OBJECTIVE:Hypocalcemia is the most common complication following thyroidectomy. Previous studies yielded inconsistent results on whether vitamin D3 prevents postoperative hypocalcemia and were conducted in non-European countries with different dietary habits and baseline vitamin D levels. Therefore, we explored the effect of preoperative vitamin D3 on post-thyroidectomy hypocalcemia in a Dutch cohort. METHODS:Patients undergoing thyroidectomy between 2023 and 2025 received 100,000 IU vitamin D3 1 week before surgery ("vitamin D group") and were compared to a historical cohort (2019-2022) without vitamin D3 supplementation ("control group"). Outcomes included incidence of hypocalcemia (albumin-adjusted calcium < 2.00 mmol/L), need for postoperative supplementation, time until normocalcemia, length of hospital stay, and readmissions. RESULTS:Fifty patients received preoperative vitamin D3 and were compared to 154 controls (82.8% female, median age: 55 years [IQR: 43-66]). Vitamin D3 supplementation was associated with a reduced risk of biochemical hypocalcemia at all postoperative time points (OR 0.28, 95% CI: 0.11-0.68, p = 0.005), corresponding to a number needed to treat of five patients to prevent one case of hypocalcemia. As compared to controls, the need for postoperative supplementation and time to recover from hypocalcemia were lower in the vitamin D group (32.0% vs. 53.9%, p = 0.007; and 0 [0-2] vs. 3 [0-11] days, p = 0.002, respectively). No differences were observed in length of hospital stay or readmissions. CONCLUSIONS:Although larger randomized trials are needed to confirm these observations, preoperative vitamin D3 was associated with a significant reduction in post-thyroidectomy hypocalcemia in this observational cohort study. Given its low costs, this intervention may be considered for routine implementation in thyroidectomy patients.

AIMS:Financial constraints often limit healthy eating among individuals with Type 2 diabetes (T2D) and lower socioeconomic status (SES). Produce Prescription Programs (PRx), which provide financial support for healthy foods, have shown promise in the United States but remain understudied in Europe. This study assessed the feasibility of a 3-month PRx intervention among adults with T2D and low SES, and explored its potential effects on dietary intake, metabolic outcomes and quality of life. MATERIALS AND METHODS:In this 3-month RCT, conducted in primary care in Rotterdam, the Netherlands, adults with T2D, BMI > 25 kg/m2 and low SES were assigned to either PRx or usual care. Both groups received three dietitian consultations and were advised to follow a Mediterranean diet. PRx additionally provided weekly plant-based food boxes, cooking workshops and educational support. Feasibility outcomes included recruitment, retention, adherence and acceptability. Exploratory efficacy outcomes included nutritional intake, anthropometric measures, metabolic outcomes and quality of life at three and 6 months. RESULTS:Seventy-seven individuals were screened and 35 participants (57.3 ± 11.8 years; 74% female; BMI 32.6 ± 6.0 kg/m2) were included, of whom 17 were allocated to PRx. Participants collected an average of 10.9 out of 12 food boxes (91%) and attended 1.8 out of 3 workshops (59%). Among the 11 participants (69%) who completed the evaluation questionnaire, satisfaction scores ranged from 4.3 to 4.7 out of 5. Exploratory between-group comparisons favoured the PRx group for dietary intake, weight, BMI and physical quality of life, while no clear differences were observed for glycaemic outcomes. These findings were supported by favourable within-group changes in dietary and anthropometric outcomes in the PRx group, several of which appeared to be maintained at 6-month follow-up. CONCLUSIONS:This pilot RCT demonstrates that a 3-month PRx intervention providing plant-based food boxes is feasible and acceptable among adults with T2D and low SES. As the first European RCT evaluating a PRx intervention in this population, it provides preliminary evidence of potential benefits for dietary, anthropometric and quality of life outcomes, warranting further investigation in adequately powered trials. TRIAL REGISTRATION:OMON: NL-OMON57037; 8 October 2024.

OBJECTIVE:The extent of surgical management of thyroglossal duct-associated differentiated thyroid carcinoma remains controversial. This study aims to evaluate the role of total thyroidectomy in patients with thyroglossal duct-associated differentiated thyroid carcinoma and provide insights to support individualized, evidence-based care. DATA SOURCES:A systematic literature search was conducted in MEDLINE, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar from inception to January 2025. REVIEW METHODS:Screening was performed independently by two reviewers. Studies were included if they reported treatment details for patients with thyroglossal duct carcinoma, and excluded if they were letters, abstracts, reviews, or meta-analyses. The primary outcome consisted of recurrent disease. Secondary outcomes were presence of synchronous thyroid cancer, surgical treatments, and mortality. The study protocol was registered in PROSPERO (CRD-42023489730). RESULTS:Three hundred thirteen studies (243 case reports, 70 case series; range 1-26 patients per study) were included compromising 645 patients with differentiated thyroid carcinoma. Notably, no cohort studies were found. Recurrent disease occurred in 24/436 (5.5%) patients with reported follow-up (median, 35.5 months [12.0-80.0]). Among patients without preoperative suspicion for synchronous cancer in the thyroid, recurrence rates did not differ significantly between the Sistrunk-only group (n = 3/92 (3.3%), median follow-up 24 months [IQR, 12-48]) and the Sistrunk plus thyroidectomy group (n = 6/101 (5.9%), median follow-up 24 months [IQR, 12-69]; P = .502). CONCLUSIONS:The Sistrunk procedure alone may be sufficient in appropriately selected patients with thyroglossal duct carcinoma. The decision to perform total thyroidectomy should be individualized based on tumor characteristics and thorough thyroid assessment.

INTRODUCTION:Levothyroxine (LT4) is recommended for intake in a fasting state to optimize absorption. However, fasting intake is often burdensome and may reduce adherence. In a previous questionnaire study, we observed a strong patient preference for taking LT4 with breakfast. Therefore, we conducted a randomized controlled trial to evaluate whether nonfasting LT4 intake-accompanied by a 15% dose increase-could maintain TSH stability compared to fasting LT4 intake. METHODS:Adults with well-controlled hypothyroidism were randomized to fasting or dose-adjusted, breakfast LT4 intake. TSH, free T4, and total T3 were measured every 6 weeks, followed by LT4 dose adjustment if needed. The primary outcome was TSH stability, defined as 2 consecutive values within the reference range and a maximum ±1 mIU/L change from baseline. Patients were followed until TSH stability was reached, with a maximum of 24 weeks. After the initial study period, patients in the fasting group were invited to cross over to nonfasting intake, with similar follow-up. RESULTS:Eighty-eight patients (80.7% female, median age 62y [interquartile range: 49-69]) were randomized to fasting (n = 43) or breakfast intake (n = 45). TSH stability was comparable between groups: 74.4% [95% confidence interval (CI): 61.0-88.0%] in the fasting vs 73.3% (95%CI: 60.0-87.0%) in the breakfast group (P = not significant). Similar findings were observed in the crossover group. The breakfast group reported greater improvement in self-reported well-being (33.3% vs 16.3%, P = .07) and a stronger preference for nonfasting intake (76.2% vs 44.2%, P < .001). By the end of the study, 88.9% chose to continue nonfasting intake. CONCLUSION:LT4 ingestion with breakfast with a 15% dose increase maintained TSH stability and improved patient well-being. Given the strong patient preference, this patient-centered approach may offer a viable alternative to fasting administration.

BACKGROUND:Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS:In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. FINDINGS:In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. INTERPRETATION:Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. FUNDING:None.

Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive condition that may lead to liver cirrhosis and hepatocellular carcinoma. It is strongly associated with cardiometabolic diseases such as type 2 diabetes (T2D) and obesity. Weight loss is a key therapeutic strategy to treat MASLD. In recent years, there has been increasing attention to weight-reducing medication, but promising dietary interventions—such as early time restricted eating (eTRE)—have also been developed. Whether these dietary interventions are a good alternative to weight-reducing medication remains unclear, as direct comparative studies are still lacking. Therefore, this study will compare the effects of an early time restricted eating Mediterranean diet (eTRE-MD) intervention with naltrexone/bupropion (N/B) treatment on liver fibrosis, measured as liver stiffness (LSM) by transient elastography, in individuals with cardiometabolic risk factors.Methods and analysis We will conduct a randomised controlled trial with a planned sample size of 70 overweight (Body mass index, BMI >27 kg/m2) adults aged 18–75 years with T2D, hypertension, dyslipidaemia or obesity and moderate to severe liver fibrosis, measured as LSM (>7.0 kPa and <13.6 kPa). The diet group will receive eTRE-MD, with a 10-hour eating time restriction (8AM–6PM). The medication group will receive 32 mg/360 mg of N/B (after a dose increase period following Summary of Product Characteristics). The main study endpoint is the between-group difference in liver fibrosis (kPa) from baseline to 6 months. Secondary endpoints are liver steatosis, weight, body composition, cardiovascular risk factors, quality of life, patient satisfaction and compliance. General linear models for repeated measurements will be applied for statistical analysis of the data.Ethics and dissemination Ethical approval from the Medical Research Ethics Committees United (MEC-U) has been obtained. The results of the study will be submitted for publication in a peer-reviewed journal.Trial registration number NCT06845345.

BACKGROUND:Thyroid hormone regulates fetal brain development. Both low and high maternal thyroid function during early pregnancy has been associated with smaller offspring total gray matter and cortex volume. However, it remains unknown whether regional gray matter differences underlie global brain morphology findings. AIM:To assess the association of gestational thyroid function with regional gray matter morphology through detailed vertex-wise analysis of cortical surface area and thickness and volumetric analyses of subcortical gray matter. METHODS:We enrolled 2426 women of the population-based prospective cohort Generation R with TSH and/or free T4 (FT4) assessment before 18 weeks of gestation and offspring brain magnetic resonance imaging scans at age 10 and/or 14 years. We studied the association of gestational TSH, FT4, and (sub)clinical thyroid disease entities with local cortical surface area, thickness, and subcortical volumes. RESULTS:There was an inverse J-shaped association of TSH with cortical surface area in the rostral middle frontal region (β [SE] for quadratic TSH: -0.005 [0.001] mm2, linear TSH 0.009 [0.004]). FT4 was not associated with cortical measures. Post hoc analyses revealed an inverse J-shaped association of TSH with gyrification in a similar region and children of hyperthyroid women had less gyrification in 3 cortical regions, mainly frontal (-0.082 [0.022], -0.077 [0.020], -0.069 [0.020]). Moreover, there was an inverse U-shaped association of FT4 with caudate volume (β [SE] for quadratic FT4: -0.004 [0.001] SD, linear FT4 0.010 [0.010]). TSH and FT4 were not associated with other subcortical volumes. CONCLUSION:Maternal thyroid function during early pregnancy is associated with offspring cerebral gray matter morphology in certain brain regions, specifically the frontal lobe. These findings expand on global brain morphology associations and support previous associations with behavioral outcomes.

Introduction: Thyroid incidentalomas are lesions detected incidentally on imaging performed for unrelated indications. Determining which lesions warrant further evaluation to exclude malignancy introduces a dilemma: intensive diagnostic strategies maximize malignancy detection but increase diagnostic workload, patient burden, and overdiagnosis of indolent cancers, whereas restrictive approaches reduce these harms but risk missing malignancies. Guidelines balance these opposing considerations differently, resulting in substantial variation in recommendations for evaluating conventional imaging-detected thyroid incidentalomas (ultrasound, computed tomography, magnetic resonance imaging). In this study, we aimed to investigate the diagnostic yield of thyroid incidentaloma evaluation and the impact of guideline variability on malignancy detection and diagnostic workload. Methods: We retrospectively assessed all patients referred to Zuyd Thyroid Center (2018-2023) for thyroid nodule evaluation. Data on diagnostic outcomes, treatments, and complications were collected. A guideline-based simulation analysis examined how applying the European Thyroid Association (ETA; most intensive), the American Thyroid Association (ATA), and the Dutch Federation of Medical Specialists (most restrictive) guidelines would affect malignancy detection and diagnostic workload. Results: Of 1825 referred patients, 630 (34.5%) had one or more incidentalomas (median age 66 years [interquartile range 54-74]; 70.6% female). Malignancy rate was significantly higher for nuclear imaging-detected incidentalomas than for conventional imaging (21.1% vs. 1.8%, p < 0.001). In the guideline-based simulation analysis, ETA recommended evaluating all cases, while ATA (without clinical warning signs) evaluated 85.3%, both identifying all malignancies. The Dutch guideline avoided evaluation in 96.9% of patients, missing 7 malignancies among 528 unevaluated cases (1.3%), all subtypes with good prognosis even if left undetected. Conclusions: Conventional imaging-detected incidentalomas carry a low malignancy risk, resulting in a high diagnostic workload to detect few malignancies. More restrictive evaluation criteria can substantially reduce diagnostic burden but may miss a small number of low-risk malignancies. These findings highlight the need for improved selection criteria that minimize unnecessary procedures while ensuring detection of clinically relevant malignancies.

CONTEXT:Genetic factors are a major contributor to variation in thyroid function. Recent studies have partly identified the responsible common genetic variants and studied their application in unraveling thyroid (patho)physiology as well as their potential clinical use. EVIDENCE ACQUISITION:This review summarizes the current state of knowledge regarding the genetic architecture of thyroid function as well as its applications to improve (patho)physiological understanding and clinical management of thyroid (dys)function. EVIDENCE SYNTHESIS:Genome-wide association studies (GWAS) have been successful in detecting numerous genetic variants affecting variation in thyrotropin (TSH), free thyroxine, and triiodothyronine concentrations. Subsequent emerging high-throughput in silico and in vitro strategies are of particular value in unraveling functionality of these novel genes and its genetic variants. Translational methods such as mendelian randomization (MR) and polygenic scores (PGSs) can provide important insights into causal associations or susceptibility to disease. Moreover, PGSs show potential in adjusting personalized TSH reference ranges by distinguishing between individual hypothalamic-pituitary-thyroid-axis set-point effects and (subclinical) thyroid dysfunction. CONCLUSION:Functional characterization of the associated genes and variants in GWAS is warranted as the majority are located in genes with a yet unknown role in thyroid hormone physiology. Integration of multi-omics data and optimalization of translational applications such as MR and PGS show potential to further unravel the underlying molecular mechanisms and pave the way for incorporation of genetics in personalized management of thyroid diseases.

BACKGROUND:Based on experimental and human studies, endocrine disrupting chemicals (EDCs) can disrupt the thyroid hormone system. However, their association with thyroid function tests when considered as part of a chemical mixture is unknown. METHODS:We used data of 1970 pregnant women from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study to investigate the cross-sectional association between exposure to 26 chemical compounds with maternal thyroid function tests in early pregnancy, using Weighted Quantile Sum (WQS) regression. RESULTS:Higher exposure to EDCs mixtures was associated with a lower FT3 [WQS Estimate per an IQR increase (95 % CI): -0.09 (-0.16 to -0.01), mostly driven by PCBs] and a lower TT3 [WQS Estimate per an IQR increase (95 % CI): -0.05 (-0.09 to -0.01), mostly driven by PFOS]. In addition, higher exposure to a mixture of short lived urinary based compounds was associated with a lower TT4/TT3 ratio while higher exposure to a mixture of persistent serum based compounds was associated with a higher TT4/TT3 ratio. CONCLUSIONS:In this proof-of-principle analysis, we show that there could be an added benefit of analyzing thyroid hormone system disrupting EDCs using a mixture-based analysis approach. Our findings pave the way and provide hypotheses for future experimental and human studies to investigate the effects of EDCs as a mixture on the thyroid hormone system, revealing information on potential biological mechanisms explaining the associations from observational data.

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.

Background: No international consensus exists on the selection and reporting of outcomes after differentiated thyroid cancer (DTC) surgery, hindering assessment of new treatments and guideline formation. Therefore, we aimed to develop an international core outcome set (COS) to be measured and reported in future studies investigating surgical treatment for DTC, as well as in clinical practice. Methods: COS development consisted of three phases: (1) collecting an initial outcome list through a literature review, (2) a two-round international Delphi process with experts and patient representatives, and (3) international expert panel meeting to finalize the COS. A steering committee including experts from varying medical (sub-)specialties and a patient representative from the Dutch Thyroid Patient Organization advised on the study protocol, Delphi rounds, and expert panel meeting. Experts were identified through scientific associations, international guidelines on DTC, ClinicalTrials.gov, and last authors of key studies and suggestions from the steering committee. The outcomes from the literature review were presented in successive rounds to experts and patient representatives to assess their importance for inclusion in the DTC surgical COS. Delphi results were analyzed for each stakeholder group on a 1-9 Likert scale. Consensus-in was defined as 70% or more of participants in both stakeholder groups rating the outcome 7-9 or 90% in one group. Consensus-out was defined as 70% or more in both groups rating the outcome 1-3. Consensus-out required agreement across both groups. Results: A total of 125 experts and 7 patient representatives from 35 countries across 5 continents completed all rounds. After two rounds, consensus was reached for 17 outcomes. Of these, 13 outcomes were ratified during the expert panel meeting: recurrence, persistent disease, location of metastatic lymph nodes, number of retrieved metastatic lymph nodes, postoperative thyroglobulin levels, surgical completeness, permanent recurrent laryngeal nerve paralysis due to surgery, permanent postoperative hypoparathyroidism, 30-day postoperative complication rate, accidental intraoperative injury to adjacent organ, unplanned reoperation rate, 30-day postoperative mortality, and quality of life. Conclusions: This international consensus on the COS for DTC surgery promotes consistent and appropriate outcome selection in clinical practice and research and may be incorporated into future study designs. Future steps include defining some outcomes.

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 (1) maternal and newborn thyroid function and (2) offspring IQ and brain morphology. METHODS:Participants were selected from 2 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, free T4 (FT4), IQ, and brain morphology were studied with multivariable linear regression. RESULTS:(1) Tg was associated with lower TSH (-0.12 [-0.16; -0.08]) and higher FT4 (0.08 [0.05; 0.12]) in pregnancy (n = 4367) but not with cord blood TSH or FT4 (n = 2008). (2) Tg was associated with lower IQ in early childhood (β [95% confidence interval]: -0.06 [-0.10; -0.01], n = 2919) but not with IQ (n = 2503) or brain morphology (n = 1180) in later childhood. None of the associations of Tg with the studied outcomes differed by the iodine-to-creatinine ratio (ie, effect modification) or changed when adjusted for thyroid function. CONCLUSION: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.

Guidelines vary in their recommendations for postoperative radioactive iodine (RAI) in differentiated thyroid cancer (DTC). Omitting RAI reduces overtreatment but poses the possibility of missing distant metastases. This study compares 4 guidelines on RAI indications and potentially missed metastases. DTC patients were included retrospectively, including 48 patients with distant metastases after first RAI cycle, and 469 without distant metastases. The percentage of distant metastases missed was calculated if RAI had been omitted following the 2015 American Thyroid Association (ATA), 2019 European Society for Medical Oncology (ESMO), 2022 European Thyroid Association (ETA), and 2022 American Society of Nuclear Medicine and Molecular Imaging/European Association of Nuclear Medicine (SNMMI/EANM) guidelines. In patients without RAI indication, 1.3% to 1.6% of distant metastases may initially be missed with the ATA, ESMO, and ETA guidelines. All these cases had postoperative thyroglobulin (Tg) between 1 and 10 ng/mL or positive Tg antibodies (Tg-abs). In patients for whom RAI should be considered following the ATA, ESMO, and ETA guidelines, 2.6% to 4.0% of distant metastases may initially be missed, with all but 1 case having Tg greater than 10 ng/mL or positive Tg-abs. With the SNMMI/EANM guideline, no distant metastases would be missed, but it resulted in markedly higher RAI use in low-risk patients (82% vs 0%). Omitting postoperative RAI in low- and intermediate-risk patients, as recommended by the 2015 ATA, 2019 ESMO, and 2022 ETA guidelines, may lead to a small number of initially undetected distant metastases. However, these metastases could potentially be detected later due to the presence of biochemical disease. In contrast, the broader RAI indications endorsed by SNMMI/EANM reduce the likelihood of missed metastases, but substantially increases RAI use, exposing patients to unnecessary treatment and side effects.

Disclosure: O. Hysaj: None. O. Efthimiou: None. T. Collet: None. A.R. Cappola: None. F. Azizi: None. A. Köttgen: None. E. Selvin: None. L. Chacker: None. R. P. Peeters: None. S. Trompet: None. J. Gussekloo: None. J. Walsh: None. S. Brown: None. M. Iacoviello: None. D. Robin P.F.: None. B. Stephan J.L.: None. C. Del Giovane: None. N. Rodondi: None. Introduction: A positive test for peroxidase antibody (TPOAb) is present in 35–65% of individuals with subclinical hypothyroidism and predicts progression to overt hypothyroidism. While both subclinical and overt hypothyroidism increase cardiovascular risk, the role of TPOAb in predicting coronary heart disease (CHD) and stroke independently of thyroid function remains unclear. Methods: We identified studies through Thyroid Studies Collaboration (TSC). Additionally, we searched MEDLINE, EMBASE, and Cochrane Library databases from inception until July 2024 for eligible prospective studies reporting baseline thyroid function, TPOAb, and any of the following outcomes: CHD events, CHD mortality, stroke events, and stroke mortality. We used Cox proportional hazards models, adjusted for age, sex, and thyroid-stimulating hormone (TSH) within each cohort, followed by a random-effects meta-analysis to examine cardiovascular outcomes by TPOAb status, overall and comparing individuals with subclinical hypothyroidism to euthyroid individuals. Additional adjustments included smoking status, body mass index (BMI), systolic blood pressure, diabetes status, and total cholesterol. Results: Among 100,250 adults from 14 cohort studies (median age 55 years, 56.7% women), 11.9% were TPOAb-positive, and 5.4% had subclinical hypothyroidism (of whom 41.6% were TPOAb-positive). We found no evidence of a risk difference between participants with positive vs. negative TPOAb in the overall population: HR 1.00 (95% CI 0.90-1.11) for CHD events; HR 0.95 (95% CI 0.78-1.16) for CHD mortality; HR 0.98 (95% CI 0.87-1.11) for stroke events; and HR 1.06 (95% CI 0.81–1.40) for stroke mortality. Comparing TPOAb-positive subclinical hypothyroidism to euthyroid individuals yielded no risk differences for CHD or stroke outcomes. Among participants with subclinical hypothyroidism, positive vs. negative TPOAb HRs were 0.87 (95% CI 0.72 to 1.05) for CHD events, 0.88 (95% CI 0.64 to 1.21) for CHD mortality, 0.68 (95% CI 0.51 to 0.90) for stroke events, and 0.93 (95% CI 0.51 to 1.90) for stroke mortality. Conclusion: Positive TPOAb does not predict CHD or stroke risk independently of thyroid function. These findings suggest that TPOAb testing is not useful for cardiovascular risk stratification in euthyroid individuals or those with subclinical hypothyroidism. Presentation: Sunday, July 13, 2025

IntroductionThere is a lack of consensus on the optimal surgical strategy for differentiated thyroid cancer (DTC), partly due to inconsistent reporting of outcomes. This limits the ability to compare study results, hindering the ability to draw conclusions regarding novel treatment strategies. The development of a core outcome set (COS) reduces heterogeneity in the selection and reporting of clinical trial outcomes. Currently, there is no COS for the surgical treatment of DTC. We aim to reach a global consensus among patients and physicians on the COS for the surgical treatment for patients with DTC of all ages.Methods and analysisThe DTC-COS development will consist of three phases: first, an extensive literature review will be performed to identify reported outcomes in studies regarding surgical treatment for DTC in patients of all ages. Second, a 2-step or 3-step Delphi procedure will be performed to identify a final set of core outcomes out of the selected outcomes from the literature review. For this Delphi survey, both healthcare professionals and patients will be invited. Third, an (online) expert meeting with participants from every stakeholder group is organised to ratify the final core outcome set. The final COS will be reported in accordance with the COS-Standards for Reporting statement.Ethics and disseminationThe medical research ethics committee of the Amsterdam UMC confirmed that the Dutch Medical Research Involving Human Subjects Act (WMO) does not apply to this study and that full approval by the committee is not required. The study is registered in the COMET initiative database (registration number 2597). Results will be presented in peer-reviewed academic journals and at (international) conferences.Trial registration numberCOMET initiative database 2597

Background:To account for pregnancy-specific changes in thyroid physiology, international guidelines recommend the use of trimester-specific reference intervals. However, the pragmatic division in trimesters does not necessarily align with the changes in thyroid physiology. While the goal of treating gestational thyroid dysfunction is to prevent thyroid hormone-mediated adverse events, it remains unclear which method of standardizing to gestational age, if any, is most effective in identifying individuals at higher risk of adverse pregnancy events. Methods:We included 5,675 women participating in a population-based prospective cohort with data on thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroperoxidase antibodies (TPOAbs) during early pregnancy (median: 13.2 weeks, 95% range: 9.8-17.6). We studied the association of TSH and FT4 with pre-eclampsia, premature delivery, birth weight and offspring IQ with or without full gestational age standardization of TSH and FT4 using multivariable regression models. Results:There was a positive association of gestational age at blood sampling with TSH (difference in mean TSH: +9.6%; P < 0.001) and a negative association with FT4 (difference in mean FT4: -20.2%; P < 0.001). Standardizing TSH to gestational age led to reclassification of 36 women as having normal TSH (9.9%) and 27 as having abnormal TSH (0.5%). For FT4, 62 women were reclassified as having normal FT4 (20.3%) and 57 as having abnormal FT4 (1.1%). Standardization of TSH and FT4 concentrations led to an attenuation of the associations with any outcome of up to 71% as compared to non-standardized TSH or FT4. Conclusions:Full standardization of TSH and FT4 to gestational age either does not affect or weakens their associations with clinical outcomes, suggesting that accounting for gestational age offers no benefit with regard to identifying high-risk thyroid dysfunction during early pregnancy.

Background: The prognosis and disease course of medullary thyroid carcinoma (MTC) can vary widely among patients. Effective risk stratification is important for ensuring timely treatment and personalized follow-up. Biomarkers can enhance risk stratification and guide the development of targeted anticancer therapies and imaging techniques. While numerous studies have explored various immunohistochemical biomarkers in MTC, an overview is still lacking. This study aimed to provide a comprehensive overview of immunohistochemical biomarkers and their role in the prognosis of MTC patients, with a primary focus on overall survival (OS). Methods: This review was preregistered in PROSPERO (CRD42023469437). A systematic search was performed using the online medical databases Embase, MEDLINE (Ovid), and Cochrane. Quality was assessed using an adapted scoring system based on the REMARK criteria and the Quality in Prognosis Studies tool. The primary outcome was OS. Secondary outcomes included other types of survival and associations with clinicopathological risk factors and recurrence. Results: Of 2992 studies, 108 were included, investigating 170 unique biomarkers and with sample sizes ranging from 11 to 327 participants. The majority (72%) were reported in only one article. A minority of studies were rated as high quality (28%). Markers of proliferation Ki-67 (Ki-67) and programmed cell death-ligand 1 (PD-L1) were significantly associated with OS (hazard ratio [HR]: 6.67, confidence interval [CI]: 1.43-31.18 and HR: 3.34, CI: 1.18-9.51). Conclusions: Our systematic review provides a comprehensive synthesis of the literature on immunohistochemical biomarkers in MTC and highlights the need for high-quality validation studies. Our meta-analysis confirms the prognostic value of Ki-67, although with varying certainty due to large differences in study quality. Furthermore, we describe the association of PD-L1 positivity with poorer OS, increased recurrence, and more aggressive clinicopathological features, which supports the rationale for further investigating the potential of anti-PD-1/PD-L1 immunotherapy for advanced MTC.

CONTEXT:Monocarboxylate transporter (MCT) 8 facilitates thyroid hormone (TH) transport across the blood-brain barrier. Pathogenic variants in SLC16A2 cause MCT8 deficiency (Allan-Herndon-Dudley syndrome), characterized by intellectual and motor disability and abnormal thyroid function tests. MCT8 deficiency typically affects males due to its X-linked inheritance. OBJECTIVE:Here, we report 8 female patients with heterozygous pathogenic variants in SLC16A2 who presented with variable neurocognitive impairment, behavioral problems, and TH function abnormalities. METHODS:We performed X-chromosome inactivation studies in female patients in whom heterozygous pathogenic variants in SLC16A2 were identified. The effect of SLC16A2 variants on TH transport was assessed in transfected cells and patient-derived fibroblasts. RESULTS:In all patients (mean age 8.6 years; range, 2.3-25 years) routine care genetic analyses identified heterozygous variants in SLC16A2 (p.(R445C), p.(N193I), p.(G276R), t(X;20), resulting in a breakpoint in intron 1, t(X;19), resulting in a breakpoint in SLC16A2, p.(I562Sfs566*), p.(G221R)). All missense variants showed substantially reduced MCT8-mediated TH uptake in transiently transfected cells. X-chromosome inactivation studies in patient cells showed skewed X-inactivation in all 7 evaluated individuals. In 5 out of 7 evaluated cases, MCT8-mediated 3,5,3'-triiodothyronine (T3) uptake in patient-derived fibroblasts was impaired to a similar degree as in fibroblasts derived from male patients with MCT8 deficiency. CONCLUSION:Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation may present with variable neuro(psycho)logical, behavioral, and thyroid function test abnormalities. Female patients presenting with neurocognitive impairment and abnormal TH function tests (low free thyroxine and/or high total T3 concentrations) should be tested for genetic variants in SLC16A2.