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Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events., Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex., Design and Setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration., Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l)., Interventions: None as this is an observational study., Main Outcome Measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP., Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05)., Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Risk factors for radioactive iodine (RAI)-refractory disease in follicular (FTC) and oncocytic thyroid carcinoma (OTC) are unknown., Objective: The aim of this study is to identify clinical and histopathological risk factors for RAI-refractory disease in FTC and OTC patients, facilitated by an extensive histopathological revision., Methods: All adult FTC and OTC patients treated at Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. The 2015 American Thyroid Association guidelines were used to define RAI-refractory disease. An extensive histopathological revision was performed applying the 2022 World Health Organization Classification using PALGA, the Dutch Pathology Databank. Logistic regression was used to identify risk factors for RAI-refractory disease, stratified by histological subtype., Results: Ninety FTC and 52 OTC patients were included, of whom 14 FTC (15.6%) and 22 OTC (42.3%) patients developed RAI-refractory disease over a follow-up time of 8.5 years. RAI-refractory disease occurred in OTC after fewer cycles than in FTC (2.0 [interquartile range (IQR): 1.0-2.0] vs 2.5 [IQR: 2.0-3.75]), and it substantially decreased 10-year disease-specific survival, especially in OTC (46.4%; FTC 85.7%). In FTC, risk factors were higher age at diagnosis, pT3/pT4 stage, N1 stage, widely invasive tumors, and extrathyroidal extension. N1 stage and M1 stage were the strongest risk factors in OTC, rather than histopathological characteristics of the primary tumor., Conclusion: To our knowledge, this is the first study that correlates clinical and histopathological risk factors with RAI-refractory disease in FTC and OTC, facilitated by a histopathological revision. In FTC, risk factors for RAI-refractory disease were foremost histopathological characteristics of the primary tumor, whereas in OTC presentation with lymph node and distant metastasis was associated with RAI-refractory disease. Our data can help clinical decision-making, particularly in patients at risk for RAI-refractory disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals., Methods: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals., Results: The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability., Conclusion: We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Low maternal urinary iodine concentration (UIC) during pregnancy is associated with adverse offspring neurodevelopment. Thyroglobulin (Tg) has been suggested as a more sensitive biomarker than UIC of long-term iodine status, but associations of Tg with neurodevelopment and the possible mediating role of thyroid function remain unknown., Aim: To study whether maternal Tg is associated with i) maternal and newborn thyroid function and ii) offspring IQ and brain morphology., Methods: Participants were selected from two population-based prospective cohorts: Generation R (the Netherlands, iodine-sufficient) and INfancia y Medio Ambiente (Spain, mildly iodine-deficient) with maternal Tg and thyroid function data in the first half of pregnancy or in cord blood, early childhood IQ (age 4.5 and 6 years), late childhood IQ (age 9 and 13), or brain morphology at 10 years. Associations of Tg with TSH, FT4, IQ and brain morphology were studied with multivariable linear regression., Results: i) Tg was associated with lower TSH (-0.12[-0.16; -0.08]) and higher FT4 (0.08[0.05;0.12]) in pregnancy (N=4,367), but not with cord blood TSH or FT4 (N=2,008). ii) Tg was associated with lower IQ in early childhood (β[95% CI]:-0.06 [-0.10; -0.01], N=2,919), but not with IQ (N=2,503) or brain morphology (N=1,180) in later childhood. None of the associations of Tg with the studied outcomes differed by the iodine-to-creatinine ratio (i.e. effect modification) or changed when adjusted for thyroid function., Conclusions: Higher Tg is associated with lower IQ in early childhood and higher thyroid function during pregnancy, but not with IQ or brain morphology in later childhood. Further research should determine the value of Tg in addition to UIC for defining iodine status., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The 2022 WHO Classification categorizes oncocytic (OTC) and follicular thyroid carcinoma (FTC) based on the degree of capsular and vascular invasion into minimally invasive (MI), encapsulated angioinvasive (EA) and widely invasive tumors (WI). While associations with clinical outcomes have been studied extensively in FTC, robust clinical data are lacking for OTC. We aimed to investigate the impact of the reclassification of OTC and FTC by the 2022 WHO Classification on clinical outcomes., Methods: All adult OTC and FTC patients treated at the Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. All tumors were extensively revised by two independent pathologists, facilitated by Palga: Dutch Pathology Databank. Kaplan-Meier curves were used to study the association of the 2004 and 2022 WHO Classification with overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and radioactive iodine (RAI) refractory disease., Results: Fifty-two OTC and 89 FTC patients were included, of which 15 (28.8%) OTC and 34 (38.2%) FTC tumors were reclassified as EAOTC or EAFTC. The 2022 WHO Classification substantially improved risk stratification in both subtypes for DSS, compared with the 2004 edition. Ten-year DSS rates were 100% for MIOTC, 92.9% for EAOTC and 56.5% for WIOTC, compared to 100% (MIOTC) and 64.2% (WIOTC) following the 2004 WHO Classification. For FTC and RAI-refractory disease, similar trends were observed., Conclusion: Classification of OTC and FTC into three subcategories as defined by the 2022 WHO Classification substantially improves discrimination between low, intermediate and high risk patients, especially for DSS and RAI-refractory disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: An association of thyroid function with mood disorders has been widely suggested, but very few studies have examined this association longitudinally., Objective: We assessed the cross-sectional and longitudinal association between thyroid function and depression in a population-based cohort., Methods: A total of 9471 individuals were included in cross-sectional analyses, of whom 8366 had longitudinal data. At baseline, we assessed thyroid function using serum samples (thyrotropin [TSH], free thyroxine (FT4), and thyroid peroxidase antibodies) and depressive symptoms using the Centre for Epidemiologic Studies Depression (CES-D) scale. Incident depressive events (n = 1366) were continuously followed up with the CES-D and clinical interviews. We analyzed the cross-sectional association of thyroid function and thyroid disease with depressive symptoms using linear and logistic regression, and the longitudinal association with Cox proportional hazard models for depressive events., Results: Lower TSH levels and lower and higher FT4 levels were cross-sectionally associated with more depressive symptoms with a B value of -0.07 per 1 unit increase of natural log-transformed TSH (95% CI -0.11; -0.04). Furthermore, hypothyroidism was cross-sectionally associated with less depressive symptoms and hyperthyroidism with more depressive symptoms. Longitudinally, there was a U-shaped association between FT4 and incident depressive events but only in euthyroid participants., Conclusion: We show a cross-sectional association between thyroid (dys)function with depressive symptoms, and a U-shaped association between FT4 and incident depressive events in euthyroid individuals. Our findings suggest an association of thyroid function with the risk of developing depression, albeit small. Reverse causation and additional underlying factors may also contribute to the association., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes., Objective: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes., Methods: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders., Results: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA., Conclusion: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Many countries have national guidelines for the management of differentiated thyroid cancer (DTC), including a risk stratification system to predict recurrence of disease. Studies whether these guidelines could also have relevance, beyond their original design, in predicting survival are lacking. Additionally, no studies evaluated these international guidelines in the same population, nor compared them with the TNM system. Therefore, we investigated the prognostic value of 6 stratification systems used by 10 international guidelines, and the TNM system with respect to predicting disease-specific survival (DSS)., Methods: We retrospectively studied adult patients with DTC from a Dutch university hospital. Patients were classified using the risk classification described in the British, Dutch, French, Italian, Polish, Spanish, European Society of Medical Oncology, European Thyroid Association, the 2009 and 2015 American Thyroid Association (ATA) guidelines, and the latest TNM system. DSS was analyzed using the Kaplan-Meier method, and the statistical model performance using the C-index, Akaike information criterion, Bayesian information criterion, and proportion of variance explained., Results: We included 857 patients with DTC (79% papillary thyroid cancer, 21% follicular thyroid cancer). Median follow-up was 9 years, and 67 (7.8%) died because of DTC. The Dutch guideline had the worst statistical model performance, whereas the 2009 ATA/2014 British guideline had the best. However, the (adapted) TNM system outperformed all stratification systems., Conclusions: In a European population of patients with DTC, of 10 international guidelines using 6 risk of recurrence stratification systems and 1 mortality-based stratification system, our optimized age-adjusted TNM system (8th edition) outperformed all other systems., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology., Objective: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts., Methods: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy., Results: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting., Conclusion: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~5% to 9% of this variance so far. Most SNPs were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we performed a large-scale candidate gene study investigating the effect of common genetic variation in established TH regulating genes on serum thyrotropin [thyroid-stimulating hormone (TSH)] and thyroxine (FT4) concentrations., Methods: SNPs in or within 10 kb of 96 TH regulating genes were included (30 031 TSH SNPs, and 29 962 FT4 SNPs). Associations were studied in 54 288 individuals from the ThyroidOmics Consortium. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software., Results: We identified 23 novel TSH-associated SNPs in predominantly hypothalamic-pituitary-thyroid axis genes and 25 novel FT4-associated SNPs in mainly peripheral metabolism and transport genes. Genome-wide SNP variation explained ~21% (SD 1.7) of the total variation in both TSH and FT4 concentrations, whereas SNPs in the 96 TH regulating genes explained 1.9% to 2.6% (SD 0.4)., Conclusion: Here we report the largest candidate gene analysis on thyroid function, resulting in a substantial increase in the number of genetic variants determining TSH and FT4 concentrations. Interestingly, these candidate gene SNPs explain only a minor part of the variation in TSH and FT4 concentrations, which substantiates the need for large genetic studies including common and rare variants to unravel novel, yet unknown, pathways in TH regulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Whether thyroid dysfunction is related to altered brain circulation in the general population remains unknown., Objective: We determined the association of thyroid hormones with different markers of brain circulation within community-dwelling elderly people., Methods: This was a population-based study of 3 subcohorts of the Rotterdam Study, starting in 1989, 2000, and 2006. A total of 5142 participants (mean age, 63.8 years; 55.4% women), underwent venipuncture to measure serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Between 2005 and 2015, all participants underwent phase-contrast brain magnetic resonance imaging to assess global brain perfusion (mL of blood flow/100 mL of brain/minute). Arteriolar retinal calibers were assessed using digitized images of stereoscopic fundus color transparencies in 3105 participants as markers of microcirculation. We investigated associations of TSH, FT4 with brain circulation measures using (non)linear regression models., Results: FT4 (in pmol/L) levels had an inverse U-shaped association with global brain perfusion, such that high and low levels of FT4 were associated with lower global brain perfusion than middle levels of FT4. The difference in global brain perfusion between high FT4 levels (25 pmol/L) and middle FT4 levels (FT4 = 15 pmol/L; P nonlinearity = .002) was up to -2.44 mL (95% CI -4.31; -0.56). Higher and lower levels of FT4, compared with middle FT4 levels, were associated with arteriolar retinal vessels (mean difference up to -2.46 µm, 95% CI -4.98; 0.05 for lower FT4)., Conclusion: These results suggest that thyroid dysfunction could lead to brain diseases such as stroke or dementia through suboptimal brain circulation that is potentially modifiable., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction., Objective: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed., Methods: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action., Results: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported., Conclusions: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status., Methods: We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (PT-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method., Results: A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (β [95% CI] = -0.14[-0.23, -0.06], P = 0.0005 and β [95%CI] = -0.12 [-0.20, -0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (PT < 1e-3: β [95% CI] = -0.02 [-0.03, -0.01], P = 0.0003 and PT < 1e-7: β [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD., Conclusions: Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes., Methods: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts., Results: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated., Conclusions: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels., Evidence Acquisition: This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease., Evidence Synthesis: Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint., Conclusions: Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Context: Current American Thyroid Association (ATA) Management Guidelines for the treatment of differentiated thyroid cancer (DTC) stratify patients to decide on additional radioiodine (RAI) therapy after surgery, and to predict recurring/persisting disease. However, studies evaluating the detection of distant metastases and how these guidelines perform in patients with distant metastases are scarce., Objective: To evaluate the 2015 ATA Guidelines in DTC patients with respect to 1) the detection of distant metastases, and 2) the accuracy of its Risk Stratification System in patients with distant metastases., Patients and Main Outcome Measures: We retrospectively included 83 DTC patients who were diagnosed with distant metastases around the time of initial therapy, and a control population of 472 patients (312 low-risk, 160 intermediate-risk) who did not have a routine indication for RAI therapy. We used the control group to assess the percentage of distant metastases that would have been missed if no RAI therapy was given., Results: Two hundred forty-six patients had no routine indication for RAI therapy of which 4 (1.6%) had distant metastases. Furthermore, among the 83 patients with distant metastases, 14 patients (17%) had excellent response, while 55 (67%) had structural disease after a median follow-up of 62 months. None of the 14 patients that achieved an excellent response had a recurrence., Conclusions: In patients without a routine indication for RAI therapy according to the 2015 ATA Guidelines, distant metastases would initially have been missed in 1.6% of the patients. Furthermore, in patients with distant metastases upon diagnosis, the 2015 ATA Guidelines are an excellent predictor of both persistent disease and recurrence., (© Endocrine Society 2019.)

Context: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established., Objective: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability., Design: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively., Setting: General community., Participants: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease., Main Outcome Measure: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age., Results: There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation., Conclusions: Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester., (Copyright © 2019 Endocrine Society.)

Context: Previous studies suggest that maternal thyroid function affects fetal growth, but the association between combined thyroid hormones from early to late pregnancy and newborn birth weight remains unknown., Objective: To explore the association of maternal thyroid function during early and late pregnancy with birth weight., Design: A large prospective cohort study of a Chinese population., Setting: This study recruited pregnant women who underwent first-trimester prenatal screenings at the International Peace Maternity and Child Health Hospital between January 2013 and December 2016., Participants: This study enrolled 46,186 mothers in whom TSH, free thyroxine (FT4), T3, and thyroid peroxidase antibody concentrations were measured in the first and third trimesters and in whom data on birth weight were available., Main Outcome Measures: Birth weight, small for gestational age, large for gestational age (LGA)., Results: A higher TSH or FT4 concentration, or a lower T3 concentration, during the first or third trimester was associated with a lower birth weight. The lowest percentiles of maternal FT4 (FT4 < 2.5th percentile) in both trimesters were associated with a 0.34-SD higher birth weight. The effect estimates were greater in those in the first trimester (0.23 SD) or in the third trimester (0.17 SD). The association of maternal TSH and FT4 with birth weight differed according to fetal sex., Conclusions: Persistently low FT4 concentrations throughout pregnancy were associated with higher birth weight and an increased risk of LGA. Based on these findings, we recommend monitoring mildly altered concentrations of thyroid hormone throughout pregnancy., (Copyright © 2019 Endocrine Society.)

Context: Mechanisms linking high and high-normal thyroid function to increased cardiovascular risk remain unclear. Hypothetically, coagulation can play a role., Objective: To investigate (i) the association of thyroid function with coagulation factors and (ii) whether coagulation factors mediate the association of thyroid function with cardiovascular disease (CVD)., Design and Setting: Rotterdam Study, a population-based prospective study., Participants and Main Outcome Measures: In 5918 participants (mean age, 69.1 years), we measured TSH, free T4 (FT4), and coagulation factors [von Willebrand factor antigen (VWF:Ag), ADAMTS13 activity, fibrinogen]. Participants were followed up for the occurrence of cardiovascular events and deaths. Associations of thyroid function with coagulation factors (standardized z scores) and CVD were assessed through linear regression and Cox proportional hazards models, adjusted for potential confounders. We performed causal mediation analyses to evaluate whether the effect of thyroid function on CVD is mediated by coagulation., Results: Higher FT4 levels were associated with higher VWF:Ag (β = 0.34; 95% CI = 0.22, 0.47), lower ADAMTS13 activity (β = -0.22; 95%CI = -0.35, -0.09), and higher fibrinogen (β = 0.26; 95% CI = 0.13, 0.39); 857 incident cardiovascular events and 690 cardiovascular deaths occurred. FT4 levels were positively associated with cardiovascular events and deaths. The effect of FT4 on incident cardiovascular events was minimally mediated by fibrinogen (1.6%) but not by VWF:Ag and ADAMTS13. VWF:Ag and fibrinogen together mediated 10.0% of the effect of FT4 on cardiovascular deaths., Conclusions: Higher FT4 levels were associated with higher VWF:Ag, lower ADAMTS13 activity, and higher fibrinogen levels, indicating a procoagulant state. VWF:Ag and fibrinogen explained up to 10% of the link between FT4 and CVD., (Copyright © 2019 Endocrine Society.)

Context: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity., Objective: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4., Methods: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed., Results: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4., Conclusions: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling.

Context: Thyroid hormone is important for normal brain development. The type 2 deiodinase (D2) controls thyroid hormone action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine for which the selenocysteine-insertion sequence (SECIS) element located in the 3' untranslated region is indispensable. We hypothesized that mutations in the SECIS element could affect D2 function, resulting in a neurocognitive phenotype., Objective: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability and to test their functional consequences., Design, Setting, and Patients: The SECIS element of DIO2 was sequenced in 387 patients with unexplained intellectual disability using a predefined pattern of thyroid function tests. SECIS element read-through in wild-type or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies., Results: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in the unaffected family members. The functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene., Conclusions: We report on two families with mutations in the SECIS element of D2. Although functional analysis showed that nucleotide 5730 is important for normal SECIS element read-through, the two variants did not segregate with a distinct phenotype., (Copyright © 2019 Endocrine Society.)

Context: Although the skeleton is a well-known thyroid hormone target organ, very little data are available on the association of thyroid function with bone outcomes during childhood., Objective: To study the association of thyroid function with bone mass during childhood., Design, Setting, and Participants: Population-based prospective cohort including 4204 children with TSH and free T4 (FT4) measured at the age of 6 years., Main Outcome Measures: Bone density was assessed by a total body dual-energy X-ray absorptiometry scan at the median age of 6 years (95% range, 5.6 to 7.9) and at the age of 10 years (95% range, 9.0 to 10.9) in 4204 and 3404 participants, respectively., Results: There was an inverse association of TSH with bone mineral density (BMD) at the age of 6 (β -0.028 ± 0.011, P = 0.009) and with follow-up measurements at the age of 10 (β -0.027 ± 0.011, P = 0.014), but not with bone mineral content (BMC) at the age of 6 (β -0.028 ± 0.015, P = 0.06) or for follow-up measurements of BMC at the age of 10 (β -0.011 ± 0.015, P = 0.47). There was an inverse association of FT4 with BMD (β -0.016 ± 0.006, P = 0.014) and BMC (β -0.023 ± 0.009, P = 0.009) cross-sectionally, and also at the age of 10 years (BMD: β -0.018 ± 0.007, P = 0.007; BMC: β -0.021 ± 0.009, P = 0.020)., Conclusion: A higher FT4 concentration is associated with lower bone mass at the age of 6 and at the age of 10 years. These data provide insights into the effects of thyroid function on bone physiology during childhood.

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce., Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia., Design: Individual participant data meta-analysis., Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162)., Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women)., Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups., Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

Context: Thyroperoxidase antibody (TPOAb) positivity is a major risk factor for gestational thyroid dysfunction. During the first 18 to 20 weeks of pregnancy, high concentrations of human chorionic gonadotropin (hCG) stimulate the thyroid to ensure adequate thyroid hormone availability for the developing fetus. However, TPOAb-positive women have an impaired thyroidal response to hCG stimulation., Objective: To study the association of maternal TPOAb positivity during pregnancy with child IQ., Design, Setting, and Participants: This study was embedded in two prospective birth cohorts: Generation R (Rotterdam, the Netherlands) and Avon Longitudinal Study of Parents and Children (ALSPAC; United Kingdom). Mother-child pairs with available data on early pregnancy TPOAb (≤18 weeks of gestation) and offspring IQ were included (n = 3637 for Generation R and n = 2396 for ALSPAC)., Main Outcome Measures: Child IQ at 5 to 10 years of age., Results: In Generation R, TPOAb positivity was associated with a 2.0 ± 0.9-point lower mean child IQ (P = 0.03). Sensitivity analyses showed negative effect estimates already from TPOAb concentrations considerably lower than currently used manufacturer cutoffs. In ALSPAC, neither TPOAb positivity nor TPOAb concentrations below manufacturer cutoffs were associated with child IQ (TPOAb positivity: 0.7 ± 1.0; P = 0.45). Adjustment for maternal TSH or free T4 concentrations or urinary iodine/creatinine ratio did not change the results., Conclusion: TPOAb positivity during pregnancy was associated with lower child IQ in Generation R but not in ALSPAC. Further studies are needed to elucidate whether differences between the study populations, such as maternal iodine status, could be the underlying cause for these differences.

Context: Establishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for triiodothyronine measurements, and most studies do not take into account thyroid antibodies or human chorionic gonadotropin., Objective: To determine reference ranges and to identify/quantify determinants of TSH, free T4 (FT4), free triiodothyronine (FT3), total T4 (TT4), and total triiodothyronine (TT3)., Design, Setting, and Participants: This study included 2314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5th to 97.5th percentiles after excluding thyroperoxidase antibody (TPOAb)-positive and/or thyroglobulin antibody (TgAb)-positive women., Intervention: None., Main Outcome Measures: TSH, FT4, FT3, TT4, and TT3 in prenatal serum., Results: After exclusion of TPOAb-positive women, reference ranges were as follows: TSH, 0.11 to 3.48 mU/L; FT4, 11.6 to 19.4 pmol/L; FT3, 3.72 to 5.92 pg/mL; TT4, 82.4 to 166.2 pmol/L; and TT3, 1.28 to 2.92 nmol/L. Additional exclusion of TgAb-positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. Body mass index (BMI) and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4, and TT3., Conclusions: We show that the exclusion of TgAb-positive women on top of excluding TPOAb-positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4, and TT3 that could reflect endocrine-disrupting effects and/or effects on thyroid hormone transport or deiodination.

Context: Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status., Objective: To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status., Design, Setting, and Participants: Meta-analysis of individual participant data from 9036 mother-child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease., Main Outcomes: Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age., Results: FT4 <2.5th percentile was associated with a 3.9-point (95% CI, -5.7 to -2.2) lower nonverbal IQ and a 2.1-point (95% CI, -4.0 to -0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH., Conclusions: Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay.

Context: A common single nucleotide polymorphism in DIO2, Thr92AlaD2, has been associated with a transcriptome typically found in neurodegenerative diseases in postmortem human brain tissue., Objective: To determine whether Thr92AlaD2 is associated with incident Alzheimer disease (AD)., Design: Population-based study; human brain tissue microarray., Setting: Community-based cohorts from Chicago and northeastern Illinois and religious clergymen from across the United States constituted the primary population. A representative sample of the U.S. population was used for secondary analyses., Participants: 3054 African Americans (AAs) and 9304 European Americans (EAs)., Main Outcome Measure: Incident AD., Results: In the primary population, AAs with Thr92AlaD2 had 1.3 times [95% confidence interval (CI), 1.02 to 1.68; P = 0.048] greater odds of developing AD. AAs from a second population with Thr92AlaD2 showed a trend toward increased odds of dementia (odds ratio, 1.33; 95% CI, 0.99 to 1.78; P = 0.06) and 1.35 times greater odds of developing cognitive impairment not demented (CIND; 95% CI, 1.09 to 1.67; P = 0.006). Meta-analysis showed that AAs with Thr92AlaD2 had 1.3 times increased odds of developing AD/dementia (95% CI, 1.07 to 1.58; P = 0.008). In EAs, no association was found between Thr92AlaD2 and AD, dementia, or CIND. Microarray of AA brain tissue identified transcriptional patterns linked to AD pathogenesis., Conclusions: Thr92AlaD2 was associated with molecular markers known to underlie AD pathogenesis in AAs, translating to an observed phenotype of increased odds of developing AD/dementia in AAs in these populations. Thr92AlaD2 might represent one factor contributing to racial discrepancies in incident AD.

Objective: To investigate a dose dependency of thyroperoxidase antibody (TPOAb) concentrations in relation to thyroid function and premature delivery and define a population-based, pregnancy-specific, functional cutoff for TPOAb positivity., Design: Individual participant meta-analysis of three prospective birth cohorts: the Amsterdam Born Children and their Development study, and the Holistic Approach to Pregnancy., Setting: Population-based studies in the Netherlands (2002 to 2014)., Participants: A total of 11,212 pregnant women (<20 weeks' gestation)., Main Outcome Measures: Thyrotropin (TSH) and FT4 concentrations, premature delivery., Results: In all cohorts, there was a dose-dependent positive association of TPOAb concentrations with TSH concentrations, as well as a dose-dependent negative association with FT4 concentrations during early pregnancy (all P < 0.0001). There was a dose-dependent association of TPOAb concentrations with the risk of premature delivery, which was also modified by TSH concentrations. Women with TPOAb concentrations from the 92nd percentile upward had a higher TSH and a higher risk of a TSH >2.5 mU/L (range, 19.4% to 51.3%). Stratified analyses showed that women with TPOAb concentrations below manufacturer cutoffs already had a higher risk of premature delivery, especially when TSH concentrations were high or in the high-normal range., Conclusions: This study demonstrated a dose-dependent relationship between TPOAbs and thyroid function as well as the risk of premature delivery. Furthermore, our results indicate that the currently used cutoffs for TPOAb positivity may be too high. Furthermore, the use of a population-based cutoff for TPOAbs may identify women with a clinically relevant extent of thyroid autoimmunity and a higher risk of premature delivery but that would not be considered TPOAb positive or eligible for treatment otherwise., (Copyright © 2017 Endocrine Society)

Context: Despite the well-recognized clinical features resulting from insufficient or excessive thyroid hormone (TH) levels in humans, it is largely unknown which genes are regulated by TH in human tissues., Objective: To study the effect of TH on human gene expression profiles in whole blood, mainly consisting of T3 receptor (TR) α-expressing cells., Methods: We performed next-generation RNA sequencing on whole blood samples from eight athyroid patients (four females) on and after 4 weeks off levothyroxine replacement. Gene expression changes were analyzed through paired differential expression analysis and confirmed in a validation cohort. Weighted gene coexpression network analysis (WGCNA) was applied to identify thyroid state-related networks., Results: We detected 486 differentially expressed genes (fold-change >1.5; multiple testing corrected P value < 0.05), of which 76% were positively and 24% were negatively regulated. Gene ontology (GO) enrichment analysis revealed that three biological processes were significantly overrepresented, of which the process translational elongation showed the highest fold enrichment (7.3-fold, P = 1.8 × 10-6). WGCNA analysis independently identified various gene clusters that correlated with thyroid state. Further GO analysis suggested that thyroid state affects platelet function., Conclusions: Changes in thyroid state regulate numerous genes in human whole blood, predominantly TRα-expressing leukocytes. In addition, TH may regulate gene transcripts in platelets., (Copyright © 2017 Endocrine Society)

Context: Thyroid hormones affect metabolism in various tissues, organs, and systems. However, the overall impact of thyroid function on an individual's vulnerability to adverse outcomes remains unclear., Objective: To investigate the cross-sectional and prospective association of thyroid function with the frailty index, a well-established measure of overall health., Design and Setting: The Rotterdam Study, a population-based, prospective cohort study., Participants and Main Outcome Measurements: Participants with baseline measurements of thyroid function and the frailty index were eligible. The frailty index was measured at baseline and after a median follow-up time of 10.1 years (interquartile range, 5.7 to 10.8 years). A higher frailty index indicated a worse health state. We assessed the association of thyroid function with frailty at baseline, frailty at follow-up, and frailty changes over time, adjusting for age, sex, cohort, smoking, alcohol, and education., Results: We included 9640 participants (mean age, 64.9 years). There was a U-shaped association of thyrotropin (TSH; P < 0.0003) and free thyroxine (FT4; P < 0.0001) with frailty at baseline. There was no association of TSH, but a positive association of FT4 with frailty at follow-up and frailty changes over time (β, 1.22; confidence interval, 0.73 to 1.72 per 1 unit FT4)., Conclusion: In this population-based study, participants with low and high thyroid function were more likely to be frail than participants with normal thyroid function. However, only those with higher FT4 levels had an increased risk of becoming more frail over time. The identification of FT4 as a potential marker of health deterioration could have future implications regarding the prediction and prevention of frailty., (Copyright © 2017 Endocrine Society)

Context: High homocysteine concentrations are associated with maternal pregnancy complications and low birth weight, jaundice, and cerebrovascular accidents in neonates. Thyroid hormone may interfere with homocysteine metabolism via stimulation of vitamin B12- and folate-dependent processes and via effects on enzymes of the remethylation pathway., Objective: Investigating the associations of maternal and neonatal thyroid function with homocysteine during pregnancy and after delivery, respectively., Design, Setting, and Participants: Within Generation R study, a population-based prospective cohort, we studied the associations of maternal and neonatal thyroid stimulating hormone (TSH) and free thyroxine (FT4) with homocysteine, folate, and vitamin B12 concentrations using multiple linear regression analyses., Main Outcome Measures: TSH, FT4, homocysteine, folate, and vitamin B12 concentrations were determined in early pregnancy (<18 weeks; N = 1094 women without folic acid supplementation) and in cord blood of 4475 neonates., Results: In neonates, there was a positive association of FT4 with homocysteine and an inverse association of TSH with homocysteine. The associations attenuated after adjustment for folate and vitamin B12 concentration (β change: for FT4, 0.00559 ± 0.001, P < 0.0001, to 0.00310 ± 0.001, P = 0.015; and for TSH, -0.00165 ± 0.001, P = 0.005, to -0.00086 ± 0.001, P = 0.11). In mothers, there was a positive association of FT4 with homocysteine (P = 0.026) but no association of FT4 with folate or vitamin B12 (P ≥ 0.08)., Conclusion: Higher thyroid function is associated with higher homocysteine concentrations in pregnant women and in neonates. These data provide new insights into the effects of thyroid hormone on folate- and vitamin B12-dependent processes during early growth and development., (Copyright © 2017 Endocrine Society)

Context: Patients with resistance to thyroid hormone (TH) α (RTHα) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHα patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)α in erythropoiesis., Objective: To investigate whether a defect in TRα affects the maturation of red blood cells in RTHα patients., Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHα patients (n = 11) harboring different inactivating mutations in TRα (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points., Results: After ∼14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHα-derived cells differentiated more slowly. During spontaneous differentiation, RTHα-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHα-derived progenitors did not correlate with severity of underlying TRα defect. Both control and RTHα-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHα patient-derived HEPs., Conclusions: Inactivating mutations in human TRα affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTHα patients.

Context: Human chorionic gonadotropin (hCG) stimulates thyroid function during pregnancy. We recently showed that thyroid autoimmunity severely attenuated the thyroidal response to hCG stimulation and that this may underlie the higher risk of premature delivery in thyroperoxidase antibody (TPOAb)-positive women. We hypothesized that a lower thyroidal response to hCG stimulation in TPOAb-negative women is also associated with a higher risk of premature delivery and preterm premature rupture of membranes (pPROM)., Design, Setting, and Participants: Thyrotropin (TSH), free thyroxine (FT4), and hCG concentrations were available in 5644 TPOAb-negative women from a prospective cohort. We tested for interaction between TSH or FT4 and hCG in linear regression models for duration of pregnancy and logistic regression models for premature delivery/pPROM. Accordingly, analyses were stratified per TSH percentile (TSH ≥ 85th percentile) and hCG per 10,000 IU/L., Results: Women with high TSH and low hCG concentrations did not have a higher risk of premature delivery or pPROM, with protective effect estimates. In contrast, women with a high TSH concentration despite a high hCG concentration had twofold to 10-fold higher risk of premature delivery (Pdifference = 0.022) and an up to fourfold higher risk of pPROM (Pdifference = 0.079). hCG concentrations were not associated with premature delivery or pPROM., Conclusion: In TPOAb-negative women with high-normal TSH concentrations, only women with high hCG concentrations had a higher risk of premature delivery or pPROM. These results suggest a lower thyroidal response to hCG stimulation is also associated with premature delivery in TPOAb-negative women and that an additional measurement of hCG may improve thyroid-related risk assessments during pregnancy., (Copyright © 2017 Endocrine Society)

Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate., Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms., Design: We performed a prospective cohort study between 2009 and 2016., Setting: This study was conducted at a tertiary referral center., Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib., Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells., Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10., Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10., (Copyright © 2017 Endocrine Society)

Context: Reference ranges of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are defined by their distribution in apparently healthy populations (2.5th and 97.5th percentiles), irrespective of disease risk, and are used as cutoffs for defining and clinically managing thyroid dysfunction., Objective: To provide proof of concept in defining optimal health ranges of thyroid function based on cardiovascular disease (CVD) mortality risk., Design and Participants: In all, 9233 participants from the Rotterdam Study (mean age, 65.0 years) were followed up (median, 8.8 years) from baseline to date of death or end of follow-up period (2012), whichever came first (689 cases of CVD mortality)., Main Outcomes: We calculated 10-year absolute risks of CVD mortality (defined according to the SCORE project) using a Fine and Gray competing risk model per percentiles of TSH and FT4, modeled nonlinearly and with sex and age adjustments., Results: Overall, FT4 level >90th percentile was associated with a predicted 10-year CVD mortality risk >7.5% (P = 0.005). In men, FT4 level >97th percentile was associated with a risk of 10.8% (P < 0.001). In participants aged ≥65 years, absolute risk estimates were <10.0% below the 30th percentile (∼14.5 pmol/L or 1.10 ng/dL) and ≥15.0% above the 97th percentile of FT4 (∼22 pmol/L or 1.70 ng/dL)., Conclusions: We describe absolute 10-year CVD mortality risks according to thyroid function (TSH and FT4) and suggest that optimal health ranges for thyroid function can be defined according to disease risk and are possibly sex and age dependent. These results need to be replicated with sufficient samples and representative populations., (Copyright © 2017 Endocrine Society)

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk., Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals., Design: Individual participant data analysis., Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002., Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L., Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts., Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses., Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests., (Copyright © 2017 Endocrine Society)

Context: Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer-specific HRQoL in survivors only., Design: Survivors diagnosed between 1970 and 2013 at age ≤18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer-specific HRQoL questionnaire., Results: Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer-specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL., Conclusions: Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration., (Copyright © 2017 Endocrine Society)

Context: Thyroperoxidase antibody (TPOAb) positivity is the main risk factor for thyroid dysfunction during pregnancy and is consistently associated with premature delivery. However, the underlying mechanism is currently unknown. We hypothesized that TPOAb positivity may interfere with gestational thyroid stimulation induced by the pregnancy hormone human chorionic gonadotropin (hCG)., Design, Setting, and Participants: Thyrotropin (TSH), free thyroxine (FT4), TPOAbs, and/or hCG concentrations were measured in early and late pregnancy of 7587 pregnant women from 2 Dutch population-based prospective cohorts (n = 5924, Generation R study; n = 1663, Holistic Approach to Pregnancy and the First Postpartum Year study)., Interventions: None., Main Outcome Measure(s): Thyroidal response to hCG stimulation, premature delivery., Results: In TPOAb-negative women, hCG was positively associated with FT4 and negatively with TSH in both cohorts (P < 0.0001). In contrast, in TPOAb-positive women, hCG was not associated with FT4 or TSH in either cohort (all P > 0.40; P for interaction TPOAb positive vs negative ≤ 0.05). Overall, TPOAb positivity was associated with a 1.7-fold higher risk of premature delivery. TPOAb-positive women with an adequate response of FT4 to hCG (high FT4 concentration with high hCG concentration) did not have a higher risk of premature delivery. In contrast, TPOAb-positive women with an inadequate FT4 response to hCG (low FT4 concentration with high hCG concentration) had a 2.2- to 2.8-fold higher risk of premature delivery., Conclusion: TPOAb-positive women display an impaired thyroidal response to hCG and this may explain the higher risk of premature delivery in these women. This abnormal response in TPOAb-positive women might suggest that these women require a different treatment approach than TPOAb-negative women., (Copyright © 2017 by the Endocrine Society)

Context: Although both overt hyper- and hypothyroidism are known to lead to cognitive impairment, data on the association between subclinical thyroid dysfunction and cognitive function are conflicting., Objective: This study sought to determine the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction among prospective cohorts., Data Sources: We searched in MEDLINE and EMBASE from inception until November 2014., Study Selection: Two physicians identified prospective cohorts that assessed thyroid function and cognitive outcomes (dementia; Mini-Mental State Examination [MMSE])., Data Extraction: Data were extracted by one reviewer following standardized protocols and verified by a second reviewer. The primary outcome was dementia and decline in cognitive function was the secondary outcome., Data Synthesis: Eleven prospective cohorts followed 16,805 participants during a median followup of 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (SHyper) (n = 6410), six in subclinical hypothyroidism (SHypo) (n = 7401). Five studies analyzed MMSE decline in SHyper (n = 7895), seven in SHypo (n = 8960). In random-effects models, the pooled adjusted risk ratio for dementia in SHyper was 1.67 (95% confidence interval, 1.04; 2.69) and 1.14 (95% confidence interval, 0.84; 1.55) in SHypo vs euthyroidism, both without evidence of significant heterogeneity (I 2 = 0.0%). The pooled mean MMSE decline from baseline to followup (mean 32 mo) did not significantly differ between SHyper or SHypo vs euthyroidism., Conclusions: SHyper might be associated with an elevated risk for dementia, whereas SHypo is not, and both conditions are not associated with faster decline in MMSE over time. Available data are limited, and additional large, high-quality studies are needed.

Context: In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results., Objective: We aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting., Design, Setting, and Participants: The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T 4 (FT 4 ) and/or TSH were available., Main Outcome Measures: Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically., Results: Higher FT 4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval [CI], 1.12-1.79), lung cancer (HR, 2.33; 95% CI, 1.39-3.92) and breast (HR, 1.77; 95% CI, 1.10-2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT 4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk., Conclusions: Higher FT 4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.

Context: During pregnancy, there is an increased demand for thyroid hormone. The pregnancy hormone human chorionic gonadotropin (hCG) is an important physiological stimulator of thyroid function. Already high-normal maternal free T 4 concentrations are associated with a higher risk of preeclampsia., Objective: The objective of the investigation was to study our hypothesis that hCG concentrations can distinguish a physiological form of high thyroid function from a more pathological form of high thyroid function and that the risk of preeclampsia would differ accordingly., Design: TSH, free T 4 , hCG, or thyroperoxidase antibody concentrations were determined in pregnant women participating in a population-based prospective cohort study., Setting: The study was conducted in the general community., Participants: A nonselected sample of 5146 pregnant women participated in the study., Interventions: There were no interventions., Main Outcome Measure(s): Preeclampsia was measured., Results: Women with high hCG-associated high thyroid function did not have a higher risk of preeclampsia than women with normal thyroid function. In contrast, women with low hCG and high thyroid function had a 3.4- to 11.1-fold higher risk of preeclampsia. These risk estimates were amplified in women with a high body mass index. Women with a low hCG and suppressed TSH (<0.10 mU/L) had a 3.2- to 8.9-fold higher risk of preeclampsia. hCG was not associated with preeclampsia, and results remained similar after exclusion of thyroperoxidase antibody-positive women., Conclusion: This study suggests that, in contrast to women with a high hCG associated high thyroid function, women with low hCG and high thyroid function during pregnancy are at a higher risk of developing preeclampsia. The additional measurement of hCG may therefore help to distinguish a more pathological form of high thyroid function and women at a high risk of preeclampsia.

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 T 4 , 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 T 4 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.

Context: Although thyroid function is associated with several risk factors of nonalcoholic fatty liver disease (NAFLD), its role in NAFLD development remains unclear., Objective: We aimed to prospectively investigate the association between variations in thyroid function and NAFLD., Design and Setting: The Rotterdam Study, a large population-based, prospective cohort study., Participants and Main Outcome Measures: Participants with thyroid function measurements at baseline and NAFLD data (ie, at baseline fatty liver index/at follow-up ultrasound) were eligible. Transient elastography was performed to assess the presence of fibrosis in patients with NAFLD, using the liver stiffness measurements more than or equal to 8 kPa as cutoff for clinically relevant fibrosis. The association between thyroid parameters and incident NAFLD was explored by using logistic regression models., Results: A total of 9419 participants (mean age, 64.75 y) were included. The median follow-up time was 10.04 years (interquartile range, 5.70-10.88 y). After adjusting for age, sex, cohort, follow-up time, use of hypolipidemic drugs, and cardiovascular risk factors, higher free T4 levels were associated with a decreased risk of NAFLD (odds ratio, 0.42; 95% confidence interval [CI], 0.28-0.63). In line, higher TSH levels were associated with an increased risk of having clinically relevant fibrosis in NAFLD (odds ratio, 1.49; CI, 1.04-2.15). Compared with euthyroidism, hypothyroidism was associated with a 1.24-fold higher NAFLD risk (CI, 1.01-1.53). Moreover, NAFLD risk decreased gradually from hypothyroidism to hyperthyroidism (P for trend = .003)., Conclusion: Lower thyroid function is associated with an increased NAFLD risk. These findings may lead to new avenues regarding NAFLD prevention and treatment.

Context: Recently several patients with resistance to thyroid hormone (RTH)-α due to T3 receptor-α (TRα) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests., Objective: The objective of the study was to describe the clinical phenotype of three new families with RTHα and thereby gain more detailed knowledge on this novel syndrome., Design, Setting, and Participants: RTHα was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TRα mutations were investigated in vitro., Results: We studied 22 individuals from three families and identified 10 patients with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T3 ranged from high-normal to high and serum free T4 and rT3 from normal to low. TSH levels were normal in all patients., Conclusions: This large case series underlines the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.

Introduction: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands., Patients and Methods: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis ≤18 y) treated in The Netherlands between 1970 and 2013 were assessed using medical records., Results: We identified 170 patients. Overall survival was 99.4% after a median follow-up of 13.5 years (range 0.3-44.7 y). Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 years (range 5.8-18.9 y). At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 GBq (range 0.74-35.15 GBq). Life-long postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (odds ratio 2.00, 95% confidence interval 0.78-5.17, P = .152)., Conclusions: Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of life-long postoperative complications. Adverse effects may be reduced by the centralization of care, which is crucial for children with DTC.