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Thyroid disorders in Brazil: the contribution of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Abstract

Thyroid disorders are common diseases, both in Brazil and worldwide. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study that investigates cardiovascular diseases, diabetes, and associated factors, including non-classical cardiovascular risk factors such as thyroid function. Thyroid function was classified according to thyrotropin stimulating hormone (TSH), free thyroxine (FT4), and use of medication to treat thyroid disorders, after excluding participants who reported use of any medication that could alter the results of the TSH and FT4 tests. All analyses included in this review are cross-sectional using baseline data (2008 to 2010). The results showed an association of subclinical thyroid disorders with biomarkers of subclinical atherosclerosis, measured by carotid intima-media thickness and coronary artery calcium, insulin resistance, metabolic syndrome, and some psychiatric disorders. No association was found with the biomarker of inflammation high-sensitivity C-reactive protein, or changes in pulse wave velocity or heart rate variability.

Subclinical thyroid diseases; Hyperthyroidism; Hypothyroidism; Subclinical atherosclerosis; Cardiovascular diseases; Mental health


Introduction

The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study with 15,105 civil servants from six cities in Brazil. The main objective of the study is to investigate the incidence of cardiovascular diseases and diabetes, and their associated factors (11. Aquino EM, Barreto SM, Bensenor IM, Carvalho MS, Chor D, Duncan BB, et al. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): objectives and design. Am J Epidemiol 2012; 175: 315–324, doi: 10.1093/aje/kwr294.
https://doi.org/10.1093/aje/kwr294...
33. Bensenor IM, Griep RH, Pinto KA, Faria CP, Felisbino-Mendes M, Caetano EI, et al. Routines of organization of clinical tests and interviews in the ELSA-Brasil investigation center. Rev Saude Publica 2013; 47(Suppl 2): 37–47, doi: 10.1590/S0034-8910.2013047003780.
https://doi.org/10.1590/S0034-8910.20130...
). However, the study attempts to capture not only the profile of classical risk factors associated with cardiovascular disease, but also the association of non-classical risk factors, such as migraine headaches, neighborhood characteristics, social capital, and other psychosocial exposures with cardiovascular diseases. In terms of non-classical risk factors, subclinical thyroid diseases were included as a factor that may be associated not only with cardiovascular disease but also with chronic kidney disease, cognitive impairment, insulin resistance, metabolic syndrome, and mental health.

Most information about chronic diseases in the literature comes from large cohort studies in the United States and Western Europe, and there is little information about non-classical risk factors associated with cardiovascular disease in low-middle income countries like Brazil. Information about thyroid disease epidemiology in Brazil is scarce, but the studies that do exist suggest a high burden associated with thyroid disorders in the country (44. Diaz-Olmos R, Nogueira AC, Penalva DQ, Lotufo PA, Benseãor IM. Frequency of subclinical thyroid dysfunction and risk factors for cardiovascular disease among women at a workplace. Sao Paulo Med J 2010; 128: 18–23, doi: 10.1590/S1516-31802010000100005.
https://doi.org/10.1590/S1516-3180201000...
66. Sichieri R, Baima J, Marante T, de Vasconcellos MT, Moura AS, Vaisman M. Low prevalence of hypothyroidism among black and Mulatto people in a population-based study of Brazilian women. Clin Endocrinol 2007; 66: 803–807, doi: 10.1111/j.1365-2265.2007.02816.x.
https://doi.org/10.1111/j.1365-2265.2007...
) Therefore, data from the ELSA-Brasil is a very good opportunity to analyze, in a multicenter sample, the relationship between subclinical thyroid disorders and other conditions in a large Brazilian sample.

Study design and objectives

The main objectives of the ELSA-Brasil are to study the incidence and progression of cardiovascular diseases and diabetes and associated factors such as biological, environmental, psychological, and social characteristics associated with these diseases. ELSA-Brasil is a multicenter prospective cohort study with investigation centers located in six cities in Brazil: Salvador, Vitória, Belo Horizonte, Rio de Janeiro, São Paulo, and Porto Alegre. All active and retired civil servants of these institutions aged between 35 to 74 years were eligible for the study. The exclusion criteria included current or recent pregnancy (at least four months before the first interview), intention to quit work in the near future, any communication impairment, or residence out the metropolitan area of the Research Center in each city. The baseline examinations were conducted from August 2008 to December 2010. After that, the participants were invited for the second visit, with further interviews and examinations, from August 2012 to December 2014. At the time of this report, the third visit was ongoing, which began in February 2017 and is planned to end in December 2018. In this review, we used only cross-sectional data from the baseline examination. Besides the visits, the study contacts all the participants by telephone once a year to ask about health outcomes, including any reason for hospitalization in the previous year, report of cardiovascular events, and cancer diagnosis (11. Aquino EM, Barreto SM, Bensenor IM, Carvalho MS, Chor D, Duncan BB, et al. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): objectives and design. Am J Epidemiol 2012; 175: 315–324, doi: 10.1093/aje/kwr294.
https://doi.org/10.1093/aje/kwr294...
).

Recruitment was performed according to sex, age, and socioeconomic status. The ELSA-Brasil sample is not representative of the country’s population, as the participants have higher levels of education and income status compared to the general Brazilian population. The applicability of the ELSA-Brasil estimates is supported by similarities in the prevalence of behavioral risk factors and chronic diseases, which were assessed using similar procedures to the Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico (VIGITEL), a telephone-based behavioral risk factor survey that is conducted annually, with adults living in Brazil (77. Brasil. Ministério da Saúde. Departamento de Análise de Situação de Saúde. Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico, Vigitel, 2010 Surveillance of Risk and Protective Factors for Chronic Diseases, Vigitel, 2010. Brasília: Ministério da Saúde, 2011.). However, the ELSA-Brasil was designed to evaluate associations between risk factors and cardiovascular diseases and diabetes.

The sample size was calculated considering an alpha value of 5%, statistical power of 80%, exposure prevalence of 20%, and relative risk of 2.0 for the incidence of myocardial infarction or diabetes, in approximately 6,400 subjects. This number was more than doubled to allow analyses by sex (11. Aquino EM, Barreto SM, Bensenor IM, Carvalho MS, Chor D, Duncan BB, et al. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): objectives and design. Am J Epidemiol 2012; 175: 315–324, doi: 10.1093/aje/kwr294.
https://doi.org/10.1093/aje/kwr294...
).

The baseline examination included a long questionnaire asking about sociodemographic risk factors, family history, morbidity, cardiovascular risk factors, psychosocial exposures, mental health, diet, and physical activity (88. Chor D, Alves MG, Giatti L, Cade NV, Nunes MA, Molina Mdel C, et al. Questionnaire development in ELSA-Brasil: challenges of a multidimensional instrument. Rev Saude Publica 2013; 47(Suppl 2): 27–36, doi: 10.1590/S0034-8910.2013047003835.
https://doi.org/10.1590/S0034-8910.20130...
). Thyrotropin (TSH) and free thyroxine (FT4) were measured using a third-generation immunoenzymatic assay (Siemens, USA) in serum obtained from centrifuged venous blood samples after overnight fasting (99. Fedeli LG, Vidigal PG, Leite CM, Castilho CD, Pimentel RA, Maniero VC, et al. Logistics of collection and transportation of biological samples and the organization of the central laboratory in the ELSA-Brasil. Rev Saude Publica 2013; 47(Suppl 2): 63–71, doi: 10.1590/S0034-8910.2013047003807.
https://doi.org/10.1590/S0034-8910.20130...
). In this review, reference range levels were 0.4–4.0 mIU/L for TSH and 10.3–24.45 pmol/L for FT4, similar to other Brazilian studies (1010. Olmos RD, Figueiredo RC, Aquino EM, Lotufo PA, Bensenor IM. Gender, race and socioeconomic influence on diagnosis and treatment of thyroid disorders in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Braz J Med Biol Res 2015; 48: 751–758, doi: 10.1590/1414-431X20154445.
https://doi.org/10.1590/1414-431X2015444...
).

ELSA-Brasil participants were classified into five categories of thyroid function, according to TSH and FT4 levels and information about use of medication to treat thyroid disorders: clinical hyperthyroidism (low serum TSH and high FT4 levels or use of medication to treat hyperthyroidism), subclinical hyperthyroidism (low serum TSH, normal FT4 levels, and no use of drugs to treat thyroid diseases), euthyroidism (normal TSH and no use of thyroid drugs), subclinical hypothyroidism (high TSH levels, normal FT4 levels, and no use of drugs to treat thyroid diseases), and clinical hypothyroidism (high TSH and low FT4 levels, or use of levothyroxine to treat hypothyroidism). Accordingly, the definition of subclinical thyroid disease included only participants who did not use any drugs to treat thyroid disorders. Participants with overt thyroid disorders were excluded from the analyses. We also excluded participants using drugs that could interfere with thyroid function: amiodarone, carbamazepine, carbidopa, phenytoin, furosemide, haloperidol, heparin, interferon, levodopa, lithium, metoclopramide, propranolol, primidone, rifampicin, and valproic acid. The examination included a standard 12-lead electrocardiogram (ECG); measurement of pulse wave velocity (PWV) obtained using a validated noninvasive automatic device (Complior SP; Artech Medical, France) (1111. Peixoto de Miranda ÉJ, Bittencourt MS, Goulart AC, Santos IS, Mill JG, Schmidt MI, et al. Lack of association between subclinical hypothyroidism and carotid-femoral pulse wave velocity in a cross-sectional analysis of the ELSA-Brasil. Am J Hypertens 2017; 30: 81–87, doi: 10.1093/ajh/hpw117.
https://doi.org/10.1093/ajh/hpw117...
); heart rate variability to study the balance of the autonomic system determined from a 10 min ECG recording obtained in the supine position from DII derivation at 250 Hz (WinCardio; Micromed, Brazil) (1212. de Miranda ÉJFP, Hoshi RA, Bittencourt MS, Goulart AC, Santos IS, Brunoni AR, et al. Relationship between heart rate variability and subclinical thyroid disorders of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Braz J Med Biol Res 2018; 51: e7704, doi: 10.1590/1414-431X20187704.
https://doi.org/10.1590/1414-431X2018770...
); carotid intima-media thickness (CIMT) using carotid ultrasonography of both common carotid arteries using a linear transducer of 7.5 MHz (Aplio XG, Toshiba, Japan) with axial resolution of approximately 0.10 mm (1313. Santos IS, Bittencourt MS, Oliveira IR, Souza AG, Meireles DP, Rundek T, et al. Carotid intima-media thickness value distributions in the Brazilian Longitudinal Study of AdultHealth (ELSA-Brasil). Atherosclerosis 2014; 237: 227–235, doi: 10.1016/j.atherosclerosis.2014.09.004.
https://doi.org/10.1016/j.atherosclerosi...
,1414. Santos IS, Alencar AP, Rundek T, Goulart AC, Barreto SM, Pereira AC, et al. Low impact of traditional risk factors on carotid intima-media thickness: The ELSA-Brasil cohort. Arterioscler Thromb Vasc Biol 2015; 35: 2054–2059, doi: 10.1161/ATVBAHA.115.305765.
https://doi.org/10.1161/ATVBAHA.115.3057...
); and measurement of coronary artery calcium (CAC) at the São Paulo Research Center as part of the baseline examination using a 64 detector computed tomography scanner (Brilliance 64; Philips Healthcare, The Netherlands). CAC is reported as Agatston units. CAC severity was further categorized with a cut-off at 100 points (<100 or ≥100) (1515. Peixoto de Miranda ÉJF, Bittencourt MS, Staniak HL, Pereira AC, Foppa M, Santos IS, et al. Thyrotrophin levels and coronary artery calcification: Cross-sectional results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Clin Endocrinol 2017; 87: 597–604, doi: 10.1111/cen.13393.
https://doi.org/10.1111/cen.13393...
).

Other measurements

Height and weight were measured using light clothes, and body mass index was calculated as weight divided by squared height in meters. Blood pressure (BP) measurements were taken using a validated Omron HEM 705CPINT (USA) oscillometric device. Three measurements were taken at one-min intervals. The mean of the two latter blood pressure measurements was considered as the participant’s casual blood pressure. Hypertension was defined as use of medication to treat hypertension, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg. Diabetes was defined as a previous medical history of diabetes, use of medication to treat diabetes, fasting plasma glucose ≥6.99 mmol/L, 2 h plasma glucose ≥11.1 mmol/L, or HbA1C ≥6.5 (1616. Schmidt MI, Hoffmann JF, de Fátima Sander Diniz M, Lotufo PA, Griep RH, Bensenor IM, et al. High prevalence of diabetes and intermediate hyperglycemia - The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetol Metab Syndr 2014; 6: 123, doi: 10.1186/1758-5996-6-123.
https://doi.org/10.1186/1758-5996-6-123...
). For measurement of fasting and post-load glucose, we used the hexokinase method (ADVIA 1200, Siemens), the immunoenzymatic assay for fasting and post-load insulin, and high-performance liquid chromatography (HPLC) (Bio-Rad Laboratories, USA) for glycated hemoglobin. Dyslipidemia was defined as LDL cholesterol ≥3.37 mmol/L or use of lipid-lowering medications. Low HDL-cholesterol was defined as HDL cholesterol <1.03 mmol/L in men and <1.29 mmol/L in women. Hypertriglyceridemia was defined as serum triglyceride levels ≥1.69 mmol/L. The enzymatic colorimetric assay (ADVIA 1200, Siemens) was used to measure total and HDL-cholesterol and triglycerides. LDL-cholesterol was calculated using the Friedewald equation, except for cases with elevated triglyceride levels (>4.52 mmol/L), when an enzymatic colorimetric assay was used (ADVIA 1200, Siemens). CKD-Epi was used to calculate the glomerular filtration rate (GFR) (1717. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604–612, doi: 10.7326/0003-4819-150-9-200905050-00006.
https://doi.org/10.7326/0003-4819-150-9-...
). Chronic kidney disease (CKD) was also defined as GFR <60 mL · min−1 · (1.73 m2)−1 and concomitance of albuminuria, according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and previously published data on CKD in the ELSA-Brasil (Definition 2). Albuminuria was defined according to the albumin/creatinine ratio (1818. Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013; 158: 825–830, doi: 10.7326/0003-4819-158-11-201306040-00007.
https://doi.org/10.7326/0003-4819-158-11...
).

Frequency of thyroid dysfunction and use of medication to treat thyroid diseases

Few studies have reported information about prevalence of thyroid diseases in Brazil (44. Diaz-Olmos R, Nogueira AC, Penalva DQ, Lotufo PA, Benseãor IM. Frequency of subclinical thyroid dysfunction and risk factors for cardiovascular disease among women at a workplace. Sao Paulo Med J 2010; 128: 18–23, doi: 10.1590/S1516-31802010000100005.
https://doi.org/10.1590/S1516-3180201000...
66. Sichieri R, Baima J, Marante T, de Vasconcellos MT, Moura AS, Vaisman M. Low prevalence of hypothyroidism among black and Mulatto people in a population-based study of Brazilian women. Clin Endocrinol 2007; 66: 803–807, doi: 10.1111/j.1365-2265.2007.02816.x.
https://doi.org/10.1111/j.1365-2265.2007...
) (Table 1). The population-based Sao Paulo Ageing & Health Study (SPAH) reported the prevalence of thyroid disorders in 1373 subjects aged 65 years or more. Frequency of thyroid diseases are higher in SPAH than in ELSA-Brasil especially for men. In the SPAH, 40% of women diagnosed with overt hypothyroidism were under treatment, compared to only 9% of men (55. Benseãor IM, Goulart AC, Lotufo PA, Menezes PR, Scazufca M. Prevalence of thyroid disorders among older people: results from the São Paulo Ageing & Health Study. Cad Saude Publica 2011; 27: 155–161, doi: 10.1590/S0102-311X2011000100016.
https://doi.org/10.1590/S0102-311X201100...
). In the ELSA-Brasil, a sample with more access to health services, we reported that the frequency of women receiving treatment for overt hypothyroidism was higher than that of men. However, the differences were smaller compared to the SPAH (97.3% of treatment in women vs 87.3% in men in the ELSA-Brasil). In the ELSA-Brasil, use of levothyroxine was very high, and was more frequent in women with higher mean monthly family income (Table 2).

Table 1.
Prevalence of thyroid disorders by sex in large, population-based studies.
Table 2.
Studies published with data from ELSA-Brasil included in this review.

In a population-sample of women in Rio de Janeiro, the prevalence of hypothyroidism was 12.3%, including overt and subclinical disease (66. Sichieri R, Baima J, Marante T, de Vasconcellos MT, Moura AS, Vaisman M. Low prevalence of hypothyroidism among black and Mulatto people in a population-based study of Brazilian women. Clin Endocrinol 2007; 66: 803–807, doi: 10.1111/j.1365-2265.2007.02816.x.
https://doi.org/10.1111/j.1365-2265.2007...
). White women presented a higher frequency of hypothyroidism than Mixed and Black women. In the ELSA-Brasil data, frequencies of subclinical and overt hypothyroidism were highest in White, intermediate in Mixed race, and lowest in Black participants (P<0.0001). After multivariate adjustment for sociodemographic variables, participants reporting Mixed or Black race presented a lower odds ratio (OR) for overt hypothyroidism using White race as reference (respectively, OR 0.73; 95%CI, 0.62–0.86 for Mixed, and OR, 0.53; 95%CI, 0.42–0.66 for Black). Regarding subclinical and clinical hyperthyroidism, White race was associated with higher frequency of hyperthyroidism compared to Mixed and Black races. In this case, after adjustment for the same variables, Black but not Mixed race was associated with overt hyperthyroidism (OR, 1.77; 95%CI, 1.03–3.03). These results agree with data from Sichieri et al. (66. Sichieri R, Baima J, Marante T, de Vasconcellos MT, Moura AS, Vaisman M. Low prevalence of hypothyroidism among black and Mulatto people in a population-based study of Brazilian women. Clin Endocrinol 2007; 66: 803–807, doi: 10.1111/j.1365-2265.2007.02816.x.
https://doi.org/10.1111/j.1365-2265.2007...
) in Rio de Janeiro that showed a lower frequency of hypothyroidism in Mixed race and Black subjects, and also with North-American results that showed an association between hyperthyroidism and Black race (1919. McLeod DS, Cooper DS, Ladenson PW, Whiteman DC, Jordan SJ. Race/Ethnicity and the prevalence of thyrotoxicosis in young Americans. Thyroid 2015; 25: 621–628, doi: 10.1089/thy.2014.0504.
https://doi.org/10.1089/thy.2014.0504...
).

Subclinical thyroid diseases: association with subclinical atherosclerosis, pulse wave velocity, and heart rate variability

Thyroid function and carotid intima-media thickness

The ELSA-Brasil explored several measures of subclinical atherosclerosis as part of the study, including carotid intima-media thickness (CIMT) and coronary artery calcium (CAC). We analyzed the association between thyroid function and CIMT in 8,623 participants with no previous history of cardiovascular disease and a valid measurement of CIMT at baseline. Median CIMT was 0.60 mm (interquartile range (IQR)=0.53–0.70) in subclinical hypothyroidism vs 0.58 (0.51–0.67) in euthyroid subjects (P<0.0001) (Supplementary Table S1). After multivariate adjustment for sociodemographic and cardiovascular risk factors, subclinical hypothyroidism was associated with higher CIMT values using euthyroid subjects as reference (OR 1.30, 95%CI 1.06–1.59). No association was found between subclinical hyperthyroidism and CIMT (2020. Peixoto de Miranda ÉJ, Bittencourt MS, Pereira AC, Goulart AC, Santos IS, Lotufo PA, et al. Subclinical hypothyroidism is associated with higher carotid intima-media thickness in cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Nutr Metab Cardiovasc Dis 2016; 26: 915–921, doi: 10.1016/j.numecd.2016.06.005.
https://doi.org/10.1016/j.numecd.2016.06...
).

Previous data on the relationship between thyroid function and CIMT showed conflicting results. Our findings were similar to a meta-analysis performed by Gao et al. (2121. Gao N, Zhang W, Zhang Y, Yang Q, Chen SH. Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis 2013; 227: 18–25, doi: 10.1016/j.atherosclerosis.2012.10.070.
https://doi.org/10.1016/j.atherosclerosi...
) that showed a consistent association between subclinical hypothyroidism and CIMT. This review evaluated data from seven case-control studies and one cross-sectional study. Two other large cross-sectional studies (2222. Jorde R, Joakimsen O, Stensland E, Mathiesen EB. Lack of significant association between intima-media thickness in the carotid artery and serum TSH level. The Tromsø Study. Thyroid 2018; 18: 21–25, doi: 10.1089/thy.2007.0165.
https://doi.org/10.1089/thy.2007.0165...
,2323. Delitala AP, Filigheddu F, Orrù M, AlGhatrif MA, Steri M, Pilia MG, et al. No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque. Nutr Metabolism Cardiovasc Dis 2015; 25: 1104–1110, doi: 10.1016/j.numecd.2015.09.001.
https://doi.org/10.1016/j.numecd.2015.09...
) that were not considered in the meta-analysis of Gao et al. showed null associations between subclinical hypothyroidism and CIMT. Contrasting with our results, Völzke et al. (2424. Völzke H, Robinson DM, Schminke U, Lüdemann J, Rettig R, Felix SB, et al. Thyroid function and carotid wall thickness. J Clin Endocrinol Metabolism 2004; 89: 2145–2149, doi: 10.1210/jc.2003-031028.
https://doi.org/10.1210/jc.2003-031028...
), in a population-based study, reported an inverse association between TSH levels and CIMT. The only association found in our study was between CIMT with subclinical hypothyroidism (SCH), but never with subclinical hyperthyroidism.

Thyroid function and CAC

In the ELSA-Brasil, the analysis of quintiles of TSH and CAC was restricted to 3836 participants of the Research Center of Sao Paulo who had undergone CAC as part of the baseline examination, and had no previous history of cardiovascular disease (Supplementary Table S1).

We found an association between low TSH levels (first quintile) and CAC with all men and women, even after multivariate adjustment for sociodemographic and cardiovascular risk factors (OR, 1.57; 95%CI, 1.05–2.35) using the third quintile as the reference. Restricting the analysis by sex, TSH in the first quintile was associated with CAC >100 Agatston units in men (OR, 1.72; 95%CI, 1.07–2.79). However, in women, we detected a U-shaped curve with an association of the first quintiles of TSH (OR, 3.31; 95%CI, 1.31–8.37 and of the fifth quintiles (OR, 3.29; 95%CI, 1.30–8.31) with CAC. It is important to note that restricting the analysis to TSH values below the reference showed similar results. Subjects with TSH within the range of subclinical hyperthyroidism and low-normal values (first quintile) had higher odds for CAC using the third quintile of TSH as reference (1515. Peixoto de Miranda ÉJF, Bittencourt MS, Staniak HL, Pereira AC, Foppa M, Santos IS, et al. Thyrotrophin levels and coronary artery calcification: Cross-sectional results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Clin Endocrinol 2017; 87: 597–604, doi: 10.1111/cen.13393.
https://doi.org/10.1111/cen.13393...
).

Few published studies analyzed the association of subclinical thyroid diseases and CAC. A large South Korean study showed an inverse association among quartiles of TSH with CAC >0 in euthyroid participants using the first quartile as reference and TSH levels within the reference. Although there are many differences from the sample of that study and our sample, e.g., age and the distribution of cardiovascular risk factors, the results were similar, with an association between low TSH values and the presence of CAC (2525. Zhang Y, Kim BK, Chang Y, Ryu S, Cho J, Lee WY, et al. Thyroid hormones and coronary artery calcification in euthyroid men and women. Arterioscler Thromb Vasc Biol 2014; 34: 2128–2134, doi: 10.1161/ATVBAHA.114.303889.
https://doi.org/10.1161/ATVBAHA.114.3038...
). Another Korean study that also evaluated participants with TSH levels within the reference values did not report an association between TSH values and CAC (2626. Zhu L, Gao C, Wang X, Qi D, Zhang Y, Li M, et al. The effect of low FT3 levels on coronary artery calcification and MACE in outpatients with suspected coronary artery disease. Coron Artery Dis 2014; 25: 427–432, doi: 10.1097/MCA.0000000000000095.
https://doi.org/10.1097/MCA.000000000000...
). One study in Brazil reported an association between subclinical hypothyroidism and CAC >100 only in men older than 55 years, with a Framingham Risk Score ≥10% (2727. Silva N, Santos O, Morais F, Gottlieb I, Hadlich M, Rothstein T, et al. Subclinical hypothyroidism represents an additional risk factor for coronary artery calcification especially in subjects of intermediary and high risk cardiovascular risk scores. Eur J Endocrinol 2014; 171: 165: 115–121, doi: 10.1530/EJE-14-0031.
https://doi.org/10.1530/EJE-14-0031...
).

Coronary heart disease using angiotomography

Data on the association between subclinical thyroid dysfunction and coronary artery disease (CAD) are scarce. In the ELSA-Brasil, we analyzed the association between thyroid function and CAD using a subsample of 767 participants who underwent complete coronary computed tomography angiography (CCTA) as part of the baseline examination (Supplementary Table S1). We included subjects with normal thyroid function, subclinical hypothyroidism, and subclinical hyperthyroidism. Logistic regression models evaluated quintiles of TSH and FT4 as independent variables, and the presence of CAD using segment involvement score (SIS) >4 and segment severity score (SSS) >4 of coronary arteries as dependent variables, adjusted for sociodemographic and cardiovascular risk factors. No association was found among TSH and FT4 quintiles and CAD prevalence, extent, or severity represented by SIS>4 and SSS>4. Restricting the analysis to euthyroid subjects did not alter the results. TSH and FT4 levels were not significantly associated with the presence, extent, or severity of CAD in a middle-aged healthy sample (2828. de Miranda EJFP, Bittencourt MS, Staniak HL, Sharovsky R, Pereira AC, Foppa M, et al. Thyrotropin and free thyroxine levels and coronary artery disease: cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Braz J Med Biol Res 2018; 51: e7196, doi: 10.1590/1414-431X20177196.
https://doi.org/10.1590/1414-431X2017719...
). The relatively small sample size may partially explain the results especially for subclinical hyperthyroidism.

Contrasting with our results, Park et al. (2929. Park YJ, Lee YJ, Choi SI, Chun EJ, Jang HC, Chang HJ. Impact of subclinical hypothyroidism on the coronary artery disease in apparently health subjects. Eur J Endocrinol 2011; 165: 115–121, doi: 10.1530/EJE-11-0014.
https://doi.org/10.1530/EJE-11-0014...
) in the largest study to date evaluating the association of CAD using CCTA, found a strong association between subclinical hypothyroidism and CAD (adjusted OR, 2.13; 95%CI, 1.05 – 4.03). This was a retrospective analysis in South Korea that included 2,404 asymptomatic outpatients, mostly men, with 2% of participants with subclinical hypothyroidism. Similar to our study, they used CCTA for CAD diagnosis, which was defined as the presence of any degree of plaque detected in at least one segment. In contrast to our analysis, they included a higher frequency of men (97 vs 50.3% in our analysis), with higher 10-year CHD risk scores and higher TSH levels, which may partially explain the differing results. Our data contrasts with findings from a large meta-analysis by Collet et al. (3030. Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, et al. Thyroid studies collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012; 172: 799–809, doi: 10.1001/archinternmed.2012.402.
https://doi.org/10.1001/archinternmed.20...
), which evaluated CAD events among subjects with subclinical hyperthyroidism in comparison with euthyroid ones. They included 52,674 participants from 10 cohort studies with available data about thyroid function, incident CAD, and mortality. However, none of those cohorts detected occult CAD using CCTA (22. Schmidt MI, Duncan BB, Mill JG, Lotufo PA, Chor D, Barreto SM, et al. Cohort profile: longitudinal study of adult health (ELSA-Brasil). Int J Epidemiol 2015; 44: 68–75, doi: 10.1093/ije/dyu027.
https://doi.org/10.1093/ije/dyu027...
). Subclinical hypothyroidism was independently associated with CAD events (hazard ratio (HR), 1.21; 95%CI, 0.99–1.46), all-cause mortality (HR, 1.29; 95%CI, 1.02–1.62), and cardiovascular mortality (HR, 1.24, 95%CI, 1.06–1.46) (3030. Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, et al. Thyroid studies collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012; 172: 799–809, doi: 10.1001/archinternmed.2012.402.
https://doi.org/10.1001/archinternmed.20...
). Another prospective study with a mean follow-up of around 3 years, 76 middle-aged subjects with subclinical hyperthyroidism and 1,062 euthyroid ones, all of them with type 2 diabetes mellitus, showed a higher incidence of CAD events with lower TSH levels (3131. Geng J, Lu W, Hu T, Tao S, Zhang H, Chen J, et al. Subclinical hypothyroidism increases risk of coronary heart disease events I type 2 diabetes mellitus. Endocrine 2015; 49: 557–559, doi: 10.1007/s12020-014-0472-y.
https://doi.org/10.1007/s12020-014-0472-...
). In our sample, only 0.5% (n=4) of the total number of subjects presented subclinical hyperthyroidism with TSH values lower than 0.1 mIU/L. Auer et al. used cineangiocoronariography to evaluate the relationship of subclinical thyroid disorders and coronary heart disease in 100 consecutive subjects, 90 euthyroid, 6 with subclinical hyperthyroidism, and 3 with subclinical hypothyroidism (59% men and mean of age 63.7 years). Contrasting with our results, they found an independent association between higher levels of TSH and severity of coronary arteries involvement, defined as two or three-vessel obstructive disease. However, they included a high frequency (35%) of double or triple-vessel disease, which may explain the difference from our results (3232. Auer J, Berent R, Weber T, Lassnig E, Eber B. Thyroid function is associated with the presence and severity of coronary atherosclerosis. Clin Cardiol 2003; 569–573, doi: 10.1002/clc.4960261205.
https://doi.org/10.1002/clc.4960261205...
).

Thyroid function and pulse wave velocity

Pulse wave velocity (PWV) measures arterial stiffness. In the ELSA-Brasil data for 8341 participants (5.6% of them with subclinical hypothyroidism), no association was detected between subclinical hypothyroidism and carotid-femoral pulse wave velocity (cfPWV) (Supplementary Table S1). The ELSA-Brasil is the largest study to investigate this association (3333. Peixoto de Miranda ÉJ, Bittencourt MS, Goulart AC, Santos IS, Mill JG, Schmidt MI, et al. Lack of association between subclinical hypothyroidism and carotid-femoral pulse wave velocity in a cross-sectional analysis of the ELSA-Brasil. Am J Hypertens 2017; 30: 81–87, doi: 10.1093/ajh/hpw117.
https://doi.org/10.1093/ajh/hpw117...
). A previous small study evaluated this association with positive results (3434. Nagasaki T, Inaba M, Kumeda Y, Hiura Y, Yamada S, Shirakawa K, et al. Central pulse wave velocity is responsible for increased brachial-ankle pulse wave velocity in subclinical hypothyroidism. Clin Endocrinol 2007; 66: 304–308, doi: 10.1111/j.1365-2265.2006.02730.x.
https://doi.org/10.1111/j.1365-2265.2006...
). One clinical trial reported lower PWV values after levothyroxine replacement (3535. Nagasaki T, Inaba M, Yamada S, Kumeda Y, Hiura Y, Nishizawa Y. Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function. Biomed Pharmacother 2007; 61: 482–487, doi: 10.1016/j.biopha.2007.04.004.
https://doi.org/10.1016/j.biopha.2007.04...
). However, this information was not confirmed by another trial of the same research group (3636. Nagasaki T, Inaba M, Yamada S, Nagata Y, Hiura Y, Tahara H, et al. Decrease on brachial-ankle pulse wave velocity in female subclinical hypothyroidism patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur J Endocrinol 2009; 160: 409–415, doi: 10.1530/EJE-08-0742.
https://doi.org/10.1530/EJE-08-0742...
). It is important to note that in the studies with positive results, Nagasaki et al. (3535. Nagasaki T, Inaba M, Yamada S, Kumeda Y, Hiura Y, Nishizawa Y. Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function. Biomed Pharmacother 2007; 61: 482–487, doi: 10.1016/j.biopha.2007.04.004.
https://doi.org/10.1016/j.biopha.2007.04...
,3636. Nagasaki T, Inaba M, Yamada S, Nagata Y, Hiura Y, Tahara H, et al. Decrease on brachial-ankle pulse wave velocity in female subclinical hypothyroidism patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur J Endocrinol 2009; 160: 409–415, doi: 10.1530/EJE-08-0742.
https://doi.org/10.1530/EJE-08-0742...
) measured brachial-ankle PWV compared to carotid-femoral PWV in the ELSA-Brasil.

Thyroid function and heart rate variability

The association between subclinical thyroid dysfunction and autonomic modulation changes was analyzed using data from the ELSA-Brasil (Supplementary Table S1). The association between subclinical hyperthyroidism, subclinical hypothyroidism, and heart rate variability (HRV) was studied in 9270 subjects (median age 50 years; interquartile range: 44–56): 8,623 (93.0%) were classified as euthyroid, 136 (1.5%) as subclinical hyperthyroidism, and 511 (5.5%) as subclinical hypothyroidism. Compared to euthyroid subjects, those with subclinical hyperthyroidism presented a significantly higher heart rate (68.8 vs 66.5 for euthyroidism, P=0.007) and shorter R-R intervals (871.4 vs 901.6, P=0.007), although subclinical hyperthyroidism was associated with a lower standard deviation of NN interval (β: –0.070; 95%CI: –0.014 to –0.009) and low-frequency (β: –0.242, 95%CI: –0.426 to –0.058) compared to the euthyroid group. These differences lost significance after multivariate adjustment for confounders. No significant difference was found for HRV in subclinical hypothyroidism compared to euthyroid participants.

Several small studies have shown an association of subclinical hypothyroidism (3737. Celik A, Aytan P, Dursun H, Koc F, Ozbek K, Sagcan M, et al. Heart rate variability and heart rate turbulence in hypothyroidism before and after treatment. Ann Noninvasive Electrocardiol 2011; 16: 344–350, doi: 10.1111/j.1542-474X.2011.00461.x.
https://doi.org/10.1111/j.1542-474X.2011...
,3838. Galetta F, Franzoni F, Fallahi P, Rossi M, Carpi A, Rubello D, et al. Heart rate variability and QT dispersion in patients with subclinical hypothyroidism. Biomed Pharmacother 2006; 60: 425–430, doi: 10.1016/j.biopha.2006.07.009.
https://doi.org/10.1016/j.biopha.2006.07...
) and subclinical hyperthyroidism (3939. Petretta M, Bonaduce D, Spinelli L, Vicario ML, Nuzzo V, Marciano F, et al. Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. Eur J Endocrinol 2001; 145: 691–696, doi: 10.1530/eje.0.1450691.
https://doi.org/10.1530/eje.0.1450691...
40. Goichot B, Brandenberger G, Vinzio S, Perrin A, Geny B, Schlienger J, et al. Sympathovagal response to orthostatism in overt and in subclinical hyperthyroidism. J Endocrinol Invest 2004; 27: 348–352, doi: 10.1007/BF03351060.
https://doi.org/10.1007/BF03351060...
4141. Falcone C, Matrone B, Bozzini S, Guasti L, Falcone R, Benzi A, et al. Time-domain heart rate variability in coronary artery disease patients affected by thyroid dysfunction. Int Heart J 2014;55: 33–38, doi: 10.1536/ihj.13-198.
https://doi.org/10.1536/ihj.13-198...
) with decreased heart rate variability. Compared to these small studies, our results did not show any association of HRV with subclinical hypothyroidism, and the association we found for subclinical hyperthyroidism lost significance after multivariate adjustment for sociodemographic and cardiovascular risk factors. The ELSA-Brasil is the largest study so far to evaluate HRV and thyroid function. The inclusion of apparently healthy individuals with lower levels of TSH than subjects selected from specialized outpatient clinics and the large sample that permitted adjustment for several confounders may help to explain differences in the results between the ELSA-Brasil and previous studies.

Subclinical thyroid diseases: association with insulin resistance, metabolic syndrome, high-sensitivity C-reactive protein, and chronic kidney disease

Insulin resistance and metabolic syndrome

In the ELSA-Brasil, after the exclusion of diabetics and individuals using cholesterol-lowering medications, we analyzed the relationship between TSH levels and insulin resistance and metabolic syndrome in a sample of 10,935 participants (54.3% women) (Supplementary Table S2). Homeostasis model insulin resistance (HOMA-IR) above the 75th percentile was defined as a surrogate for insulin resistance (HOMA-IR). Metabolic syndrome was diagnosed using NCEP ATP III criteria. We reported an association of quintiles of TSH and HOMA-IR above P75th percentile using the first quintile of TSH values as reference. Logistic regression models were built using HOMA-IR, with metabolic syndrome as the dependent variable and TSH quintiles as the independent variable (first quintile as reference). Subjects in the fifth TSH quintile presented an OR for association with insulin resistance of 1.86 (95%CI, 1.26–2.75), independent of sex. For the metabolic syndrome, subjects in the fifth quintile presented an OR of 1.21 (95%CI, 1.01–1.45). The analysis by sex remained positive only for men (OR 1.37; 95%CI 1.07–1.76). Restricting the analysis to TSH quintiles in the normal range did not affect the results (4242. Benseãor IM, Goulart AC, Molina Mdel C, de Miranda ÉJ, Santos IS, Lotufo PA. Thyrotropin levels, insulin resistance, and metabolic syndrome: a cross-sectional analysis in the Brazilian longitudinal study of adult health (ELSA-Brasil). Metab Syndr Relat Disord 2015; 13: 362–369, doi: 10.1089/met.2015.0045.
https://doi.org/10.1089/met.2015.0045...
).

Few studies have analyzed the association of thyroid function with insulin resistance and metabolic syndrome. For insulin resistance, most studies investigated small samples, consisting mainly of women, selected from tertiary care facilities, with conflicting positive (4343. Singh BM, Goswami B, Mallika V. Association between insulin resistance and hypothyroidism in females attending tertiary care hospital. Indian J Clin Biochem 2010; 25: 141–145, doi: 10.1007/s12291-010-0026-x.
https://doi.org/10.1007/s12291-010-0026-...
,4444. Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, Alevizaki M, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol 2009;160: 785–790, doi: 10.1530/EJE-08-0797.
https://doi.org/10.1530/EJE-08-0797...
) and negative (4545. Tuzcu A, Bahceci M, Gokalp D, Tuzun Y, Gunes K. Subclinical hypothyroidism may be associated with elevated high-sensitive c-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocr J 2005; 52: 89–94, doi: 10.1507/endocrj.52.89.
https://doi.org/10.1507/endocrj.52.89...
,4646. Al Sayed A, Al Ali N, Abbas YB, Alfadhli E. Subclinical hypothyroidism is associated with early insulin resistance in Kwait women. Endocr J 2006; 53: 653–657, doi: 10.1507/endocrj.K06-018.
https://doi.org/10.1507/endocrj.K06-018...
) results. Furthermore, all these previous analyses categorized thyroid function as subclinical or clinical hypothyroidism. Compared to these small studies, the ELSA-Brasil included a high number of apparently healthy men and women, in a large sample of nondiabetics, more similar to the general population. Consistent with our findings, Garduão-Garcia, studying a sample of 3,148 Hispanics, reported an association between TSH values and HOMA-IR, with borderline significance (4747. Garduão-Garcia J de J, Alvirde-Garcia U, López-Carrasco G, Padilla Mendoza ME, Mehta R, Arellano-Campos O, et al. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol 2010; 163: 273–278, doi: 10.1530/EJE-10-0312.
https://doi.org/10.1530/EJE-10-0312...
). However, our data contrast with those of Lai et al. (4848. Lai Y, Wang J, Jiang F, Wang B, Chen Y, Li M, et al. The relationship between serum thyrotropin and components of metabolic syndrome. Endocr J 2001; 58: 23–30, doi: 10.1507/endocrj.K10E-272.
https://doi.org/10.1507/endocrj.K10E-272...
), who studied 1,534 participants in China and did not find any association between TSH in the normal range and HOMA-IR. Differences in study samples and the analysis strategy used could help explain some differences in results. For metabolic syndrome, most studies found a positive association with subclinical hypothyroidism for both sexes (4949. Liu C, Dcherbaym WA, Schott M, Schinner S. Subclinical hypothyroidism and the prevalence of metabolic syndrome. Horm Metab Res 2011; 417–421, doi: 10.1055/s-0031-1275719.
https://doi.org/10.1055/s-0031-1275719...
,5050. Uzunlulu M, Yorulmaz E, Oguz A. Prevalence of subclinical hypothyroidism in patients with metabolic syndrome. Endocric J 2007; 54: 71–76, doi: 10.1507/endocrj.K06-124.
https://doi.org/10.1507/endocrj.K06-124...
), although the study of Garduão-Garcia et al. (4747. Garduão-Garcia J de J, Alvirde-Garcia U, López-Carrasco G, Padilla Mendoza ME, Mehta R, Arellano-Campos O, et al. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol 2010; 163: 273–278, doi: 10.1530/EJE-10-0312.
https://doi.org/10.1530/EJE-10-0312...
) did not find any association. Although studies to evaluate the association between thyroid function and metabolic syndrome included a high number of participants, most of them also categorized thyroid function according to TSH and free thyroxine values, and restricted the evaluation to individuals with subclinical hypothyroidism compared with the present analysis that evaluated all ranges of TSH values categorized in quintiles. Our results for metabolic syndrome are not as clear as those for insulin resistance. We only found an association of TSH quintiles with metabolic syndrome in the overall sample, and only for men. However, our results for men are consistent with the findings of Lee et al. (5151. Lee YK, Kim JE, Oh HJ, Park KS, Kim SK, Park SW, et al. Serum TSH levels in healthy Koreans and the association of TSH with serum lipid concentration and metabolic syndrome. Serum TSH level in healthy Koreans and the association of TSH with serum lipid concentration and metabolic syndrome. Korean J Int Med 2011; 26: 432–439, doi: 10.3904/kjim.2011.26.4.432.
https://doi.org/10.3904/kjim.2011.26.4.4...
), who found an association between high-normal TSH concentration (still within the normal range) and metabolic syndrome.

High-sensitivity C-reactive protein (hs-CRP)

A possible mechanism to explain the association of subclinical thyroid disorders and insulin resistance and metabolic syndrome is inflammation. Data from the ELSA-Brasil for the association of subclinical hypothyroidism and hs-CRP in 12,284 subjects (52.2% of women) with a median age of 50 years (interquartile range 45–57) reported that TSH was not associated with elevated hs-CRP, (OR, 1.11; 95%CI, 0.98–1.26) in a fully adjusted logistic model, also consistent with a linear model that analyzed the same relationship (β=0.024, P=0.145) (5252. Peixoto de Miranda ÉJ, Bittencourt MS, Santos IS, Lotufo PA, Benseãor IM. Thyroid function and high-sensitivity c-reactive protein in cross-sectional results from the brazilian longitudinal study of adult health (Elsa-Brasil): effect of adiposity and insulin resistance. Eur Thyroid J 2016; 5: 240–246, doi: 10.1159/000448683.
https://doi.org/10.1159/000448683...
) (Supplementary Table S2). Except for one large study that found a positive association between subclinical hypothyroidism and hs-CRP (5353. Yu YT, Ho CT, Hsu HS, Li CI, Davidson LE, Liu CS, et al. Subclinical hypothyroidism is associated with elevated high-sensitive C-reactive protein among adult Taiwanese. Endocrine 2013; 44: 716–722, doi: 10.1007/s12020-013-9915-0.
https://doi.org/10.1007/s12020-013-9915-...
), most studies using different populations and analysis strategies reported no association between thyroid function and hs-CRP (5454. Hueston WJ, King DE, Geesey ME. Serum biomarkers for cardiovascular inflammation in subclinical hypothyroidism. Clin Endocrinol 2005; 63: 582–587, doi: 10.1111/j.1365-2265.2005.02388.x.
https://doi.org/10.1111/j.1365-2265.2005...
55. Christ-Crain M, Meier C, Guglielmetti M, Huber PR, Riesen W, Staub JJ, et al. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis 2003; 166: 379–386, doi: 10.1016/S0021-9150(02)00372-6.
https://doi.org/10.1016/S0021-9150(02)00...
5656. Lee MW, Shin DY, Kim KJ, Hwang S, Lee EJ. The biochemical prognostic factors of subclinical hypothyroidism. Endocrinol Metab 2014; 29: 154–162, doi: 10.3803/EnM.2014.29.2.154.
https://doi.org/10.3803/EnM.2014.29.2.15...
).

Chronic kidney disease

Few studies have evaluated a possible relationship between TSH levels, glomerular filtration rate (GFR), and albumin/creatinine ratio in euthyroid subjects. We analyzed this association in a cross-sectional analysis in the ELSA-Brasil using GFR estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi), with albuminuria/creatinine ratio as dependent variables and thyrotropin quartiles in individuals with euthyroidism and subclinical hypothyroidism as independent variables, adjusted for sociodemographic characteristics and diseases related to CKD (Supplementary Table S2). The definition of CKD was according to the Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (KDIGO) (5757. Peixoto de Miranda ÉJF, Bittencourt MS, Goulart AC, Santos IS, de Oliveira Titan SM, Ladeira RM, et al. Thyrotropin levels are associated with chronic kidney disease among healthy subjects in cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Clin Exp Nephrol 2017; 21: 1035–1043, doi: 10.1007/s10157-017-1400-2.
https://doi.org/10.1007/s10157-017-1400-...
).

We included 13,193 subjects with a median age of 51 years, IQR: 45–58, 51.8% women, and 5.9% with subclinical hypothyroidism. In the adjusted models, log-transformed TSH in euthyroid subjects was inversely and strongly associated with CKD (β = –2.181, 95%CI –2.714 to –1.648; P<0.0001) for glomerular filtration rate and for albuminuria/creatinine ratio (β =4.528; 1.190–7.865). Multivariate logistic models for euthyroid subjects showed an OR of 1.45 (95%CI, 1.15–1.83) for estimated GFR and of 1.95 (95%CI, 1.08–3.54) for albuminuria/creatinine ratio in the fourth TSH quartile, using the first quartile as the reference (6262. Rhee CM, Kalantar-Zadeh K, Streja E, Carrero JJ, Ma JZ, Lu JL, et al. The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease. Nephrol Dial Transplant 2015; 30: 282–287, doi: 10.1093/ndt/gfu303.
https://doi.org/10.1093/ndt/gfu303...
). Two large studies showed a higher prevalence of subclinical hypothyroidism among subjects with CKD, increasing with kidney dysfunction, using the abbreviated MDRD equation (5858. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005; 67: 1047–1052, doi: 10.1111/j.1523-1755.2005.00169.x.
https://doi.org/10.1111/j.1523-1755.2005...
,5959. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3: 1296–1300, doi: 10.2215/CJN.00800208.
https://doi.org/10.2215/CJN.00800208...
). In addition, similar to our findings, a large Norwegian population-based cross-sectional analysis found that TSH was negatively associated with GFR estimated using the MDRD equation, even in the reference range for TSH (6060. Asvold BO, Bjøro T, Vatten LJ. Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study. Eur J Endocrinol 2011; 164: 101–105, doi: 10.1530/EJE-10-0705.
https://doi.org/10.1530/EJE-10-0705...
). Similarly, a prospective cohort study with 104,633 subjects and a mean follow-up of 3.5 years showed that high levels of TSH, even though still within the normal range, were modestly associated with an increased risk of incident CKD, defined as GFR <60 mL · min−1 · (1.73 m2)−1 using the CKD-Epi equation (6161. Zhang Y, Chang Y, Ryu S, Cho J, Lee WY, Rhee EJ, et al. Thyroid hormone levels and incident chronic kidney disease in euthyroid individuals: the Kangbuk Samsung health study. Int J Epidemiol 2014; 43: 1624–1632, doi: 10.1093/ije/dyu126.
https://doi.org/10.1093/ije/dyu126...
). Our study adds some new information to the previous published data. Some previous studies evaluating the relationship of thyroid disorders and CKD studied this association in a sample of individuals with hypothyroidism, including overt and subclinical disease (5858. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005; 67: 1047–1052, doi: 10.1111/j.1523-1755.2005.00169.x.
https://doi.org/10.1111/j.1523-1755.2005...
,6262. Rhee CM, Kalantar-Zadeh K, Streja E, Carrero JJ, Ma JZ, Lu JL, et al. The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease. Nephrol Dial Transplant 2015; 30: 282–287, doi: 10.1093/ndt/gfu303.
https://doi.org/10.1093/ndt/gfu303...
). In our study, we restricted our analysis to subclinical hypothyroidism as in the Chonchol et al. (5959. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3: 1296–1300, doi: 10.2215/CJN.00800208.
https://doi.org/10.2215/CJN.00800208...
) study. None of these previous studies have analyzed the relationship of thyroid disorders with albuminuria or with a combined endpoint of GFR <60 mL · min−1 · (1.73 m2) −1 and albuminuria as in our study. Moreover, we studied this association in a different population, unlike previous studies conducted in the USA and Australia (5858. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005; 67: 1047–1052, doi: 10.1111/j.1523-1755.2005.00169.x.
https://doi.org/10.1111/j.1523-1755.2005...
,5959. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3: 1296–1300, doi: 10.2215/CJN.00800208.
https://doi.org/10.2215/CJN.00800208...
,6262. Rhee CM, Kalantar-Zadeh K, Streja E, Carrero JJ, Ma JZ, Lu JL, et al. The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease. Nephrol Dial Transplant 2015; 30: 282–287, doi: 10.1093/ndt/gfu303.
https://doi.org/10.1093/ndt/gfu303...
).

Subclinical thyroid diseases: association with mental health and cognition

Mental health

The ELSA-Brasil investigated the association between subclinical thyroid dysfunction and psychiatric disorders using baseline data in a cross-sectional analysis. The study included 12,437 participants with normal thyroid function (92.8%), 193 (1.4%) with subclinical hyperthyroidism, and 784 (5.8%) with subclinical hypothyroidism, totaling 13,414 participants (50.6% women) (6363. Benseãor IM, Nunes MA, Sander Diniz MF, Santos IS, Brunoni AR, Lotufo PA. Subclinical thyroid dysfunction and psychiatric disorders: cross-sectional results from the Brazilian Study of Adult Health (ELSA-Brasil). Clin Endocrinol 2016; 84: 250–256, doi: 10.1111/cen.12719.
https://doi.org/10.1111/cen.12719...
) (Supplementary Table S3). The mental health of the participants were assessed by trained health professionals, using the Clinical Interview Schedule - Revised (CIS-R) (6464. Lewis G, Pelosi AJ, Araya R, Dunn G. Measuring psychiatric disorder in the community: a standardized assessment for use by lay interviewers. Psychol Med 1992; 22: 465–486, doi: 10.1017/S0033291700030415.
https://doi.org/10.1017/S003329170003041...
) and grouped according to the International Classification of Diseases 10 (ICD-10). After multivariate adjustment for possible confounders, we found a direct association between subclinical hyperthyroidism and panic disorder (OR, 2.55; 95%CI, 1.09–5.94), and an inverse association between subclinical hypothyroidism and generalized anxiety disorder (OR, 0.75; 95%CI, 0.59–0.96). However, both lost significance after correction for multiple comparisons (6363. Benseãor IM, Nunes MA, Sander Diniz MF, Santos IS, Brunoni AR, Lotufo PA. Subclinical thyroid dysfunction and psychiatric disorders: cross-sectional results from the Brazilian Study of Adult Health (ELSA-Brasil). Clin Endocrinol 2016; 84: 250–256, doi: 10.1111/cen.12719.
https://doi.org/10.1111/cen.12719...
).

Some previous studies with small samples detected changes in the hypothalamic-pituitary-thyroid axis in cases of panic disorder (6565. Tukel R, Kora K, Hekim N, Oğuz H, Alagöl F. Thyrotropin stimulating hormone response to thyrotropin releasing hormone response in patients with panic disorder. Psychoneuroendocrinology 1999; 24: 155–160, doi: 10.1016/S0306-4530(98)00067-5.
https://doi.org/10.1016/S0306-4530(98)00...
66. Yeragani VK, Rainey JM, Pohl R, Ortiz A, Weinberg P, Gershon S. Thyroid hormone levels in panic disorder. Can J Psychiatry 1987; 32: 467–469, doi: 10.1177/070674378703200615.
https://doi.org/10.1177/0706743787032006...
6767. Kikuchi M, Komuro R, Oka H, Kidani T, Hanaoka A, Koshino Y. Relationship between anxiety and thyroid function in patients with panic disorder. Progr Neuropsychopharmacol Biol Psychiatry 2005; 29: 77–81, doi: 10.1016/j.pnpbp.2004.10.008.
https://doi.org/10.1016/j.pnpbp.2004.10....
). Although the association between panic disorder and subclinical hyperthyroidism in our sample lost significance after correction for multiple comparisons, we have the possibility of analyzing the data prospectively in the near future. Interestingly, in another cohort in Brazil, we found an association between subclinical hyperthyroidism and dementia in a cross-sectional analysis of people ≥65 years old in a poor neighborhood of Sao Paulo (6868. Bensenor IM, Lotufo PA, Menezes PR, Scazufca M. Subclinical hyperthyroidism and dementia: the São Paulo Ageing & Health Study (SPAH). BMC Public Health 2010; 10: 298, doi: 10.1186/1471-2458-10-298.
https://doi.org/10.1186/1471-2458-10-298...
). These findings, together with the results of this study, suggest that subclinical hyperthyroidism may be associated with psychiatric disorders and dementia in the Brazilian population.

Our analysis also detected a possible protective effect of subclinical hypothyroidism for anxiety disorder. Panicker et al. (6969. Panicker V, Evans J, Bjøro T, Asvold BO, Dayan CM, Bjerkeset O. A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the HUNT study. Clin Endocrinol 2009: 71: 574–580, doi: 10.1111/j.1365-2265.2008.03521.x.
https://doi.org/10.1111/j.1365-2265.2008...
) reported a trend towards a low inverse relationship with anxiety: 19% less anxiety cases per mIU/l increase in TSH in men, and a trend towards less anxiety in women, both not using thyroxine in the HUNT Study. Our results for subclinical hypothyroidism suggest an association with depression, although not statistically significant. A previous population-based study in Rio de Janeiro, Brazil, found a positive association between subclinical hypothyroidism and depressive symptoms in women with TSH levels higher than 10 mIU/l. The ELSA-Brasil included a high number of men compared to the Guimarães study, which only included women (7070. Guimarães JM, de Souza Lopes C, Baima J, Sichieri R. Depression symptoms and hypothyroidism in a population-based study of middle-aged Brazilian women. Journal of Affective Disorders 2009; 117: 120–123, doi: 10.1016/j.jad.2008.12.012.
https://doi.org/10.1016/j.jad.2008.12.01...
). Three other studies in Brazil have reported a positive association between subclinical hypothyroidism and psychiatric symptoms and depression. However, all of them include only a small number of patients, mainly women referred to specialized clinics (7171. Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk of depression in the elderly. Arch Gerontol Geriatr 2007; 44: 21–28, doi: 10.1016/j.archger.2006.02.001.
https://doi.org/10.1016/j.archger.2006.0...
72. Teixeira PF, Reuters VS, Almeida CP, et al. Evaluation of clinical and psychiatric symptoms in subclinical hypothyroidism. Rev Assoc Med Bras 2006; 52: 222–228, doi: 10.1590/S0104-42302006000400020.
https://doi.org/10.1590/S0104-4230200600...
7373. Almeida C, Brasil MA, Costa AJ, Reis FA, Reuters V, Teixeira P, et al. Subclinical hypothyroidism: psychiatric disorders and symptoms. Braz J Psiquiatr 2007; 29: 157–159, doi: 10.1590/S1516-44462007000200013.
https://doi.org/10.1590/S1516-4446200700...
). Differences in study population and total sample size may partially explain the minor differences in the results.

Cognitive impairment and dementia

The role of subtle thyroid alterations, such as subclinical thyroid disease and low/high serum TSH within the normal range, in cognitive decline is controversial. The aim of this study was to evaluate the association of serum TSH levels and subclinical thyroid dysfunction with performance in cognitive tests in a large sample of Brazilian middle-aged adults without overt thyroid disease. In this cross-sectional analysis, we excluded individuals aged 65 years and older, and with overt thyroid dysfunction (Supplementary Table S3). Cognition was evaluated using delayed word recall test, semantic verbal fluency test, and trail making test version B. The associations of cognitive tests performance with TSH tertiles (using the middle tertile as reference) and thyroid function were investigated using linear regression models, adjusted for an extensive set of possible confounders (sociodemographic characteristics, cardiovascular risk factors, and depression). The mean age of the 10,362 participants was 49.5±7.4 years with 52.3% women. After adjustment for confounders, the first TSH tertile was associated with worse performance on the trail making test (β=–0.05, 95%CI=–0.09; –0.01, P=0.017). When restricting the analysis to the 9,769 individuals with TSH within the normal range, the association between TSH and performance on the trail making test remained significant (β=–0.05, 95%CI=–0.09; –0.01, P=0.020) in the multiple linear regression. Subclinical thyroid disease was not associated with performance on cognitive tests. Our results showed that low TSH is associated with poorer performance in an executive function test in middle-aged adults without overt thyroid dysfunction (7474. Szlejf C, Suemoto CK, Santos IS, Lotufo PA, Haueisen Sander Diniz MF, Barreto SM, et al. Thyrotropin level and cognitive performance: Baseline results from the ELSA-Brasil Study. Psychoneuroendocrinology 2018; 87: 152–158, doi: 10.1016/j.psyneuen.2017.10.017.
https://doi.org/10.1016/j.psyneuen.2017....
).

Our study is similar to Wahlin et al. (7575. Wahlin A, Bunce D, Wahlin TB. Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age. Psychoneuroendocrinology 2005; 30: 625–637, doi: 10.1016/j.psyneuen.2005.01.010.
https://doi.org/10.1016/j.psyneuen.2005....
) who evaluated TSH levels and performance on cognitive tests and found that lower TSH was correlated with poorer performance in episodic memory, although TSH was not correlated with verbal fluency and visuospatial ability. A cross-sectional study in older adults without overt thyroid dysfunction and free of dementia found that participants in the lowest and second lowest quintiles of TSH had higher odds of cognitive impairment, assessed by the Mini-Mental State Examination, when compared to participants in the higher quintile of TSH (7676. Juárez-Cedillo T, Basurto-Acevedo L, Vega-García S, Sánchez-Rodríguez MA, Retana-Ugalde R, Juárez-Cedillo E, et al. Prevalence of thyroid dysfunction and its impact on cognition in older Mexican adults: (SADEM study) J Endocrinol Invest 2017; 40: 945–952, doi: 10.1007/s40618-017-0654-6.
https://doi.org/10.1007/s40618-017-0654-...
). In our study, we found an association between low TSH levels and poorer performance in executive function, but no association with performance on episodic memory and verbal fluency. Other studies have also shown correlated results: low TSH associated with dementia or mild cognitive impairment (6868. Bensenor IM, Lotufo PA, Menezes PR, Scazufca M. Subclinical hyperthyroidism and dementia: the São Paulo Ageing & Health Study (SPAH). BMC Public Health 2010; 10: 298, doi: 10.1186/1471-2458-10-298.
https://doi.org/10.1186/1471-2458-10-298...
,7777. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008; 168: 1514–1520, doi: 10.1001/archinte.168.14.1514.
https://doi.org/10.1001/archinte.168.14....
), or subclinical hyperthyroidism associated with dementia (6868. Bensenor IM, Lotufo PA, Menezes PR, Scazufca M. Subclinical hyperthyroidism and dementia: the São Paulo Ageing & Health Study (SPAH). BMC Public Health 2010; 10: 298, doi: 10.1186/1471-2458-10-298.
https://doi.org/10.1186/1471-2458-10-298...
,7878. Kalmijn KM, Mehta HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia: the Rotterdam study. Clin Endocrinol 2000; 53: 733–737, doi: 10.1046/j.1365-2265.2000.01146.x.
https://doi.org/10.1046/j.1365-2265.2000...
) and poor performance in cognitive tests (7979. Cereseni G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, et al. Thyroid function abnormalities and cognitive impairment in elderly people: results of the Invecchiare in Chianti study. J Am Geriatr Soc 2009; 57: 89–93, doi: 10.1111/j.1532-5415.2008.02080.x.
https://doi.org/10.1111/j.1532-5415.2008...
). However, some studies have shown the opposite: higher TSH levels related to dementia or poor cognitive performance (7777. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008; 168: 1514–1520, doi: 10.1001/archinte.168.14.1514.
https://doi.org/10.1001/archinte.168.14....
,8080. Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and cognitive decline in the MRC cognitive function and ageing study. Psychoneuroendocrinology 2008; 33: 1013–1022, doi: 10.1016/j.psyneuen.2008.05.008.
https://doi.org/10.1016/j.psyneuen.2008....
), or no association at all between TSH and cognition (8181. Volpato S, Guralnik JM, Fried LP, Remaley AT, Cappola AR, Launer LJ. Serum thyroxine level and cognitive decline in thyroid older women. Neurology 2002; 58: 1055–1061, doi: 10.1212/WNL.58.7.1055.
https://doi.org/10.1212/WNL.58.7.1055...
,8282. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004; 292: 2591–2599, doi: 10.1001/jama.292.21.2591.
https://doi.org/10.1001/jama.292.21.2591...
). These discrepancies can be explained by the differences in sample, design, cognitive tests applied, selected covariates for adjustment, and outcomes between the studies. In addition, the association between TSH tertiles and the trail making test had only a small effect, which is expected in middle-aged subjects without overt thyroid disease and free of dementia and stroke at baseline. When considering the association between TSH levels within the normal range and cognition, studies also yield conflicting conclusions: some had results comparable to ours, showing an association between low TSH and dementia, mild cognitive impairment, or cognitive decline (6868. Bensenor IM, Lotufo PA, Menezes PR, Scazufca M. Subclinical hyperthyroidism and dementia: the São Paulo Ageing & Health Study (SPAH). BMC Public Health 2010; 10: 298, doi: 10.1186/1471-2458-10-298.
https://doi.org/10.1186/1471-2458-10-298...
), but some did not find an association (8181. Volpato S, Guralnik JM, Fried LP, Remaley AT, Cappola AR, Launer LJ. Serum thyroxine level and cognitive decline in thyroid older women. Neurology 2002; 58: 1055–1061, doi: 10.1212/WNL.58.7.1055.
https://doi.org/10.1212/WNL.58.7.1055...
,7777. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008; 168: 1514–1520, doi: 10.1001/archinte.168.14.1514.
https://doi.org/10.1001/archinte.168.14....
).

Conclusions

Data from the ELSA-Brasil added important information about the association of subclinical thyroid disorders and subclinical atherosclerosis measured by carotid intima-media thickness and coronary artery calcium in a sample with different characteristics compared to previous published studies. We also detected an association with insulin resistance and metabolic syndrome, although no association was found for subclinical hypothyroidism with hs-CRP. Regarding chronic kidney disease, the ELSA-Brasil was the first study to include creatinine-albuminuria rate as part of the renal function evaluation. The association between subclinical hypothyroidism and chronic kidney disease in a cross-sectional analysis needs to be explored in a near-future prospective analysis, as this may be a consequence of reverse causation, as demonstrated by previous studies in other samples. A prospective association will be tested in the ELSA-Brasil in the near future. The association of subclinical hyperthyroidism with cognitive impairment corroborates with a previous study in Brazil. The association with psychiatric disorders needs to be tested in prospective analysis, since the number of psychiatric diagnoses at baseline was not enough to permit more complex analyses. Moreover, it is important to note that the use of L-thyroxine in this sample was higher in women and in participants in higher income strata, compared to others, and the frequency of treatment was lower in men with overt hypothyroidism compared to women. Thus, the importance of highlighting diagnosis and treatment of thyroid diseases in men is emphasized.

Supplementary Material

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Publication Dates

  • Publication in this collection
    2019

History

  • Received
    19 Dec 2018
  • Accepted
    9 Jan 2019
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