RESEARCH ARTICLE

Association of hyperuricemia with disease

severity in chronic hepatitis C patients
Tyng-Yuan Jang ID1, Ming-Lun Yeh1,2, Ching-I Huang1, Zu-Yau Lin1,2, Shinn-
Cherng Chen1,2, Meng-Hsuan Hsieh3,4, Chia-Yen Dai1,2,3,4, Jee-Fu Huang1,2, Chung-
Feng Huang1,2,3*, Wan-Long Chuang1,2, Ming-Lung Yu1,2,5,6
1 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan, 2 Faculty of Internal Medicine, School of Medicine, College of
Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, 3 Department of Occupational Medicine,
Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, 4 Department of
a1111111111 Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung,
Taiwan, 5 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, 6 College
a1111111111
of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
a1111111111
a1111111111 * fengcheerup@gmail.com
a1111111111

Abstract
OPEN ACCESS
Background/aims
Citation: Jang T-Y, Yeh M-L, Huang C-I, Lin Z-Y,
Chen S-C, Hsieh M-H, et al. (2018) Association of Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as
hyperuricemia with disease severity in chronic metabolic abnormalities. The association between chronic hepatitis C (CHC) and uric acid
hepatitis C patients. PLoS ONE 13(11): e0207043. levels has rarely been investigated. We aimed to evaluate the levels of serum uric acid in
https://doi.org/10.1371/journal.pone.0207043
CHC patients.
Editor: Tatsuo Kanda, Nihon University School of
Medicine, JAPAN
Methods
Received: September 9, 2018
Three hundred and seventy-three histologically confirmed CHC patients who were sched-
Accepted: October 23, 2018 uled to receive antiviral therapy were consecutively enrolled, and 746 age- and sex-matched
Published: November 5, 2018 uninfected controls were included for comparison. Hyperuricemia was defined as a uric acid
Copyright: © 2018 Jang et al. This is an open level > 7 mg/dL in men and > 6.0 mg/dL in women.
access article distributed under the terms of the
Creative Commons Attribution License, which Results
permits unrestricted use, distribution, and
reproduction in any medium, provided the original Hyperuricemia was identified in 15.8% of the CHC patients. The uric acid levels did not differ
author and source are credited. between the CHC patients and the controls (5.54 ± 1.20 mg/dL vs. 5.45 ± 1.45 mg/dL, P =
Data Availability Statement: All relevant data are
0.3). Among the 373 CHC patients, the factors associated with hyperuricemia included body
within the manuscript. mass index (BMI) (OR/CI: 1.13/1.04–1.21, P = 0.003) and estimated glomerular filtration rate
Funding: This study was supported by Kaohsiung
(eGFR) (OR/CI: 0.98/0.97–1.00, P = 0.02). Logistic regression analysis revealed that the fac-
Medical University Hospital (KMUH104-4R06 and tors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05–1.30, P
KMUH105-5R05) and Kaohsiung Medical = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09–0.83, P = 0.02), whereas the factors
University (NSC 103-2314-B-037-055-MY3). The
associated with hyperuricemia in female patients included eGFR (OR/CI: 0.97/0.95–0.99, P
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of = 0.02) and diabetes (OR/CI: 3.03/1.11–8.25, P = 0.03). There was a significant decreasing
the manuscript. trend of serum uric acid levels with the progression of fibrotic stages among male patients
Competing interests: The authors have declared (6.21 ± 1.03 mg/dL 5.82 ± 1.16 mg/dL and 5.44 ± 1.28 mg/dL in stages F0-2, F3, and F4,
that no competing interests exist. respectively, trend P = 0.01).

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 Uric acid in CHC

Conclusions
Hyperuricemia was inversely associated with liver disease severity in CHC male patients.

Introduction
Hepatitis C virus (HCV) infection is one of the major etiologies of chronic liver disease world-
wide, and it is estimated that >185 million people are anti-HCV seropositive globally[1]. Once
chronic hepatitis C (CHC) has developed, it may progress to liver fibrosis, and 10% to 20%
subjects develop cirrhosis or hepatocellular carcinoma within 10 to 30 years[2, 3]. HCV infec-
tion is also associated with extrahepatic manifestations including variable metabolic abnormal-
ities, such as insulin resistance, metabolic syndrome and lipid derangement[4–6]. However,
the association of CHC with serum uric acid has not been frequently investigated.
Uric acid is the end product of purine metabolism and is metabolized by the liver, muscles
and the intestines[7]. Hyperuricemia is an indicator of many diseases such as cardiovascular
disease[8], liver disease[9], and renal diseases[10]. The association of serum uric acid and liver
disease has been more broadly explored in non-alcoholic fatty liver disease (NAFLD) and/or
non-alcoholic steatohepatitis (NASH) patients, with inconsistent results obtained across stud-
ies[11–13]. Notably, less is known about the presentation of serum uric acid in CHC patients
as compared to the general population. Moreover, its correlation to liver disease severity
among CHC patients remains elusive. This study aimed to address the issue by comparing the
uric acid levels between CHC patients and uninfected controls. Meanwhile, the level of uric
acid was also studied within the well-characterized CHC cohort.

Materials and methods

Patients
Patients with CHC confirmed by biopsy scheduled to receive interferon-based antiviral treat-
ment were consecutively recruited in a medical center in Taiwan from January 2006 to Decem-
ber 2010. CHC patients were excluded if they had the following conditions: a current or past
history of alcohol abuse (�20 g daily), co-infected with hepatitis B virus (HBV) and human
immunodeficiency virus (HIV), and receiving anti-hyperuricemic agents. Another age- and
sex-matched control group without HBV, HCV and HIV infections were recruited at a 1:2
ratio for comparison of the uric acid levels. Uric acid levels were tested before antiviral therapy
in the CHC patients. For the controls, it was measured during the health check-up held in the
Department of Preventive Medicine of the participating hospital. All patients were written
informed consent before enrollment. The study was conducted according to the Declaration
of Helsinki. The ethical committee of the Kaohsiung Medical University Hospital approved
the study.

Laboratory and histological analyses

Biochemical analyses including serum aspartate aminotransferase (AST) levels, alanine amino-
transferase (ALT) levels and uric acid levels were measured on a multichannel autoanalyzer
(Hitachi Inc, Tokyo, Japan). HCV antibodies (anti-HCV) were tested by a third-generation
enzyme immunoassay (Abbott Laboratories, North Chicago, IL). Serum levels of HCV RNA
were measured using the branched DNA assay (Versant HCV RNA 3.0, Bayer, Tarrytown, NJ;
quantification limit: 615 IU/ml) for qualitative HCV RNA seropositivity. HCV genotypes were
determined by the method described by Okamoto et al.[14].

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 Uric acid in CHC

Liver specimens were obtained from all CHC patients by liver biopsy within the six months
prior to recruitment. The liver histology was staged as F0–4, according to the Metavir scoring
system[15]. The association of uric acid with liver disease severity was judged and stratified by
advanced fibrosis (F3-4) or no advanced fibrosis (F0-2)[16, 17]. The estimated glomerular fil-
tration rate (eGFR) was calculated using the modification of diet in renal disease (MDRD)
equation[18].

Statistical analyses
The frequencies were compared between groups using the χ2 test with the Yates correction or
Fisher’s exact test. Group means are presented as the mean (standard deviation) and were
compared using analysis of variance and Student’s t-test or the nonparametric Mann-Whitney
test, when appropriate. Hyperuricemia was defined as a uric acid level > 7 mg/dL in men
and > 6.0 mg/dL in women[19]. Stepwise logistic regression analysis was applied to assess the
factors associated with hyperuricemia by analyzing the co-variants with P values < 0.1 in the
univariate analysis. Linear regression analysis was used to assess the factors correlated with
serum uric acid levels. The Cochran-Armitage test was used to evaluate the trends of uric acid
levels in patients with different disease severities. The statistical analyses were performed using
the SPSS 20 statistical package (SPSS, Chicago, IL, USA). All statistical analyses were based on
two-sided hypothesis tests with a significance level of p < 0.05.

Results
Patient characteristics
Three hundred and seventy-three histologically proven CHC patients and 746 age- and sex-
matched uninfected controls were enrolled in the study. The mean age was 53.6 years (range:
18–80 years), and males accounted for 49.7% (n = 556) of the entire population. Compared to
the uninfected individuals, CHC patients had significantly higher levels of AST, ALT and
eGFR. The proportions of fibrotic stages F0-1, F2, F3 and F4 were 23.1% (n = 86), 42.9%
(n = 160), 18.0% (n = 67) and 16.1% (n = 60), respectively, in CHC patients (Table 1).

Factors associated with hyperuricemia in the entire population

Among the study population, the mean uric acid level was 5.48 ±1.37 mg/dL, and the propor-
tion of individuals with hyperuricemia was 17.1%. Univariate analysis revealed that the factors
associated with hyperuricemia included male gender, higher BMI and lower eGFR. Multivari-
ate analysis revealed that the factors associated with hyperuricemia included male gender
(odds ratio [OR]/95% confidence intervals [CI]: 1.43/1.01–2.03, P = 0.04), BMI (OR/CI: 1.10/
1.05–1.14, P < 0.001) and eGFR (OR/CI: 0.99/0.98–1.00, P = 0.01) (Table 2). The uric acid
level did not differ between the CHC patients and the controls (5.54 ± 1.20 mg/dL
vs.5.45 ± 1.45 mg/dL, P = 0.3) (Table 1)

Factors associated with hyperuricemia in CHC patients

Among the 373 CHC patients, univariate analysis revealed that the factors associated with
hyperuricemia included higher BMI and lower eGFR. Multivariate analysis revealed that the
factors associated with hyperuricemia included BMI (OR/CI: 1.13/1.04–1.21, P = 0.003) and
eGFR (OR/CI: 0.98/0.97–1.00, P = 0.02) (Table 3). Male patients had a significantly higher
serum uric acid level than female patients (6.03 ± 1.12 vs 5.08 ± 1.09 mg/dL, P < 0.001),
although the proportion of individuals with hyperuricemia did not differ between genders. We
further analyzed the uric acid levels in CHC patients according to gender. Among the 183

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 Uric acid in CHC

Table 1. Characteristics of the 373chronic hepatitis C patients and 746 uninfected controls.

All subjects (n = 1119) Hepatitis C (n = 373) Uninfected control (n = 746) P value

Age (years, mean(SD)) 53.6 (7.4) 53.6 (11.3) 53.6 (4.3) 0.90
Male, n (%) 556 (49.7) 183 (49.1) 373 (50.0) 0.77
BMI (kg/m2, mean (SD)) 25.0 (3.8) 24.7 (3.6) 25.1 (3.9) 0.13
Uric acid (mg/dL) 5.48 (1.37) 5.54 (1.20) 5.45 (1.45) 0.30
Hyperuricemia, � n (%) 191 (17.1) 59 (15.8) 132 (17.7) 0.43
Diabetes, n (%) 153 (13.7) 57 (15.3) 96 (12.9) 0.27
AST (IU/L, mean (SD)) 57.4 (58.1) 105.3 (55.5) 33.6 (42.6) <0.001
ALT (IU/L, mean (SD)) 73.8 (81.6) 153.5 (82.9) 33.9 (42.2) <0.001
Serum creatinine ((mg/dL, mean (SD)) 0.86 (0.16) 0.79 (0.21) 0.90 (0.12) <0.001
Hemoglobin (g/dL, mean (SD)) 14.1 (1.6) 14.0 (1.5) 14.1 (1.7) 0.24
Platelet count (x103u/L, mean (SD)) 217.3 (72.2) 167.2 (60.8) 242.3 (64.0) <0.001
eGFR (ml/min/1.73m2, mean (SD)) 80.7 (21.5) 100.8 (23.1) 70.6 (11.1) <0.001
HCV RNA (log IU/mL, mean (SD)) - 5.34 (0.94) - -
HCV genotype 1/2/mixed1+2/others (n) 175/164/22/12 -
Fibrosis, n (%)
F0-1 - 86 (23.1) - -
F2 - 160 (42.9) - -
F3 - 67 (18.0) - -
F4 - 60 (16.1) - -

Note: SD: standard deviation; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate.
�
Hyperuricemia defined as serum uric acid>7mg/dL in male and>6mg/dL in female

https://doi.org/10.1371/journal.pone.0207043.t001

male patients, univariate analysis revealed that the factors associated with hyperuricemia
included higher BMI and mild fibrotic stages (Table 4). Multivariate analysis showed that the
factors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05–1.30,
P = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09–0.83, P = 0.02) (Table 5).
On the other hand, univariate analysis revealed that the factors associated with hyperurice-
mia in the 190 female patients included older age, lower eGFR and the presence of diabetes
mellitus (DM) (Table 4). Multivariate analysis showed that the factors associated with

Table 2. Factors associated with hyperuricemia of all subjects.

Hyperuricemia � Non-hyperuricemia P value Logistic regression analysis

(n = 191, 17.1%) (n = 928, 82.9%)
OR 95% CI P value
Age (years, mean(SD)) 53.5 (7.6) 53.7 (7.4) 0.80
Male, n (%) 116 (60.7) 440 (47.4) 0.001 1.43 1.01–2.03 0.04
BMI (kg/m2, mean (SD)) 26.1 (3.8) 24.7 (3.7) <0.001 1.10 1.05–1.14 <0.001
AST (IU/L, mean (SD)) 59.5 (56.0) 57.0 (58.5) 0.57
ALT (IU/L, mean (SD)) 72.8 (70.8) 74.0 (83.6) 0.84
HCV infection, n (%) 59 (30.9) 314 (33.8) 0.43
eGFR (ml/min/1.73m2, mean (SD)) 75.3 (20.0) 81.8 (21.6) <0.001 0.99 0.98–1.00 0.01
Diabetes, n (%) 23 (12.0) 130 (14.0) 0.47

Note: SD: standard deviation; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate. OR:
odds ratio; CI: confidence intervals
�
Hyperuricemia was defined as serum uric acid >7mg/dL in male and >6mg/dL in female

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 Uric acid in CHC

Table 3. Factors associated with hyperuricemia in 373 chronic hepatitis C patients.

Hyperuricemia � Non-hyperuricemia P value Logistic regression analysis

(n = 59, 15.8%) (n = 314, 84.2%)
OR 95% CI P value
Age (years, mean(SD)) 53.4 (12.4) 53.5 (11.2) 0.96
Male, n (%) 28 (47.5%) 155 (49.4%) 0.79
2
BMI (kg/m , mean (SD)) 26.2 (3.4) 24.4 (3.6) 0.002 1.13 1.04–1.21 0.003
AST (IU/L, mean (SD)) 107.1 (49.5) 104.9 (56.8) 0.75
ALT (IU/L, mean (SD)) 152.5 (72.1) 153.7 (85.2) 0.67
eGFR (ml/min/1.73m2, mean (SD)) 92.3 (23.5) 102.7 (22.6) 0.002 0.98 0.97–1.00 0.02
Advanced fibrosis (F3-4), n (%) 19 (32.2%) 108 (34.3%) 0.74
Diabetes, n (%) 12 (20.3%) 45 (14.3%) 0.24
HCV RNA (log IU/mL, mean (SD)) 5.43 (1.03) 5.32 (0.92) 0.46
HCV genotype 1, n (%) 29 (49.2%) 168 (53.5%) 0.54

Note: SD: standard deviation; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; OR:
odds ratio; CI: confidence intervals
�
Hyperuricemia defined as serum uric acid >7mg/dL in male and >6mg/dL in female

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hyperuricemia in females included eGFR (OR/CI: 0.97/0.95–0.99, P = 0.02) and DM (OR/CI:

3.03/1.11–8.25, P = 0.03) (Table 5). There was a significant decreasing trend of serum uric acid
level with the progression of fibrotic stages (5.62 ± 1.18 mg/dL 5.61 ± 1.16 mg/dL and
5.17 ± 1.29 mg/dL in patients with F0-2, F3, and F4, respectively, trend P = 0.02). However, the
significant association existed only in male patients (6.21 ± 1.03 mg/dL, 5.82 ± 1.16 mg/dL and
5.44 ± 1.28 mg/dL in male patients with F0-2, F3, and F4, respectively, trend P = 0.01) and not
in female patients (5.02 ± 1.10 mg/dL, 5.40 ± 1.14 mg/dL and 4.98 ± 1.27 mg/dL in female
patients F0-2, F3, and F4, respectively, trend P = 0.74) (Fig 1). Linear regression analysis also
demonstrated that stages F3-4 were inversely correlated with uric acid levels only in male
patients (β: -0.389; 95% CI: -0.718–0.060, P = 0.001) (Table 6).

Table 4. Univariate analysis of factors associated with hyperuricemia in chronic hepatitis C patients stratified by gender.

Male P value Female P value

� �
Hyperuricemia Non-hyperuricemia Hyperuricemia Non-hyperuricemia
(n = 28, 15.3%) (n = 155, 84.7%) (n = 31, 16.3%) (n = 159, 83.7%)
Age (years, mean(SD)) 46.9 (11.7) 51.6 (12.5) 0.06 59.4 (8.2) 55.4 (9.6) 0.02
BMI (kg/m2, mean (SD)) 26.4 (3.6) 24.5 (3.4) 0.01 25.8 (3.6) 24.5 (3.7) 0.06
AST (IU/L, mean (SD)) 109.4 (56.2) 96.6 (52.9) 0.27 105.4 (47.4) 112.9 (58.5) 0.44
ALT (IU/L, mean (SD)) 169.3 (72.0) 157.5 (90.4) 0.45 132.0 (65.1) 150.9 (79.8) 0.16
2
eGFR (ml/min/1.73m , mean (SD)) 93.0 (25.3) 100.5 (23.5) 0.15 90.4 (24.0) 104.5 (21.5) 0.004
Advanced fibrosis (F3-4), n (%) 4 (14.3) 55 (35.5) 0.03 15 (48.4%) 53 (33.3%) 0.11
Diabetes, n (%) 4 (14.3%) 28 (18.1%) 0.63 8 (25.8%) 17 (10.7%) 0.02
HCV RNA (log IU/mL, mean (SD)) 5.44 (1.03) 5.34 (0.91) 0.62 5.42 (1.05) 5.30 (0.93) 0.58
HCV genotype 1, n (%) 16 (57.1%) 92 (59.4%) 0.83 13 (41.9%) 76 (47.8%) 0.55

Note: SD: standard deviation; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; OR:
odds ratio; CI: confidence intervals
�
Hyperuricemia defined as serum uric acid >7mg/dL in male and >6mg/dL in female

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 Uric acid in CHC

Table 5. Multivariate analysis of factors associated with hyperuricemia in chronic hepatitis C patients stratified
by gender.

OR 95% CI P value
Male
BMI (Per 1 kg/m2 increased) 1.12 1.05–1.30 0.006
Fibrotic stage
F0-2 1
F3-4 0.27 0.09–0.83 0.02
Female
eGFR (Per 1 ml/min/1.73m2 increased) 0.97 0.95–0.99 0.02
Diabetes
No 1
Yes 3.03 1.11–8.25 0.03

Note: SD: standard deviation; BMI: body mass index; eGFR: estimated glomerular filtration rate; OR: odds ratio; CI:
confidence intervals

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Fig 1. a. Serum uric acid levels in all patients with different fibrotic stages. b. Serum uric acid levels in male patients with different fibrotic stages. c. Serum uric acid levels
in female patients with different fibrotic stages.
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 Uric acid in CHC

Table 6. Stepwise linear regression analysis of factors associated with serum uric acid levels in chronic hepatitis C patients stratified by gender.

B Standard error 95% Confidence Interval for B Beta P value

Male
Age -0.017 0.007 -0.030 -0.004 -0.194 0.01
eGFR -0.020 0.003 -0.026 -0.013 -0.414 <0.001
BMI 0.069 0.021 0.028 0.111 0.215 0.001
F3-4 -0.394 0.165 -0.720 -0.068 -0.165 0.02
Female
eGFR -0.011 0.003 -0.017 -0.004 -0.220 0.002
BMI 0.067 0.020 0.028 0.107 0.231 0.001

Note: Independent variables including age, eGFR, BMI, liver fibrosis and DM. BMI: body mass index; Odds ratio (OR) are for age (per 1 year increased), eGFR (per 1
ml/min/1.73m2 increased), BMI (per 1 kg/m2 increased), liver fibrosis (F3-4 vs F0-2)

https://doi.org/10.1371/journal.pone.0207043.t006

Discussion
In the current study, we demonstrated that the levels of serum uric acid were similar between
CHC patients and the general population. The seroprevalence of hyperuricemia in the current
survey was similar to that in a previous report from Taiwan[20]. Intriguingly, we noticed that
there existed differences in uric acid levels in CHC patients according to gender and disease
severity. Patients with the advanced liver disease had significantly lower uric acid levels. How-
ever, the clinical significance was only present in male patients. The more advanced the liver
fibrosis, the lower the level of uric acid noted in male CHC patients.
Uric acid is the end product of purine metabolism, which is derived from endogenous and
exogenous sources[21]. It is metabolized by the muscles, the intestines and the liver and is cata-
lyzed by xanthine oxidase (XO). Approximately two-thirds of uric acid is excreted in urine,
and the remaining one third is excreted in feces[7]. Female subjects have lower serum uric
acid levels than male patients because of their higher plasma estrogen levels, which may con-
tribute to a higher urate clearance in urine[22]. Several other risk factors have also been docu-
mented as being associated with hyperuricemia[23–26]. CHC patients are viewed as a special
population with metabolic derangement. In the current study, we identified similar risk factors
for hyperuricemia in CHC patients as in the general population[23, 26].
Hyperuricemia was associated with diabetes in particular among female patients. It might
in part attribute to different physiologies between genders. Diabetes, being as a metabolic dis-
order, may enhance the impact of hyperuricemia in females who are with relatively low serum
uric acid in nature [27]. Despite that the pathophysiology remains elusive, the current finding
was in line with several previous studies [28–31].
Hyperuricemia was positively correlated to BMI, which also echoed the previous study[32].
Muscle volume is associated with hyperuricemia. Recently, sarcopenia is paid much attention
in liver disease.[33, 34]. One of the risk populations is patients with catastrophic cirrhosis[34,
35]. Patients enrolled in the current study were planned to receive interferon-based therapy
and all of them were with compensated liver disease. Although BMI could not completely rep-
resent the presence of sarcopenia, BMI did not differ between patients with or without
advanced liver disease (data not shown). Moreover, only nine (2.4%) patients were lean
(BMI<18.5 kg/m2) and none of them was cirrhotic. The issue and interference of sarcopenia
in the current study may be less significant.
Previous studies that have addressed the relationship between liver diseases and uric acid
have been largely restricted to patients with NAFLD or NASH. However, studies regarding the

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 Uric acid in CHC

association of uric acid with disease severities have produced inconsistent results. Some reports
demonstrated that hyperuricemia had no correlation with fibrotic stage in NASH or NAFLD
patients[12, 13, 36, 37]. However, some other Asian studies have shown an inverse correlation
between uric acid and liver fibrosis[11, 38]. On the other hand, the issue of serum uric acid level
has been less often studied in CHC patients. Some have proposed its impact on antiviral treat-
ment efficacy in the previous interferon era[39]. With respect to liver disease severity, Petta, S.
et al. did not observe an association of uric acid level with liver fibrosis in Caucasians[40],
which conflicts with our observation that there exists a dose-response relationship between liver
fibrotic stages and uric acid levels in Chinese patients. Uric acid is metabolized by the liver, and
it has been suggested that progressive liver damage may result in decreased serum uric acid pro-
duction[11]. In addition, it has been suggested that cirrhotic patients have higher uric acid clear-
ance than non-cirrhotic patients[41]. All the pathophysiological mechanisms support our
finding. The percentage of individuals with hyperuricemia in an Italian cohort was only 7.5%,
which may partially explain the insignificant differences in that study[40]. Further studies are
needed to determine whether ethnic differences or diverse genetic backgrounds are responsible
for the inconsistent results. Notably, uric acid metabolism was significantly different between
male and female subjects in our study. When we separated patients by gender, uric acid levels
had an inverse relationship with liver fibrosis only in male patients. The reason for this remains
elusive. It has been suggested that testosterone has a negative impact on liver fibrosis[42].
Whether it enhances uric acid metabolism in male subjects[43] deserves further investigation.
The proportion of anti-hyperuricemic agents prescription in hyperuricemic subjects has
been as low as 2.7% in Taiwan[44]. Only two biopsy-proven CHC patients received anti-
hyperuricemic agents and were excluded before enrollment. The selection bias for interpreting
the association of SUA with liver disease severity in this regard would be limited.
There were some limitations in the current study. Although we adjusted for certain critical
confounders including DM and BMI, some documented risk factors of hyperuricemia includ-
ing nutrition supplements and food intake, diuretics use, definite amounts of alcohol con-
sumption and lifestyle were not taken into consideration precisely. CHC patients were
preselected from a hospital-based cohort who were scheduled to receive interferon-based ther-
apy in the era before direct-acting antivirals. Many of the CHC patients with the deteriorated
renal function may have been excluded which may cause selection bias[45, 46]. CHC patients
also had substantially lower body mass index. This may account for a lower creatinine level
than was observed in the age- and sex-matched controls. We cannot exclude the possibility of
altered uric acid levels in CHC patients provided by a similar renal function to that of the con-
trols. The solution should be to recruit a large cohort of viremic patients without antiviral
treatment from the community. However, that approach may be impractical, especially if his-
tological data by invasive liver biopsy is needed. Notably, it held true that there was a negative
correlation between serum uric acid levels and liver disease severity in CHC patients, regard-
less of the control group selection. In conclusion, hyperuricemia was inversely associated with
liver disease severity in male CHC patients. As the metabolic derangements may be amelio-
rated after antiviral treatment [47, 48], further studies are warranted to clarify the potential
alterations of serum uric acid levels after viral eradication.

Acknowledgments
This study was supported by Kaohsiung Medical University Hospital (KMUH104-4R06 and
KMUH105-5R05) and Kaohsiung Medical University (NSC 103-2314-B-037-055-MY3). The
funders had no role in study design, data collection and analysis, decision to publish, or prepa-
ration of the manuscript.

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 Uric acid in CHC

Author Contributions
Conceptualization: Ching-I Huang, Ming-Lung Yu.
Data curation: Ming-Lun Yeh.
Formal analysis: Ming-Lung Yu.
Methodology: Zu-Yau Lin.
Project administration: Wan-Long Chuang.
Resources: Shinn-Cherng Chen, Meng-Hsuan Hsieh.
Supervision: Chia-Yen Dai.
Validation: Jee-Fu Huang.
Writing – original draft: Tyng-Yuan Jang.
Writing – review & editing: Chung-Feng Huang.

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