Gout and Hyperuricemia

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1 Gout and Hyperuricemia 116 Access publication Dec Is thyroid function associated with hyperuricemia? A discovery of the health-screening population in China Yi-zhou Zou 1,#, Shu-ting Huang 1, 2,#, Hai-yan Lin 3, Xin-li Zhou 1,* Objective: The objective of this study is to investigate thyroid function in people with different serum uric acid (SUA) levels, and to further analyze their potential relationship. Methods: In this cross-sectional study, a total of 4248 health-screening participants treated in Shandong Provincial Hospital affiliated to Shandong University were included. Participants were categorized as hyperuricemic or normouricemic according to their SUA levels, and thyroid dysfunctions were identified according to standard diagnosis guidelines. Results: There is no statistical difference between thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) and SUA levels in both males and females. The related s of TSH, FT4, and FT3 with SUA are -0.07, 0.15, and 0.21 respectively. The contribution of FT3 to SUA is not statistical significance among multiple factors, and vice versa. The test of prevalence rate between certain thyroid dysfunction and euthyroid in hyperuricemia and normouricemia participants showed no statistical significance and Chi-square test results suggest that the distribution of thyroid function conditions are not different in hyperuricemic and normouricemic participants both in males and females. Conclusion: The relationships between TSH, FT4, FT3 and SUA are very weak and, among multiple factors, cannot account for hyperuricemia. There is no difference in the prevalence of certain thyroid dysfunction, as well as the distribution of thyroid function conditions in both males and females with various SUA levels in the total population. Key words: Uric acid; Hyperuricemia; Thyroid function; Thyroid-stimulating hormone 1 Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Shandong Clinical Medical Center of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China. 2 Graduate School, Shandong University of Traditional Chinese Medicine, China 3 Health Examination Center, Shandong Provincial Hospital affiliated to Shandong University, China. # These authors contributed equally to this work. * Corresponding author: Xin-li Zhou, Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, 324 Jing 5 Road, Jinan, , P.R. China. zhouxinli0301@163.com Tel: Submitted on Nov. 24, 2016; accepted on Dec. 19, , Gout and Hyperuricemia. Published by Dong Fong Health Co. LTD in Taiwan. All right reserved. Introduction Uric acid as the end product of purine metabolism [1] and concentration is determined by the balance between production and elimination. Hyperuricemia is considered as the early stage of gout. When serum uric acid becomes greater than the limit of its solubility in serum, crystals precipitate and trigger the inflammatory response central to gout pathogenesis [2]. In spite of primary urate underexcretion, hyperuricema risk factors include gender, age, systemic illnesses, drugs, and particularly some metabolic states [3]. Thyroid related hormones, the key metabolic regulators, are reportedly associated with hyperuricemia. In 1955, Kuzell and colleagues found hypothyroidism in 520 gout patients they examined [4]. Following studies [5-7] further suggest that hyperuricemia accompanies elevated serum creatinine [8] and could be due to a decrease in renal uric acid clearance [9]. On the contrary, Ford [10] and colleagues demonstrated that hyperthyroidism could also cause hyperuricemia, and Sato et al. [11] indicated that renal handling of uric acid in the tubule affects uric acid excretion. Previous studies have not completely settled the existing contradictions regarding the relationship between uric acid metabolism and thyroid function, and

2 117 Association of SUA and thyroid function the underlying mechanism is still obscure. Thus, our data, obtained from individuals undergoing health-screening, provides new insights emphasizing serum uric acid level than former studies. Methods Study population This study used anonymous data and was exempted from participant consents individuals in routine health check-up at Shandong Provincial Hospital affiliated to Shandong University in 2015 were enrolled in this study (IRB: NO ). Subjects were excluded for the following criterion: (1) those without complete tests such as thyroid-stimulating hormone, serum uric acid levels, free thyroxine etc. (2) those on uric acid lowering agents, diuretics, anti-thyroid drugs, or thyroxine (3) those with a history of kidney surgery or known kidney diseases such as chronic nephritis, nephritic syndrome, urinary tract infection etc. (4) those with a history of thyroid or adenohypophysis surgery and previously diagnosed overt hypothyroid or hyperthyroid, thyroid cancer or thyroid nodules. Measurement and classification A structured health check-up questionnaire was completed by each participant, which included personal information and medical history. An anthropometric assessment and laboratory tests were provided on the same day. Height and body weight were measured by an ultrasonic digital scale, and body mass index (BMI) was calculated as weight (kg) divided by height squared (m 2 ). Sitting blood pressure after at least 5 minutes of rest was measured by trained nurses using an automated sphygmomanometer. Fasting venous blood samples were drawn from each individual at 7:30am-8:30am after 8 hours or more of fasting, and the samples were used for the analysis of biochemical values. Serum uric acid (SUA), total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), creatinine (CRE), and blood urea nitrogen (BUN) were determined by standard methods using a Beckman Coulter AU5800 chemistry auto-analyzer. Thyroidstimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) were measured by automated chemiluminescence immunoassay analyzer Siemens Advia CentaurXP. Hyperuricemia was defined as SUA level >420.00μmol/L in men and >360.00μmol/L in women, and normouricemia was defined as SUA level μmol/L in men and μmol/L in women. According to the laboratory test reference range of Shandong Provincial Hospital affiliated to Shandong University and China s guidelines of diagnosis and treatment of thyroid disease [12,13], thyroid dysfunctions were diagnosed using the following criterion: (1) hyperthyroid: TSH <0.55μIU/ ml, FT4>22.7pmol/L and/or FT3>6.5pmol/L (2) subclinical hyperthyroid: TSH<0.55μIU/ml, FT4= pmol/L, FT3= pmol/L (3) hypothyroid: TSH>4.78μIU/ml, FT4<11.5pmol/L (4) subclinical hypothyroid: TSH>4.78μIU/ml, FT4= pmol/ L, FT3= pmol/L. Moreover, euthyroid is regarded as TSH= μIU/ml, FT4= pmol/L, and FT3= pmol/L. Participants who do not meet any of the above criterion were not measured in chi-square test. Statistical analysis Health-screening participants were divided according to the aforementioned criteria. Hypothyroid, subclinical hypothyroid, subclinical hyperthyroid, and hyperthyroid groups were subcategorized into hyperuricaemia and normouricemia groups. The differences in baseline characteristics were tested using the Student s t test for normal distribution continuous data, and chi-square test for categorical data. Pearson correlation was used to examine the related s between TSH, FT4, FT3 and SUA. Multiple linear regression was used to determine the risk factors of FT3 and SUA level. Analyses were conducted separately for men and women in baseline characteristics test and chi-square test. p<0.05 was considered statistically significant. All analyses were performed using IBM SPSS statistics software, version Results General data characteristics A total of 4248 participants of a regular healthscreening were enrolled in our study; their mean age was ± years. Baseline characteristics stratified by gender and SUA level are shown in Table 1. BMI, SBP, DBP, TG, TC, LDL-C, BUN, and CRE were all increased in the groups with hyperuricemia for both males and females, while HDL-C was decreased. On the other hand, there is no significant correlation between TSH, FT3,

3 Association of SUA and thyroid function 118 Table 1. Baseline characteristics of study subjects. Male (n=2566) Female (n=1682) Variables Hyperuricemia Normouricemia p 1 Hyperuricemia Normouricemia p 2 n (%) 699 (27.2%) 1867 (72.8%) 139 (8.3%) 1543 (91.7%) Age (year) a ± ± ± ± <0.001 BMI (kg/m 2 ) a ± ± 3.13 < ± ± 3.26 <0.001 SBP (mmhg) a ± ± < ± ± <0.001 DBP (mmhg) a ± ± < ± ± <0.001 TSH (μiu/ml) a 2.07 ± ± ± ± FT4 (pmol/l) a ± ± ± ± FT3 (pmol/l) a 5.30 ± ± ± ± TC (mmol/l) a 5.45 ± ± 0.96 < ± ± 1.03 <0.001 TG (mmol/l) a 2.22 ± ± 1.36 < ± ± 0.68 <0.001 HDL-C (mmol/l) a 1.12 ± ± 0.28 < ± ± 0.33 <0.001 LDL-C (mmol/l) a 3.24 ± ± ± ± 0.78 <0.001 FPG (mmol/l) a 5.66 ± ± ± ± CRE (μmol/l) a ± ± 9.76 < ± ± 7.49 <0.001 BUN (mmol/l) a 5.68 ± ± ± ± 1.16 <0.001 BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, TSH: thyroid stimulating hormone, FT4: free thyroxine, FT3: free triiodothyronine, TC: total cholesterol, TG: total triglycerides, HDL-C: high density lipoprotein cholesterol, LDL-C: low density lipoprotein cholesterol, FPG: fasting plasma glucose, CRE: creatinine, BUN: blood urea nitrogen, a : expressed as mean ± standard deviation. p 1 <0.05 means differences of variables in male with hyperuricemia vs. normouricemia have statistical significance, p 2 <0.05 means differences of variables in female with hyperuricemia vs. normouricemia have statistical significance. Figure 1. The association between TSH, FT4, FT3 and the SUA (n=4248). TSH: thyroid stimulating hormone, FT4: free thyroxine, FT3: free triiodothyronine. Between TSH and SUA, r=-0.07, Pearson, p<0.001; between FT4 and SUA, r=0.15, Pearson, p<0.001; between FT3 and SUA, r=0.21, Pearson, p< FT4 and SUA levels; in males, FPG also does not show statistically significant difference. The relationships between TSH, FT4, FT3 and the SUA Figure 1 shows the scatter diagram results of the association between TSH, FT4, FT3 and SUA separately in the whole study population, and each spot represents the data of one participant. The relationships between TSH, FT4 and the SUA are extremely weak(r=-0.07 Pearson, p<0.001; r=0.15, Pearson, p<0.001 respectively), and FT3 is weakly correlated with SUA (r=0.21, Pearson, p<0.001), although stronger than the prior two. To further explore the underlying relationship, multiple linear regressions were also applied to determine the risk factors affecting the level of FT3 and SUA in the whole study population. When we used FT3 as the dependent variable, β of SUA was 0.017, p=0.351 (Table 2). Otherwise, when SUA was used as the dependent variable, β of FT3 was 0.012, p=0.351 (Table 3). Above all, both of the results were not statistically significant.

4 119 Association of SUA and thyroid function Table 2. Multiple linear regression results of FT3 (n=4248). non-standardized β S.E. standardized Model Constant <0.001 Sex <0.001 Age <0.001 BMI <0.001 SBP BUN <0.001 CRE <0.001 FPG <0.001 TG LDL-C TSH FT <0.001 SUA S.E.: standard error, BMI: body mass index, SBP: systolic blood pressure, BUN: blood urea nitrogen, CRE: creatinine, FPG: fasting plasma glucose, TG: total triglyceride, LDL-C: low density lipoprotein cholesterol, TSH: thyroid stimulating hormone, FT4: free thyroxine, FT3: free triiodothyronine. Dependent variable: FT3. Model: Enter. All the variables were introduced into the regression equation simultaneously; p<0.05 was considered statistically significant. Table 3. Multiple linear regression results of SUA (n=4248). non-standardized β S.E. standardized Model Constant <0.001 Sex <0.001 Age <0.001 BMI <0.001 SBP <0.001 BUN <0.001 CRE <0.001 FPG <0.001 TG <0.001 LDL-C <0.001 TSH FT FT S.E.: standard error, BMI: body mass index, SBP: systolic blood pressure, BUN: blood urea nitrogen, CRE: creatinine, FPG: fasting plasma glucose, TC: total triglyceride, LDL-C: Low density lipoprotein cholesterol, TSH: thyroid stimulating hormone, FT4: free thyroxine, FT3: free triiodothyronine. Dependent variable: SUA. Model: Enter. All the variables were introduced into the regression equation simultaneously; p<0.05 was considered statistically significant. t t p p Table 4. Examination of the prevalence rate between certain thyroid dysfunction and euthyroid in hyperuricemia and normouricemia participants. Different thyroid function conditions in hyperuricemia and normouricemia participants We calculated participants different thyroid function conditions on the basis of their SUA levels. According to criterion listed before, the study population was divided into five groups: euthyroid, subclinical hypothyroid, hypothyroid, subclinical hyperthyroid, and hyperthyroid. As shown in Table 4, we compared the prevalence of hypothyroid, subclinical hypothyroid, hyperthyroid and subclinical hyperthyroid with euthyroid separately in hyperuricaemia and nomouricemia groups, and the results suggested that there were no statistical significance between certain thyroid dysfunction and euthyroid in both males and females. As shown in Table 5, the data was analyzed separately in males and females that were hyperuricaemic or normouricemic to test the difference in thyroid function conditions as a whole. Chi-square test results show that χ 2 =7.64 in males, p=0.054, and χ 2 =3.06, in females p=0.904, which means the distribution of thyroid function conditions are not significantly different in hyperuricemic and normouricemic participants. Discussion Male (n=2503) Female (n=1660) vs. euthyroid χ 2 p χ 2 p Hyperthyroid Fisher Subclinical hyperthyroid Hypothyroid Subclinical hypothyroid The p<0.05 was considered statistically significant. This cross-sectional study investigated 4248 healthscreening participants in Jinan, the capital of Shandong province of China. The relationship we observed between thyroid function and SUA levels was not statistically different in both males and females. This means that the association between SUA level and thyroid function is at best very weak. At first, we tested the baseline characteristics in males and females and found that the level of TSH, FT4, and FT3 were not significantly different between hyperuricemia and normouricemia groups. Secondly,

5 Association of SUA and thyroid function 120 Table 5. Percentages of thyroid function conditions in hyperuricemia (HUA) and normouricemia (NUA) participants. Male (n=2503) Thyroid function HUA NUA HUA NUA Euthyroid (%) Subclinical hyperthyroid (%) Hyperthyroid (%) Subclinical hypothyroid (%) Hypothyroid (%) χ p The p<0.05 was considered statistically significant. Female (n=1660) scatter diagrams were made to investigate thyroid function indicators in individuals with different SUA levels and explore their potential correlation. Through statistical analysis, the associations between TSH, FT4, FT3 and SUA are all extremely weak, while the related of FT3 reflects the strongest correlation among the three. Next, multiple linear regressions were made between FT3 and SUA bilaterally in order to find correlations among the various risk factors. However, the results show that their interaction is not statistically significant when adding other effective indexes together. Past studies have inconclusively reported associations between hyperuricaemia and thyroid disorders. Therefore, to investigate if SUA correlated with prevalence of thyroid dysfunction, we compared the prevalence of certain thyroid dysfunction and euthyroid in hyperuricemia and normouricemia groups, and examined the distribution of thyroid function conditions in the two distinguishing SUA groups in both genders. There was no significant correlation. Just like Giordano et al. [14], who investigated 46 patients with primary hypothyroidism and primary hyperthyroidism, and reported significantly higher prevalence of hyperuricaemia in patients with hypothyroidism, potential biases could not be avoided due to the limitation of the patient number and the pathological states of thyroid disorders. We could not neglect the fact that a lot of previous studies reporting the correlations between hyperuricemia, gout and thyroid dysfunctions were taken in the population with diagnosed thyroid disorders or uric acid metabolic disorders, and the confounding factors were hard to be excluded adequately. In addition, the direct effect mechanisms between thyroid and uric acid have not been reported as of yet. There are still studies using health-screening populations reporting that hyperthyroid and hypothyroid status were weakly associated with hyperuricaemia, consistent with our results [15]. Moreover, the related s of TSH, FT4, FT3 and SUA indicate a slight hyperthyroid trend in the whole study population, though the difference could not be counted as important risk factors. This is consistent with past studies showing the difference in SUA between hyperthyroid and euthyroid patients being clinically of no significance [16]. One plausible explanation is that thyroid hyperfunction promotes generalized body metabolism, which includes purine metabolism, and accelerates SUA level indirectly. There are some limitations to our study. Firstly, we only observed TSH, FT4, and FT3 which reflect limited angles of thyroid function. In addition, we identified that there is no obvious linear dependence between TSH, FT4, FT3 and SUA, but could not exclude other potential correlations, such as the balance between TSH and FT4 or the transformation rate of thyroxine. Finally, we used health-screening subjects, which are more representative of the general population than previous hospital-based studies. In conclusion, the relationships between TSH, FT4, FT3 and SUA are very weak, and cannot explain hyperuricemia. The prevalence of certain thyroid dysfunction, and the distribution of thyroid function conditions are not different in hyperuricemic and normouricemic individuals of both genders. Conflicts of interest statement The authors who have taken part in this study declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript. Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No ) and Promotive Research Fund for Excellent Young and Middle-aged Scientists of Shandong Province (Grant No. BS2011SW034). We also thank the Health Examination Center of Shandong Provincial Hospital affiliated to Shandong University for its support of Health Examination database. References 1.Arthur CG, John EH. Urine Formation by the Kidneys: I. Glomerular

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