ContextData regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.ObjectiveTo assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.Data Sources and Study SelectionThe databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.Data ExtractionIndividual data on 55 287 participants with 542 494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25 977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.ResultsAmong 55 287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51 837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.ConclusionsSubclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

Subclinical hyperthyroidism, defined by low thyrotropin level with normal concentrations of free thyroxine (FT₄) and triiodothyronine (T₃),^1-4 has been associated with several biological effects on cardiovascular system, such as increased heart rate, left ventricular mass, carotid intima-media thickness, and plasma fibrinogen levels.^3,5 Observational studies have reported an association between subclinical hyperthyroidism and coronary heart disease (CHD),^6-8 incident atrial fibrillation (AF),^9-12 and cardiac dysfunction.^13,14 Results from prospective cohort studies are conflicting,^6,10 and study-level meta-analyses have reached contradictory conclusions, for example, regarding the association between subclinical hyperthyroidism and cardiovascular mortality.^15-17 In fact, interpretation of these studies is hampered by several methodological factors: population heterogeneity, different thyrotropin cutoff levels for subclinical hyperthyroidism definition, different use of covariates, and different CHD definitions.¹⁶ Although no large randomized controlled trials have examined the effects of treating subclinical hyperthyroidism on clinically relevant outcomes, a consensus statement² and recent guidelines⁴ advocate treatment of subclinical hyperthyroidism, particularly when thyrotropin level is lower than 0.10 mIU/L, to avoid long-term complications.

Objective: The objective was to determine the risk of stroke associated with subclinical hypothyroidism. Data Sources and Study Selection: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45–4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5–19.9 mIU/L with normal T₄ levels. Data Extraction and Synthesis: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972–2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91–1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80–1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25–8.80) for individuals aged 18–49 years. There was an increased risk of fatal stroke in the age groups 18–49 and 50–64 years, with a HR of 4.22 (95% CI, 1.08–16.55) and 2.86 (95% CI, 1.31–6.26), respectively (p trend 0.04). We found no increased risk for those 65–79 years old (HR, 1.00; 95% CI, 0.86–1.18) or ≥80 years old (HR, 1.31; 95% CI, 0.79–2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. Conclusions: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Subclinical hyperthyroidism has been associated with harmful cardiac effects, but its treatment remains controversial. This study was designed to assess the cardiac effects of the normalization of serum TSH concentration in patients with endogenous subclinical hyperthyroidism. Ten patients (median age, 59 yr; range, 16-72 yr) with normal serum free T(4) and free T(3) concentration and a stable suppression of serum TSH levels were evaluated by Doppler-echocardiography, by standard and 24-h electrocardiography monitoring (Holter), and by the clinical Wayne index. Ten subjects, matched for age and sex, were used as controls. Patients were reevaluated 6 months after achieving stabilized euthyroidism by using methimazole with a median initial dose of 20 mg daily (10-30 mg daily). After reaching euthyroidism, we found a significant decrease in the heart rate (P = 0.008), the total number of beats during 24 h (P = 0.004), and the number of atrial (P = 0.002) and ventricular (P = 0.003) premature beats. Echocardiographical data resulted in a reduction of the left ventricular mass index (P = 0.009), interventricular septum thickness (P = 0.008), and left ventricular posterior wall thickness (P = 0.004) at diastole. Furthermore, the early diastolic peak flow velocity deceleration rate was significantly higher (P = 0.02) in the untreated patients compared with controls. The Wayne clinical index was higher in patients than in controls (P = 0.001) and decreased after treatment (P = 0.004). Serum TSH concentration returned to normal values after 2.5 months (range, 1.0-7.0 months) on methimazole therapy (0.05 vs. 1.42 mU/liter; P = 0.002). Serum free T(4) values were normal in patients before treatment but significantly decreased after reaching the euthyroidism (16.9 vs. 11.5 pmol/liter; P = 0.002). In contrast, serum free T(3) concentration did not differ among the groups. In conclusion, our findings support that early antithyroid therapy should be considered in patients with endogenous subclinical hyperthyroidism, where it is needed to prevent potential progression to a more advanced heart disease.

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.

Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. Design and Setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T₄, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1–13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65–0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62–1.09) for fatal stroke. For the free T₄ analyses, the hazard ratio was 1.08 (95% CI 0.99–1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04–1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. Conclusion: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.