BACKGROUND:We previously reported that lowering serum thyrotropin (TSH) levels with levothyroxine (LT4) during active surveillance (AS) of papillary thyroid microcarcinoma (PTMC) was associated with a trend toward a lower rate of disease progression. In euthyroid patients with PTMC managed with mild TSH-lowering therapy, free thyroxine (fT4) levels increased, whereas free triiodothyronine (fT3) levels remained unchanged overall, thereby raising questions regarding thyroid hormone metabolism. We therefore investigated thyroid hormone balance, with particular focus on thyroxine (T4) metabolism, including serum reverse triiodothyronine (rT3). METHODS:This retrospective study included patients with PTMC undergoing AS who were initially euthyroid and treated with LT4. At the final follow-up, patients were classified according to the detailed TSH score 209 in the low normal group (lower half of the reference range) and 110 in the high subnormal group (mildly subnormal range). Age- and sex-matched controls were selected from euthyroid PTMC patients undergoing AS who had not received LT4. TSH, fT4, fT3, triiodothyronine (T3), and rT3 levels were analyzed. TSH, fT4, and fT3 were measured using an electrochemiluminescence immunoassay, and T3 and rT3 were measured using liquid chromatography-tandem mass spectrometry. RESULTS:Compared with matched controls, both the low normal and high subnormal groups showed significantly higher fT4 levels (p < 0.001), while fT3 levels did not differ significantly. The fT3/fT4 ratio was significantly lower, whereas the rT3 levels and the rT3/T3 ratio were significantly higher in both the low normal and high subnormal groups (all p < 0.001). In analyses combining the low normal and high subnormal groups, rT3 levels were significantly and positively correlated with fT4 (r = 0.51, p < 0.001), whereas no significant correlations were observed with TSH, fT3, or T3. CONCLUSIONS:In euthyroid patients with PTMC undergoing AS, LT4 therapy aimed at maintaining TSH within the lower half of the reference range or within the mildly subnormal range was associated with higher rT3 and stable fT3 levels. These findings raise the possibility of a compensatory buffering mechanism in thyroid hormone metabolism.
Background: Macrophages are versatile phagocytes of the innate immune system with functions ranging from pro-inflammatory to immunomodulatory. Macrophages are receptive to signals from thyroid hormones (THs). Here, we studied the role of the TH receptor (TR)α1 in macrophage function. Methods: Using wild type (WT) and transgenic mice with a mutation in the T3 binding domain of the TRα1 (TRα1PV), we generated bone marrow derived macrophages (BMDMs) and subsequently polarized them into pro-inflammatory or immunomodulatory phenotypes. The phenotype and function of the unpolarized, pro-inflammatory and immunomodulatory TRα1PV BMDMs was compared with the respective WT BMDMs. Results: RNA sequencing revealed different expression profiles and alterations of biological pathways, including immune functions in all TRα1PV BMDM phenotypes. The pro-inflammatory TRα1PV BMDMs exhibited decreased marker expression associated with this phenotype, while marker expression of unpolarized and immunomodulatory TRα1PV BMDMs was unaltered. Glycolysis, a characteristic of pro-inflammatory macrophages, was reduced in all three TRα1PV macrophage phenotypes. Conclusions: Altogether, we observed that the TRα1PV mutation results in phenotypical and functional different BMDMs, with most striking changes in the pro-inflammatory phenotype, underlining the significance of adequate T3-TRα1 signaling in pro-inflammatory macrophage responses.
BACKGROUND:Differentiated thyroid cancer (DTC) is the most common endocrine malignancy among children, adolescents, and young adults (CAYA). While prognosis is generally favorable, rising incidence, longer survivorship, and radioactive iodine (RAI) treatment raise concern for late effects, particularly second primary malignancies (SPMs) and late mortality. OBJECTIVE:To evaluate SPM risk, all-cause mortality, and the impact of RAI in CAYA DTC survivors. METHODS:Retrospective cohort study (1982-2022) using Clalit Health Services records, including DTC patients diagnosed <40 years, who survived ≥2 years. Participants were matched to cancer-free controls (1:4) by birth year, sex, ethnicity, and socioeconomic status. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS:Among 5267 DTC survivors (n = 497 [∼9.5%] diagnosed before age 20 years) and 21,062 matched controls, SPM incidence was higher in survivors with 50% increased risk (500 vs. 360 per 100,000 person-years; HR 1.50, CI 1.34-1.67) and occurred after a shorter latency (13.8 vs. 15.1 years; p = 0.042). Survivors diagnosed before age 20 were significantly younger at data retrieval than those diagnosed at 20-40 years (median 33 vs. 47 years; p < 0.001) and had significantly lower SPM rates (n = 28 [5.6%] vs. n = 398 [9.0%]; p = 0.012). Compared with RAI-untreated survivors, SPM risk increased after one RAI treatment (HR 1.91, CI 1.52-2.40) and further after ≥2 RAI treatments (HR 2.73, CI 2.13-3.50). Overall mortality rate was low (n = 148, 2.8%) and similar to that of matched controls (n = 517, 2.5%) but was significantly higher among survivors who developed SPMs and/or received RAI treatment (p < 0.001). CONCLUSIONS:Over four decades of follow-up, SPMs were identified as a significant long-term risk among CAYA DTC survivors, frequently manifesting many years after the initial diagnosis. Both SPM occurrence and higher cumulative RAI doses were associated with increased mortality. These findings support careful risk-adapted use of RAI and underscore the need for extended surveillance, particularly for those diagnosed in childhood or adolescence, as malignancies may arise many years after diagnosis.
BACKGROUND:Ultrasound risk stratification systems for thyroid nodules worldwide describe different types of echogenic foci, including punctate echogenic foci (microcalcifications), coarse internal calcifications, and peripheral (rim) calcifications (complete or incomplete), with different levels of association with malignancy. We identified a previously undescribed pattern of small, discontinuous peripheral punctate echogenic foci (DPEF) associated with papillary thyroid carcinoma (PTC). METHODS:This multicenter retrospective case series included thyroid ultrasound images from five countries (Brazil, United States, Italy, France, and Romania) between January 2020 and September 2025. Cases were included solely based on the presence of discontinuous peripheral punctate hyperechoic foci, defined as small echogenic dots arranged along the nodule periphery, regardless of nodule echogenicity or morphology. Each nodule underwent comprehensive evaluation by a multidisciplinary team, including experienced radiologists, endocrinologists, head and neck surgeons, and pathologists. The final diagnosis was confirmed by histopathological examination after surgical resection. RESULTS:Twenty-three thyroid nodules from 22 patients met the inclusion criteria across all participating centers. Patient demographics included 17 women and 5 men, with ages ranging from 17 to 57 years (mean age, 36.1 years; median age, 37.5 years). Nodule size ranged from 0.4 cm to 4.8 cm in maximum diameter. All nodules exhibited the characteristic discontinuous peripheral arrangement of punctate echogenic foci on high-resolution ultrasonography. Histopathological examination confirmed PTC in 100% of the sample (n = 23), including 16 classical variants, 1 "hobnail" subtype, and 3 cases of papillary carcinoma not otherwise specified. CONCLUSIONS:In this hypothesis-generating case series, DPEF was strongly associated with PTC. Further studies are needed to determine the sensitivity and specificity of this new sign. Recognition and reporting of this pattern, which was consistently observed in PTC, are important for raising awareness among thyroid radiologists and sonographers.
BACKGROUND:Patient distress associated with thyroid cancer greatly influences treatment choice, yet is underestimated by clinicians. We developed and validated the Thyroid Cancer Modified Anxiety Scale (TC-MAX) to measure patient-reported thyroid cancer-related worry. METHODS:Development entailed (1) conceptualization (systematic literature review, expert panel [n = 4], patient focus groups [n = 10]); (2) qualitative revision (pilot testing [n = 59], expert panel [n = 4], patient feedback [n = 4]); (3) internal validation (n = 148); and (4) external validation (n = 1002), with papillary thyroid cancer patients. Internal consistency, test-retest reliability, exploratory/confirmatory factor analysis, and construct validity were evaluated. Severity categories and minimal clinically important differences (MCIDs) were determined. RESULTS:An 18-question scale was constructed, encompassing three subscales (Collective Anxiety, Ultrasound Anxiety, and Fear of Recurrence/Progression). Internal validation revealed high internal consistency (Cronbach's α = 0.93), excellent test-retest reliability (intraclass correlation coefficient [ICC] 0.86), and significant construct validity (Distress Thermometer [Spearman's ρ = 0.56, p < 0.001], Hospital Anxiety Depression Scale [HADS] [Spearman's ρ = 0.52, p < 0.001], and Functional Assessment of Cancer Therapy-General [FACT-G] [Spearman's ρ = -0.50, p < 0.001]). Exploratory factor analysis showed expected loadings for respective subscales, and confirmatory factor analysis confirmed that the structure was parsimonious. External validation exhibited similar psychometrics, including internal consistency (Cronbach's α = 0.94), test-retest reliability (ICC 0.87), and construct validity (Distress Thermometer [Spearman's ρ = 0.54, p < 0.001], HADS [Spearman's ρ = 0.67, p < 0.001], and FACT-G [Spearman's ρ = -0.62, p < 0.001]). Proposed ranges (low = 0-26, moderate = 26-43, and severe = 43-100) were in excellent agreement between internal and external validation cohorts (weighted κ = 0.84, p < 0.001). Anchor-based MCID was found to be 16.7 (active surveillance vs. surgery) (25.9 [standard deviation (SD) ± 16.4] vs. 42.6 [SD ± 23.3], p < 0.001) or 16.9 (hemithyroidectomy vs. thyroidectomy) (33.6 [SD ± 17.4] vs. 50.5 [SD ± 24.1], p = 0.005). CONCLUSIONS:TC-MAX represents the first dedicated measure of anxiety in thyroid cancer. It exhibits robust psychometric properties in a vulnerable population, accounting for complex viewpoints. The scale effectively assesses preference and informs patients, including determining fit for active surveillance or extent of surgery.
BACKGROUND:Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. METHODS:To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. RESULTS:In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. CONCLUSIONS:Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
BACKGROUND:Children carrying germline RET mutations associated with multiple endocrine neoplasia type 2 (MEN2) are at high risk of developing medullary thyroid carcinoma (MTC). Prophylactic-intent thyroidectomy is recommended during childhood to prevent progression to advanced disease. Genotype-based recommendations combined with calcitonin measurements allow more individualized surgical timing. However, performing thyroidectomy at very young ages may expose children to long-term morbidity, particularly permanent hypoparathyroidism. METHODS:We conducted a retrospective national multicenter cohort study within the French Groupe d'Étude des Tumeurs Endocrines, including children younger than 15 years who underwent prophylactic-intent total thyroidectomy between 2010 and 2020 in the absence of clinically apparent structural disease. Data collected included RET genotype, age at surgery, preoperative calcitonin values interpreted relative to each laboratory's upper limit of normal, surgical procedures performed, histopathologic findings, postoperative complications, and clinical status at last follow-up. RESULTS:Sixty-four children (61 MEN2A, 3 MEN2B) underwent surgery at a median age of 4.6 years (interquartile range [IQR] = 3.2-8.3 years). Preoperative calcitonin was elevated in 44% of evaluable patients. Histopathology demonstrated C-cell hyperplasia in 52% and micro-MTC in 34%, while lymph node metastases were rare (3%). After a median follow-up of 6 years (IQR = 2.4-8.5 years), no patient had persistent structural disease. One patient had persistent moderate biochemical disease without structural evidence of MTC, although follow-up duration limits definitive long-term oncologic outcomes. Postoperative morbidity was notable: hypoparathyroidism occurred in 31% of patients and was permanent in 16%, predominantly among children operated before age 5 years. CONCLUSIONS:In this national contemporary cohort, prophylactic-intent thyroidectomy in pediatric MEN2 was associated with excellent short-term oncologic outcomes but also with a substantial rate of permanent hypoparathyroidism, particularly in very young children. These findings underscore the importance of multidisciplinary evaluation of both the timing and extent of surgery in expert centers.
BACKGROUND:Thermal ablation has emerged as a minimally invasive alternative for low-risk papillary thyroid cancer (PTC). However, data from Latin America remain scarce. This multicenter study evaluated the early efficacy and safety of thermal ablation for low-risk PTC across multiple Latin American centers. METHODS:Retrospective cohort study including 251 patients with 252 tumors (T1N0M0 PTC, ≤2 cm) treated with ultrasound-guided radiofrequency ablation (RFA) at 12 centers across 6 Latin American countries from January 2019 to June 2025. Primary outcomes were complete tumor disappearance, disease progression, and complications. RESULTS:Median age was 45.5 years (interquartile range [IQR]: 36.5-56), with 74.2% female patients. Median tumor size was 6.7 mm (IQR: 5-8); 92.1% were T1a (≤10 mm). After a median follow-up of 18 months (IQR 12-24, range 12-72), complete tumor disappearance was achieved in 89.7% overall (226/252), reaching 97.0% in tumors with ≥18 months and 100% with ≥36 months of follow-up. Tumor persistence was observed in 10.3% (26/252) at last follow-up, with no lymph node or distant metastases. The overall complication rate was 2.4% (6/252), all consisting of transient dysphonia. On multivariable analysis, tumor size >10 mm was independently associated with a lower likelihood of complete tumor disappearance (adjusted odds ratios [OR] 0.23 [CI: 0.07-0.78]), whereas follow-up >12 months was associated with a higher likelihood (adjusted OR: 11.33 [CI: 3.61-35.6]). A supplementary post hoc analysis suggested a possible association between higher general operator volume (≥250 RFA procedures) and complete disappearance. CONCLUSIONS:RFA demonstrates excellent efficacy and acceptable safety for T1a low-risk PTC in Latin American patients, with outcomes comparable with other series, supporting it as a viable alternative to surgery or active surveillance in selected patients. Efficacy for T1b tumors was lower and based on a small number of cases; ablation of T1b disease should therefore be regarded as requiring further investigation, ideally within the framework of a clinical trial.
BACKGROUND:The liver is a central organ in thyroid hormone (TH) metabolism, mediating the conversion of thyroxine (T4) to bioactive triiodothyronine (T3) via type 1 deiodinase and the clearance of reverse T3 (rT3). Selective thyromimetics targeting the TH receptor β in the liver are in development and, recently, are FDA-approved for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). To unravel TH metabolism during MASH in patients, we aim to determine specific alterations in TH concentrations in both the liver and circulation in patients with end-stage MASH. METHODS:In this cross-sectional study, liver tissue, portal plasma, and systemic plasma were collected intraoperatively from 12 patients with MASH cirrhosis undergoing liver transplantation and 12 living liver donors serving as healthy controls (fibrosis stage F0-F1). Total T4, T3, and rT3 were quantified by liquid chromatography-tandem mass spectrometry. RESULTS:Patients with MASH cirrhosis exhibited substantially lower total T3 and T4 across all three compartments, with elevated rT3 in portal and systemic plasma. The T3/rT3 ratio, a functional index of deiodinase-mediated TH metabolism, was markedly suppressed (-65% to -83%). For disease discrimination, hepatic T3 demonstrated the strongest capacity (body mass index [BMI]-adjusted odds ratios [OR] = 0.009, 95% confidence intervals [CI]: 0.001-0.190; p < 0.001), followed by the systemic T3/rT3 ratio (BMI-adjusted OR = 0.045, 95% CI: 0.001-0.328; p < 0.001). Within the MASH cohort, systemic T4 correlated inversely with model for end-stage liver disease score (r = -0.867, adjusted p = 0.005) and Child-Pugh score (r = -0.760, adjusted p = 0.033), confirmed as the predominant severity correlate by multivariable regression independent of BMI (standardized β = -0.744, adjusted p = 0.004). CONCLUSIONS:This study characterized TH metabolism in human end-stage MASH, which provides direct tissue-level evidence supporting intrahepatic hypothyroidism. The systemic T3/rT3 ratio and hepatic T3 potently discriminate MASH from healthy liver, while total systemic T4 tracks disease severity within established cirrhosis. Our findings suggest that distinct TH parameters serve complementary roles as biomarkers in diagnosis and prognosis.
BACKGROUND:Maternal Graves' disease (GD) has been linked to neonatal thyroid dysfunction, but its relationship with offspring neurodevelopment remains unclear. We examined the associations of maternal GD-related thyroid factors with neonatal thyroid function and neurodevelopment at 24 months. We also explored whether neonatal thyroid function might partly explain this association. METHODS:This single-center bidirectional cohort study included pregnant women with GD and their offspring delivered between January 1, 2019, and December 31, 2023. Maternal thyroid-related variables, including thyrotropin (TSH), free T4, thyrotropin receptor antibodies (TRAbs), and antithyroid drug exposure, were collected across pregnancy. Neonatal thyroid function was assessed at 7-14 days after birth, and neurodevelopmental screening at a corrected age of 24 months was performed using the Ages and Stages Questionnaire, Third Edition. Logistic regression was used to identify factors associated with neonatal thyroid dysfunction and abnormal neurodevelopmental screening results. Covariates were selected with guidance from a directed acyclic graph, and exploratory mediation analysis was performed using PROCESS Model 4. RESULTS:Among 159 neonates, 60 (37.7%) had thyroid dysfunction, with hyperthyrotropinemia as the most common abnormality (28.9%). Higher maternal third-trimester TRAb was independently associated with neonatal thyroid dysfunction (odds ratio [OR] = 1.59 [confidence interval or CI: 1.29-1.97], p < 0.001). Of the 143 offspring with follow-up data, 23 (16.1%) had abnormal neurodevelopmental screening results at 24 months. Higher maternal third-trimester TRAb (OR = 1.15 [CI: 1.04-1.27], p = 0.005) and higher neonatal TSH (OR = 1.11 [CI: 1.02-1.20], p = 0.016) were independently associated with abnormal neurodevelopmental screening results. Exploratory mediation analysis did not support a significant mediating role of neonatal TSH. CONCLUSIONS:Higher maternal third-trimester TRAb levels were associated with both neonatal thyroid dysfunction and abnormal neurodevelopmental screening results at 24 months in offspring of mothers with GD. This association with neurodevelopmental screening results may not be explained primarily by neonatal thyroid function alone.
BACKGROUND:Brain metastases (BMs) from nonanaplastic follicular cell-derived thyroid carcinoma (hereinafter referred to as non-ATC) are rare and not well characterized, with limited evidence guiding treatment and prognostic stratification. We aimed to describe clinical features, treatment patterns, and outcomes of patients with BMs from non-ATC and to develop and validate a disease-specific prognostic score. METHODS:This retrospective international multicenter study included adults with histologically confirmed non-ATC and radiologically documented BMs treated at 19 tertiary referral centers. Clinical, radiological, treatment, and outcome data were collected. Independent predictors of progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression, and variables identified were used to develop a disease-specific Graded Prognostic Assessment (non-ATC GPA), exploratorily assessed in an independent SEER cohort. RESULTS:A total of 189 patients were included; median age at BM diagnosis was 59 years (interquartile range [IQR] 48-67). First-line BM treatments included stereotactic radiosurgery (27.0%), neurosurgery (23.8%), whole-brain radiotherapy (18.5%), and best supportive care (10.6%). Median PFS was 7.0 months (IQR: 2.9-22.4), and median OS was 15.0 months (IQR: 4.0-38.4). Independent predictors of shorter OS were age >75 years, Eastern Cooperative Oncology Group performance status ≥2, papillary histology, extracranial metastases, and ≥4 BM. The GPA stratified patients into four prognostic groups with median OS ranging from 72.6 months in the highest-score group to 3.7 months in the lowest. An exploratory SEER-based assessment showed survival differences across adapted prognostic groups (p = 0.036), although this analysis was limited by the absence of all key GPA variables. CONCLUSIONS:BMs from non-ATC are associated with poor survival and marked prognostic heterogeneity. The proposed GPA may provide a useful framework for prognostic stratification, pending further validation in independent datasets to support individualized management.
Background: Thyroid radiofrequency ablation (RFA) is a minimally invasive treatment for thyroid nodules. However, the health system costs of thyroid RFA are not well defined in the current literature. As its use expands, the objective of this study was to conduct a micro-costing analysis comparing RFA and hemithyroidectomy in outpatient and inpatient settings. Methods: A retrospective micro-costing analysis of 112 hemithyroidectomies and 42 thyroid RFAs was performed between January 2023 and May 2025 at two tertiary hospitals in Toronto, Canada. Costs were calculated in 2025 Canadian Dollars from the perspective of a publicly funded, single-payer health care system using a bottom-up approach across a one-year patient care cycle from initial consultation to one year of follow-up. Deterministic one-way sensitivity analyses were performed to assess cost-equivalence thresholds and the impact of procedural volume, repeat ablation, and delayed future surgery. Results: The base-case cost of RFA was $3985.05 over a one-year care cycle, including initial consultation and follow-up. RFA procedure costs accounted for $3107.61 (78.0%), which were primarily driven by consumables and supplies ($2022.21, 50.7%). Mean hemithyroidectomy costs were $4730.48 for outpatient cases and $5739.39 for inpatient cases, with an overall mean cost of $5613.28 across a one-year care cycle. For all hemithyroidectomy cases, procedure costs were driven primarily by operating room facility fees ($2344.86, 41.8%), physician fees for the surgeon and anesthesiologist ($943.38, 16.8%), and laboratory and pathology services ($486.12, 8.7%). Sensitivity analyses demonstrated that cost equivalence between RFA and outpatient hemithyroidectomy occurred when 13.3% of patients required delayed surgery and 18.7% required repeat RFA. For inpatient hemithyroidectomy, cost equivalence was reached when 31.3% required delayed surgery and 44.0% required repeat RFA. Conclusions: Over one year, the base-case cost for thyroid RFA was $1628.23 lower (29.0%) than the mean cost of all hemithyroidectomies. The cost savings of thyroid RFA are driven by eliminating the need for operating room and inpatient admission resources. Nodule regrowth requiring repeat ablation or delayed surgery is a critical factor that significantly affects the overall cost of RFA. Ultimately, proper patient selection, ablation technique, and evidence-informed implementation are needed to fully realize RFA’s clinical and economic benefits.
BACKGROUND:Graves' disease (GD) is rare in children, and methimazole (MMI) is recommended as the first-line therapy. However, data on MMI-associated neutropenia and agranulocytosis in pediatric patients remain limited. In this study, we aimed to characterize the clinical features of these adverse events and to identify their associated risk factors. METHODS:A cohort study was conducted involving 432 pediatric patients with GD treated with MMI. Clinical and biochemical data were collected retrospectively and prospectively, with follow-up 0.5, 1, 2, 3, 4, 5, 6, 7-9, and 10-12 months after treatment initiation. Multivariable logistic regression analysis was performed to identify risk factors for MMI-associated neutropenia. RESULTS:During the 12-month follow-up period, 104 (24.1%) patients developed neutropenia, with 84.6% developing neutropenia within the first 3 months, 72.1% within 1 month, and 59.6% within 2 weeks. Among the affected patients, 83.7%, 13.5%, and 2.8% had mild, moderate, and severe neutropenia (agranulocytosis), respectively. All patients with moderate or severe neutropenia were asymptomatic and were identified through routine monitoring within the first month. Multivariable analysis revealed that a thyroid peroxidase antibody (TPOAb)-negative status (odds ratio [OR], 2.020; confidence interval [CI], 1.113-3.666) was associated with a higher prevalence of MMI-associated neutropenia, whereas older age (OR, 0.916; CI, 0.848-0.989) and higher baseline absolute neutrophil count (ANC; OR, 0.775; CI, 0.665-0.903) were protective factors. CONCLUSIONS:ANC monitoring is recommended every 1 to 2 weeks during the first month and monthly for the first 3 months after MMI initiation. Pediatric patients with GD younger than 3 years with TPOAb-negative status or a baseline ANC < 3 × 109/L may have a higher prevalence of MMI-associated neutropenia.
BACKGROUND:The optimal duration of antithyroid drug (ATD) therapy in Graves' disease is uncertain. Although guidelines recommend 12-18 months, shorter courses may be sufficient in selected patients. We evaluated whether ATD duration <12 months is non-inferior to 12-18 months for relapse among patients with Graves' disease and lower thyrotropin receptor antibody (TRAb) levels (>1.8 and <10.0 U/L) at diagnosis. METHODS:We analyzed real-world data from adults with Graves' disease and baseline TRAb <10 U/L treated with ATDs at a single center. The primary endpoint was relapse within 12 months of ATD cessation. A prespecified risk-difference non-inferiority framework was used, with a primary margin of +5% and an exploratory margin of +10%. Treatment effects were estimated using unadjusted analyses, inverse-probability-of-treatment weighting (IPTW; n = 369), and 1:1 propensity-score matching (PSM; 104 matched pairs). Secondary outcomes included long-term relapse (median follow-up 58 months), TRAb levels at cessation, and restricted mean survival time (RMST) over 60 months. FINDINGS:At 12 months, relapse occurred in 23/134 (17.2%) patients treated <12 months and 48/235 (20.4%) treated for 12-18 months. The IPTW-adjusted risk difference was -1.5% (CI -11.0 to +8.0), meeting the 10% but not the 5% non-inferiority margin. The unadjusted estimate (-3.2%) met both margins, whereas the PSM estimate (+2.9%, CI -7.3 to +13.1) met neither because of reduced precision. Long-term outcomes were similar between groups (IPTW Cox HR 0.92 [CI 0.65-1.31]; RMST difference +3.2 months over 60 months [-2.1 to +8.4]). TRAb levels at cessation were comparable. CONCLUSIONS:Among patients with Graves' disease and lower TRAb levels, shorter ATD courses (<12 months) produced outcomes broadly comparable to 12-18 months. Although strict non-inferiority was not confirmed at a 5% margin, findings meeting an exploratory 10% threshold support TRAb-guided individualization of ATD duration and justify prospective randomized evaluation.
BACKGROUND:We report a cross-sectional analysis of prevalence and distribution of goiter among commercially insured adults ages 18-64 in the United States using the 2022-2023 Merative™ MarketScan® Commercial Claims and Encounters Database. METHODS:Cases of goiter were identified using ICD-10 diagnosis codes. Prevalence was estimated under nested case definitions and by goiter subtype. Estimates were compared across U.S. Census regions. Multivariable regression was used to model the association of demographic, clinical, and regional variables on goiter prevalence. RESULTS:Among 15.2 million commercially insured adults enrolled in MarketScan on December 31, 2023, overall goiter prevalence was 12.7-24.6 per 1000 persons. Prevalence was substantially higher among women and increased steadily with age. Non-toxic multinodular goiter accounted for most cases. Prevalence varied by U.S. Census region after adjusting for age, sex, toxic status, and diagnostic intensity. CONCLUSIONS:The prevalence of goiter, comprised predominantly of non-toxic multinodular goiter, is estimated to be 1.3-2.5% among working-age adults in the U.S. and varies by sex, age, and potentially by geography. Further research is needed to investigate environmental and social drivers of the goiter burden.
Background: Due to an impaired thyroid hormone (TH) transport across brain barriers, inactivation of the murine TH transporters Mct8/Oatp1c1 causes a profound TH deficiency of the CNS that greatly impacts neural development and function. Since oligodendrocyte maturation and myelination are dependent on local TH signaling, Mct8/Oatp1c1 double knockout (DKO) mice exhibit a persistent state of hypomyelination. Yet, to which extent Mct8/Oatp1c1 inactivation also affects TH transport into oligodendroglia cells has not been addressed. Here, we studied oligodendrocyte maturation and myelination in mice lacking Mct8/Oatp1c1 specifically in oligodendroglia lineage (OL) cells and compared their phenotype with that of control and DKO animals. Method: Conditional Mct8/Oatp1c1 mutants were crossed with mice expressing constitutively Cre-recombinase under the control of the Olig2 promoter to inactivate both transporters in OL cells (so-called OL CKO mice). Neural maturation and myelination were assessed by immunofluorescence (IF) and fluorescence in situ hybridization (FISH) studies at different postnatal time points. Oligodendrocyte precursor cells (OPCs), premyelinating, and myelinating oligodendrocytes were visualized by coimmunolabeling. Results: OL CKO mice exhibited normal serum TH concentrations and hypothalamic Trh transcript levels. Quantification of neuronal TH-target gene transcript levels ( Rc3; Klf9; Pde10a ) revealed no alterations. Abundance of myelin sheaths-related proteins Mbp and Cnp was significantly reduced in OL CKO mice at postnatal day P12 but reached normal levels at P21 and P120. Quantification of OPC, premyelinating, and myelinating oligodendrocytes disclosed a strongly reduced number of mature OL at P6 and P12, while cell numbers normalized in adult OL CKO mice. Conclusions: Inactivation of murine TH transporters Mct8/Oatp1c1 in OL cells causes a delayed oligodendroglia maturation and myelination. These findings highlight a physiologically relevant function of Mct8/Oatp1c1 in developmental oligodendrogenesis and myelin formation. In contrast to the persistent myelination defect seen in central hypothyroid DKO mice, OL CKO mice exhibit only a transient oligodendrocyte differentiation impairment and transient hypomyelination. These observations indicate the presence of additional, yet unknown, TH transporters that ultimately enable cellular TH entry into oligodendroglia cells even in the absence of Mct8/Oatp1c1.
