Original Paper

Ann Nutr Metab 2013;62:158163

DOI: 10.1159/000346202

Received: July 16, 2012

Accepted after revision: November 21, 2012
Published online: February 13, 2013

Relationship between Serum Uric Acid Level

and Nonalcoholic Fatty Liver Disease in PreandPostmenopausal Women
Seong-SuMoon
Department of Internal Medicine, Dongguk University College of Medicine and Medical Institute of
DonggukUniversity, Gyeongju, South Korea

Key Words
Nonalcoholic fatty liver disease Uric acid Metabolic
syndrome Postmenopause

women, but in postmenopausal women. Postmenopausal

women with increased levels of serum uric acid were more
likely to have NAFLD than those without increased levels.
Copyright 2013 S. Karger AG, Basel

Abstract
Background/Aims: Nonalcoholic fatty liver disease (NAFLD)
is an emerging health problem worldwide. No study specifically examining the relationship between serum uric acid
level (UA) and NAFLD in females according to menopausal
status has been reported. We conducted this study in order
to assess the association of UA with NAFLD in pre- and postmenopausal women. Methods: A total of 487 female subjects (221 premenopausal and 266 postmenopausal) with a
normal UA, who underwent a health check-up, were enrolled
in this study. NAFLD was defined as a hepatic steatosis observed on liver ultrasonography in the absence of a secondary cause. Results: Among postmenopausal women, a higher UA was observed in subjects with NAFLD than in those
without (3.95 0.10 vs. 4.38 0.80 mg/dl, p = 0.001). Results
of multiple correlation analysis revealed a significant association between UA and NAFLD in postmenopausal subjects
after adjusting for confounding variables including age,
body mass index and the presence of metabolic syndrome (
coefficient 1.149, 95% confidence interval 1.0551.910, p =
0.021). However, no association in premenopausal women
was observed. Conclusions: UA within the normal range
showed an association with NAFLD, not in premenopausal

2013 S. Karger AG, Basel

02506807/13/06220158$38.00/0
E-Mail karger@karger.com
www.karger.com/anm

Introduction

Nonalcoholic fatty liver disease (NAFLD), defined as

a hepatic steatosis without a secondary cause, has been
recognized as an emerging health problem worldwide [1
3]. NAFLD, the most common form of chronic liver disease, affects 2030% of the Western population [4, 5].
NAFLD is recognized as the hepatic manifestation of
metabolic syndrome, characterized as a constellation of
cardiovascular disease risks, including central obesity,
dyslipidemia, hypertension and impaired glucose tolerance [6, 7]. In the context of pathophysiology, NAFLD is
not a simple disease confined to the liver; it is also associated with systemic metabolic disturbance. Therefore, for
prevention of NAFLD, identification of risk factors is
critical.
In humans, serum uric acid is the metabolic endproduct of purine degradation. Production of uric acid
occurs in the liver and small intestine, which contain
xanthine oxidase. Hyperinsulinemia leads to an increase
in uric acid synthesis and a reduction of renal excretion
of uric acid and sodium. Previous studies have reported
Seong-Su Moon, MD, PhD, Assistant Professor
Department of Internal Medicine
Dongguk University College of Medicine, Dongdae-ro 87
Gyeongju, Gyeongbuk Province, 780-350 (South Korea)
E-Mail drmoonss@hanmail.net

an association of serum uric acid with insulin resistance,

hypertension, metabolic syndrome and cardiovascular
disease [811].
Although several studies have suggested an association
of hyperuricemia with NAFLD [1214], the underlying
mechanism and causal relationship between them have
not yet been clarified.The pro- or antioxidant property of
uric acid was suspected as the potential reason [15, 16].
However, whether these results can also be extrapolated
to the case in women is not certain. The prevalence of
NAFLD before menopause is lower in women compared
to that in men. However, after menopause, the prevalence
of NAFLD among women is higher than that among men
[17]. NAFLD was found to be less prevalent in postmenopausal women taking hormone replacement therapy than
in those taking no hormone therapy [18]. A decline in
estrogen level may lead to hepatic steatosis through a reduction of fatty acid oxidation and an increase in lipogenesis within the liver [19].
To the best of our knowledge, no study specifically examining the relationship between uric acid level and
NAFLD in females according to menopausal status has
been reported. Therefore, in this study, we examined the
association between serum uric acid and NAFLD in preand postmenopausal Korean women.

Subjects and Methods

A total of 487 subjects (221 premenopausal and 266 postmenopausal) who voluntarily visited Kyungpook National University
Hospital in order to undergo a health check-up from October to
December, 2009, were enrolled in this retrospective cross-sectional
study. All subjects were of Korean ethnicity and were residents of
Korea. Subjects with a significant history of alcohol abuse (>20 g of
ethanol per week), previous use of steatogenic medications, any evidence of chronic viral liver disease, cholestasis or other metabolic
liver diseases were excluded. Subjects were asked about medications, sociodemographic characteristics and other important medical history. Postmenopausal women were defined as women who
had not menstruated for at least 1 year. Physical examination included measurement of height, body weight and blood pressure,
using standard methods. Prior to measurement of blood pressure,
subjects were instructed to rest for a period of 10 min, and, while
seated, measurements of systolic and diastolic blood pressure (SBP
and DBP) in the upper arm were performed twice.
For all subjects, blood tests were performed in the morning,
after an overnight fast. Fasting plasma glucose (FPG) levels, total
serum cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), -glutamyltranspeptidase (-GTP) levels and uric acid
were determined using a Hitachi Modular Analytics D2400 apparatus (Roche, Tokyo, Japan). The uricase enzyme method was used

NAFLD and Uric Acid

for measurement of uric acid (normal reference range 2.55.7 mg/

dl). Subjects with serum uric acid levels (UAs) that were out of the
normal reference range were excluded.
Subjects having any three of the following five characteristics
were classified as having metabolic syndrome: obesity [body mass
index (BMI) 25], hypertriglyceridemia (triglycerides 150 mg/dl
or triglyceride-lowering medication), HDL-C <50 mg/dl, hypertension [130 mm Hg SBP, 85 mm Hg DBP or use of antihypertensive medication) and hyperglycemia (FPG 100 mg/dl or use
of antihyperglycemic medication, or previously diagnosed type 2
diabetes). For abdominal obesity, because waist circumference
measurements were not available for all subjects, we substituted
overall adiposity (i.e. BMI 25, which has been proposed as a cutoff for diagnosis of obesity in Asians) [20]. This study was approved by the institutional review board of the Kyungpook National University Hospital.
Ultrasonography for Liver and Criteria of NAFLD
NAFLD was defined as the presence of definite hepatic steatosis on ultrasonography, such as a bright hepatic echo pattern, increased attenuation of the echo beam and loss of intrahepatic architectural detail [21, 22] without a secondary cause, including significant alcohol abuse (>20 g of ethanol per week), previous use of
steatogenic medications, any evidence of chronic viral liver disease
and other metabolic liver diseases. Ultrasonography of the liver
was performed using a 4-MHz probe (Acuson Sequoia, Calif.,
USA) and graded by an experienced radiologist.
Statistical Analyses
The Statistical Package for Social Science 15.0 software (SPSS,
Chicago, Ill., USA) was used in performance of all analyses. Nominal variables are presented as the number of cases with the percentage and continuous variables as the mean standard of error.
The Student t test was used to evaluate the significance of the mean
differences between the 2 groups and 2 analysis was used for comparison of categorical variables of the groups. Univariate logistic
regression analysis was performed using NAFLD as a dependent
variable and with other variables as covariates for the identification
of factors associated with NAFLD. Multivariate regression analyses were performed for investigation of the association between
serum uric acid and NAFLD, with serum uric acid serving as the
independent variable and NAFLD serving as the dependent variable. These analyses were adjusted for age, BMI, smoking status
and alcohol consumption status, which are known risk factors for
NAFLD (model 1). Body weight, height, SBP, history of type 2
diabetes and dyslipidemia, which were statistically significant variables (p < 0.05) according to the results of univariate regression
analysis, were adjusted in model 2. In model 3, age, smoking status,
alcohol consumption status and the presence of metabolic syndrome were adjusted. p < 0.05 was considered significant.

Results

Characteristics of All Subjects According to

Menopausal State
General characteristics of pre- and postmenopausal
subjects are shown in table1. Compared with premenoAnn Nutr Metab 2013;62:158163
DOI: 10.1159/000346202

159

Table 1. General characteristics of subjects according to their

menopausal status

Age, years
39.60.5
Body weight, kg
56.80.5
Height, cm
159.70.6
BMI
22.70.6
SBP, mm Hg
117.21.4
DBP, mm Hg
71.40.7
FPG, mg/dl
95.21.5
Total cholesterol, mg/dl 183.82.0
Triglyceride, mg/dl
91.93.6
HDL-C, mg/dl
61.20.9
LDL-C, mg/dl
107.91.8
AST, U/l
18.10.3
ALT, U/l
16.40.6
-GTP, U/l
17.40.9
Total bilirubin, mg/dl
0.680.02
Creatinine, mg/dl
0.650.01
Uric acid, mg/dl
3.820.05
Metabolic syndrome
12 (5.4)
NAFLD
55 (24.9)
Smoking status
Exsmoker
2 (0.9)
Nonsmoker
205 (92.8)
Smoker
14 (6.3)
Alcohol consumption status
Exdrinker
1 (0.5)
Nondrinker
138 (63.3)
Drinker
79 (36.2)
Type 2 diabetes
11 (5.0)
Hypertension
3 (1.4)
Dyslipidemia
5 (2.3)

Postmenopausal p
(n = 266)

59.00.4
58.70.4
156.20.3
24.00.2
132.91.5
75.20.6
100.61.6
205.12.5
126.74.1
56.50.8
129.94.1
22.50.4
20.70.7
23.41.5
0.620.01
0.710.04
4.220.06
81 (30.5)
164 (61.7)

<0.001*
0.004*
<0.001*
0.013*
<0.001*
<0.001*
0.012*
<0.001*
<0.001*
<0.001*
<0.001*
<0.001*
<0.001*
0.001*
0.018*
0.160
<0.001*
<0.001*
<0.001*
0.043*

6 (2.3)
252 (95.5)
6 (2.3)
<0.001*
3 (1.1)
214 (82.0)
44 (16.9)
60 (22.6)
16 (6.0)
33 (12.4)

<0.001*
0.008*
<0.001*

Data indicate mean standard of error, number and percentage for metabolic syndrome, smoking, alcohol drinking, diabetes,
hypertension, dylipidemia and NAFLD. n = Number of patients.
*p < 0.05.

pausal women, age, body weight, BMI, SBP, DBP, FPG,

total cholesterol, triglyceride, LDL-C, AST, ALT, -GTP,
total bilirubin, serum uric acid, prevalence of metabolic
syndrome, NAFLD, smoking and alcohol consumption
as well as a history of type 2 diabetes, hypertension and
dyslipidemia were higher for postmenopausal women (p
< 0.05). Height and HDL-C were significantly higher in
premenopausal women than in menopausal women (p <
0.05). In postmenopausal women, UA was higher in subjects with NAFLD than in those without NAFLD (4.38
0.80 vs. 3.95 0.10 mg/dl, p = 0.001); however, such a difference was not observed in premenopausal women
(fig.1). In premenopausal women, UA did not differ be160

Ann Nutr Metab 2013;62:158163

DOI: 10.1159/000346202

Uric acid(mg/dl)

Premenopausal
(n = 221)

p = 0.353

*p = 0.001

6
4
2

Normal

NAFLD

Premenopausal

Normal

NAFLD

Postmenopausal

Fig. 1. Comparison of UA between subjects with NAFLD and those

without, according to menopausal status. There was a higher UA

in subjects with NAFLD than in those without NAFLD in postmenopausal women (4.38 0.80 vs. 3.95 0.10 mg/dl, p = 0.001)
*p < 0.05.

tween subjects with metabolic syndrome and those without (3.81 0.23 vs. 3.81 0.05 mg/dl, p = 0.976). However, in postmenopausal women, higher UAs were observed in participants with metabolic syndrome than in
those without metabolic syndrome after adjustment for
age (4.53 0.11 vs. 4.08 0.07 mg/dl, p = 0.001) (data not
shown).
Univariate Regression Analysis: Effect of Variables on
NAFLD
As shown in table2, univariate regression analysis was
performed in order to examine the association between
NAFLD and the other variables listed in table1. In the
postmenopausal group, serum uric acid [ coefficient
1.547, 95% confidence interval (CI) 1.1882.014, p =
0.001] was identified as a variable that showed a significant correlation with NAFLD. Body weight, height, BMI,
SBP, DBP, FPG, triglyceride, AST, ALT, prevalence of
metabolic syndrome and a history of type 2 diabetes and
dyslipidemia also showed an association with NAFLD.
However, in premenopausal women, no association of serum uric acid with NAFLD was observed.
Multiple Regression Analysis: Adjusted Effect of
Serum Uric Acid on NAFLD
In postmenopausal women, multiple regression analysis was performed using NAFLD as a dependent variable
and serum uric acid as an independent variable (table3).
After adjustment for variables that were known risk factors for NAFLD including age, BMI, smoking status and
alcohol consumption status (model 1), serum uric acid
Moon

Table 2. Univariate regression analysis: the effect of the study variables on NAFLD

Premenopausal

Age, years
Body weight, kg
Height, cm
BMI
SBP, mm Hg
DBP, mm Hg
FPG, mg/dl
Total cholesterol, mg/dl
Triglyceride, mg/dl
HDL-C, mg/dl
LDL-C, mg/dl
AST, U/l
ALT, U/l
-GTP, U/l
Total bilirubin, mg/dl
Creatinine, mg/dl
Uric acid, mg/dl
Metabolic syndrome
Smoking status
Alcohol consumption status
Type 2 diabetes
Hypertension
Dyslipidemia

Postmenopausal

(95% CI)

(95% CI)

1.124 (1.0631.188)
1.159 (1.0991.222)
1.003 (0.9671.040)
1.030 (0.9761.088)
1.024 (1.0101.038)
1.027 (0.9981.056)
1.057 (1.0251.089)
1.021 (1.0101.032)
1.022 (1.0141.031)
0.939 (0.9140.966)
1.031 (1.0171.043)
1.076 (1.0141.142)
1.114 (1.0641.166)
1.057 (1.0231.093)
0.989 (0.3942.841)
0.267 (0.0107.063)
1.218 (0.8031.848)
41.250 (5.185328.193)
0.995 (0.3133.163)
1.836 (0.9463.561)
1.139 (0.2914.455)
6.226 (0.55370.044)
4.731 (0.76929.086)

<0.001*
<0.001*
0.880
0.280
0.001*
0.067
<0.001*
<0.001*
<0.001*
<0.001*
<0.001*
0.015*
<0.001*
0.001*
0.981
0.429
0.353
<0.001*
0.994
0.072
0.851
0.139
0.094

1.032 (0.9931.074)
1.098 (1.0541.143)
0.939 (0.8930.988)
1.484 (1.3071.684)
1.022 (1.0111.034)
1.078 (1.0451.112)
1.041 (1.0191.064)
1.005 (0.9991.012)
1.013 (1.0081.019)
0.971 (0.9540.989)
1.006 (0.9991.014)
1.067 (1.0201.115)
1.087 (1.0451.131)
1.006 (0.9941.019)
1.295 (0.4603.642)
0.987 (0.6981.396)
1.547 (1.1882.014)
8.087 (3.81817.129)
1.000 (0.3123.203)
1.048 (0.5571.973)
1.971 (1.0443.722)
1.934 (0.6076.168)
2.557 (1.0666.131)

0.110
<0.001*
0.015*
<0.001*
<0.001*
<0.001*
<0.001*
0.116
<0.001*
0.001*
0.094
0.004*
<0.001*
0.312
0.625
0.941
0.001*
<0.001*
0.999
0.885
0.036*
0.265
0.035*

*p < 0.05.

Table 3. Summary of regression analysis of the correlation between

serum uric acid and NAFLD, adjusted for multiple variables in
postmenopausal women

Model 1
Model 2
Model 3

R2

coefficient

95% CI

p value

0.261
0.315
0.219

1.430
1.394
1.419

1.0621.925
1.0321.884
1.0551.910

0.018*
0.031*
0.021*

Model 1 = Adjusted for age, BMI, smoking status, alcohol consumption status and uric acid. Model 2 = Adjusted for body weight,
height, SBP, dyslipidemia, type 2 diabetes and uric acid. Model 3
= Adjusted for age, the presence of metabolic syndrome, smoking
status, alcohol consumption status and uric acid. *p < 0.05.

was found to have an association with NAFLD ( coefficient 1.430, 95% CI 1.0621.925, p = 0.018). This association remained statistically significant after adjustment for
other variables that were found by univariate regression
to show a significant correlation with NAFLD, including
NAFLD and Uric Acid

body weight, height, SBP, a history of type 2 diabetes and

dyslipidemia ( coefficient 1.394, 95% CI 1.3021.884, p
= 0.031) (model 2). Note that, because they showed close
correlation clinically with the other variables, BMI, FPG
and triglyceride were excluded from model 2 in order to
avoid collinearity. In addition, the significance was maintained after adjustment for metabolic syndrome ( coefficient 1.419, 95% CI 1.0551.910, p = 0.021) (model 3).

Discussion

The findings of this study revealed a significant association of UA, within the normal range, with NAFLD in postmenopausal women, and this significance was maintained
after adjustment for the concerned variables including age,
BMI, alcohol consumption, smoking status and components of metabolic syndrome, even after taking the presence of metabolic syndrome into account. No such relationship was observed in premenopausal women. The effect of estrogen may explain the discrepancy between
Ann Nutr Metab 2013;62:158163
DOI: 10.1159/000346202

161

pre- and postmenopausal women. Incidence of NAFLD

increases after menopause [17] and the prevalence of
NAFLD is lower in postmenopausal women with hormone
replacement therapy than in those without [18]. A decline
in estrogen, which has been suggested as having powerful
antioxidant properties, may result in reduced fatty acid oxidation and increased steatosis within the liver [19].
NAFLD, which is characterized as hepatic steatosis in
the absence of a secondary cause, and is the most common form of chronic liver disease [23, 24], is regarded as
the hepatic manifestation of metabolic syndrome. An association of pathogenesis of NAFLD with insulin resistance and inflammation has been reported [25]. Increased
visceral adiposity, such as that seen in patients with central obesity, results in the production of inflammatory
adipokines and hormones, including tumor necrosis
factor- (TNF-), interleukin (IL)-6, IL-1 and resistin
and increased lipolysis and influx of free fatty acid to the
liver, which eventually leads to the synthesis of hepatic
triglyceride. Infiltration of visceral fat by macrophages
follows the release of adipokines and contributes to the
chronic low-grade inflammatory status [26, 27].
Hyperuricemia is also related to insulin resistance and
inflammation. Insulin resistance leads to hyperinsulinemia, resulting in an increase in uric acid synthesis and
a reduction of renal excretion of uric acid [28, 29]. Under
the conditions of metabolic syndrome, serum uric acid
can act as a prooxidant and is proinflammatory. Uric acid
stimulates the synthesis of monocyte chemoattractant
protein-1 (MCP-1) and induces an increase in levels of
IL-6 and TNF- [30], which are regarded as possible
mechanisms of uric acid contributing to the pathogenesis
of NAFLD.
Several studies have demonstrated the relationship between serum uric acid and NAFLD [12, 14, 31]. According to findings reported from a 5-year retrospective cohort study, when compared to subjects with quartile 1 of
serum uric acid, subjects with quartiles 2, 3 and 4 showed
a higher incidence of NAFLD [odds ratio (OR) 1.53,1.69
and 1.84 respectively, p < 0.05]. In that study, multivariate
analysis was performed after adjustment for gender; however, the specific relationship in the female group was not
investigated [14]. In a 3-year prospective observational
study, elevation of UAs was found to be an independent
predictor of increased risk for incident NAFLD. In contrast to participants without NAFLD, subjects with incident NAFLD were relatively older and were predominantly male [12]. Among subjects having levels of serum
uric acid within the normal range, increased concentrations of serum uric acid showed an independent associa162

Ann Nutr Metab 2013;62:158163

DOI: 10.1159/000346202

tion with the presence of NAFLD in each gender group.

However, the study did not examine the relationship according to the menopausal status of females [31].
To the best of our knowledge, this is the first study to
examine the relationship between serum uric acid and
NAFLD in females according to their menopausal status.
An association of UA with NAFLD was observed in postmenopausal women, but not in premenopausal women.
Mean serum uric acid concentration of postmenopausal
women was higher than that of premenopausal women.
In postmenopausal women, not in premenopausal women, higher UAs were observed in participants with metabolic syndrome than in those without metabolic syndrome. Although UA might, at least in part, contribute to
the higher incidence of NAFLD or be a mediator between
metabolic syndrome and NAFLD in postmenopausal
women, we cannot affirm that the discrepancy was due to
the effect of uric acid. However, this result suggests that
risk factors for NAFLD in females may be considered differently according to their menopausal status.
This study has several limitations. First, due to the
cross-sectional design, we were not able to confirm that
uric acid causes development of NAFLD. The relationship
between uric acid and NAFLD according to menopausal
status should be verified in longitudinal studies in the future. In addition, although we classified women according
to the definition of postmenopausal women being those
who had not menstruated for at least 1 year, we could not
provide any mechanistic explanation regarding the discrepancy between pre- and postmenopausal women because we did not measure the blood estrogen level in each
participant. Second, although the results of this study indicate that uric acid is an independent risk factor for
NAFLD in addition to metabolic syndrome, we did not
measure any inflammatory markers, such as MCP-1, IL-6,
TNF- or oxidative stress. Therefore, we were not able to
confirm any mechanism for development of NAFLD in
subjects with increased UAs. Third, in defining subjects
with metabolic syndrome, because waist circumference
measurements were not available for all of the subjects, we
substituted overall adiposity for abdominal obesity. This
might also have been a limitation. Fourth, because all participants of this study, who were of Korean ethnicity and
were residents of Korea, were enrolled in a single hospital,
our results cannot be extrapolated beyond this group. Finally, we did not perform a biopsy to define NAFLD and
we categorized the study subjects into 2 groups according
to the presence of hepatic steatosis on ultrasonography.
Although ultrasonography is widely used in epidemiological surveys of NAFLD and a diagnosis of NAFLD on the
Moon

basis on ultrasonographic findings is clinically acceptable

[5, 1214, 22, 32], ultrasonography may not detect the entire spectrum of NAFLD, from mild steatosis to nonalcoholic steatohepatitis and cirrhosis; therefore, the true
prevalence of NAFLD may have been underestimated.
Despite these limitations, the results of this study demonstrate an association of serum uric acid with NAFLD
in postmenopausal females. Postmenopausal women
with increased UAs were more likely to have NAFLD
compared to those without increased UAs. Further research is needed in order to confirm this finding and to
understand its implications.

Acknowledgment
This work was funded by the Daegu and Kyungpook local
committee of the Korean Diabetes Association and the author appreciates the assistance of Professor Jong-Sup Kim of Kyungpook
National University Hospital in the collection of data.

Disclosure Statement
The author declares that he has no conflict of interest.

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