High serum uric acid increases the risk for nonalcoholic Fatty liver disease: a prospective observational study.
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD. A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively; P value for trend <0.001). Cox proportional hazards regression analyses showed that serum uric acid levels were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91-1.54), 1.32 (1.03-1.70), 1.39 (1.09-1.78) and 1.50 (1.18-1.92), respectively. Taken together, our prospective observational study showed that elevation of serum uric acid levels independently predicts increase risk for incident NAFLD.
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ABSTRACT: Serum uric acid levels are significantly associated with nonalcoholic fatty liver disease (NAFLD). Xanthine oxidoreductase (XOR) is the key enzyme that catalyzes the formation of uric acid. The aim of this study was to investigate the association between serum XOR activity and NAFLD.Clinical laboratory 01/2014; 60(8):1301-7. · 1.08 Impact Factor
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ABSTRACT: Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved.Nutrients 12/2014; 6(12):5679-5703. · 3.15 Impact Factor
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. Therefore, the detection of early-stage NAFLD is important. Many studies have described the factors that predict the presence of NAFLD and its onset, and several markers have been identified. These markers have enabled the identification of high-risk patients and have improved routine medical practice. To prevent advanced disease, clinicians need to have simple markers that predict the onset of NAFLD so that interventions can be started at much earlier stages of disease. This review summarizes the current state of knowledge regarding independent factors, as reported in large studies, that predict the presence of NAFLD and its onset, especially markers that can be used in daily medical practice, such as physical measurements and blood tests.Journal of Gastroenterology and Hepatology 12/2013; 28(S4). · 3.33 Impact Factor
High Serum Uric Acid Increases the Risk for Nonalcoholic
Fatty Liver Disease: A Prospective Observational Study
Chengfu Xu1., Chaohui Yu1., Lei Xu1,2, Min Miao2, Youming Li1*
1Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, 2Department of Gastroenterology, Ningbo
No. 1 Hospital, Ningbo, China
Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be
significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD
remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining &
Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD.
A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed
NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum
uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5,
respectively; P value for trend ,0.001). Cox proportional hazards regression analyses showed that serum uric acid levels
were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome
adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91–1.54), 1.32 (1.03–1.70),
1.39 (1.09–1.78) and 1.50 (1.18–1.92), respectively. Taken together, our prospective observational study showed that
elevation of serum uric acid levels independently predicts increase risk for incident NAFLD.
Citation: Xu C, Yu C, Xu L, Miao M, Li Y (2010) High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational
Study. PLoS ONE 5(7): e11578. doi:10.1371/journal.pone.0011578
Editor: Irene Oi Lin Ng, The University of Hong Kong, Hong Kong
Received April 1, 2010; Accepted June 22, 2010; Published July 14, 2010
Copyright: ? 2010 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by Chinese State Key Project for High-tech (No. 2006AA02A308), National Science & Technology Pillar Program
(No. 2008BAI52B03), National Natural Science Foundation of China (No. 30871154) and Science & Technology Foundation of Zhejiang Province (No. 2008C13027-
1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
. These authors contributed equally to this work.
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum
of conditions from simple steatosis to nonalcoholic steatohepatitis
(NASH) and cirrhosis. It has become one of the most prevalent
liver diseases in Western countries, affecting 20%–30% of the
general population [1,2]. NAFLD is an emerging problem in the
Asia-Pacific region and the prevalence is likely to increase in the
future [3,4]. Simple steatosis is generally a benign condition;
however, NASH can progress to cirrhosis and liver failure  and
the 5-year survival rate for individuals diagnosed with NASH is
estimated to be only 67% .
Identifying risk factors is essential for prevention of NAFLD.
The development of NAFLD is a multifaceted cascade of
physiologic and biochemical events, including genetic ,
environmental , metabolic , and stress-related factors
; the exact risk factors for NAFLD have not been fully
clarified. Recent studies showed that NAFLD is closely associated
with obesity, hypertension, dyslipidemia, and glucose intolerance,
a cluster of metabolic disorders that is now recognized as
metabolic syndrome [11,12]. For this reason, NAFLD has been
considered as the hepatic manifestation of metabolic syndrome
Uric acid is the end product of purine metabolism and the
serum uric acid (SUA) level is maintained by the balance
between uric acid production and excretion . During last
decade, an association between elevated SUA levels and
metabolic syndrome has been reported [14–16]. However, the
relationship between NAFLD and SUA has not been clarified.
Our recent cross-sectional study demonstrated that SUA levels
are significantly elevated in NAFLD patients and that the
prevalence rate of NAFLD increases as SUA levels increase
. These results suggested that elevated SUA levels may be
associated with NAFLD . However, whether this association
is causal, a bystander, or a consequence of NAFLD remains
Therefore, in this study, we performed a population-based
prospective study to investigate whether the elevation of SUA has
a casual role for NAFLD in the Chinese population.
Materials and Methods
Verbal informed consent was obtained from each subject before
participation in the study after all procedures had been explained.
Verbal consent was recorded by the physician who explained the
study procedures. Written informed consent was not required
because of the observational nature of the investigation. The study
protocol and the form of consent were approved by the Ethics
Committee of the First Affiliated Hospital, College of Medicine,
PLoS ONE | www.plosone.org1 July 2010 | Volume 5 | Issue 7 | e11578
Study design and subjects
To identify whether SUA plays a causal role in development of
NAFLD, a population-based prospective study was conducted
among the employees of Zhenhai Refining & Chemical Company
Ltd., Ningbo, China beginning in 2006. The majority of these
subjects had taken part in our 2005 cross-sectional study .
Certain subjects were excluded at study entry: (i) those
diagnosed with fatty liver based on ultrasonography (n=1795);
(ii) those with alcohol consumption greater than 140 g/week for
men and 70 g/week for women (n=596); (iii) those taking
antihypertensive or antidiabetic agents, lipid-lowering agents, or
hypouricemic agents based on self-reported medical history and
medication use (n=705); (iv) those with a positive history of known
liver disease, such as viral hepatitis B or C, or autoimmune
hepatitis, or those using hepatotoxic medications (n=958).
The NAFLD-free cohort thus comprised 7412 subjects (4842
male and 2570 female) with a mean age of 44.4 years. These
subjects were classified into various groups according to employee
number and scheduled for annual evaluation for 3 years. We
excluded 522 subjects (350 male and 172 female, mean age 45.0
years) who did not complete the follow-up examinations. A total of
6890 initially NAFLD-free subjects (4492 male and 2398 female,
mean age 44.4 years) were evaluated for the development of
Baseline examinations included a medical history and health
habit inventory taken by a physician, anthropometric measure-
ments, hepatic ultrasonic examination, and biochemical measure-
ments. The examinations were administered in the morning. The
subjects were instructed to fast for at least 12 hours prior to the
examination and to refrain from exercise during the day before
Blood pressure was measured using an automated sphygmo-
manometer with the subject in a sitting position. Systolic blood
pressure (SBP) and diastolic blood pressure (DBP) were measured
at the first and fifth Korotkoff phases, respectively. Standing height
and body weight were measured without shoes or outer clothing.
Body mass index (BMI, kg/m2), used as an index of body fat, was
calculated as weight in kilograms divided by height in meters
squared. Waist circumference was measured with the measuring
tape positioned midway between the lowest rib and the superior
border of the iliac crest as the patient exhaled normally [17,18]. A
baseline hepatic ultrasonic examination was also conducted to
exclude the subjects with fatty liver or other forms of chronic liver
Biochemical measurements were conducted as our previously
described . In brief, fasting whole blood samples were
obtained from an antecubital vein and serum samples were
separated for the analysis of biochemical values without frozen.
The biochemical values included alanine aminotransferase (ALT),
aspartate aminotransferase (AST), c-glutamyltransferase (GGT),
triglyceride, total cholesterol, high-density lipoprotein cholesterol
(HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting
plasma glucose (FPG), creatinine, blood urea nitrogen (BUN), and
uric acid. All values were measured by an Olympus AU640
autoanalyzer (Olympus, Kobe, Japan) using standard methods.
Assessment on outcomes and definitions
The diagnosis of fatty liver was based on the results of
abdominal ultrasonography using a Toshiba Nemio 20 sonogra-
phy machine with a 3.5-MHz probe (Toshiba, Tokyo, Japan).
Ultrasound studies were carried out by a trained ultrasonographist
who was unaware of the clinical and laboratory data. Hepatic
steatosis was diagnosed by characteristic echo patterns according
to conventional criteria, such as the evidence of diffuse
hyperechogenicity of the liver relative to the kidneys, ultrasound
beam attenuation, and poor visualization of intrahepatic structures
. NAFLD was diagnosed by abdominal ultrasound following
exclusion of alcohol consumption, viral, or autoimmune liver
Hyperuricemia was defined as a SUA level.420 mmol/L in
men and.360 mmol/L in women . The diagnosis of
metabolic syndrome was based on the new International Diabetes
Federation definition . For a person to be defined as having
the metabolic syndrome they must have: central obesity (defined as
waist circumference $90 cm for Chinese men and $80 cm for
Chinese women), plus any two of the following four factors: (i)
raised triglyceride level, defined as triglycerides $1.7 mmol/L or
specific treatment for this lipid abnormality; (ii) reduced HDL-C,
defined as HDL-C,1.03 mmol/L in males and ,1.29 mmol/L
in females; (iii) raised blood pressure, SBP$130 mmHg or
DBP$85 mmHg, or treatment of previously diagnosed hyperten-
sion; (iv) raised FPG, defined as FPG$5.6 mmol/L, or previously
diagnosed type 2 diabetes.
To explore the association between SUA level and risk for
incident NAFLD, subjects were stratified according to their
baseline SUA levels: quintile 1, #295 mmol/L; quintile 2, 296–
332 mmol/L; quintile 3, 333–367 mmol/L; quintile 4, 368–
409 mmol/L; and quintile 5, $410 mmol/L for males; and quintile
1, #205 mmol/L; quintile 2, 206–232 mmol/L; quintile 3, 233–
262 mmol/L; quintile 4, 263–298 mmol/L; and quintile 5,
$299 mmol/L for females. The baseline characteristics of the
subjects in each quintile were compared. The cumulative
incidence of NAFLD was calculated by dividing the number of
cases by the numbers of subjects followed up for each SUA
We applied Cox proportional hazards regression analyses,
which are commonly used for risk assessments in prospective
studies [24,25], to estimate hazard ratios for incident NAFLD for
each baseline SUA quintile. The subjects within the first quintile
were used as reference group. The data were first adjusted for age
and gender and then for multiple covariates that might confound
the relationship between the SUA and NAFLD. For linear trends
of risk, the number of quintiles was used as a continuous variable
and tested on each model.
Continuous variables are presented as mean and standard
deviation (SD) or medians and interquartile range (IQR), as
appropriate. Categorical variables were compared using the x2
test; continuous variables were compared with Mann-Whitney U
test, student’s t-test, Kruskal-Wallis H test or one-way analysis of
variance, depending on the normality of the data. All statistical
analyses were performed using the SPSS software package version
11.5 for Windows (SPSS Inc., Chicago, IL). P,0.05 (2-tailed) was
considered to be statistically significant.
At baseline, the mean age (6SD, range) of the 7412 participants
was 44.4 years (613.0, 20–88). Of the 7412 eligible participants,
522 (7.04%) participants did not complete the follow-up
examinations. Baseline characteristics, including age, gender,
BMI, waist circumference, and blood pressure, and serum liver
enzyme, lipid, glucose, creatinine, BUN, and SUA levels were not
Uric Acid and NAFLD
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different between the participants lost to follow-up and those with
successful follow-up (Table S1).
A total of 6890 subjects (4492 male and 2398 female) were
evaluated yearly over the course of the study. The baseline
characteristics of subjects in each SUA quintile are shown in
Table 1. Age, BMI, waist circumference, blood pressure, serum
liver enzymes (including ALT, AST, and GGT), serum lipids
(including TC, TG and LDL-C), FPG, creatinine and BUN all
tended to increase at higher SUA levels (all P,0.001). In contrast,
HDL-C decreased with as SUA increased (P,0.001). The gender
proportion was not significantly different among the subjects with
all five SUA quintiles (P=0.81).
Association of SUA with incident NAFLD
To explore the association of SUA with incident NAFLD,
subjects were stratified into quartiles according to their baseline
SUA levels. The cumulative incidence of NAFLD was calculated
by dividing the number of cases by the numbers of subjects in each
Overall, 813 subjects (605 male and 208 female) developed
NAFLD during the 3 year study, corresponding to 13.5% and
8.7% cumulative incidence of NAFLD in men and women,
respectively. We observed that baseline SUA quintiles predicted
the incidence of NAFLD in a graded and dose-responsive manner
(Figure 1). The overall 3-year cumulative incidence of NAFLD was
11.80%, ranging from 7.2% in quintile 1 to 9.5%, 11.5%, 13.8%,
and 17.2% in quintile 2, quintile 3, quintile 4, and quintile 5,
respectively (P for trend,0.001; Figure 1). This tendency also held
true for 1-year and 2-year cumulative incidences. The overall 1-
year cumulative incidence was 5.3%, ranging from 2.5% in
quintile 1 to 9.9% in quintile 5 (P for trend,0.001; Figure 1). The
overall 2-year cumulative incidence was 9.7%, ranging from 6.0%
in quintile 1 to 14.7% in quintile 5 (P for trend,0.001; Figure 1).
These observations indicated that the subjects with higher baseline
SUA levels were more likely to develop NAFLD than those with
In contrast to participants without incident NAFLD, those with
incident NAFLD were relatively older and predominantly male
(Table 2). As expected, baseline BMI, waist circumference, blood
pressure, serum liver enzymes, lipids, glucose, renal function and
SUA level were significantly different between subjects with and
without NAFLD (Table 2).
High SUA increases the risk of NAFLD
To estimate hazard ratios for incident NAFLD, Cox propor-
tional hazards regression analyses (both univariate and multivar-
iable models) were applied. As shown in Table 3, certain variables
were correlated with incident NAFLD in the univariate models:
higher SUA level, older age, male gender, higher BMI, higher
waist circumference, higher blood pressure, higher serum liver
enzymes (including ALT, AST and GGT), higher serum lipids
(including TC, TG, and LDL-C), higher FPG, higher creatinine,
and lower HDL-C (Table 3). In multivariable models, SUA level
was an independent factor related with incident NAFLD
(P=0.004; Table 3). BMI, waist circumference, diastolic blood
pressure, ALT, AST, TG, HDL-C, and creatinine were also
independent factors related with incident NAFLD; whereas age,
systolic blood pressure, GGT, TC, LDL-C and FPG were
excluded during the multivariable analysis (Table 3).
We also analyzed the hazard ratio of each SUA quartile for
incident NAFLD. Baseline SUA levels were positively correlated
with the hazard ratios for incident NAFLD, after adjustment for
Table 1. Baseline characteristics of study subjects according to serum uric acid quintiles.
Serum uric acid quintile
1 (n=1383) 2 (n=1380) 3 (n=1390)4 (n=1397)5 (n=1340)
Age (yr)44.4 (12.7)43.7 (12.2) 43.6 (12.5)43.9 (13.0) 44.1 (13.0)46.8 (14.1)
Gender (male/female, n) 4492/2398886/497 911/469903/487922/475870/4700.81
Body mass index (kg/m2) 22.40 (2.71)21.60 (2.56)22.01 (2.67)22.29 (2.58)22.72 (2.66)23.32 (2.77)
Waist circumference (cm) 76.9 (8.2)74.6 (8.0)75.8 (7.9) 76.6 (8.2)77.9 (7.9)79.6 (7.9)
Systolic blood pressure (mmHg)119.8 (14.8)117.3 (14.8)117.9 (14.1)119.4 (15.2)121.0 (14.7)123.6 (15.1)
Diastolic blood pressure (mmHg)75.6 (9.2) 74.2 (9.2)74.5 (8.9)75.4 (9.2) 76.3 (9.2)77.5 (9.1)
Alanine aminotransferase (U/L)21.0 (15.0–29.0)19.0 (14.0–27.0) 20.0 (15.0–27.0)21.0 (15.0–29.0)22.0 (16.0–30.0)23.0 (17.0–33.0)
Aspartate aminotransferase (U/L)19.0 (16.0–23.0)18.0 (16.0–21.0)19.0 (16.0–22.0)19.0 (16.0–23.0) 19.0 (17.0–23.0)20.0 (17.0–24.0)
c-Glutamyltransferase (U/L)17.0 (12.0–26.0)15.0 (11.0–21.0) 16.0 (12.0–23.0)17.0 (12.0–25.0)18.0 (13.0–28.0)20.0 (14.0–32.0)
Triglyceride (mmol/L)1.15 (0.84–1.63)0.99 (0.76–1.33) 1.06 (080–1.44) 1.13 (0.84–1.58)1.25 (0.90–1.77)1.42 (1.02–2.04)
Total cholesterol (mmol/L)4.76 (0.93)4.63 (0.89) 4.70 (0.90) 4.74 (0.89)4.79 (0.95) 4.96 (1.01)
HDL cholesterol (mmol/L) 1.29 (1.08–1.57)1.32 (1.10–1.62)1.30 (1.08–1.59) 1.28 (1.08–1.58) 1.27 (1.08–1.54)1.26 (1.08–1.53)
LDL cholesterol (mmol/L)2.68 (0.75)2.58 (0.73)2.65 (0.74)2.68 (0.74)2.70 (0.77)2.82 (0.78)
Fasting plasma glucose (mmol/L)4.44 (4.14–4.81)4.41 (4.13–4.75) 4.43 (4.13–4.78)4.43 (4.14–4.78)4.46 (4.15–4.82) 4.52 (4.18–4.94)
Creatinine (mmol/L)72.0 (60.0–81.0)67.0 (56.0–77.0) 71.0 (59.0–80.0)72.0 (60.0–80.0) 73.0 (61.0–82.0)76.0 (65.0–86.0)
Blood urea nitrogen (mmol/L)4.99 (4.21–5.87) 4.74 (3.98–5.53)4.91 (4.17–5.79) 4.99 (4.20–5.86)5.06 (4.29–5.93) 5.28 (4.50–6.18)
Data are presented as mean (SD) or median (IQR). The subjects were grouped according to quintiles of serum uric acid: quintile 1 (#295 mmol/L), quintile 2 (296–
332 mmol/L), quintile 3 (333–367 mmol/L), quintile 4 (368–409 mmol/L), and quintile 5 ($410 mmol/L), for male; and quintile 1 (#205 mmol/L), quintile 2 (206–232 mmol/
L), quintile 3 (233–262 mmol/L), quintile 4 (263–298 mmol/L), and quintile 5 ($299 mmol/L), for female. HDL, high-density lipoprotein; LDL, low-density lipoprotein.
aP values are based on x2test for categorical data and on Kruskal-Wallis H test or one-way analysis of variance for continuous data, depending on the normality of the
Uric Acid and NAFLD
PLoS ONE | www.plosone.org3July 2010 | Volume 5 | Issue 7 | e11578
age and gender. In comparison with subjects in quintile 1, the
hazard ratios (95% CI) for subjects in quintile 2, quintile 3, quintile
4, and quintile 5 were 1.32 (1.02–1.72), 1.60 (1.25–2.06), 1.92
(1.50–2.44), and 2.34 (1.85–2.97), respectively (P for trend
,0.001). The relationship of SUA with incident NAFLD
remained significant even further adjustment for indictors of
metabolic syndrome including waist circumference, systolic blood
pressure, diastolic blood pressure, triglyceride, HDL cholesterol
and fasting plasma glucose (Table 4). These results demonstrated
that SUA level is an independent factor that predicts the
development of NAFLD and the risk increases with increase in
baseline SUA levels.
When baseline SUA level was entered as a dichotomous
variable, that is, hyperuricemia vs. normouricemia, the 3-year
cumulative incidence of NAFLD was 17.75% in subjects with
hyperuricemia vs. 10.98% in subjects with normouricemia
(P,0.001). In the univariable Cox model, hyperuricemia con-
ferred a hazard ratio of 1.62 (95% CI, 1.35–1.93; P,0.001).
Adjusting for age, gender, and metabolic syndrome slightly
attenuated the hazard ratio value to 1.32 (95% CI, 1.10–1.58;
P=0.003). This subgroup analysis further demonstrated that
hyperuricemia is an independent risk factor for NAFLD.
Our recent cross-sectional study showed that NAFLD patients
had higher SUA levels than healthy controls and that the
prevalence of NAFLD was increased at higher SUA levels,
suggesting significant association between SUA and NAFLD .
However, whether elevated SUA level is a primary cause or a
secondary response of NAFLD could not be determined from the
cross-sectional study. Therefore, we performed the prospective
study described here. We observed that baseline elevation of SUA
was positively and significantly associated with increased risk of
incident NAFLD in initially NAFLD-free subjects. This associa-
tion was significant even in the normal range of SUA and was
independent of baseline gender, age, metabolic syndrome, and all
other clinical variables. These results provide novel evidences for a
significant association between SUA and development of NAFLD.
The significant association between SUA and development of
NAFLD suggest that high SUA levels may play a causal role in the
development of NAFLD. Two potential reasons could explain the
mechanism by which high SUA levels participates in the
development of NAFLD. The first is that uric acid acts as a
strong oxidant in the environment of metabolic syndrome .
Recent studies have suggested that elevation of SUA levels is a
novel risk factor for the development of metabolic diseases,
including hypertension , cardiovascular disease  and type
Table 2. Baseline characteristics of study subjects according to follow-up outcomes.
Subjects developed NAFLD
Subjects did not develop NAFLD
(n=6077)t valueP value
Age (yr) 46.0 (12.4) 44.2 (12.8)3.89
Gender (male/female, n) 606/2083887/219034.53a
Body mass index (kg/m2)23.94 (2.72) 22.20 (2.65)17.57
Waist circumference (cm)81.8 (8.0) 76.2 (8.0) 18.76
Systolic blood pressure (mmHg) 124.5 (14.8)119.2 (14.7)9.71
Diastolic blood pressure (mmHg) 78.8 (9.1) 75.2 (9.1)10.53
Alanine aminotransferase (U/L) 26.0 (19.0–36.0) 20.0 (15.0–28.0)12.35b
Aspartate aminotransferase (U/L)20.0 (17.0–24.0) 19.0 (16.0–23.0) 5.43b
c-Glutamyltransferase (U/L) 21.0 (15.0–35.0) 16.0 (12.0–24.0) 11.75b
Triglyceride (mmol/L)1.52 (1.09–2.20)1.12 (0.82–1.56) 15.23b
Total cholesterol (mmol/L) 4.92 (1.00)4.74 (0.92)8.07
HDL cholesterol (mmol/L)1.21 (1.06–1.45) 1.30 (1.09–1.58)6.05b
LDL cholesterol (mmol/L) 2.80 (0.79)2.67 (0.75)4.95
Fasting plasma glucose (mmol/L) 4.50 (4.18–4.91) 4.44 (4.14–4.79)3.58b
Creatinine (mmol/L)73.0 (62.0–82.0)71.0 (60.0–81.0)3.400.108
Blood urea nitrogen (mmol/L)4.99 (4.29–5.92)4.99 (4.20–5.87)1.060.695
Serum uric acid level (mmol/L)347.4 (77.1)314.9 (81.1) 10.80
Data are presented as mean (SD) or median (IQR).
bZ value; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Figure 1. The association between baseline SUA and cumula-
tive incidence of NAFLD. Subjects were stratified into quartiles
according to their baseline SUA levels; patients will higher levels of SUA
had an increased incidence of NAFLD.
Uric Acid and NAFLD
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2 diabetes mellitus . As NAFLD is a condition closely related
to metabolic syndrome, oxidative stress directly caused by uric
acid may partially explain why elevation of SUA significant
increased the risk of NAFLD. The other explanation is that the
generation of uric acid, which is catalyzed by xanthine
oxidoreductase, is accompanied by generation of reactive oxygen
species. Therefore, increased uric acid generation may result in
increased oxidative stress to the liver [30,31]. Xanthine oxidore-
ductase-dependent reactive oxygen species might act as the
‘‘second hit’’ that induces NAFLD development .
The significant association between SUA and development of
NAFLD cannot exclude the possibility that high SUA levels may
Table 3. Univariable and multivariable Cox Proportional Hazard models of development of NAFLD during 3-year follow-up.
Mean (SD) or
Univariable models Multivariable models
x2testHR (95% CI)P value
x2test HR (95% CI)P value
Age (yr) 44.4 (12.7)13.291.01 (1.01–1.02)
Gender (male, n) 449229.97 1.55 (1.33–1.82)
,0.001 0.671.11 (0.87–1.42) 0.41
Alcohol intake (non-/mild-, n)a
5882/10080.361 1.06 (0.88–1.28)0.554.120.81 (0.66–0.99) 0.04
Body mass index (kg/m2) 22.40 (2.71)275.541.19 (1.17–1.22)
,0.001 11.201.07 (1.03–1.11) 0.001
Waist circumference (cm)76.9 (8.2) 292.471.07 (1.07–1.08)
,0.001 26.461.04 (1.03–1.06)
Systolic blood pressure (mmHg)119.8 (14.8)82.651.02 (1.01–1.02)
Diastolic blood pressure (mmHg)75.6 (9.2)96.321.04 (1.03–1.04)
,0.0015.111.01 (1.00–1.02) 0.02
Alanine aminotransferase (U/L) 21.0 (15.0–29.0)41.39 1.00 (1.00–1.01)
Aspartate aminotransferase (U/L)19.0 (16.0–23.0)15.631.01 (1.00–1.01)
,0.001 3.330.99 (0.97–1.00) 0.07
c–Glutamyltransferase (U/L)17.0 (12.0–26.0) 60.821.00 (1.00–1.01)
,0.0012.651.00 (1.00–1.00) 0.10
Triglyceride (mmol/L)1.15 (0.84–1.63) 194.361.30 (1.26–1.35)
,0.001 10.81.12 (1.05–1.20) 0.001
Total cholesterol (mmol/L) 4.76 (0.93)21.621.18 (1.10–1.27)
,0.001 2.06 1.22 (0.93–1.60) 0.15
HDL cholesterol (mmol/L)1.29 (1.08–1.57) 29.110.58 (0.48–0.71)
,0.0014.37 0.67 (0.46–0.98)0.04
LDL cholesterol (mmol/L)2.68 (0.75) 20.71 1.22 (1.12–1.34)
,0.0011.51 0.84 (0.64–1.11)0.22
Fasting plasma glucose (mmol/L)4.44 (4.14–4.81)5.881.09 (1.02–1.17) 0.02 0.300.98 (0.89–1.07)0.59
Creatinine (mmol/L)72.0 (60.0–81.0)3.311.00 (1.00–1.00)0.07 6.220.99 (0.99–1.00)0.01
Blood urea nitrogen (mmol/L)4.99 (4.21–5.87)0.771.02 (0.97–1.08)0.380.061.00 (0.94–1.06)0.94
Serum uric acid (mmol/L)318.7 (81.3) 66.65
Q2 vs Q11.33 (1.02–1.72)1.22 (0.94–1.59)
Q3 vs Q11.61 (1.25–2.07)1.39 (1.07–1.79)
Q4 vs Q11.93 (1.52–2.46)1.45 (1.13–1.87)
Q5 vs Q12.40 (1.89–3.04)1.62 (1.26–2.08)
aMild alcohol intake is defined as alcohol consumption less than 140 g/week for men and 70 g/week for women.
CI, confidence interval; HDL, high-density lipoprotein; HR, hazard ratio; IQR, interquartile range; LDL, low-density lipoprotein; Q, quintile; SD, standard deviation.
Table 4. Risk of development of NAFLD according to baseline serum uric acid quintiles in unadjusted and adjusted models.
Quintile of baseline serum uric acid Hazard ratio (95% confidence interval)
1 (n=1383) 2 (n=1380) 3 (n=1390)4 (n=1397)5 (n=1340)
Unadjusted 1 [reference] 1.33 (1.02–1.72)1.61 (1.25–2.07) 1.93 (1.52–2.46)2.40 (1.89–3.04)66.65
Adjusted for age and gender1 [reference]1.32 (1.02–1.72)1.60 (1.25–2.06)1.92 (1.50–2.44)2.34 (1.85–2.97)62.91
Adjusted for age, gender and BMI1 [reference]1.23 (0.94–1.59)1.43 (1.11–1.84)1.60 (1.25–2.04)1.80 (1.42–2.28)28.81
Adjusted for age, gender and indictors
1 [reference]1.18 (0.91–1.54)1.32 (1.03–1.70)1.39 (1.09–1.78)1.50 (1.18–1.92)12.660.01
Adjusted for all clinical variablesb
1 [reference]1.22 (0.94–1.59)1.39 (1.07–1.79)1.45 (1.13–1.87)1.62 (1.26–2.08)15.780.003
The subjects were grouped according to quintiles of serum uric acid: quintile 1 (#295 mmol/L), quintile 2 (296–332 mmol/L), quintile 3 (333–367 mmol/L), quintile 4 (368–
409 mmol/L), and quintile 5 ($410 mmol/L), for male; and quintile 1 (#205 mmol/L), quintile 2 (206–232 mmol/L), quintile 3 (233–262 mmol/L), quintile 4 (263–298 mmol/
L), and quintile 5 ($299 mmol/L), for female. BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MS, metabolic syndrome.
aIncluding age, gender, waist circumference, systolic blood pressure, diastolic blood pressure, triglyceride, HDL cholesterol and fasting plasma glucose.
bIncluding age, gender, alcohol intake, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, alanine aminotransferase, aspartate aminotransferase,
c-glutamyltransferase, triglyceride, total cholesterol, HDL cholesterol, LDL cholesterol, fasting plasma glucose, creatinine and blood urea nitrogen.
Uric Acid and NAFLD
PLoS ONE | www.plosone.org5 July 2010 | Volume 5 | Issue 7 | e11578
be just a marker for the development of NAFLD. However, even if
this possibility is true, our findings may also have significant
clinical implications. Since high SUA levels could predict the
development of NAFLD independent of gender, age, metabolic
syndrome, and other currently available clinical variables.
Furthermore, our recent experimental study observed that
hypouricemic therapy consisting of allopurine and benzbromar-
one, two drugs used clinically to lowering SUA levels, significantly
ameliorated hepatic steatosis and decreased serum cholesterol
levels in a Mongolian gerbil model of NAFLD . This
observation indirectly suggested that SUA may act more than a
marker for the development of NAFLD.
The interpretation of this study has several potential limitations.
First, the diagnosis of NAFLD was based on ultrasonography,
which is not sensitive enough to detect mild steatosis. However,
ultrasonography is widely used in epidemiological surveys of
NAFLD because it is non-invasive, safe, widely available, portable
and sensitivity for detecting hepatic steatosis is acceptable. Sceond,
SUA level during follow-up was not included in the analysis.
Spearman’s rank correlation coefficient was 0.589 (P,0.001) for
SUA between the baseline examination and the last follow-up
examination. This indicates that those who had the higher baseline
SUA level tended to be so during follow-up. Therefore, the
observedassociationbetween elevated baseline
increased risk of incident NAFLD could reflect the effects of
SUA over the observed period.
In conclusion, our population-based prospective study clearly
demonstrated that SUA is a significant factor associated with the
development of NAFLD. Further studies on the precise role of uric
acid on the development of NAFLD will enhance our under-
standing of NAFLD and will eventually guide development of
novel therapeutic and prevention strategies for the disease.
Found at: doi:10.1371/journal.pone.0011578.s001 (0.04 MB
Baseline characteristics of study subjects according to
Conceived and designed the experiments: YL. Performed the experiments:
CX CY LX MM. Analyzed the data: CX CY. Contributed reagents/
materials/analysis tools: LX MM. Wrote the paper: CX CY.
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