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Hepatology Research 2017; 47: E104–E112 doi: 10.1111/hepr.

12734

Original Article

Relationship of serum uric acid level with non-alcoholic fatty


liver disease and its inflammation progression in non-obese
adults
Jing Liu,1 Chengfu Xu,2 Limei Ying,3 Shufei Zang,4 Zhenjie Zhuang,5 Haifeng Lv,6 Wenjun Yang,7
Yan Luo,5 Xaojie Ma,1 Lei Wang,8 Yunhao Xun,9 Dewei Ye10 and Junping Shi1†
Departments of 1Liver Diseases, 4Endocrine Diseases, 5Center for Translational Medicine, and 7Pathology, The
Affiliated Hospital of Hangzhou Normal University, 2Department of Gastroenterology, The First Affiliated Hospital,
College of Medicine, Zhejiang University, 8Second Clinical Medical College, Zhejiang Chinese Medicine University,
and 9Department of Liver Diseases, Xixi Hospital of Hangzhou, Hangzhou, Zhejiang, 3Dalian University of Medicine,
Dalian, Liaoning and 10Department of Medicine, Faculty of Medicine, The University of Hong Kong, and 6Department
of Surgical Intensive Care Unit, The First Affiliated Hospital of Zhejiang University, China

Aim: This study aimed to evaluate the relationship between se- proven NAFLD, SUA levels were significantly higher in those with
rum uric acid (SUA) level and non-alcoholic fatty liver disease non-alcoholic steatohepatitis. The prevalence of non-alcoholic
(NAFLD) in non-obese adults. steatohepatitis and lobule inflammation tended to increase to
Methods: A cross-sectional study was carried out among 4098 57.58% and 66.67% as the SUA level increased to the fourth quar-
adults, including 1936 non-obese and 2162 obese individuals. An tile. Subjects with hyperuricemia had significantly higher NAFLD
additional 93 non-obese adults with biopsy-proven NAFLD were activity scores and more serious lobule inflammation than the
also included. normal group.
Results: The overall prevalence of NAFLD was 39.51% in the Conclusion: Non-obese adults have higher NAFLD risk with in-
study group, and 14.88% in non-obese adults. The NAFLD pa- creased SUA levels than obese individuals, and the inflammation
tients had significantly higher SUA levels than controls in both progression of NAFLD is associated with increased SUA level in
men and women. The non-obese group had a higher NAFLD risk non-obese subjects.
with increased SUA levels than the obese group, with odd ratios Key words: inflammation progression, non-obese adults, non-
(95% confidence interval) of 2.559 (1.870–3.503) and 1.692 alcoholic fatty liver disease, uric acid
(1.371–2.087), respectively. In 93 non-obese adults with biopsy-

INTRODUCTION Europe and North America, but also becoming increas-


ingly prevalent in the Asia-Pacific region, especially in
N ON-ALCOHOLIC FATTY LIVER disease (NAFLD) is
characterized by significant lipid deposition, usually
greater than 5% of the liver weight deposited as triglycer-
China with the prevalence of 15–30% in the general pop-
ulation.2 Non-alcoholic fatty liver disease mainly occurs in
obese individuals, but recent studies revealed that NAFLD
ide, in the liver parenchyma, without history of excessive
is also not rare in non-obese adults.3 The prevalence of
alcohol consumption. The NAFLD spectrum ranges from
NAFLD in non-obese adults was 15.2% in a Japanese study
simple steatosis (non-alcoholic fatty liver), to non-
group.4 So it is time to pay attention to NAFLD in non-
alcoholic steatohepatitis (NASH), to cirrhosis, ultimately
obese adults.
developing into hepatocellular carcinoma.1 Nowadays,
There is growing evidence that serum uric acid (SUA)
NAFLD is not only the most common liver disease in
level, the final product of purine degradation, is elevated
in metabolic syndrome (MetS) and strongly associated
Correspondence: Professor Jun-ping Shi, Department of Liver Diseases, The
with insulin resistance. The level of SUA is maintained
Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road,
Hangzhou 310015, Zhejiang, China. Email: 13957121199@126.com by the balance between uric acid production and excre-
Conflict of interest: The authors have no conflict of interest. tion in physiological conditions. However, the preva-
Received 6 February 2016; revision 12 April 2016; accepted 26 April 2016. lence and incidence of hyperuricemia in the world

© 2016 The Japan Society of Hepatology E104


Hepatology Research 2017; 47: E104–E112 Serum uric acid level E105

population have steadily increased over the past to their examination. The examination consisted of a
40 years.5 Although uric acid is recognized as an antiox- physical examination and a health habit inventory by a
idant, hyperuricemia has been implicated in the develop- physician.
ment of gout, coronary artery disease, type 2 diabetes, Fasting blood samples were obtained from an
MetS, and NAFLD.6–9 Increased SUA has been linked to antecubital vein, and the samples were used for the
increased oxidative stress, chronic low grade inflamma- analysis of biochemical values. The values included al-
tion, and insulin resistance,10,11 which are the basic anine aminotransferase (ALT), aspartate aminotransfer-
pathophysiology of NAFLD. ase (AST), triglyceride (TG), total cholesterol (TC),
Although numerous studies have reported that SUA high-density lipoprotein cholesterol (HDL-C), low-
level is associated with NAFLD,12,13 no study has aimed density lipoprotein cholesterol (LDL-C), c-
to investigate the association of SUA level with NAFLD glutamyltransferase, SUA, and fasting plasma glucose
and its inflammation progression in non-obese adults. (FPG). All values were measured by an automatic bio-
This study aimed to investigate the clinical and histopath- chemical analyzer (model 7180; Hitachi, Tokyo, Japan)
ologic characteristics of NAFLD, and then analyze the rela- using standard methods.
tionships between SUA, NAFLD, and degree of
inflammation in non-obese adults. Ultrasonography
Hepatic ultrasonic examination was carried out in all
MATERIALS AND METHODS subjects by two trained ultrasound doctors who were
blinded to the clinical and laboratory data, using a
Study design and subjects Toshiba Nemio 20 sonography machine (Toshiba, To-

A CROSS-SECTIONAL STUDY was carried out to evalu-


ate the relationship between SUA level and NAFLD.
This study initially enrolled all of the adults who took their
kyo, Japan) with a 3.5-MHz probe. Hepatic steatosis
was diagnosed by characteristic echo patterns according
to conventional criteria, such as the evidence of diffuse
health examination at Xixi Hospital (Hangzhou, China) hyperechogenicity of the liver relative to the kidneys, ul-
and the Affiliated Hospital of Hangzhou Normal Univer- trasound beam attenuation, and poor visualization of
sity (Hangzhou, China) between January 1, 2013 and De- intrahepatic structures.14
cember 31, 2014. Subjects meeting the following criteria
were excluded: (i) those taking antihypertensive or antidi- Liver histology
abetic agents, lipid-lowering agents, or hypouricemic The histopathological diagnosis of NAFLD was
agents; (ii) those with alcohol consumption greater than established by two expert liver pathologist, blinded to
140 g/week for men and 70 g/week for women; (iii) those subjects’ details. Liver biopsy specimens were scored
with a history of other known causes of chronic liver dis- using the NASH CRN scoring system.15 In brief, the de-
ease, such as viral hepatitis or autoimmune hepatitis, and gree of steatosis, liver injury, and inflammatory activity
(iv) those using hepatotoxic medications. A total of 4098 were scored using an 8-point scale: steatosis, 0–3; lobular
eligible subjects were enrolled. An additional 93 non- inflammation, 0–3; ballooning hepatocyte degeneration,
obese adults with biopsy-proven NAFLD were also in- 0–2. The stage of fibrosis was scored using a 6-point
cluded. The study protocol was approved by the ethics scale: 1a, mild zone 3 perisinusoidal fibrosis; 1b, moder-
committee, complying with the ethical guidelines of the ate zone 3 perisinusoidal fibrosis; 1c, portal fibrosis only;
Declaration of Helsinki in 1995 (as revised in Edinburgh 2, zone 3 and portal/periportal fibrosis; 3, bridging fibro-
2000). And written informed consent was obtained from sis; 4, cirrhosis. In addition to determining the NAFLD
all subjects. activity score (NAS), an overall diagnostic categorization
was determined for each case as simple steatosis (NAS,
Clinical examination and biochemical analyses 0–2), indefinite NASH (NAS, 3–4), and NASH (NAS,
All participants underwent routine medical history and 5–8). According to the fibrosis stage, cases were divided
physical examination including blood pressure measure- into non-advanced fibrosis (stage of fibrosis, 0–2) and
ment, anthropometry, and laboratory assessments. Body advanced fibrosis.
mass index (BMI) was calculated as weight (kg) divided
by height (m) squared (kg/m2) and used as an index of Definitions and statistical analyses
body fat. Clinical examinations were undertaken in the Non-alcoholic fatty liver disease was diagnosed by abdom-
morning after an overnight fast, and subjects were also inal ultrasound following exclusion of alcohol consump-
instructed to refrain from exercise during the day prior tion and viral or autoimmune liver disease.16,17 A BMI of

© 2016 The Japan Society of Hepatology


E106 J. Liu et al. Hepatology Research 2017; 47: E104–E112

≥18.5 kg/m2 and <25 kg/m2 for non-obese subjects, and RESULTS
BMI ≥25 kg/m2 for obese subjects was defined according
Clinical and laboratory characteristics of
to the World Health Organization guidelines of categoriz-
subjects
ing obesity in Asian populations as proposed in 2000. Hy-
peruricemia was defined as an SUA level >420 μmol/L in
male subjects and >360 μmol/L in female subjects. For
men, quartiles (Q) were defined as: Q1,
O F 4098 SUBJECTS enrolled in this study, 1619
(39.51%) fulfilled NAFLD diagnostic criteria. An-
thropometric, clinical, and laboratory data of 4098 sub-
SUA ≤ 309 μmol/L; Q2, SUA 310–353 μmol/L; Q3, SUA jects are shown in Table 1. Compared with healthy
354–401 μmol/L; and Q4, SUA ≥ 402 μmol/L. For women, subjects, NAFLD patients were older, had significantly
quartiles were defined as: Q1, SUA ≤ 217 μmol/L; Q2, SUA higher BMI, FPG, TG, TC, LDL-C, ALT, AST, serum creati-
218–253 μmol/L; Q3, SUA 254–298 μmol/L; and Q4, nine (SCr), blood urea nitrogen (BUN), and SUA levels,
SUA ≤ 299 μmol/L. and lower HDL-C levels.
Statistical analyses were carried out using the SPSS There were 1936 non-obese subjects
software package version 13.0 for Windows (SPSS Inc., (18.5 ≤ BMI < 25 kg/m2) and 2162 obesity subjects
Chicago, IL, USA). Continuous variables are presented as (BMI ≥ 25 kg/m2). The prevalence of NAFLD was 14.88%
the mean and standard deviation (SD) or the median (288/1936) in the non-obese group, and 61.56% in the
and interquartile range (IQR), as appropriate. Student’s obese group. In the non-obese study group, NAFLD pa-
t-test or the Mann–Whitney U-test was used for two-group tients were older, and they had significantly higher BMI,
comparisons of continuous data; categorical variables were FPG, TG, TC, LDL-C, ALT, AST, SCr, and BUN levels, and
compared using the χ 2-test. One-way ANOVA followed by lower HDL-C levels than controls. Notably, significantly
Dunnett’s test was used for multiple group comparisons. higher SUA levels were observed in subjects with NAFLD
Linear correlation analysis was used to determine the rela- than in those without NAFLD in the non-obese group
tionship between SUA level and other parameters of (men, 368.00 ± 75.45 vs. 332.72 ± 72.82 μmol/L; women,
NAFLD patients. Multivariate logistic regression (back- 272.00 ± 71.84 vs. 232.46 ± 54.72 μmol/L) (Fig. 1a). Com-
ward Wald; entry, 0.05; removal, 0.10) was used to evalu- pared with NAFLD patients in the obese group, non-obese
ate the risk factors for NAFLD. P < 0.05 was considered patients were older and had significantly lower BMI, TG,
statistically significant. ALT, SCr, and SUA levels (Table 2). In female subjects,

Table 1 Clinical and laboratory characteristics of 4098 adults, including 1619 adults with non-alcoholic fatty liver disease (NAFLD)

Variable Total Healthy group NAFLD group P-value

n (women) 4098 (1515) 2479 (1096) 1619 (419) 0.000†


Age, years 41.73 ± 11.62 39.38 ± 11.34 45.52 ± 11.07 0.000
BMI, kg/m2 25.31 ± 3.94 23.62 ± 3.23 28.02 ± 3.45 0.000
SUA, μmol/L 316.63 ± 97.11 294.15 ± 93.94 353.08 ± 90.95 0.000
FPG, mmol/L 5.31 ± 1.32 5.12 ± 1.08 5.62 ± 1.60 0.000
TG, mmol/L 1.34 (0.88–2.08) 1.07 (0.75–163) 1.89 (1.31–2.82) 0.000‡
TC, mmol/L 4.69 ± 0.89 4.50 ± 0.92 5.00 ± 1.01 0.000
HDL-C, mmol/L 1.24 ± 0.37 1.31 ± 0.37 1.13 ± 0.35 0.000
LDL-C, mmol/L 2.88 ± 0.79 2.74 ± 0.75 3.11 ± 0.80 0.000
ALT, U/L 20.70 (14.90–30.40) 17.60 (13.00–24.90) 27.00 (19.00–39.00) 0.000‡
AST, U/L 19.00 (16.00–23.40) 18.00 (15.50–22.00) 21.00 (17.70–26.00) 0.000‡
BUN, mmol/L 5.09 ± 1.48 4.97 ± 1.43 5.29 ± 1.54 0.000
SCr, mmol/L 71.36 ± 19.58 69.80 ± 16.91 73.89 ± 23.04 0.000

Data are expressed as mean ± standard deviation or median (interquartile range).


‡P-value calculated using the Mann–Whitney U-test.
2
†P-value calculated using the χ -test.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; FPG, fasting plasma glucose;
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SCr, serum creatinine; SUA, serum uric acid; TC, total
cholesterol; TG, triglyceride.

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Hepatology Research 2017; 47: E104–E112 Serum uric acid level E107

Figure 1 Serum uric acid (SUA) level distribution according to sex and age of study participants. (a) SUA levels in men and women.
*P < 0.05 versus non-obese non-alcoholic fatty liver disease (NAFLD) absent; ‡P < 0.05 versus non-obese NAFLD present. (b) SUA level
separated by age in female adults. *P < 0.05 versus their corresponding group aged <45 years; ‡P < 0.05 versus their corresponding
group aged >55 years. , Nonobese NAFLD Absent; , Nonobese NAFLD Present; , Obesity NAFLD Present; , Obesity NAFLD
Absent; , Nonobese NAFLD Absent; , Nonobese NAFLD Present; , Obesity NAFLD Present; , Obesity NAFLD Absent.

Table 2 Clinical and laboratory characteristics of adults with non-alcoholic fatty liver disease (NAFLD) according to body mass index (BMI)

Variable Non-obese subjects (n = 1936 ) Obese subjects (n = 2162 )

NAFLD absent NAFLD present P-value NAFLD absent NAFLD present P-value

n (women) 1648 ( 871 ) 288 ( 99 ) 0.001† 831 ( 225 ) 1331( 320 ) 0.026†
Age, years 37.89 ± 11.22 46.86 ± 10.99 0.000 42.50 ± 10.96 45.16 ± 11.03‡ 0.000
BMI, kg/m2 21.87 ± 1.99 23.56 ± 1.27 0.000 27.26 ± 2.04 28.93 ± 2.93‡ 0.000
SUA, μmol/L 279.13 ± 81.05 335.15 ± 87.03 0.000 326.12 ± 90.90 356.78 ± 90.90‡ 0.000
FPG, mmol/L 5.06 ± 1.07 5.53 ± 1.68 0.000 5.25 ± 1.09 5.64 ± 1.57 0.000
TG, mmol/L 0.96 (0.69–1.41) 1.77 (1.30–2.58) 0.001§ 1.41 (0.97–2.06) 1.93 (1.31–2.87)‡ 0.000§
TC, mmol/L 4.38 ± 0.90 5.01 ± 1.68 0.000 4.77 ± 0.94 5.00 ± 0.99 0.000
HDL-C, mmol/L 1.37 ± 0.37 1.16 ± 0.31 0.000 1.19 ± 0.33 1.13 ± 0.35 0.001
LDL-C, mmol/L 2.60 ± 0.72 3.01 ± 0.80 0.000 3.02 ± 0.74 3.11 ± 0.80 0.010
ALT, U/L 16.00 (12.00–21.85) 20.00 (17.00–23.40) 0.001§ 19.40 (16.20–23.62) 28.07 (20.00–40.00)‡ 0.000§
AST, U/L 17.80 (15.00–21.00) 23.65 (17.95–31.93) 0.001§ 22.35 (16.76–31.06) 21.20 (17.80–26.90)‡ 0.000§
BUN, mmol/L 4.88 ± 1.46 5.32 ± 1.48 0.000 5.14 ± 1.35 5.28 ± 1.55 0.033
SCr, mmol/L 67.59 ± 16.42 70.68 ± 16.37 0.009 75.03 ± 16.78 74.61 ± 26.36‡ 0.630

Data are expressed as mean ± standard deviation or median (interquartile range). Calculated by comparison of subjects with NAFLD within each
BMI group. Significant values appear in boldface type.
2
†P-value calculated using the χ -test.
‡For comparison of non-obese subjects and obese subjects with NALFD, P < 0.05.
§P-value calculated using the Mann–Whitney U-test.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FPG, fasting plasma glucose; HDL-C, high-density li-
poprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SCr, serum creatinine; SUA, serum uric acid; TC, total cholesterol; TG, triglyceride.

SUA level increased with age in both non-obese and obese parameters. Eleven variables including age, BMI, TG,
groups. Among non-obese NAFLD patients, women after TC, HDL-C, LDL-C, ALT, AST, FPG, SCr, and BUN were
menopause had significantly higher SUA levels than involved (Table 3). There were extremely significant pos-
women before menopause (286.44 ± 63.60 vs. 254.96 itive correlations between BMI, TG, TC, LDL-C, ALT, AST,
± 70.88 μmol/L) (Fig. 1b). SCr, BUN and SUA, whereas HDL-C had negative corre-
lations in both non-obese and obese subject groups. Re-
Association between SUA and other clinical markably, compared with the obese group, the
parameters correlation coefficients between BMI, TG, TC, LDL-C,
Linear correlation analysis was used to determine the re- HDL-C, ALT, SCr, BUN, and SUA were all higher in the
lationship between SUA level and other clinical non-obese group.

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E108 J. Liu et al. Hepatology Research 2017; 47: E104–E112

Table 3 Association between serum uric acid (SUA) level and NAFLD in non-obese subjects. Remarkably, the non-obese
other parameters in non-obese and obese adults group had higher NAFLD risk with increased SUA levels
Variable Non-obese subjects Obese subjects than the obese group (odds ratio, 2.559 and 95% confi-
(n = 2038 ) (n = 2164 ) dence interval, 1.870–3.503 vs. odds ratio, 1.692 and
95% confidence interval, 1.371–2.087).
r P-value r P-value

Age, years 0.004 0.840 0.107 0.000 Correlation of SUA level with histological
BMI, kg/m2 0.218 0.000 0.059 0.007 severity in non-obese adults
FPG, mmol/L 0.061 0.006 0.098 0.000 To investigate the relationship between SUA level and dif-
TG, mmol/L 0.298 0.000 0.278 0.000
ferent stages of NAFLD in non-obese adults, 93 NAFLD pa-
TC, mmol/L 0.138 0.000 0.130 0.000
tients were divided into three groups according to biopsy
HDL-C, mmol/L 0.273 0.000 0.238 0.000
LDL-C, mmol/L 0.203 0.000 0.095 0.000
result (Table 5). An analysis using one-way ANOVA followed
ALT, U/L 0.185 0.000 0.129 0.000 by Dunnett’s test revealed that none of the variables had sig-
AST, U/L 0.093 0.000 0.186 0.000 nificant differences between non-NASH and NASH groups,
BUN, mmol/L 0.224 0.000 0.176 0.000 except for ALT and SUA. Notably, compared with the non-
SCr, mmol/L 0.421 0.000 0.320 0.000 NASH group, SUA levels were significantly higher in indefi-
nite NASH and NASH groups (344.53 ± 87.62 μmol/L vs.
Significant values appear in boldface type.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI,
397.71 ± 92.53 μmol/L and 403.21 ± 74.98 μmol/L, respec-
body mass index; BUN, blood urea nitrogen; FPG, fasting plasma tively). These results showed that non-obese adults had
glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low- higher SUA levels as the inflammation advanced in NAFLD.
density lipoprotein cholesterol; r, correlation coefficient; SCr, serum
creatinine; TC, total cholesterol; TG, triglyceride.
Relationship between SUA level and
histopathological characteristics of NAFLD in
Risk factors analysis for NAFLD in non-obese non-obese adults
adults
The score distribution of NAS and its components accord-
Multivariate logistic regression analysis was undertaken to ing to SUA level is shown in Figure 2. The group with hy-
evaluate risk factors for NAFLD. Ten variables including peruricemia had significantly higher NAS scores and
male gender, age, TG, TC, HDL-C, LDL-C, FPG, SUA, more serious lobule inflammation than the normal group,
SCr, and BUN were entered into the original equation. whereas hepatic steatosis and ballooning degeneration
Our results showed that all variables except for male gen- had no significant difference between the two groups.
der, TC, SCr, and BUN remained in the final equation in To get a deeper understanding of the relationship be-
non-obese subjects. In obese subjects, male gender, age, tween SUA level and histopathological characteristics of
TG, FPG, and SUA remained in the final equation NAFLD patients in the non-obese group, the impact of
(Table 4). It was suggested that older age, hypertriglyc- SUA level on the prevalence rates of different NAS scores
eridemia, low HDL-C, elevated LDL-C and FPG, and hy- and its components were studied. Our results showed that
peruricemia are closely associated with the risk for the prevalence rates of high NAS and lobule inflammation

Table 4 Risk factors for non-alcoholic fatty liver disease in non-obese and obese adults

Variables Non-obese subjects Obese subjects

β P-value OR 95% CI β P-value OR 95% CI

Male gender – – – – 0.294 0.012 1.341 1.066–1.687


Older age 1.113 0.000 3.613 2.714–4.150 0.431 0.000 1.539 1.270–1.865
Elevated FPG 0.684 0.003 1.983 1.269–3.099 0.656 0.000 1.928 1.454–2.555
Hypertriglyceridemia 1.285 0.000 3.613 2.714–4.810 0.779 0.000 2.179 1.807–2.626
Low HDL-C 0.680 0.051 1.974 0.998–3.906 – – – –
Elevated LDL-C 0.684 0.000 1.981 1.483–2.648 – – – –
Hyperuricemia 0.940 0.000 2.559 1.870–3.503 0.526 0.000 1.692 1.371–2.087

–, none data; β, partial regression coefficient; CI, confidence interval; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol;
LDL-C, low-density lipoprotein cholesterol; OR, odds ratio.

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Hepatology Research 2017; 47: E104–E112 Serum uric acid level E109

Table 5 Comparison of serum uric acid (SUA) level and other characteristics between non-alcoholic steatohepatitis (NASH), indefinite
NASH, and non-NASH in non-obese adults

Variable Total Non-NASH Indefinite NASH NASH P-value

n (male / female) 93 (67/26) 19 (15/4) 41 (28/13) 33 (24/9) 0.689


Age, years 36.84 ± 11.08 37.58 ± 9.71 35.83 ± 11.54 37.79 ± 11.59 0.738
BMI, kg/m2 23.44 ± 1.24 23.22 ± 1.23 23.62 ± 1.11 23.31 ± 1.41 0.469
TG, mmol/L 1.71 (1.27–2.79) 1.33(1.16–2.72) 1.62 (1.25–2.67) 1.94 (1.56–2.98) 0.307†
TC, mmol/L 5.06 ± 1.33 4.76 ± 0.99 5.08 ± 1.65 5.20 ± 1.01 0.324
HDL-C, mmol/L 1.27 ± 0.33 1.34 ± 0.29 1.20 ± 0.22 1.31 ± 0.43 0.193
LDL-C, mmol/L 3.08 ± 0.76 2.84 ± 0.70 3.25 ± 0.81 3.01 ± 0.69 0.295
FPG, mmol/L 5.26 ± 0.84 5.35 ± 1.15 5.20 ± 0.67 5.29 ± 0.82 0.835
Insulin, mU/mL 10.30 (8.77–15.30) 11.14 (7.38–18.19) 9.61 (8.77–15.30) 10.30 (8.00–12.30) 0.713†
HOMA-IR 2.20 (1.60–3.15) 2.30 (1.55–3.95) 2.05 (1.48–3.18) 2.30 (1.70–3.10) 0.615†
TNF-α, nmol/L 12.35 (8.48–17.85) 13.70 (9.70–17.02) 11.55 (6.00–18.24) 12.80 (8.85–19.55) 0.976†
AST, U/L 45.00 (30.00–69.5) 38.00 (24.00–55.00) 44.00 (28.00–62.50) 55.00 (33.00–80.50) 0.056†
ALT, U/L 75.00(42.00–116.50) 46.00 (28.00–98.00) 70.00 (44.00–96.5)‡ 100.00 (59.25–139.00)§ 0.009†
SUA, μmol/L 388.80 ± 87.72 344.53 ± 87.62 397.71 ± 92.53‡ 403.21 ± 74.98§ 0.030
Leptin, ng/mL 4.80 (2.60–9.30) 4.83 (2.53–15.6) 4.80 (2.68–9.30) 3.27 (1.90–10.00) 0.775†

Data are expressed as mean ± standard deviation or median (interquartile range). P-values calculated using one-way ANOVA, based on post hoc
multiple comparison between quartile groups.
†P-value was calculated using the Mann–Whitney U-test.
‡Compared with non-NASH, P < 0.05.
§Compared with indefinite NASH, P < 0.05.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; FPG, fasting plasma glucose; HDL-C, high-density li-
poprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; TC, total
cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor-α.

score tended to increase as the SUA level increased, increased SUA level is associated with an exacerbated risk
whereas this trend was not apparent in hepatic steatosis of NAFLD. This increased risk is probably independent of
and ballooning degeneration (Fig. 3). In Q4, the preva- conventional NAFLD risk factors.21 In our study, we also
lence rates of NAS ≥ 5 reached 57.58%, and the prevalence found hyperuricemia was an risk factor of NAFLD. Non-
rates of lobule inflammation score = 3 was 66.67% (Fig. 3). obese adults have higher NAFLD risk with increased SUA
It suggested that the inflammation of NAFLD tended to in- levels than obese adults, suggesting that increased SUA
crease as the SUA level increased in non-obese subjects. concentrations, even within the normal range, are associ-
ated with the presence of NAFLD in non-obese subjects.
Therefore, it is time to pay attention to the exact relation-
DISCUSSION
ship between SUA level and NAFLD in non-obese adults.

R ECENTLY, AN INCREASING number of studies have


examined the significance of NAFLD in non-obese
adults as NAFLD is increasingly prevalent in this group,
Large clinical studies have indicated that hyperuricemia
is associated with obesity, dyslipidemia, type 2 diabetes
mellitus, and MetS.22 There are also several studies suggest-
with reported prevalence from 11.5% to 16.1%.18,19 In this ing that SUA level is significantly associated with
study, we found that the prevalence of NAFLD was 14.88% NAFLD.12,13 However, few data are available about the re-
in non-obese adults. The NAFLD patients had higher SUA lationship between SUA level and inflammation associ-
levels than the control group. Previous studies showed that ated with NAFLD in non-obese adults. In 93 cases of
hyperuricemia is a significant and independent predictor non-obese biopsy-proven NAFLD we found that there
of MetS, and MetS risk increases with increased serum uric were no significant differences between non-NASH and
acid levels.20 Interestingly, the present study showed that NASH groups, except for ALT and SUA levels. The SUA
SUA levels were significantly and positively correlated with levels were significantly higher in indefinite NASH and
BMI, TG, TC, LDL-C, ALT, SCr, and BUN, and the correla- NASH groups. These results showed that higher SUA
tion coefficient in the non-obese group was higher than levels correlated with increased inflammation in NAFLD.
in the obese group. A meta-analysis suggested that One of the possible explanations for the relationship

© 2016 The Japan Society of Hepatology


E110 J. Liu et al. Hepatology Research 2017; 47: E104–E112

Figure 2 Score distribution of non-alcoholic fatty liver disease activity score (NAS) and its components according to serum uric acid (SUA)
level. (a) NAS. (b) Hepatic steatosis. (c) Ballooning degeneration. (d) Lobule inflammation. P-values calculated using the Mann–Whitney U-test.

Figure 3 Prevalence of different quartile (Q) levels of serum uric acid according to the non-alcoholic fatty liver disease activity score
(NAS) and its components. (a) NAS. (b) Hepatic steatosis. (c) Ballooning degeneration. (d) Lobule inflammation. P-values calculated
using one-way ANOVA.*P < 0.05 versus Q1; †P < 0.05 versus Q2; ‡P < 0.05 versus Q3, based on post hoc multiple comparison between
quartile groups. , Q1; , Q2; , Q3; , Q4.

© 2016 The Japan Society of Hepatology


Hepatology Research 2017; 47: E104–E112 Serum uric acid level E111

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© 2016 The Japan Society of Hepatology