ABSTRACT Objective: To evaluate the association of TSH, free T3 (FT3), free T4 (FT4), and conversion (FT3:FT4) ratio values with incident hypertension. Materials and methods: The study included data from participants of the ELSA-Brasil study without baseline hypertension. Serum TSH, FT4 and FT3 levels, and FT3:FT4 ratio values were assessed at baseline, and incident hypertension (defined by blood pressure levels ≥ 140/90 mmHg) was estimated over a median of 8.2 years of follow-up. The risk of incident hypertension was evaluated considering a 1-unit increase in TSH, FT4, FT3, and conversion ratio values and after dividing these variables into quintiles for further analysis using Poisson regression with robust variance. The results are presented as relative risks (RR) and 95% confidence intervals (CIs) before and after adjustment for multiple variables. Results: The primary analysis incorporated data from 5,915 euthyroid individuals, and the secondary analysis combined data from all euthyroid individuals, 587 individuals with subclinical hypothyroidism, and 31 individuals with subclinical hyperthyroidism. The rate of incident hypertension was 28% (95% CI: 27%-29.3%). The FT4 levels in the first quintile (0.18-1.06 ng/dL) were significantly associated with incident hypertension (RR: 1.03, 95% CI: 1.01-1.06) at follow-up. The association between FT4 levels in the first quintile and incident hypertension was also observed in the analysis of combined data from euthyroid individuals and participants with subclinical thyroid dysfunction (RR: 1.04, 95% CI: 1.01-1.07). The associations were predominantly observed with systolic blood pressure levels in euthyroid individuals. However, in the combined analysis incorporating euthyroid participants and individuals with subclinical thyroid dysfunction, the associations were more pronounced with diastolic blood pressure levels. Conclusion: Low FT4 levels may be a mild risk factor for incident hypertension in euthyroid individuals and persons with subclinical thyroid dysfunction. Objective TSH T FT , (FT3) (FT4) FT3FT4 FTFT (FT3:FT4 methods ELSABrasil ELSA Brasil FT3:FT defined 14090 140 90 140/9 mmHg 82 8 2 8. followup. followup follow up. up follow-up 1unit unit 1 variance RR (RR 95 CIs (CIs Results 5915 5 915 5,91 58 hypothyroidism 3 hyperthyroidism 28 (95 CI 27%29.3%. 27293 27% 29.3% . 27 29 27%-29.3%) 0.181.06 018106 0.18 1.06 0 18 06 (0.18-1.0 ng/dL ngdL ng dL 103 03 1.03 1.011.06 101106 1.01 01 1.01-1.06 104 04 1.04 1.011.07. 101107 1.07 07 1.01-1.07) However Conclusion (FT3 (FT4 FT3FT (FT3:FT 1409 14 9 140/ 591 91 5,9 (9 27%29.3% 2729 293 29.3 27%-29.3% 181 0.181.0 01810 018 0.1 106 1.0 (0.18-1. 10 011 1.011.0 10110 101 1.01-1.0 1.011.07 107 1.01-1.07 (FT 59 5, ( 27%29.3 272 29. 27%-29.3 0.181. 0181 0. 1. (0.18-1 1.011. 1011 1.01-1. 27%29. 27%-29. 0.181 (0.18- 1.011 1.01-1 27%29 27%-29 (0.18 1.01- 27%2 27%-2 (0.1 27%- (0. (0

ABSTRACT Primary hypothyroidism is a common disorder in clinical practice. The management of most cases of hypothyroidism is usually straightforward, but the best approach in some special situations may raise questions among physicians. This position statement was prepared by experts from the Brazilian Society of Endocrinology and Metabolism to guide the management of three special situations, namely, hypothyroidism in the elderly, subclinical hypothyroidism in patients with heart disease, and difficult-to-control hypothyroidism. The authors prepared the present statement after conducting a search on the databases MEDLINE/PubMed, LILACS, and SciELO and selecting articles with the best evidence quality addressing the selected situations. The statement presents information about the current approach to patients in these special situations.

Abstract Objectives This analysis describes the protocol of a study with a case-cohort to design to prospectively evaluate the incidence of subclinical atherosclerosis and Cardiovascular Disease (CVD) in Chronic Inflammatory Disease (CID) participants compared to non-diseased ones. Methods A high-risk group for CID was defined based on data collected in all visits on self-reported medical diagnosis, use of medicines, and levels of high-sensitivity C-Reactive Protein >10 mg/L. The comparison group is the Aleatory Cohort Sample (ACS): a group with 10% of participants selected at baseline who represent the entire cohort. In both groups, specific biomarkers for DIC, markers of subclinical atherosclerosis, and CVD morbimortality will be tested using weighted Cox. Results The high-risk group (n = 2,949; aged 53.6 ± 9.2; 65.5% women) and the ACS (n=1543; 52.2±8.8; 54.1% women) were identified. Beyond being older and mostly women, participants in the high-risk group present low average income (29.1% vs. 24.8%, p < 0.0001), higher BMI (Kg/m2) (28.1 vs. 26.9, p < 0.0001), higher waist circumference (cm) (93.3 vs. 91, p < 0.0001), higher frequencies of hypertension (40.2% vs. 34.5%, p < 0.0001), diabetes (20.7% vs. 17%, p = 0.003) depression (5.8% vs. 3.9%, p = 0.007) and higher levels of GlycA a new inflammatory marker (p < 0.0001) compared to the ACS. Conclusions The high-risk group selected mostly women, older, lower-income/education, higher BMI, waist circumference, and of hypertension, diabetes, depression, and higher levels of GlycA when compared to the ACS. The strategy chosen to define the high-risk group seems adequate given that multiple sociodemographic and clinical characteristics are compatible with CID.

ABSTRACT Objective: Although some previous data have suggested a high iodine intake in Brazil, the prevalence of antithyroperoxidase antibodies (TPOAb) in the country is compatible with rates from countries with adequate iodine intake. This observation emphasizes the importance of knowing the incidence of TPOAb in Brazil. Materials and methods: This prospective analysis included euthyroid participants with negative TPOAb at baseline and a thyroid function assessment at a 4-year follow-up. TPOAb was measured by electrochemiluminescence and considered positive when titers were ≥34 IU/mL. TSH and free T4 (FT4) levels were determined by a third-generation immunoenzymatic assay. The incidence of TPOAb is expressed in percentage per year or as a cumulative incidence within the 4-year follow-up period. Results: Of 8,922 euthyroid participants (mean age 51.1 years; 50.9% women) with a negative TPOAb test at baseline, 130 presented incident TPOAb at the 4-year follow-up, yielding an annual incidence of TPOAb of 0.38%/year (95% confidence interval [95% CI], 0.37-0.39%/year) and a cumulative incidence over 4 years of 1.46% (95% CI, 1.21-1.71%). In men, the annual incidence was 0.32% (95% CI, 0.31-0.33%), and the cumulative incidence over 4 years was 1.23% (95% CI, 0.90-1.56%). In women, the annual incidence was 0.43%/year (95% CI, 0.42-0.44%/year) and the cumulative incidence over 4 years was 1.67% (95% CI, 1.30-2.04%). The only factor associated with incident TPOAb was the occurrence of thyroid diseases at follow-up. No differences in TPOAb incidence were detected across ELSA-Brasil research centers. Conclusion: Based on the results of this study, the incidence of TPOAb per year and at a 4-year follow-up period are compatible with those of a country with adequate iodine intake.

ABSTRACT Objective: To evaluate incidence of subclinical and overt hyperthyroidism and hypothyroidism. Subjects and methods: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study of 15,105 civil servants, examined at baseline and over a 4-year follow-up. This analysis included 9,705 participants with normal thyroid function at baseline, follow-up information about thyroid function and with no report of using drugs that may interfere in the thyroid function. Thyroid function was defined by TSH/FT4 levels or routine use of thyroid hormones/anti-thyroid medications. Annual and cumulative (over 4-year) incidence rates were presented as percentages (95% Confidence Intervals). Results: The incidence of all overt and subclinical thyroid disease was 6.7% (1.73%/year): 0.19% for overt hyperthyroidism (0.048%/year), 0.54% for subclinical hyperthyroidism (0.14%/year), 1.98% for overt hypothyroidism (0.51%/year), and 3.99% for subclinical hypothyroidism (1.03%/year). The incidence of all thyroid diseases was higher in women, when compared to men, with a low women:men ratio (1.36). For Blacks the highest incidence was for overt hyperthyroidism, while for Whites, the highest incidence was for overt hypothyroidism. However, the highest incidence of overt hyperthyroidism was detected in Asian descendants. The presence of antithyroperoxidase antibodies at baseline was associated with higher incidence of overt thyroid diseases. Conclusion: These results showed a high incidence of hypothyroidism, which is compatible with a country with a more-than-adequate iodine intake. The low women:men ratio of the incidence of thyroid dysfunction highlights the importance of the diagnosis of thyroid diseases among men in Brazil.

ABSTRACT Subclinical hypothyroidism (Shypo) is an increasingly frequent condition in common medical practice. Its diagnosis continues to pose a challenge since a series of non-thyroidal and temporary conditions can elevate serum TSH levels. In addition, the consequences of Shypo are still up for debate. Although detrimental cardiovascular effects have been consistently demonstrated in the young, they are less evident in older adults (65-79 years), and even more so in the oldest old (≥80 years). In the absence of evidence of any benefits of treating Shypo in patients’ clinical manifestations and unfavorable outcomes, the most effective decision-making approach should include a thorough investigation of the patient's condition integrating all relevant clinical data, such as TSH levels, age, quality of life, comorbidities, cardiovascular risk, safety, and personal preferences. The decision-making process needs to take into account the risk of levothyroxine overtreatment and the resulting adverse consequences, such as reduction of bone mineral density, heart failure, and atrial fibrillation. Hence, current evidence suggests that individuals with TSH > 10 mU/L, who test positive for TPO Ab or are symptomatic may benefit from levothyroxine treatment. However, a more cautious and conservative approach is required in older (≥65 years of age), and oldest-old (≥80 years) patients, particularly those with frailty, in which the risk of treatment can outweigh potential benefits. The latter may benefit from a wait-and-see approach.

INTRODUÇÃO: O hipotiroidismo é amplamente reconhecido por seus efeitos sobre os diferentes sistemas orgânicos, levando ao hipometabolismo. No entanto, o hipotiroidismo subclínico, sua apresentação mais prevalente, tem sido recentemente relacionado ao risco cardiovascular e também com complicações materno-fetais em gestantes. OBJETIVOS: Nestas diretrizes clínicas, vários aspectos do hipotiroidismo foram discutidos com objetivos claros de ajudar os médicos a tratar pacientes com hipotiroidismo e de compartilhar algumas das nossas experiências clínicas na América Latina. MATERIAIS E MÉTODOS: A Sociedade Latino-Americana de Tireoide formou uma Força-Tarefa para desenvolver diretrizes baseadas em evidências clínicas sobre o hipotiroidismo. Foi realizada uma revisão sistemática da literatura existente, com foco em bancos de dados primários do MedLine/PubMed e Lilacs/SciELO. Foram feitas análises para avaliar a qualidade metodológica no sentido de selecionar os melhores estudos. A força de recomendação em uma escala de A-D foi baseada no Centro de Oxford para a Medicina Baseada em Evidência - Níveis de Evidência 2009 - , permitindo uma opinião imparcial, desprovida de pontos de vista subjetivos. As áreas de interesse compreenderam estudos de diagnóstico, triagem, tratamento e uma seção especial de hipotiroidismo na gravidez. RESULTADOS: Foram feitos vários questionamentos relacionados ao diagnóstico, triagem e tratamento do hipotiroidismo na população adulta e, especificamente, em mulheres grávidas. Foram elaboradas vinte e seis recomendações baseadas nas respostas a essas perguntas. Apesar da falta de evidências em algumas áreas como o tratamento do hipotiroidismo, de 279 referências, 73% eram de Grau A e B, 8% de Grau C e 19% de Grau D. CONCLUSÕES: Essas diretrizes baseadas em evidências clínicas sobre o hipotiroidismo poderão fornecer um critério consensual de como tratar o hipotiroidismo na América Latina. Apesar de a maior parte dos estudos referidos ser da experiência internacional em hipotiroidismo, o ponto de vista dos tiroidologistas da América Latina foi contemplado.

INTRODUCTION: Hypothyroidism has long been known for its effects on different organ systems, leading to hypometabolism. However, subclinical hypothyroidism, its most prevalent form, has been recently related to cardiovascular risk and also to maternal-fetal complications in pregnant women. OBJECTIVES: In these clinical practice guidelines, several aspects of this field have been discussed with the clear objectives of helping physicians treat patients with hypothyroidism, and of sharing some of our Latin American-based clinical experience. MATERIALS AND METHODS: The Latin American Thyroid Society commissioned a Task Force on Hypothyroidism to develop evidence-based clinical guidelines on hypothyroidism. A systematic review of the available literature, focused on the primary databases of MedLine/PubMed and Lilacs/SciELO was performed. Filters to assess methodological quality were applied to select the best quality studies. The strength of recommendation on a scale from A-D was based on the Oxford Centre for Evidence--based Medicine, Levels of Evidence 2009, allowing an unbiased opinion devoid of subjective viewpoints. The areas of interest for the studies comprised diagnosis, screening, treatment and a special section for hypothyroidism in pregnancy. RESULTS: Several questions based on diagnosis, screening, treatment of hypothyroidism in adult population and specifically in pregnant women were posed. Twenty six recommendations were created based on the answers to these questions. Despite the fact that evidence in some areas of hypothyroidism, such as therapy, is lacking, out of 279 references, 73% were Grade A and B, 8% Grade C and 19% Grade D. CONCLUSIONS: These evidence-based clinical guidelines on hypothyroidism will provide unified criteria for management of hypothyroidism throughout Latin America. Although most of the studies referred to are from all over the world, the point of view of thyroidologists from Latin America is also given.

A doença tiroidiana autoimune (DAIT), que afeta de 2% a 5% da população ocidental, é o transtorno autoimune órgão-específico mais comum. Sua apresentação clínica varia do hipertiroidismo da doença de Graves (DG) ao hipotiroidismo associado à tiroidite de Hashimoto (TH). A exata etiologia da DAIT permanece desconhecida, mas a interação entre suscetibilidade genética e fatores ambientais desencadeadores parece ser de fundamental importância no seu desenvolvimento. Postula-se que fatores genéticos responderiam por 79% da suscetibilidade à DAIT e os ambientais por 21%. Genes imunomoduladores, como o complexo maior de histocompatibilidade (MHC), antígeno-4 associado ao linfócito T citotóxico (CTLA-4), a molécula CD40 e a proteína tirosina fosfatase-22 (PTPN22) e os genes específicos da glândula tiróide, como receptor do TSH (TSHR) e tiroglobulina (TG) têm sido identificados. A natureza exata do envolvimento do meio ambiente no desenvolvimento da DAIT não é bem conhecida, mas vários fatores ambientais têm sido envolvidos, como o conteúdo de iodo na dieta, estresse, drogas e infecções. Entretanto, não há evidência clara de causalidade e os mecanismos pelos quais fatores ambientais desencadeariam a autoimunidade tiroidiana, em indivíduos geneticamente predispostos, ainda permanecem não completamente entendidos. O conhecimento dos mecanismos precisos de interação entre fatores ambientais e genes na indução da autoimunidade tiroidiana poderia resultar desenvolvimento de novas estratégias de prevenção e tratamento.

Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder affecting 2% to 5% of the population in Western countries. Clinical presentation varies from hyperthyroidism in Graves' Disease to hypothyroidism in Hashimoto's thyroiditis. While the exact etiology of thyroid autoimmunity is not known, interaction between genetic susceptibility and environmental factors appears to be of fundamental importance to initiate the process of thyroid autoimmunity. It has been postulated that 79% of the susceptibility to develop AITD is attributed to genetic factors, while environmental factors contribute to 21%. The identified AITD susceptibility genes include immune-modulating genes, such as the major histocompatibility complex (MHC), cytotoxic T lymphocyte antigen-4 (CTLA-4), CD40 molecule, and protein tyrosine phosphatase-22 (PTPN22), and thyroid-specific genes, including TSH receptor (TSHR) and thyroglobulin (TG). The exact nature of the role environmental factors play in AITD is still not well known, but the involvement of several factors such as iodine diet content, stress, drugs and infections has been reported. However, there is no clear evidence of causality and the mechanisms by which environmental factors trigger thyroid autoimmunity in genetically predisposed individuals remain not fully understood. Knowledge of the precise mechanisms of interaction between environmental factors and genes in inducing thyroid autoimmunity could result in the development of new strategies for prevention and treatment.

Hipotiroidismo subclínico (SHT) e hipertiroidismo subclínico (SCH) são definidos pelas concentrações normais de T4 e T3 livres séricos associadas com valores de TSH elevado (SHT) ou suprimido (SCH). As prevalências são baixas e sintomas e sinais de disfunção tiroideana escassos. No SHT, colesterol total e LDL-C estão ligeiramente elevados, e tratamento com levotiroxina pode influir nos valores dos lipídeos. Ocorre diminuição da contratilidade do miocárdio e aumento da resistência vascular periférica, que melhoram com o tratamento. Fibrilação atrial é mais freqüente no SCH, e há aumento do índice de massa do ventrículo esquerdo, da contratilidade cardíaca, disfunção diastólica e indução de batimentos atriais ectópicos que regridem com uso de beta-bloqueadores. No SCH, ocorre diminuição da densidade óssea. Depressão, doença do pânico e alterações de testes cognitivos são freqüentes no SHT. O tratamento do SHT é indicado com TSH sérico maior do que 8mU/L e presença de anticorpos antitiroideanos, e do SCH endógeno, quando existem sintomas, em idosos ou concentração de TSH menor do que 0,1mU/L.

Subclinical hypothyroidism (SHT) and subclinical hyperthyroidism (SCH) are defined as normal serum free T4 and T3 levels associated with elevated (SHT) or subnormal (SCH) serum TSH levels, respectively. Symptoms and signs of thyroid dysfunction are scarce. The prevalence is low. In SHT, total cholesterol and LDL-C are modestly elevated and levothyroxine may influence the lipids levels. There is decreased cardiac contractility and increased peripheral vascular resistance that improve with treatment. SCH is associated with atrial fibrillation, increased cardiac contractility and left ventricular mass, diastolic and systolic dysfunction that can be reversed with beta-adrenergic antagonists. Bone density is reduced in SCH. Depression, panic disorders and alterations in cognitive testing are frequent in SHT. Treatment of SHT is recommended for serum TSH levels greater than 8mU/L and presence of thyroid antibodies. Endogenous SCH should be treated for serum TSH levels less than 0.1mU/L, in the presence of symptoms and in elderly patents.