Introduction
Hyperuricemia, a metabolic state characterized by elevated serum uric acid levels, can lead to gout [
1]. Due to changes in dietary factors and lifestyles, the prevalence of gout is increasing globally, posing a serious public health concern [
2]. Epidemiological data indicate that hyperuricemia is more prevalent in high-income countries than in developing regions [
3‐
5]. The National Health and Nutrition Examination Survey reported that the prevalence of hyperuricemia among US adults was 20.1% during 2015–2016 [
6]. A Chinese health survey found that the prevalence of hyperuricemia among individuals aged 20–80 was 25.1% in males and 15.9% in females [
7]. In addition to gout, hyperuricemia is an independent risk factor for metabolic diseases (such as diabetes, metabolic syndrome, and hyperlipidemia), chronic kidney disease and cardiovascular diseases [
8‐
12]. Therefore, it is crucial to identify the related risk factors and high-risk individuals for hyperuricemia.
Thyroid hormones play an important role in regulating biological metabolism, and free thyroxine (FT4) and thyroid-stimulating hormone (TSH) are regulated by a negative feedback mechanism in the hypothalamic-pituitary-thyroid axis. We searched PubMed and Web of Science with the terms “(thyroid hormones sensitivity OR thyroid hormones) AND (metabolic health OR metabolic disorder)” for papers published from database inception to Dec 31, 2022. The separate relationships of TSH and FT4 with hyperuricemia have been reported. We found that previous studies have reported the associations between hypothyroidism and various metabolic disorders, including dyslipidemia [
13,
14], obesity [
15], diabetes [
16,
17] and hyperuricemia [
18,
19]. However, the reported relationships between FT4 or TSH alone and hyperuricemia were inconsistent. Thyroid hormones sensitivity is a newly proposed functional entity that takes into account both FT4 and TSH levels. Both high FT4 and high TSH are present in the resistance to thyroid hormones syndrome, reflecting energy balance problems. It was first reported by Refetoff et al. [
20] and is characterized by elevated serum levels of FT4 and free triiodothyronine accompanied by normal or slightly elevated thyrotropin [
21]. Subsequently, researchers have proposed indices representing impaired sensitivity to central thyroid hormones, including the thyroid feedback quantile-based index [TFQI] [
22], parametric thyroid feedback quantile-based index (PTFQI) [
22], thyrotrophic thyroxine resistance index (TT4RI) [
23] and thyroid-stimulating hormone index (TSHI) [
24]. Previous studies have shown that impaired thyroid hormones sensitivity is associated with prediabetes [
25], diabetes [
22,
26], cardiovascular disease [
27], metabolic syndrome [
22], obesity [
27], hypertension [
28], nonalcoholic fatty liver [
29], hyperhomocysteinaemia [
30] and osteoarthritis [
31]. Notably, Sun et al. [
27] reported that impaired sensitivity to thyroid hormones is associated with a higher risk of hyperuricemia in patients with subclinical hypothyroidism. However, further studies are needed to determine whether impaired sensitivity to thyroid hormones is associated with hyperuricemia in the euthyroid population. Currently, there is a lack of interventions to address impaired sensitivity to thyroid hormones. It is noteworthy that mediation analysis can reveal indirect pathways for potential intervention strategies, particularly through nonpharmaceutical and modifiable factors such as lifestyle changes [
32,
33].
In this study, we aimed to investigate the relationship between impaired sensitivity to thyroid hormones and hyperuricemia in the euthyroid population and quantify the direct and indirect associations by body mass index (BMI), thus providing potential interventions for those with impaired thyroid hormones sensitivity to achieve metabolic health status from the perspective of energy balance.
Discussion
Using mediation analysis, we quantified the direct and indirect associations between impaired sensitivity to thyroid hormones and hyperuricemia through BMI in a large sample of euthyroid individuals. We found that impaired thyroid hormones sensitivity determined by the TFQI, PTFQI, TT4RI and TSHI was independently associated with prevalent hyperuricemia and that BMI significantly mediated the associations. To our knowledge, this is the first study to quantify the extent to which BMI mediates the association of impaired sensitivity to thyroid hormones with metabolic status. Our findings indicated that active weight control may be a practical intervention for individuals with impaired sensitivity to thyroid hormones to achieve metabolic health and homeostasis.
Physiologically, TSH and FT4 are regulated by a negative feedback mechanism in the hypothalamic-pituitary-thyroid axis. The cooccurrence of high TSH and high FT4 levels represents acquired resistance to thyroid hormones, which is a newly proposed clinical entity. In 2019, Laclaustra et al. [
22] proposed the thyroid hormones sensitivity index (TFQI) to track the risk of metabolic syndrome, diabetes and diabetes-related mortality in euthyroid individuals. Previous studies have also confirmed the adverse effect of impaired sensitivity to thyroid hormones. For example, thyroid hormones resistance, as represented by TFQI, was significantly associated with an increased risk of diabetes and hypertension in euthyroid individuals according to a cross-sectional study [
26]. In addition, a study showed that impaired sensitivity to thyroid hormones was associated with decreased kidney function [
44]. A cross-sectional study of 8,957 adults with normal thyroid function reported that TFQI, PTFQI, TSHI and TT4RI were significantly associated with higher homocysteine levels [
30]. A recent study reported a positive relationship between impaired sensitivity to thyroid hormones and hyperuricemia among individuals with subclinical hypothyroidism. Our findings supplemented the evidence that impaired sensitivity to thyroid hormones was also associated with hyperuricemia in euthyroid individuals, reinforcing an adverse effect of impaired sensitivity to thyroid hormones in the general population.
Previous studies on the separate relationships of TSH and FT4 with uric acid have yielded inconsistent results. One study found a negative correlation between TSH and uric acid [
45], while another reported a positive association between elevated TSH levels and hyperuricemia regardless of age or sex [
46]. On the other hand, a cross-sectional study [
47] showed a linear positive association between FT4 level and serum uric acid among individuals without thyroid dysfunction. Our study highlighted the clinical importance of considering the interaction between TSH and FT4 (i.e., impaired sensitivity to thyroid hormones) on hyperuricemia and metabolic status, which partially explains the inconsistent findings from previous studies.
A recent study found a relationship between impaired sensitivity to thyroid hormones and obesity [
27]. We investigated the direct and indirect effects of impaired thyroid hormones sensitivity on hyperuricemia through BMI. Our study indicated that BMI significantly mediated 32.3–39.6% of the associations between impaired sensitivity to thyroid hormones and hyperuricemia. Currently, there is no clinical consensus or intervention recommendations for individuals with impaired sensitivity to thyroid hormones. Our findings provide a practicable behavioral intervention through weight management for individuals with impaired sensitivity to thyroid hormones to achieve metabolic health. Several potential mechanisms may explain the association between thyroid hormones sensitivity and hyperuricemia mediated through BMI. Studies have demonstrated that serum TSH can promote weight gain, probably by stimulating preadipocyte differentiation and inducing adipogenesis [
48,
49]. In addition, Nannipieri et al. [
50] found that thyroid gene expression (especially TSH receptor) was reduced and plasma TSH concentration was higher among those with obesity. TSH exerts a beneficial effect on adipocytes through the TSH receptor to induce weight loss. These biological mechanisms indicate that weight intervention could potentially improve sensitivity to thyroid hormones. Moreover, aging could be another explanation linking thyroid hormones sensitivity and metabolic status [
51,
52]. In recent years, the technique of mitochondria-targeting nanotechnology has provided broad prospects for the treatment of cancer and other mitochondria-related diseases (such as cardiovascular and neurological diseases), while the potential for impaired thyroid hormones sensitivity and hyperuricemia has not been studied. It is hoped that these advanced technologies could provide alternative therapies for metabolic health and hemostasis [
53].
A major strength of this study relies on the large sample size. Individuals with higher levels of thyroid hormone sensitivity indices should be aware of the increased risk of hyperuricemia even with normal thyroid function. In addition, we estimated a potential pathway from impaired thyroid hormones sensitivity to hyperuricemia through BMI. To our knowledge, this is the first study to investigate the indirect effect of impaired thyroid hormones sensitivity on metabolic health through modifiable risk factors, which provided a behavioral recommendation through active weight management for individuals with impaired sensitivity to thyroid hormones. However, several limitations should be acknowledged. First, this cross-sectional study cannot establish longitudinal or causal associations of thyroid hormones sensitivity, BMI and hyperuricemia, and the possibility of reverse causality cannot be ruled out. Although we adjusted for several confounding factors, there could be residual confounding bias (e.g., thyroid-related antibody level) and recall bias in the effect estimation. Further studies (e.g., Mendelian randomization research) on the causal inference between thyroid hormones sensitivity and hyperuricemia are expected. Second, our study was based on the Chinese population, and the generalization of our findings requires further validation. The benefit of active weight management for individuals with impaired sensitivity to thyroid hormones should be evaluated in further clinical studies.
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