Variation of iodine status during pregnancy and its associations with thyroid function in women from Rio de Janeiro, Brazil.

OBJECTIVE: To assess iodine status and its effects on maternal thyroid function throughout pregnancy. DESIGN: In the present prospective cohort study, three urinary samples were requested for urinary iodine concentration (UIC) determinations in both the first and third gestational trimesters. Serum thyrotropin (TSH) and free thyroxine (FT4) were analysed in both trimesters and thyroid antibodies were assessed once. SETTING: Rio de Janeiro, Brazil.ParticipantsFirst-trimester pregnant women (n 243), of whom 100 were re-evaluated during the third trimester. RESULTS: Iodine sufficiency was found in the studied population (median UIC=216·7 µg/l). The first- and third-trimester median UIC was 221·0 and 208·0 µg/l, respectively. TSH levels (mean (sd)) were higher in the third trimester (1·08 (0·67) v. 1·67 (0·86) mIU/l; P<0·001), while FT4 levels decreased significantly (1·18 (0·16) v. 0·88 (0·12) ng/dl; P<0·001), regardless the presence of iodine deficiency (UIC<150 µg/l) or circulating thyroid antibodies. UIC correlated (ß; 95% CI) independently and negatively with age (-0·43; -0·71, -0·17) and positively with multiparity (0·15; 0·02, 0·28) and BMI (0·25; 0·00, 0·50). Furthermore, median UIC per pregnant woman tended to correlate positively with TSH (0·07; -0·01, 0·14). Women with median UIC≥250 µg/l and at least one sample ≥500 µg/l throughout pregnancy had a higher risk of subclinical hypothyroidism (OR=6·6; 95% CI 1·2, 37·4). CONCLUSIONS: In this cohort with adequate iodine status during pregnancy, excessive UIC was associated with an increased risk of subclinical hypothyroidism.

Use of transient elastography for hepatic steatosis and fibrosis evaluation in patients with subclinical hypothyroidism.

Objective: To evaluate the association between subclinical hypothyroidism and hepatic steatosis and fibrosis using the noninvasive diagnostic methods transient hepatic elastography (TE) and controlled attenuation parameter (CAP) in patients with subclinical hypothyroidism. Subjects and methods: This was a cross-sectional study including women with confirmed spontaneous subclinical hypothyroidism and an age- and body mass index (BMI)-matched control group without thyroid disease or circulating antithyroperoxidase (anti-TPO) antibodies. Exclusion criteria were age > 65 years, thyroid-stimulating hormone (TSH) > 10.0 mIUI/L, BMI ≥ 35 kg/m2, diabetes, or other chronic liver diseases. Liver stiffness was classified according to TE values (in kPa) and ranged from absence of fibrosis (F0) to advanced fibrosis (F3). Hepatic steatosis was classified according to CAP values (in dB/m) and ranged from low-grade (S1) to advanced (S3) steatosis. Results: Of 68 women enrolled, 27 were included in the subclinical hypothyroidism group and 41 in the control group. Advanced steatosis (S3) was more frequent in the subclinical hypothyroidism group (25.9% versus 7.3%, respectively, p = 0.034). Circulating anti-TPO was an independent factor associated with advanced steatosis (odds ratio 9.5, 95% confidence interval 1.3-68.3). In multiple linear regression analysis, TE values (which evaluated fibrosis) correlated negatively with free thyroxine levels. Conclusion: The results of this study strengthen the hypothesis that hepatic steatosis is associated with autoimmune (positive anti-TPO) subclinical hypothyroidism, independently from BMI. However, subclinical hypothyroidism alone does not appear to be associated with a significantly increased risk of hepatic fibrosis.

Associations of TSH, free T3, free T4, and conversion ratio with incident hypertension: results from the prospective Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

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.

Potential Determinants of Thyroid Peroxidase Antibodies and Mortality Risk: Results From the ELSA-Brasil Study.

CONTEXT: The presence of thyroid peroxidase antibodies (TPOAbs) may be considered as an indicator of adverse health outcomes. OBJECTIVE: We aimed to investigate the potential determinants of TPOAb levels and to analyze the association between TPOAb titers and the risk of all- and specific-cause mortality. METHODS: Baseline and longitudinal data of 13 187 participants from the ELSA-Brasil Study were analyzed. We investigated the association of TPOAb, detectability, positivity, and persistent positivity with sociodemographic and lifestyle factors using logistic regressions. Cox proportional hazards and Fine-Gray subdistribution hazard regression analyses were used to verify the association of TPOAbs with mortality. RESULTS: The determinants of TPOAb detectability and positivity were younger age, higher body mass index, female sex, and former and current smoking status. Black, mixed, and other self-reported races, intermediate and higher education, and heavy drinking were determinants of detectable and positive TPOAb levels. Female sex, White race, and former smoking were determinants of persistent TPOAb positivity at 2 visits, although only the female sex maintained its association at 3 visits. Moreover, after multivariate adjustment, there were associations between higher levels of TPOAbs and higher risk of cancer-related mortality among men, and TPOAb detectability and mortality by other causes among women. CONCLUSION: Sociodemographic and lifestyle-related factors were determinants of multiple TPOAb categories. TPOAb levels were associated with mortality risk; however, the low mortality rate in this sample might have compromised this finding. We suggest further studies to explore the clinical importance of detectable TPOAb levels, not only its positivity, as a potential marker of inflammation.

Branched-Chain Amino Acids, Alanine, and Thyroid Function: A Cross-Sectional, Nuclear Magnetic Resonance (NMR)-Based Approach from ELSA-Brasil.

The association of thyroid function with essential and non-essential amino acids is understudied, despite their common metabolic roles. Thus, our aim was to evaluate the association of thyroid function with the levels of branched-chain amino acids (BCAAs-leucine, isoleucine, and valine) and of alanine in the general population. We utilized data from the São Paulo research center of ELSA-Brasil, a longitudinal population-based cohort study. Thyroid parameters included thyroid stimulating hormone (TSH), free T4 and free T3 levels, and the FT4:FT3 ratio. BCAAs and alanine were analyzed on a fully automated NMR platform. The current analysis included euthyroid participants and participants with subclinical hyperthyroidism and hypothyroidism. We used Pearson's coefficient to quantify the correlation between thyroid-related parameters and amino acids. Linear regression models were performed to analyze whether thyroid parameters were associated with BCAAs and alanine levels. We included 4098 participants (51.3 ± 9.0 years old, 51.5% women) in this study. In the most adjusted model, higher levels of TSH were associated with higher levels of alanine, FT4 levels were inversely associated with isoleucine levels, FT3 levels were statistically significant and positively associated with valine and leucine, and the T3:T4 ratio was positively associated with all amino acids. We observed that subclinical hypothyroidism was positively associated with isoleucine and alanine levels in all models, even after full adjustment. Our findings highlight the association of subclinical hypothyroidism and thyroid-related parameters (including TSH, free T4, free T3, and FT4:FT3 ratio) with BCAAs and alanine. Further studies are needed to explore the mechanisms underlying this association. These insights contribute to our understanding of the influence of thyroid-related parameters on BCAA and alanine metabolism.

GlycA as a Novel Biomarker of Systemic Inflammation in Hypothyroidism.

Background: GlycA is a novel glycoprotein biomarker of systemic inflammation and cardiovascular risk. Our objective was to assess the levels of GlycA in individuals with hypothyroidism. We also explored whether levothyroxine (LT4)-treated patients had different levels of GlycA, with attention to thyrotropin (TSH) levels. Methods: We performed a cross-sectional analysis, using baseline data from the ELSA-Brasil cohort study. We included only participants with serum TSH and GlycA levels measurements, using magnetic resonance spectroscopy (n = 4745). We excluded individuals with endogenous hyperthyroidism and those using drugs impacting thyroid function. Participants not taking LT4 and whose serum TSH was 0.4-4.0 mIU/L were classified as euthyroid (EU) and those with elevated TSH as undiagnosed hypothyroidism (UH). For those on LT4 (n = 345), adequacy of treatment was defined as TSH within the reference range. Those with TSH <0.4 mIU/L were considered over-treated (OT), and those >4.0 mIU/L, under-treated (UT). Both (UT+OT) were considered inadequately treated (IT). Group comparisons were performed by Kruskal-Wallis, adjusted Chi-square, and the post hoc Dunn test. Additional subgroup analysis were performed in patients with circulating thyroperoxidase antibodies (TPO-Ab+). Respective multivariable analyses were performed to evaluate the relationship between thyroid-related variables and GlycA levels (Generalized Linear Model), as well as an abnormal GlycA (>400 µmol/L; Logistic Binary Regression). Results: The prevalence rate of UH was 9.8% (467/4745) and, among those on LT4, only 61.7% (213/345) were adequately treated (AT). GlycA levels were higher in IT in comparison to EU (429 vs. 410 µmol/L, p < 0.01) but did not differ between UH (413 µmol/L) and euthyroidism. However, the subgroup analysis of those TPO-Ab+ showed that not only those with IT, but also those with UH, had higher levels of GlycA in comparison to euthyroidism (423 and 424 vs. 402 µmol/L, p = 0.04). This association between higher levels of GlycA and IT was maintained even in multivariable analysis (odds ratio 1.53, confidence interval 1.03 to 2.31) Lower levels of GlycA were detected in AT (405 µmol/L,) compared with OT (432 µmol/L, 0.04) and UT (423 µmol/L, p = 0.02). Conclusions: Patients with IT, both OT and UT, had higher GlycA levels, which may be associated with low-grade systemic inflammation and, possibly, increased cardiovascular risk.

Thyroid-Stimulating Hormone and Thyroid Hormones and Incidence of Diabetes: Prospective Results of the Brazilian Longitudinal Study of Adult Health (ELSA-BRASIL).

Background: There are conflicting data regarding the association of thyroid function with incident diabetes. We prospectively investigated thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and its conversion ratio (fT3:fT4) with the risk of developing diabetes in euthyroid subjects and those with subclinical thyroid dysfunction. Our hypothesis is that this relationship is a U-shaped curve since both subclinical thyroid diseases may be associated with diabetes. Methods: ELSA-Brasil is a highly admixed cohort study of 35-74 years old at baseline (2008-2010). Levels of TSH, fT4, fT3, and fT3:fT4 ratio were evaluated at baseline and incident diabetes was estimated over an 8.2-year follow-up (2017-2019). Diabetes was identified based on medical diagnosis, prescriptions, and laboratory tests. The risk of diabetes was evaluated according to quintiles of TSH, fT4, fT3, and fT3:fT4 ratio using Poisson regression with robust variance presented as relative risk (RR) with confidence interval [CI] of 95% after multivariable adjustment for sociodemographic and cardiovascular risk factors (reference third quintile), and as continuous variables. Results: We included 7948 participants (mean age, 50.2 [standard deviation 8.6] years; 54.4% female): 7177 euthyroid, 726 with subclinical hypothyroidism, and 45 with subclinical hyperthyroidism. Incidence of diabetes was 14.8%. No association was found for TSH, fT4, fT3, and fT3:fT4 ratio quintiles with incident diabetes. Using continuous variables, the increase of 1-unit (1-U) of fT4 decreased the risk of diabetes (RR 0.94 [CI 0.91-0.99]), while the increase of 1-U of the fT3:fT4 ratio increased the diabetes risk (RR 1.37 [CI 1.15-1.63]). The increase of 1-U of fT3 was associated with an increased risk of diabetes, but without significance after multivariable adjustment. In body mass index-stratified analysis, people with overweight or obesity presented a modest significantly higher risk of diabetes in the lowest quintile of fT4 (RR 1.04 [CI 1.01-1.07]) and an inverse association with incident diabetes in the first quintile of fT3:fT4 ratio (RR, 0.95 [CI 0.93-0.98]). The analyses using continuous variables presented similar findings. Conclusion: These findings suggest that fT4 and fT3 levels and the conversion rate might be additional risk factors associated with incident diabetes, especially in the presence of overweight or obesity. However, they need to be confirmed in future studies. (ClinicalTrials.gov Identifier: NCT02320461).

Combining the American Thyroid Association's Ultrasound Classification with Cytological Subcategorization Improves the Assessment of Malignancy Risk in Indeterminate Thyroid Nodules.

Background: The risk of malignancy (RoM) of indeterminate thyroid nodules (ITNs) shows a high variability in interinstitutional cohorts. The RoM is partially associated with the cytological degree of atypia and the ultrasound (US) pattern. This study evaluated the cancer risk of ITNs by jointly considering the cytological subcategory and the American Thyroid Association (ATA)-based US risk classification. Methods: This study features a retrospective cohort from two Brazilian centers comprising 238 ITNs with confirmed outcomes. US classification, according to ATA-based guidelines, and cytological subcategorization were determined. The cytological subgroups were as follows: (1) nuclear atypia (NA) related to papillary thyroid carcinoma (PTC) but insufficient to categorize the cytology as suspicious for malignancy; (2) architectural atypia without NA (AA); (3) both architectural and nuclear atypia (ANA); (4) oncocytic pattern (OP) without NA; and (5) NA not related to PTC (NANP). NA was divided into three subgroups: nuclear size and shape, nuclear membrane appearance, and/or chromatin aspects. Results: The overall frequency of malignancy was 39.5%. Among the cytological subcategories, the highest RoM was related to the NA (43.9%) and to the ANA (43.5%), followed by AA (29.4%), and OP (9.4%). NA was positively and independently associated with cancer (odds ratio [OR]: 4.5; confidence interval [CI: 1.2-16.6]) as was the occurrence of ANA (OR 6.6 [CI 1.5-29.5]). AA and OP were not independently associated with cancer. Both ATA-based high- and intermediate-risk categories showed an independent association with cancer (OR 6.8 [CI 2.9-15.5] and OR: 2.6 [CI 1.1-5.8], respectively). ITNs with cytological findings of NA or ANA when combined with intermediate US patterns had RoM values of 47.5% and 56.7%, respectively. Both cytological subcategories, when combined with the ATA high-suspicion class reached an RoM >70%. The type of NA with the highest odds for cancer was related to the nuclear membrane (OR 11.5). Conclusions: The RoM of ITNs can reach almost 80% when both NA and ATA-based high-risk US features are present. The presence of such cytological features also increased the RoM in the ATA-based intermediate-risk US category. In addition, AA and OP were not independently related to higher cancer risk. These results strengthen the recommendations for combing cytological subcategorization and US risk classification in the workup for ITNs before the decision of a molecular testing, clinical observation, or diagnostic surgery.

The role of thyroid hormone in metabolism and metabolic syndrome.

Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.

Selective case finding versus universal screening for detecting hypothyroidism in the first trimester of pregnancy: a comparative evaluation of a group of pregnant women from Rio de Janeiro.

Objective Maternal hypothyroidism during pregnancy may lead to adverse outcomes. Recently published guidelines by the American Thyroid Association (ATA) do not advocate for universal screening but recommend a case-finding approach in high-risk pregnant women. The present study aims to evaluate the accuracy of this approach in identifying women with thyroid dysfunction during early pregnancy. Subjects and methods This is a multiple-center, cross-sectional study. Three hundred and one pregnant women were enrolled. Anamnesis and a physical examination were performed to detect which women fulfilled the criteria to undergo laboratory screening of thyroid dysfunction, according to the ATA's 2017 guidelines. The Zulewski's validated clinical score was applied to assess signs and symptoms of hypothyroidism. Serum levels of thyrotropin (TSH), free thyroxine (FT4), anti-thyroperoxidase (TPO-Ab), and anti-thyroglobulin (Tg-Ab) antibodies were determined. Results Two hundred and thirty one women (78%) were classified as high risk, and 65 (22%) were classified as low risk for thyroid dysfunction. Regarding the clinical score, 75 patients (31.2%) presented mild symptoms that were compatible with SCH, of which 22 (7.4%) had symptoms as the only risk factor for thyroid disease. 17 patients (5.7%) had SCH, of which 10 (58.8%) belonged to the high-risk group, and 7 (41.2%) belonged to the low-risk group. OH was found in 4 patients (1.4%): 3 (75%) in the high-risk group and 1 (25%) in the low-risk group. Conclusions The ATA's proposed screening criteria were not accurate in the diagnosis of thyroid dysfunction in pregnancy. Testing only the high-risk pregnant women would miss approximately 40% of all hypothyroid patients.

Adrenal Venous Sampling in Primary Aldosteronism: The Usefulness of Contralateral Suppression Index.

Adrenal venous sampling (AVS) is the gold standard test to differentiate the unilateral from the bilateral form in patients with primary aldosteronism (PA) although it may be a difficult procedure, especially the successful cannulation of the right adrenal vein. In this report, we describe a 49-year-old female patient diagnosed with PA, after investigating resistant hypertension and refractory hypokalemia. Abdominal computed tomography scan revealed a 2.5 cm adenoma on the right adrenal vein. AVS was performed under cosyntropin infusion. Aldosterone and cortisol concentrations were obtained from the right and left adrenal veins and inferior vena cava (IVC). Cortisol on each adrenal vein divided by cortisol on IVC confirmed successful cannulation of the left side only, which makes it impossible to calculate the lateralization index (LI). From the data on the left adrenal vein and IVC, the aldosterone-to-cortisol ratio divided by the IVC aldosterone-to-cortisol ratio was less than 1.0, suggesting that the left adrenal vein was suppressed with the excess aldosterone originating from the contralateral side (contralateral suppression index (CSI)). Right adrenalectomy was performed; postoperative hypoaldosteronism was confirmed. This report highlights the importance of CSI obtained in AVS when technical difficulties occur making it impossible to obtain LI, which is most commonly used to decide between surgical and clinical management of PA.

Technetium-99m-anti-tumour necrosis factor alpha scintigraphy as promising predictor of response to corticotherapy in chronic active Graves' ophthalmopathy.

It has been suggested that technetium-99m (99mTc)-anti-tumour necrosis factor alpha (TNF-α) scintigraphy (SCI) may be a useful diagnostic tool in Graves' ophthalmopathy (GO). This study evaluated whether orbit total radioactivity uptake on SCI could be used to predict corticosteroid therapy (CorT) responses in active-GO patients. A longitudinal study of patients with active GO defined by Clinical Active Score (CAS) >3/7 was done. Clinical, laboratory and SCI evaluations were performed at baseline and 3 months after concluding intravenous CorT. SCI (planar and tomographic) was assessed after intravenous injection of 10 mCi of 99mTc-anti-TNF-α. Orbits and cerebral hemispheres were defined as regions of interest (ROIs) to enable orbit/hemisphere ROI-ratios of total radioactive uptake. ROI-ratios were considered positive at >2·5. Average total radiation uptake (TRU) was also determined for each orbit (AVGROI ). Clinical, laboratory and SCI data were compared between responders (CAS became inactive) and non-responders to CorT (18 patients). At baseline, AVGROI were higher in active OG orbits (67·3 cps) than in inactive ones (33·6 cps; P<0·05). AVGROI (absolute values) reduced (-29·9 cps) in CorT responders and tended (P = 0·067) to differ from variations occurred in non-responders (+6·9 cps in patients with maintained CAS positivity post-treatment). Higher baseline ROI-ratios (4·9 versus 3·3; P = 0·056) and its pronounced reductions following CorT (-37% versus +56% in non-responders; P = 0·036) tended to be associated with good CorT responses in the subgroup of GO history ≥1 year. SCI showed a good association with active eye disease and may be an additional tool to identify CorT responders.

Effects of Metformin on TSH Levels and Benign Nodular Goiter Volume in Patients Without Insulin Resistance or Iodine Insufficiency.

Objectives: To evaluate the impact of metformin (MTF) use on TSH levels, thyroid volume and volume of benign thyroid nodules (TNs). Additionally, to study if iodine status influences the outcomes. Methods: A total of 23 euthyroid patients (42 TNs) with benign thyroid nodules, diagnosed by fine needle aspiration biopsy, were randomly assigned to MTF or placebo (P) use for 6 months. Serum TSH, homeostatic model assessment for insulin resistance (HOMA-IR), and urinary iodine concentrations (UIC) were assessed. Ultrasound was used to evaluate TNs and thyroid volumes (TV) and their variations throughout the study. Diabetic patients, those undergoing levothyroxine replacement, and/or using thyroid- or insulin level-influencing drugs were excluded. Results: The sample consisted predominantly of patients without IR. Both intervention groups were similar regarding several confounding variables and showed a comparable median UIC. Serum TSH decreased significantly after MTF (-0.21 vs. 0.09 mUI/L in the P group; p = 0.015). At 6 months, no significant variations were found between groups with respect to TN volumes, TV, HOMA-IR, or body mass index (BMI). However, a tendency toward enlargement of TV with placebo (16.0%; p = 0.09) and a protective effect of MTF on growing TN (OR: 0.25; CI 0.05-1.20) was detected after excluding patients with IR (a lower UIC subgroup). The reduction on TSH levels with MTF maintained in the population without iodine insufficiency (-0.24 vs. +0.07 in the P group; p = 0.046) and was accentuated in those with excessive or more than adequate UIC (-0.69; p = 0.043). A protective effect of MTF on growing TN was suggested (OR: 0.11; IC: 0.02-0.84) in those with higher UIC. Conclusions: This study demonstrated that MTF caused a reduction in TSH levels in benign nodular goiter. This effect was more accentuated in patients with higher levels of UIC and was accompanied by a suggested protective effect on TN enlargement.

Associations of TSH, free T3, free T4, and conversion ratio with incident hypertension: results from the prospective Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

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.

Does a three-degree hypoechogenicity grading improve ultrasound thyroid nodule risk stratification and affect the TI-RADS 4 category? A retrospective observational study

ABSTRACT Objective: The aim of this study was to determine whether classifying hypoechogenicity in three degrees (mild, moderate, and marked) could improve the distinction between benign and malignant nodules and whether such an approach could influence Category 4 of the Thyroid Imaging Reporting and Data System (TI-RADS). Materials and methods: In total, 2,574 nodules submitted to fine needle aspiration, classified by the Bethesda System, were retrospectively assessed. Further, a subanalysis considering solid nodules without any additional suspicious findings (n = 565) was performed with the purpose of evaluating mainly TI-RADS 4 nodules. Results: Mild hypoechogenicity was significantly less related to malignancy (odds ratio [OR]: 1.409; CI: 1.086-1.829; p = 0.01), compared to moderate (OR: 4.775; CI: 3.700-6.163; p < 0.001) and marked hypoechogenicity (OR: 8.540; CI: 6.355-11.445; p < 0.001). In addition, mild hypoechogenicity (20.7%) and iso-hyperechogenicity (20.5%) presented a similar rate in the malignant sample. Regarding the subanalysis, no significant association was found between mildly hypoechoic solid nodules and cancer. Conclusion: Stratifying hypoechogenicity into three degrees influences the confidence in the assessment of the rate of malignancy, indicating that mild hypoechogenicity has a unique low-risk biological behavior that resembles iso-hyperechogenicity, but with minor malignant potential when compared to moderate and marked hypoechogenicity, with special influence on the TI-RADS 4 category.

Heart rate response to graded exercise test of elderly subjects in different ranges of TSH levels.

OBJECTIVE: Life expectancy is increasing worldwide and studies have been demonstrating that elevated serum thyroid stimulating hormone (TSH) concentration in elderly is associated with some better health outcomes. This elevation is somewhat physiological as aging. The aim of this study was to investigate the heart rate (HR) response during a graded exercise test and its recovery in healthy elderly, comparing subjects within serum TSH in the lower limit of reference range to those within the TSH in the upper limit. SUBJECTS AND METHODS: A cross-sectional study was conducted with 86 healthy elderly aged 71.5 ± 5.1 years, with serum TSH between 0.4 - 4.0 mUl/mL. The participants were divided into two groups according to TSH level: < 1.0 mUl/mL (n = 13) and ≥ 1.0 µUI/mL (n = 73). All participants performed an ergometric test on a treadmill. The HR was recorded and analyzed at rest, during exercise and during the three minutes immediately after exercise. RESULTS: No differences were observed in relation to HR at peak of exercise (TSH < 1.0 µUI/mL: 133.9 ± 22.5 bpm vs. TSH ≥ 1.0 µUI/mL: 132.4 ± 21.3 bpm; p = 0.70) and during the first minute of recovery phase (TSH < 1.0 µUI/mL: 122.3 ± 23.1 bpm vs. TSH ≥ 1.0 µUI/mL: 115.7 ± 18.4 bpm p = 0.33). The groups also presented similar chronotropic index (TSH < 1.0 µUI/mL: 78.1 ± 30.6 vs. TSH ≥ 1.0 µUI/mL: 79.5 ± 26.4; p = 0.74). CONCLUSION: In this sample studied, there were no difference between lower and upper TSH level concerning HR response during rest, peak of exercise and exercise recovery.

Exercise training improves quality of life in women with subclinical hypothyroidism: a randomized clinical trial.

OBJECTIVE: The aim was to evaluate the quality of life (HRQoL) in women with subclinical hypothyroidism (sHT) after 16 weeks of endurance training. SUBJECTS AND METHODS: In the first phase, a cross-sectional study was conducted in which 22 women with sHT (median age: 41.5 (interquartile range: 175) years, body mass index: 26.2 (8.7) kg/m2, thyroid stimulating hormone > 4.94 mIU/L and free thyroxine between 0.8 and 1.3 ng/dL were compared to a group of 33 euthyroid women concerned to HRQoL. In the second phase, a randomized clinical trial was conducted where only women with sHT were randomly divided into two groups: sHT-Tr (n = 10) - participants that performed an exercise program - and sHT-Sed (n = 10) - controls. Exercise training consisted of 60 minutes of aerobic activities (bike and treadmill), three times a week, for 16 weeks. The HRQoL was assessed by the SF-36 questionnaire in the early and at the end of four months. RESULTS: Women with sHT had lower scores on functional capacity domain in relation to the euthyroid ones (770 ± 23.0 vs. 88.8 ± 14.6; p = 0.020). The sHT-Tr group improved functional capacity, general health, emotional aspects, mental and physical component of HRQoL after training period, while the sHT-Sed group showed no significant changes. CONCLUSION: After 16 weeks of aerobic exercise training, there were remarkable improvements in HRQoL in women with sHT.

Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro.

OBJECTIVES: American Thyroid Association (ATA)'s new guidelines recommend use of population-based trimester-specific reference range (RR) for thyrotropin (TSH) in pregnancy. The aim of this study was to determine first trimester TSH RR for a population of pregnant women in Rio de Janeiro State. SUBJECTS AND METHODS: Two hundred and seventy pregnant women without thyroid illness, defined by National Academy of Clinical Biochemistry, and normal iodine status were included in this sectional study. This reference group (RG) had normal median urinary iodine concentration (UIC = 219 µg/L) and negative anti-thyroperoxidase antibodies (TPOAb). Twin pregnancy, trophoblastic disease and use of drugs or supplements that influence thyroid function were excluded. In a second step, we defined a more selective reference group (SRG, n = 170) by excluding patients with thyroiditis pattern on thyroid ultrasound and positive anti-thyroglobulin antibodies. This group also had normal median UIC. At a final step, a more selective reference group (MSRG, n = 130) was defined by excluding any pregnant women with UIC < 150 µg/L. RESULTS: In the RG, median, 2.5th and 97.5th percentiles of TSH were 1.3, 0.1, and 4.4 mIU/L, respectively. The mean age was 270 ± 5.0 and the mean body mass index was 25.6 ± 5.2 kg/m2. In the SRG and MSRG, 2.5th and 975th percentiles were 0.06 and 4.0 (SRG) and 0.1 and 3.6 mIU/L (MSRG), respectively. CONCLUSIONS: In the population studied,TSH upper limit in the first trimester of pregnancy was above 2.5 mIU/L. The value of 3.6 mIU/L, found when iodine deficiency and thyroiditis (defined by antibodies and ultrasound characteristics) were excluded, matches recent ATA guidelines.

Heart rate kinetics during exercise in patients with subclinical hypothyroidism.

Studies suggest that patients with subclinical hypothyroidism (SH) have sympathovagal imbalance, which could lead to a slower heart rate (HR) response in the transition from rest to exercise. Thus the objective of this study was to investigate the behavior of the HR kinetics in patients with SH during the transition from rest to exercise. The study included 18 SH women [thyroid stimulating hormone (TSH) = 6.95 ± 2.94 µIU/ml and free thyroxine (FT4) = 0.96 ± 0.15 ng/dl] and 17 euthyroid women (TSH = 2.28 ± 0.84 µIU/ml and FT4 = 0.98 ± 0.07 ng/dl). Both groups were matched for physical activity, menopausal status, and age. The HR kinetics was obtained during the course of a constant-load exercise (50 W), for 6 min, in a cycle ergometer, and quantified from the mean response time (MRT), which is equivalent to the time taken to reach 63% of the HR at steady state. SH patients showed slower HR kinetics than the control group (MRT = 48.5 ± 17.6 vs. 36.0 ± 10.3 s, P = 0.015). The MRT has been shown to correlate with the level of physical activity (r = -0.361; P = 0.033) and with the subjective perception of exertion at the end of the exercise (r = 0.365; P = 0.031). It is concluded that SH patients have slower HR kinetics in the transition from rest to exercise compared with euthyroid women, with this impairment being associated with lower levels of physical activity.NEW & NOTEWORTHY Subclinical hypothyroidism patients have slower heart rate kinetics in the transition from rest to exercise when performing a constant-load exercise at 50 W.

Likelihood of malignancy in thyroid nodules according to a proposed Thyroid Imaging Reporting and Data System (TI-RADS) classification merging suspicious and benign ultrasound features.

OBJECTIVE: The aim of this study was to describe the ultrasound features of benign and malignant thyroid nodules and evaluate the likelihood of malignancy associated with each feature according to the Bethesda System for Reporting Thyroid Cytopathology and histopathology. With this analysis, we propose a new TI-RADS classification system. MATERIALS AND METHODS: The likelihood of malignancy from ultrasound features were assessed in 1413 thyroid nodules according to the Bethesda System for Reporting Thyroid Cytopathology and histopathological findings. A score was established by attributing different weights to each ultrasound feature evaluated. RESULTS: Features positively associated with malignancy in bivariate analysis received a score weight of +1. We attributed a weight of +2 to features which were independently associated with malignancy in a multivariate analysis and +3 for those associated with the highest odds ratio for malignancy (> 10.0). Hence, hypoechogenicity (graded as mild, moderate or marked, according to a comparison with the overlying strap muscle), microcalcification and irregular/microlobulated margin received the highest weights in our scoring system. Features that were negatively associated with malignancy received weights of -2 or -1. In the proposed system a cutoff score of 2 (sensitivity 97.4% and specificity 51.6%) was adopted as a transition between probably benign (TI-RADS 3) and TI-RADS 4a nodules. Overall, the frequency of malignancy in thyroid nodules according to the categories was 1.0% for TI-RADS 3, 7.8% for TI-RADS 4a, 35.3% for TI-RADS 4b, and 84.7% for TI-RADS 5. CONCLUSION: A newly proposed TI-RADS classification adequately assessed the likelihood of malignancy in thyroid nodules.