.0
44.8
37.9
48.3
0.035
0.78
< 0.001
0.001
0.006
0.023
< 0.001
< 0.001
37
20
8
2
1
0
54.4
29.4
11.8
2.9
1.5
0.0
4.4
17.7
82.4
17
20
19
10
4
2
16
12
59
23.6
27.8
26.4
13.9
5.6
2.8
22.2
16.7¶
81.9
2
5
6
8
7
1
6.9
17.2
20.7
27.6
24.1
3.5
55.2
41.4¶
82.8
316
12
24
< 0.001
0.015
0.99
12
56
†All 68 subjects had normal ALT levels (initial no. subjects was 69, but one subject with ALT elevation was excluded from all analyses).
‡P value of chi-squared test for the comparisons among the three groups (controls, NAFLD + normal ALT and NAFLD + elevated ALT).
§No. metabolic syndrome components ? 3.
¶Exact two-sided P-value by hypergeometric distribution was 0.018 (Fisher’s exact test).
ALT, alanine aminotransferase; HDL-C, high-density lipoprotein–cholesterol; NAFLD, non-alcoholic fatty liver disease.
Table 4
sclerosis in 101 patients with NAFLD
Multivariate analysis of factors associated with carotid athero-
Variables included in each model OR(95% CI)
Model I
Sex (male vs female)
Age (every 10-year increment)
ALT (every 10-IU/L increment)
No. metabolic syndrome components
(every one increment)
Model II
Sex (male vs female)
Age (every 10-year increment)
ALT (every 10-IU/L increment)
Status of metabolic syndrome (yes vs no)
2.67*
1.69*
1.44**
1.32
(0.87–8.23)
(0.95–2.99)
(1.09–1.89)
(0.89–1.97)
2.84*
1.77*
1.45**
2.05
(0.90–8.91)
(1.00–3.14)
(1.11–1.91)
(0.68–6.22)
*0.05 < P < 0.1; **0.01 < P < 0.05.
ALT, alanine aminotransferase; CI, confidence interval; NAFLD, non-
alcoholic fatty liver disease; OR, odds ratio.
ALT and carotid atherosclerosis in NAFLD
C-C Wang et al.
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Page 5

risk. Therefore, it is important for practicing physicians to have
clinical predictors to identify at-risk NAFLD patients. In this
study, we found that serum ALT levels could serve as a good
predictor for cardiovascular risk in these patients (Fig. 1).
We excluded subjects with existing cardiovascular disease, viral
hepatitis, drug-related or alcoholic liver diseases that may interfere
with serum ALT levels or the results of carotid duplex examina-
tion. Furthermore, metabolic syndrome is closely associated with
the risk of cardiovascular disease. Therefore, while we explored
the association between serum ALT levels and carotid atheroscle-
rosis by using multivariate analyses, the status of metabolic syn-
drome, an important confounding factor, must be adjusted. It is
known that metabolic syndrome consists of five components
including central obesity, high blood pressure, decreased HDL-C,
increased fasting glucose and increased triglyceride. The presence
of metabolic syndrome is defined as three or more of these com-
ponents. In Model I, we used ‘the number of metabolic syndrome
components’, which is a semi-quantitative method to represent its
influence on cardiovascular risk. Multivariate analyses by two
models consistently confirmed the association between serum
ALT levels (every 10-IU/L increment) and carotid atherosclerosis,
suggesting our data could reflect the genuine association of serum
ALT levels with carotid atherosclerosis in NAFLD patients.
However, our findings were limited by the cross-sectional
design, and the causal relationship between liver injury and
carotid atherosclerosis could not be demonstrated. Further large
prospective studies are awaited to confirm the complex inter-
play between serum ALT levels and the development of carotid
atherosclerosis.
In summary, serumALTlevels are positively associated with the
risk of carotid atherosclerosis in patients with NAFLD, indepen-
dent of metabolic syndrome. Serum ALT level may be a surrogate
marker of cardiovascular risk in such patients. By using serum
ALT levels and the status of fatty liver, we could identify patients
who have increased risk of cardiovascular disease. In addition,
NAFLD patients should undergo aggressive treatment of
coexisting metabolic disorders and strict lifestyle modification to
improve their insulin sensitivity and reduce the risk of cardiovas-
cular disease.
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Predictors of NAFLD
NASH
Cirrhosis
End-stage liver disease
Hepatocellular carcinoma
Extra-hepatic complications Hepatic complications
Insulin resistance
Cardiovascular disease
Liver biopsy Serum ALT levels
Figure 1
notransferase; NAFLD, non-alcoholic fatty liver disease; NASH, non-
alcoholic steatohepatitis.
Predictors of complications in NAFLD. ALT, alanine ami-
C-C Wang et al.
ALT and carotid atherosclerosis in NAFLD
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Journal of Gastroenterology and Hepatology 24 (2009) 1411–1416 © 2009 The Authors
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd