Thyroid最新文献

Objective: Deiodinase type I (DIO1) is crucial in maintaining thyroid hormone (TH) balance. It converts the prohormone thyroxine (T4) to the active triiodothyronine (T3) and degrades T3 to inactive 3,3'-diiodothyronine (3,3'-T2). It also acts on reverse T3 (rT3) and sulfated TH metabolites, thus contributing to TH elimination. Upregulation of DIO1 is linked to hyperthyroid conditions such as Graves' disease and autonomous thyroid adenoma, making it a promising target for pharmacological intervention. The adverse side effects of the antithyroid drug propylthiouracil (PTU), used in clinics to treat hyperthyroidism due to its thyroid peroxidase- and DIO1-blocking action, highlight the need for novel and potent DIO1-selective inhibitors. Methods: Using a semiautomatic high-throughput screening (HTS) assay based on the Sandell-Kolthoff (SK) reaction in 384-well plates, we screened 69,344 low-molecular-weight compounds for DIO1-inhibitory effects. Shortlisted hits underwent detailed manual characterization, where we evaluated the potency and isoenzyme specificity by assessing their DIO-inhibitory effects on enzyme preparations from all three DIO isoenzymes, over a wide concentration range (5 nM-20 µM). To evaluate the DIO1 inhibitory effects in intact cells, we applied a novel protocol based on the SK reaction to cell culture supernatants and assessed the intracellular deiodinase activity in DIO1 overexpressing HEK293 cells. Results: The robust HTS assay flagged 436 (<1%) of the screened compounds as hits, also including known DIO1 inhibitors such as PTU and genistein. Based on a validation screen of 298 compounds, we prioritized 26 compounds to comprehensively characterize their DIO1-selective inhibition. We identified 15 DIO1-selective compounds (IC₅₀ < 1 µM), more potent than the bonafide DIO1-selective inhibitor PTU. Additionally, 8 of the 13 tested compounds were found capable of inhibiting DIO1 in intact cells. Conclusions: With a successful SK-reaction-based HTS application, we identified novel, potent, and selective inhibitors of DIO1 with nanomolar IC₅₀ values. Furthermore, we successfully showed that some of these compounds were also capable of inhibiting intracellular DIO1 in intact cells. These novel compounds hold immense potential in studying TH modulation, deciphering DIO1 enzyme structure, and developing structure-activity relationships. Furthermore, our novel inhibitors act as lead compounds in developing strategies to combat hyperthyroidism.

Background: The necessity of prophylactic central lymph node dissection (p-CLND) in patients with clinically node-negative papillary thyroid carcinoma (PTC) is unclear. The present study evaluated the central lymph node (LN) metastases status in patients with clinically node-negative PTC on both preoperative thyroid ultrasonography (USG) and neck computed tomography (CT) who underwent p-CLND. Methods: This retrospective cohort study included 3002 clinically node-negative patients diagnosed with PTC who had undergone thyroidectomy with p-CLND from January 2000 to September 2022. Clinically node-negative was defined as the absence of suspicious metastatic LNs on preoperative USG and neck CT. Low-risk central LN metastases were defined as LN metastases <2 mm in size with metastatic LNs ≤5. The median follow-up duration was 4.52 (interquartile range [IQR]: 1.6-7.5) years. Results: Of the 3002 patients, 1194 (39.7%) had central LN metastases, whereas 1808 (60.3%) did not. The 1194 patients with central LN metastases included 507 (16.9%) with intermediate-risk metastases and 610 (20.3%) with low-risk LN metastases, with a total of 2428 (80.5%) patients having low-risk LN metastases or no central LN metastases. High-risk metastases were observed in only 77 (2.5%) patients. Of the 584 patients with intermediate-/high-risk metastases, 577 (98.8%) had central LN metastases <1 cm in size, whereas only 7 (1.2%) had central LN metastases ≥1 cm. The disease recurrence rates for the no LN metastases, low-risk LN metastases, and intermediate-/high-risk LN metastases groups were 0.4%, 1.1%, and 1.9%, respectively (p = 0.012). Factors independently associated with intermediate-/high-risk central LN metastases included age <55 years (odds ratio [OR] = 2.29), male sex (OR = 2.33), tumor size >1 cm on USG (OR = 1.94), and the presence of extrathyroidal extension on CT scans (OR = 1.53), with p < 0.001 for all factors. Conclusions: Most LNs confirmed after CLND in cN0 PTC patients assessed by USG and CT were either metastasis-free or classified as low-risk metastatic LNs. Furthermore, the majority of metastatic LNs were small in size, typically measuring <1 cm. p-CLND may be unnecessary if preoperative thyroid USG and neck CT show no evidence of central neck LN metastaes.

Background: Differentiated thyroid carcinoma (DTC) is occurring three times more frequently in females than in males. However, the underlying biological mechanisms driving this discrepancy remain poorly understood. To investigate the causal role of sex hormones and reproductive factors in the risk of DTC, we implemented a two-sample Mendelian randomization (MR) analysis. Methods: We utilized genome-wide association studies (GWAS) summary statistics to explore these associations. GWAS data on DTC were derived from a meta-analysis of six studies including 7705 cases and 963,612 controls of European ancestry. GWAS summary statistics on sex hormones, reproductive factors, and gynecological conditions were retrieved from publicly available sources. We used the inverse-variance weighted (IVW) method to estimate odds ratio (OR), with additional sensitivity analyses and conducted multivariable MR (MVMR) to account for potential confounding by body mass index (BMI) and thyrotropin (TSH). Results: We identified a positive association between sex hormone binding globulin (SHBG) and DTC (OR_ivw = 1.13, p = 0.046). After controlling for TSH and BMI in a MVMR analysis, the strength of this association remained similar but lost statistical significance. Bioavailable testosterone also showed a positive but marginally significant association with DTC after adjustment for BMI in the MVMR (OR_ivw = 1.13, p = 0.07). Putative causal association was observed with uterine fibroids in females under 50 years old (OR_ivw = 1.52, p = 0.017). Endometrial cancer was associated with DTC (OR_ivw = 1.15, p = 9.0 × 10^-3); however, a genetic correlation of r² = 13% suggested potential pleiotropy. No significant associations were observed for other investigated factors. Conclusions: Our study does not provide strong evidence for a causal role of reproductive and hormonal factors in DTC risk, despite the observed sex disparity in incidence rates. The associations observed with SHBG, bioavailable testosterone, uterine fibroids, and endometrial cancer indicate potential risk factors, but further investigation is required.

Background: Overtreatment with thyroid hormone is common and is associated with multiple adverse health outcomes, especially in older adults. Higher overtreatment rates have been reported among women. Understanding this sex difference could lead to better clinical utilization of therapy in at-risk populations. Methods: We performed a retrospective cohort study to examine the relationship between iatrogenic thyrotoxicosis and patient sex, adjusting for demographics, comorbidities, body composition, and thyroid hormone dosing using electronic health records for adults age 50 and older in a large community health system in the United States. Results: A total of 20,724 patients met all inclusion criteria, of whom 77% were female and 23% non-White. Women were more likely to have a low thyrotropin (TSH) compared to men (36.7% vs. 23.9%; unadjusted hazard ratio [HR] = 1.67 [95% confidence interval {CI} 1.56-1.79]). Many covariates varied by sex, including rates of several comorbidities, and there was a small but statistically significant difference in the median daily levothyroxine dose per actual body mass: 1.1 μg/kg in male patients compared with 1.2 μg/kg in female patients (p < 0.001). Adjusting for covariates other than dose did not significantly change the sex-related risk of iatrogenic thyrotoxicosis. In fully adjusted Cox models including dose per actual body mass, the female versus male HR = 1.50 [CI 1.34-1.69] was also not different from models which did not account for dose (p = 0.422). However, the association between female sex and thyrotoxicosis risk was partially mediated when adjusting for dose per ideal body mass (HR = 1.30 [CI: 1.16-1.46]; p < 0.001) and was fully mediated by dose calculated using lean body mass (HR = 1.06 [CI: 0.95-1.19]; p < 0.001). That is, women had higher risk of iatrogenic thyrotoxicosis compared to men receiving similar actual body mass doses, whereas women and men receiving comparable lean body mass doses had comparable risk. Conclusions: Mediation analysis demonstrates that the increased risk of iatrogenic thyrotoxicosis in older women may be attributable to differences in body composition between men and women. The use of ideal or lean body weight-based dose calculators in place of actual body weight dosing could reduce this potential source of iatrogenic thyrotoxicosis risk in older women.

Background: This retrospective case-control study aimed to investigate the effects of thyroid-stimulating hormone (TSH) suppression on vascular wall inflammation, assessed by [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Vascular [¹⁸F]FDG-uptake is highly correlated with arterial inflammation, which represents a major risk factor for atherosclerotic plaques. Methods: Forty patients with differentiated thyroid cancer underwent [¹⁸F]FDG-PET/CTs under TSH suppression therapy following surgical removal of the thyroid and subsequent radioiodine ablation. The [¹⁸F]FDG-uptake was measured in the carotid arteries, aortic arch, and the ascending, descending, and abdominal aorta. All measurements in the PET scans were normalized to body weight and corrected for blood pool activity in the superior vena cava, creating target-to-background ratios (TBRs). Twenty-five patients with euthyroid hormone status were used as a control group. In addition, to evaluate long-term changes, the follow-up PET/CTs of 24 thyroid carcinoma patients under continued TSH suppression therapy were analyzed. Results: In patients with TSH suppression, significantly higher arterial [¹⁸F]FDG-uptake (p < 0.001) was observed in the ascending aorta, aortic arch, abdominal aorta, carotid artery, and for all arterial vessels combined (mean TBR_max ± standard deviation [SD]: 1.8 ± 0.4, 1.8 ± 0.3, 1.9 ± 0.4, 1.4 ± 0.3, 1.7 ± 0.2, respectively) compared with the euthyroid control group (TBR_max ± SD: 1.4 ± 0.2, 1.4 ± 0.2, 1.4 ± 0.2, 1.1 ± 0.2, 1.3 ± 0.1, respectively). In the subgroup of patients who received an additional follow-up scan after a mean duration of 1.9 ± 1.1 years of continued TSH suppression therapy, no significant changes in arterial [¹⁸F]FDG-uptake were found in the five arterial sites when both scans were compared over time (p > 0.05). Conclusions: Our study suggests that patients under TSH suppression may experience a significant increase in vascular [¹⁸F]FDG-uptake, a marker of arterial inflammation, and, therefore, might be at higher risk for cardiovascular disease. Interestingly, the duration of TSH suppression was not significantly associated with vascular [¹⁸F]FDG-uptake in our study, indicating that the observed increase in arterial inflammation may not be influenced by the duration of TSH suppression.

Background: Thyroid hormones (THs) are essential endocrine hormones that play key roles in individual's growth and development. There is limited knowledge about the association between maternal TH concentrations variations with normal thyroid function during pregnancy and offspring's glycolipid metabolism. Methods: A total of 1130 mother-child pairs from the Ma'anshan birth cohort were included in this prospective study. Maternal TH levels and thyroid peroxidase antibodies were measured in the 1st, 2nd, and 3rd trimesters of pregnancy during the childhood follow-up period. Fasting venous blood was collected from children at 4-6 years of age and glycolipid metabolic indicators were assayed. Analyses were performed using Binary logistic regression models, linear regression models, and Generalized linear regression model. Results: Maternal TH trajectories were fitted via latent category growth models. During the 1st trimester of pregnancy, maternal T3 and free thyroxine (fT4) levels were positively associated with children's blood glucose levels (β = 0.007 [CI 0.028-0.181]; β = 0.022 [CI 0.004-0.040]), whereas high levels of fT4 may be associated with decreased risk of children's hypercholesterolemia (OR = 0.870 [CI 0.768-0.986]). Maternal T4 concentrations during the 3rd trimester of pregnancy were negatively associated with children's cholesterol levels (β = -0.002 [CI -0.003-0.00]). High maternal TH levels were associated with high fasting glucose level and low low-density lipoprotein concentrations in children. Conclusions: Maternal TH dynamic variations may be associated with glycolipid metabolism in preschoolers, even when women do not have clinically diagnosed thyroid disorders. The exact associations between maternal THs in specific trimesters of pregnancy under normal thyroid function conditions and glycolipid metabolism in offspring require further investigation.

Background: Intravenous glucocorticoids (IVGCs) are the first-line treatment for active moderate-to-severe thyroid eye disease (TED) in many countries worldwide, mainly because of their anti-inflammatory efficacy. Methods: Retrospective cohort study of 64 patients with active moderate-to-severe TED, without dysthyroid optic neuropathy, treated between 2003 and 2023 at a single tertiary centre with the 12 weeks IVGC EUGOGO (European Group on Graves Orbitopathy) protocol. All patients were evaluated for response to IVGC according to the clinical judgment (CL) and 44/64 (69%) patients were also evaluated with the EUGOGO 2021 revised composite index (CI). Results: The mean patients' age at IVGC initiation was 51.7 ± 11 years, 47/64 (73.5%) were women, 56/64 (87.5%) were Caucasians, and 33/64 (51.5%) were active smokers. At 6 months after IVGC, 48 out of 64 (75%) patients evaluated with CL and 32 out of 44 (73%) patients evaluated with EUGOGO CI responded to the treatment. Nonresponders tended to be older than responders (56.6 ± 10.2 vs. 50.1 ± 10.8 years, p = 0.040 for CL and 56.5 ± 11.9 vs. 50.3 ± 11.6 years, p = 0.131 for EUGOGO CI) and had higher clinical activity score (CAS) before IVGC (5.0 ± 1.1 vs.4.2 ± 1.1, p = 0.022 for CL and 4.7 ± 0.6 vs. 3.1 ± 0.8, p < 0.001 for EUGOGO CI). In patients evaluated with CL or EUGOGO CI, respectively, multivariable logistic regression identified age at IVGC initiation (odds ratio [OR] = 0.92 [95% confidence interval (CI) 0.86-0.99], p = 0.024 and OR = 0.88 [CI 0.77-0.99], p = 0.046) and CAS before IVGC (OR = 0.53 [CI 0.31-0.90], p = 0.021 and OR= 0.08 [CI 0.01-0.38], p = 0.001) but not active smoking as independent factors associated with response to IVGC. The optimal cut-off associated with poorer response to IVGC was CAS ≥4.5/7 (66.7% specificity, 56.3% sensitivity; Area Under the Curve [AUC] = 0.689 [CI 0.54-0.83], p = 0.010) in patients evaluated with CL and CAS ≥3.5/5 (65.6% specificity, 91.7% sensitivity; AUC = 0.910 [CI 0.80-1.01], p < 0.001) in patients evaluated with EUGOGO CI. Conclusion: Older age and higher CAS before treatment were associated with poorer response to IVGC. Patients with these characteristics could be offered other immunotherapies as a first-line treatment for active moderate-to-severe TED.

Background: Distant metastases (DM) are the leading cause of thyroid cancer-related death in patients with differentiated thyroid cancer (DTC). Despite significant progress in understanding DNA methylation in DTC, the methylation landscape of metastatic primary tumors and DM remains unclear. Our primary objective was to investigate DNA methylation dynamics during DTC progression, with a secondary goal of assessing potential clinical implications. Materials and Methods: We conducted a multicenter retrospective study in patients with DTC who underwent surgery at five university hospitals. We profiled DNA methylation in a discovery series of 97 samples (15 normal tissues, 30 non-metastatic [non-mDTC], and 35 metastatic [mDTC] primary DTC, and 17 paired metastases [lymph nodes and DM]). Results were validated in an independent series of 17 non-mDTC and 13 mDTC. We used receiver operating characteristic curve analysis to evaluate the identified prognostic CpG-signature. Results: DNA methylation alterations, mostly hypomethylation, increased progressively from primary tumors to DM, both in papillary (PTC) and follicular (FTC) thyroid carcinomas. Compared with normal tissue, non-metastatic primary PTC (non-mPTC) exhibited more hypomethylated than hypermethylated CpGs in contrast to non-metastatic primary FTC (non-mFTC). However, metastatic tumors, both mPTC and mFTC, predominantly exhibited hypomethylated CpGs. The overlap of differentially methylated CpGs (DMe-CpGs) was low between non-mPTC and non-mFTC (14% non-mPTC DMe-CpGs present in non-mFTC) but significantly higher between mPTC and mFTC (60% mPTC DMe-CpGs present in mFTC), underscoring the convergence of epigenetic changes during metastatic progression. The presence of many de novo DMe-CpGs from metastatic primary tumors (83% from mPTC and 40% from mFTC) in DM, including metachronous DM, supports the hypothesis that DM originates from a major subclone of the primary tumor. We identified and validated a 156-CpG signature in primary tumors capable of distinguishing between non-mDTC and mDTC, offering potential prognostic value for DM development regardless of histology. Conclusions: These results show a progressive increase in DNA methylation alterations, mainly hypomethylation, during PTC and FTC metastatic progression, suggesting a linear model, though the DNA methylation dynamics differs between the two histological types. The analysis of the 156-CpG signature in primary tumors may help identify patients with DTC at high risk for DM, enhancing a more personalized treatment.