Increased waist circumference is independently associated with hypothyroidism in Mexican Americans: replicative evidence from two large, population-based studies

Reportedly 5-10% of the United States population has subclinical or clinical hypothyroidism[1, 2]. It is of clinical interest that differential prevalence estimates of hypothyroidism are influenced by age[3], sex , ethnicity[4] and other risk factors like presence of type 2 diabetes (T2D)[5, 6]. Further, Mexican American and white ethnicity is associated with a high risk of thyroid dysfunction[3, 7‐9]. Knowledge of these risk factors is crucial to identify hypothyroidism in its nascent, subclinical stage since it is associated with preventable but dangerous complications like hyperlipidemia, insulin resistance, atherosclerosis and additional risks to mothers and infants[10]. The accuracy of traditional strategies to detect thyroid dysfunction that use a constellation of symptoms and signs has been greatly increased by recent improvements in the assays for thyroxine and thyroid stimulating hormone (TSH). For example, Helfand and Crapo[10] have described that the sensitivity and specificity of TSH to confirm thyroid disease is 98% and 92%, respectively. In primary care settings however, the observed accuracy is not as high. For example, the positive predictive value of a low TSH to detect hyperthyroidism has been reported to be only 24% while that of a high TSH to detect hypothyroidism is only 6%[10]. Improved screening programs for thyroid dysfunction will therefore need detection of differential thyroid dysfunction risks across epidemiologically diverse groups.

There is now burgeoning evidence that vindicates a potential link between thyroid dysfunction and metabolic syndrome (MS). Even in a euthyroid state, a high normal TSH is strongly associated with MS[11]. Similarly, in the National Health and Nutrition Examination Survey (NHANES) 2007–2008 data[4], body mass index (BMI) and waist circumference (WC) were associated with serum TSH levels. More recently, the Health, Ageing and Body Composition Study[12] reported that unit increase in TSH was associated with a 3% increase in the odds of MS. It is also instructive in this regard that mutations in the thyroid hormone receptor beta (THRB) gene are associated with increased energy intake, hyperphagia and resting energy expenditure[13]. It is noteworthy, however, that MS represents a constellation of correlated phenotypic traits that together capture a wide spectrum of metabolic disorders including prediabetes, type 2 diabetes, insulin resistance, hypertension, obesity and dyslipidemia[14]. However, the relative and comparative contribution of these individual components of MS to thyroid dysfunction is currently unknown.

Since Mexican Americans are at an increased risk of MS, here we investigated the associations of MS-related traits with indicators of thyroid dysfunction in Mexican Americans from two large studies – San Antonio Family Heart Study (SAFHS)[15, 16] and NHANES 2007–10. The former study is uniquely suited to investigate the hypothesized association between MS and thyroid function in families who are at a high risk of both MS and thyroid abnormalities while the latter study provides a rich, nationally representative population based setting. We aimed to investigate and replicate the MS-thyroid function nexus in these epidemiologically distinct scenarios using an appropriate and robust analytical approach. Here we report our finding that central obesity – a component of MS – is additively, independently and significantly associated with altered thyroid function.

Our results demonstrate that WC, as a measure of central obesity, is a significant and independent indicator of thyroid dysfunction in Mexican Americans. These results are substantiated by the fact that the associative patterns were consistently observed in two large and disparate studies on the same ethnic population. Interestingly, the prevalence of clinical and subclinical hypothyroidism was higher in the SAFHS than that in the NHANES 2007–10 participants. This finding is important because subjects with subclinical hypothyroidism are at a higher risk of eventual overt hypothyroidism in future as compared to the euthyroid subjects[27] and our results imply that such subjects may be concentrated within families. Our findings therefore indicate that central obesity may be not only an important player in the multifactorial web of thyroid dysfunction but may also contribute to the development of future clinical hypothyroidism by predicting the subjects who are currently at a high risk of subclinical hypothyroidism.

The prevalence of subclinical and clinical hypothyroidism estimated in this study may be somewhat higher than its true population value for two reasons. First, there is substantial evidence in the literature supporting the view that TSH values may be increased in obesity and morbid obesity[28‐31]. Second, the TSH cutoff used to define hypothyroidism here is restrictive. It is not uncommon to use 5 μU/ml as the upper limit of normal TSH[19, 32, 33]. If this high cutoff value is used then expectedly the prevalence of hypothyroidism will be less than that reported here. We chose to use the cutoff of 3 μU/ml for the following three reasons: i) The main objective of this study was not to estimate prevalence of hypothyroidism but rather to compare the prevalence estimates across categories of predictor variables like waist circumference; ii) The criteria used for diagnosis of clinical thyroid states used in this study are based on clinical practice guidelines recommended by the American Association of Clinical Endocrinologists and the American Thyroid Association[34] and therefore follow the standards-of-care; and iii) Using these criteria, cross-ethnicity comparisons in American populations can be undertaken in future even if we have not included other ethnic groups in this study. In addition, we used TFI as a surrogate measure of thyroid function. This novel measure has the advantage that it combines the information content of TSH, FT3 and FT4 in the identification of hypothyroidism. However, we would like to point out that the clinical use of TFI has thus far not been validated in other populations and should be considered only illustrative rather than conclusive.

Biological plausibility in support of our findings is provided by a series of recent observations. First, thyroid stimulating hormone receptors (TSHR) are present in tissues other than the thyroid, especially in differentiating adipocytes[35]. Whilst it is conceivable that increasing TSHR concentration in obesity may attract additional release of TSH through a positive feedback to the pituitary, direct data in this regard are currently unavailable. As explained by Skudlinski et al.[36] and Mueller et al.[37], however the interactions between TSH and TSHR are very complex and therefore expectation of a simple positive feedback loop conjectured here may be overly simplistic. Second, thyroid hormone has been shown[38] to regulate expression of the gene encoding apolipoprotein M by binding to a hormone response element in the promoter of this gene. It is noteworthy that apolipoprotein M plays an important role in MS and obesity[38‐40]. Third, in the 3 T3-L1 adipocytes it was observed[41] that in vitro treatment with triiodothyronine and thyroxine increased the expression of the gene encoding Plasminogen activator inhibitor 1, a key contributor in the inflammatory and cardiovascular complications of obesity. Fourth, triiodothyronine regulates the expression of the apolipoprotein AV gene, another important contributor to the complex pathogenesis of obesity and its complications[42]. Considered in totality, these studies lend biological credibility to our observation that WC is associated with thyroid function although the exact mechanism of this association remains unknown.

Our results are conceptually in agreement with the observed association of WC-based indices with altered thyroid function in other populations like Chinese children[43], Turkish women[44], other US ethnic groups[4], Italian euthyroid subjects[45] and Korean adults[46]. It is interesting that these studies have addressed different aspects of metabolic syndrome but none of these studies has directly and simultaneously assessed associations of the components of MS with thyroid dysfunction. For example, the study by Kitahara et al.[4], demonstrated that in a predominantly non-Hispanic white population of US men and women, higher values of BMI and WC were associated with increased TSH levels. However, a direct comparison of WC and BMI was not done in that study. Similarly, two studies[44, 45] have specifically evaluated the association with a focus on insulin sensitivity and resistance with thyroid dysfunction. The study by Jung et al., used WHR as the index of central obesity and found similar results as those of ours but they did not include all the components included in this study. As a consequence of these differences a direct comparison of our results with other studies is not possible but all these studies support the paradigm that obesity and thyroid dysfunction are associated with each other.

Some limitations need to be considered before generalizing these results. First, both SAFHS and NHANES 2007–10 studies did not permit a direct investigation of a predictive value of future hypothyroidism – an important requirement before central obesity can be considered as a marker of thyroid dysfunction. Also, it has been argued that hypothyroidism itself may lead to obesity[47]. The direction of causal pathways cannot be established from this study. Second, we did not use the age-specific diagnostic criteria for defining hypothyroidism that are now in vogue[48]. However, since our results were adjusted for age, age², sex and their interactions, we do not anticipate that our results would be influenced by any latent misclassification. Third, both SAFHS and NHANES 2007–10 datasets are, by design, cross-sectional in nature and follow-up data on these subjects is not available. Our reasoning that waist circumference might contribute to an increased risk of clinical hypothyroidism by predicting existing subclinical hypothyroidism is only a notional argument and can be affirmed only by longitudinal studies. Fourth, the reasons for some differences observed between males and females in the two SAFHS and NHANES 2007–10 datasets (for example, WC was significantly associated with TFI in females in SAFHS but in males in NHANES 2007–2010) are unclear and need to be investigated in future studies. It is possible that these significance values are primarily a result of the gender differential across the two datasets (SAFHS had 61% females while NHANES 2007–2010 had only 48% females). However, other reasons of biological of epidemiological dispositions cannot be overruled. Nevertheless, the fact that sex-adjusted results showed significant association of WC with TFI in both datasets demonstrates that the stratification due to sex may be minimal. Fifth, in our study we used the recommended[49] cutoffs for WC and BMI however there is now a growing opinion that “metabolically healthy obese” (MHO) subgroup[50] of MS is a special group with subclinical obesity or an overweight status that is associated with increased cardiovascular risks. Our study cannot directly comment on this but it is conceivable that this group may also be associated with altered thyroid disease risks. Future studies need to consider if central and general obesity are also associated with MHO status and therefore are able to identify individuals with increased likelihood of thyroid dysfunction.

Lastly, for dichotomizing the WC values we used cutoffs of ≥102 cm in men and ≥88 cm in women. While these cutoffs have been previously used for all US populations[49], lower cutoffs – especially those associated with increased likelihood of cardiovascular diseases – may provide even more sensitive prediction of thyroid dysfunction at the expense of specificity. The IDF recommends a cutoff of ≥90 cm and ≥80 cm for men and women of Mexican American and Hispanic origin[51]. As demonstrated by Ford et al.[52], these differences in the cutoffs can significantly influence the estimates of prevalence of abdominal obesity. At this time it is unclear how these definitions might impact the association of central obesity with thyroid dysfunction. Therefore, additional studies are required to investigate the potential effect of sliding cutoffs on the association of dichotomized WC with thyroid dysfunction.

Our study has an important indirect implication. Combined with the results of previous studies our results raise the possibility of considering central obesity as a screening adjunct to detect thyroid dysfunction. Recommendations for thyroid disease screening vary widely. The American Thyroid Association recommends[53] beginning screening at 35 y with 5-yearly follow-ups. The American College of Physicians recoomends screening in women over 50 who have at least one symptom suggestive of thyroid disease[54]. The American Academy of Family Physicians recommends[55] screening for high risk populations but the list of high-risk groups includes diabetes, autoimmune disorders, women with a history of thyroid disease, pregnant women and women over 35 years. The American Association of Clinical Endocrinologists recommends screening before childbearing age or pregnancy or during the first trimester[56]. Despite these varied recommendations the emerging common thread is that thyroid screening is likely to be beneficial in high-risk populations. In this vein, our observations raise the possibility that screening for thyroid dysfunction in Mexican Americans based on waist circumference, especially at younger ages, may yield additional benefits. Future studies need to carefully address this possibility.

In two disparate and large population based studies of Mexican Americans, we found that WC is an independent predictor of thyroid function. This association is independent of age, gender and BMI. These results implore that in high-risk, high-prevalence populations like Mexican Americans, consideration needs to be given to WC as a potential screening tool for thyroid dysfunction Future studies need to evaluate the screening benefits, harms and costs associated with prediction of incident thyroid dysfunction based on current evidence of central obesity.