Thyroid最新文献

{"title":"The Association between Lymphocytic Thyroiditis and Papillary Thyroid Cancer Harboring Mutant <i>BRAF</i>: A Systematic Review and Meta-Analysis.","authors":"Sumathy Perampalam, Katherine Wu, Matti Gild, Lyndal Tacon, Martyn Bullock, Roderick Clifton-Bligh","doi":"10.1089/thy.2024.0142","DOIUrl":"10.1089/thy.2024.0142","url":null,"abstract":"<p><p><b><i>Background:</i></b> Papillary thyroid cancer (PTC) and lymphocytic thyroiditis (LT) co-occur with a prevalence of about 30%. PTC harboring <i>BRAF^V600E</i> (PTC-<i>BRAF</i>) confers a worse prognosis, but it is unclear if LT alters prognostic features and recurrence of PTC. <b><i>Objective:</i></b> We compared the prevalence of PTC-<i>BRAF</i> with and without LT. The risk of adverse pathological features in (i) PTC in the presence and absence of <i>BRAF</i> mutation, irrespective of LT status, was compared to (ii) PTC in the presence and absence of LT, irrespective of <i>BRAF</i> status. <b><i>Methods:</i></b> We searched PubMed, Embase, and Web of Science Core Collection for observational studies published from 2010 to June 2023 on adult patients with PTC. The search strategy yielded 47 studies with relevant data. Data of baseline characteristics, clinicopathological features, and the quality assessment tool were extracted by two reviewers. The study was registered with PROSPERO (CRD42023437492). <b><i>Results:</i></b> Of the 47 studies, 39 studies with a total cohort of 28 143, demonstrated that the odds of PTC-<i>BRAF</i> were significantly lower in the presence of LT compared to its absence (odds ratio [OR] 0.53, 95% confidence interval [CI]: 0.48-0.58, <i>p</i> < 0.00001). In PTC-<i>BRAF</i> patients, there was a positive association of central neck nodal disease (CNND), PTC > 1 cm, extra-thyroidal extension, American Joint Committee on Cancer (AJCC) Stage 3-4, and multifocality with pooled ORs of 1.54 (95% CI: 1.16-2.04), 1.14 (95% CI: 0.82-1.58), 1.66 (95% CI: 1.40-1.97), 1.53 (95% CI: 1.35-1.75), and 1.24 (95% CI: 1.11-1.40) respectively, compared to wild-type PTC, irrespective of LT status. In the same studies, PTC with LT patients had lower pooled ORs of 0.64 (95% CI: 0.51-0.81) for CNND, 0.83 (95% CI: 0.73-0.95) for PTC > 1 cm, 0.71 (95% CI: 0.58-0.86) for ETE, 0.84 (95% CI: 0.75-0.94) for AJCC Stage 3-4 compared to PTC without LT, irrespective of <i>BRAF</i> status. PTC recurrence was not affected by <i>BRAF</i> or LT, with pooled ORs of 1.12 (95% CI: 0.66-1.90, <i>p</i> = 0.67) and 0.60 (95% CI: 0.28-1.30, <i>p</i> = 0.20) respectively. Similar results were seen with recurrence expressed as hazard ratio in this limited data-set. <b><i>Conclusion:</i></b> The odds of PTC-<i>BRAF</i> are significantly lower in the presence of LT than without. PTC with LT, irrespective of <i>BRAF</i> status, was significantly associated with better prognostic factors. Further studies are required to evaluate if LT inhibits PTC-<i>BRAF</i>, and whether this is relevant to the role of immunotherapy in advanced thyroid cancer.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1082-1093"},"PeriodicalIF":5.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgeon Preference for Maximizing Medical Care Is Associated with Recommending More Extensive Surgery for Low-Risk Thyroid Cancer.","authors":"Alexis G Antunez, Megan C Saucke, Kyle J Bushaw, Alexander Chiu, Susan C Pitt","doi":"10.1089/thy.2024.0170","DOIUrl":"10.1089/thy.2024.0170","url":null,"abstract":"<p><p><b><i>Background:</i></b> While patient-level determinants of total thyroidectomy use have been well described, surgeon-level drivers of more extensive surgery are present and less well described. This survey sought to examine the associations between surgeons' operative recommendations, their beliefs about cancer, and their attitudes about medical maximizing-minimizing. <b><i>Methods:</i></b> A mixed-mode, cross-sectional survey was administered in September 2020 via mail and email to 222 thyroid surgeons identified in the Centers for Medicare & Medicaid Services Provider Utilization and Payment Physician and Other Practitioners dataset. Participants were asked their treatment recommendation for a healthy 45-year-old woman with a solitary 2.0-cm papillary thyroid cancer. Surgeons were assessed with the Brief Worry Scale and a validated, single-item measure of cancer-related worry. The Clinician Maximizer-Minimizer scale was used to assess the extent of medical care that physicians tend to favor with their patients. Participants were categorized into terciles based on their responses to the Maximizer-Minimizer scale. The highest scoring tercile (\"Maximizers\") was compared with the two lower terciles by Student's <i>t</i>-tests, chi-square, ANOVA, and logistic regression. <b><i>Results:</i></b> Of the 149 surgeons (response rate 67.1%), 34.9% recommended total thyroidectomy with or without central neck dissection (CND), and 65.1% recommended lobectomy. Overall, the medical Maximizer-Minimizer scale had an average score of 24.6 (SD 6.8). There were no differences between surgeons' age, race, annual thyroidectomy volume, or practice setting by their Maximizer-Minimizer classification. Participants who recommended total thyroidectomy with or without CND had significantly higher Maximizer-Minimizer scores than those recommending lobectomy (25.9 ± 7.2 vs. 23.8 ± 6.4, <i>p</i> = 0.03). Those classified as maximizers also had more cancer-related worry on both the single-item and Brief Worry Scales (<i>p</i> = 0.02). On logistic regression controlling for age, sex, race, specialty training, practice setting, and annual thyroidectomy volume, maximizers were still more likely to recommend total thyroidectomy with or without a CND (OR 2.4, [CI 1.01-5.55], <i>p</i> = 0.047). <b><i>Conclusions:</i></b> Medical maximizing-minimizing tendencies represent one of potentially many unmeasured surgeon characteristics that may explain persistent patterns of over-diagnosis, over-treatment, and over-screening. Surgeons may benefit from awareness of how their own tendencies influence their surgical recommendations in patients with low-risk thyroid cancer.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1181-1185"},"PeriodicalIF":5.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Thyroid.","authors":"Anita Boelen","doi":"10.1089/thy.2024.88794.rfs2023","DOIUrl":"https://doi.org/10.1089/thy.2024.88794.rfs2023","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":"19 1","pages":"1065"},"PeriodicalIF":6.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erectile Dysfunction in Patients Treated with Selpercatinib for <i>RET</i>-Altered Thyroid Cancer.","authors":"Antonio Matrone, Matthias Kroiss, Matti L Gild, Sarah Hamidi, Cyrus Michael Sayehli, Rhonda Siddal, Carla Gambale, Alessandro Prete, Mimi I Hu, Bruce G Robinson, Rossella Elisei","doi":"10.1089/thy.2024.0129","DOIUrl":"10.1089/thy.2024.0129","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1177-1180"},"PeriodicalIF":5.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progression of Gestational Subclinical Hypothyroidism and Hypothyroxinemia to Overt Hypothyroidism After Pregnancy: Pooled Analysis of Data from Two Randomized Controlled Trials.","authors":"Michael W Varner, Lisa Mele, Brian M Casey, Alan M Peaceman, Uma M Reddy, Ronald J Wapner, John M Thorp, George R Saade, Alan T N Tita, Dwight J Rouse, Baha M Sibai, Maged M Costantine, Brian M Mercer, Steve N Caritis","doi":"10.1089/thy.2023.0616","DOIUrl":"10.1089/thy.2023.0616","url":null,"abstract":"<p><p><b><i>Background:</i></b> To examine the incidence of overt hypothyroidism 1 and 5 years after pregnancies where screening before 21 weeks identified subclinical hypothyroidism (SH) or hypothyroxinemia (HT). <b><i>Methods:</i></b> Secondary analysis of two multicenter treatment trials for either SH or HT diagnosed between 8 and 20 weeks gestation. Current analyses focus only on individuals randomized to the placebo groups in the two parallel studies. SH was diagnosed with thyrotropin (TSH) ≥4.0 mU/L and normal free T4 (fT4) (0.86-1.9 ng/dL). HT was diagnosed with normal TSH (0.08-3.99 mU/L) but fT4 <0.86 ng/dL. Serum from initial testing was stored for later thyroid peroxidase (TPO) antibody assay; results were not returned for clinical management. At 1 and 5 years after delivery, participants were asked whether they had either been diagnosed with or were being treated for a thyroid condition. Maternal serum was collected at these visits and thyroid function measured. Subsequent overt hypothyroidism was defined as TSH ≥4.0 mU/L with fT4 <0.86 ng/dL. <b><i>Results:</i></b> Data for 1- and 5-year follow-up were available in 307 of the 338 participants with SH and 229 of the 261 with HT. Subsequent hypothyroidism was more common both at year 1 (13.4% vs. 3.1%, <i>p</i> < 0.001) and year 5 (15.6% vs. 2.6%, <i>p</i> < 0.001) for participants with SH compared with those with HT. This progression was more common in individuals with TSH values >10 mIU/mL. Baseline TPO level >50 IU/mL in participants with SH was associated with higher rates of hypothyroidism at year 1 (26.7% vs. 6.5%, odds ratio [OR] = 5.3 [confidence interval (CI) 2.6-10.7]) and year 5 (30.5% vs. 7.5%, OR = 5.4 [CI: 2.8-10.6]) compared with those with TPO levels ≤50 IU/mL. For participants with HT, no differences in overt hypothyroidism were seen at 1 year related to baseline TPO level >50 IU/mL (1/10 (10%) vs. 6/218 (2.8%), OR = 3.9 [CI: 0.43-36.1]), but more participants with TPO levels >50 IU/mL developed hypothyroidism by year 5 (2/10 (20%) vs. 4/218 (1.8%), OR = 13.4 [CI: 2.1-84.1]). <b><i>Conclusion:</i></b> SH is associated with higher rates of overt hypothyroidism or thyroid replacement therapy within 5 years of delivery than is HT when these conditions are diagnosed in the first half of pregnancy.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1171-1176"},"PeriodicalIF":8.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Multi-Institutional Medullary Thyroid Cancer Collaborative Registry: Can a Rare Tumor Registry Accurately Represent the Real-World Patient Population?","authors":"Thomas Szabo Yamashita, Sophia M Williams-Perez, Sara Ehsan, Michelle Mulder, Daniel Kronenfeld, Chiang-Yu Huang, Hui Zhao, Kelly Merriman, Susan K Peterson, Mimi I Hu, Mark Zafereo, Julie Ann Sosa, Elizabeth G Grubbs","doi":"10.1089/thy.2024.0239","DOIUrl":"10.1089/thy.2024.0239","url":null,"abstract":"<p><p><b><i>Background:</i></b> Large population-based registries, such as the Surveillance, Epidemiology and End Results (SEER) Registry, help in the study of rare tumors, including medullary thyroid cancer (MTC), but lack data to understand the natural history of the disease. The Medullary Thyroid Cancer Collaborative Registry (MTCCoRe) is an exhaustive multi-institutional collection of demographic, clinical, and pathological data. To determine the extent to which MTCCoRe represents the real-world MTC population, we compared the characteristics of patients enrolled in MTCCoRe with patients enrolled in population-based cancer registries. <b><i>Methods:</i></b> Comparison of demographic and clinical characteristics of MTC patients who were enrolled in MTCCoRe, Texas Cancer Registry (TCR), California Cancer Registry (CCR), and SEER between 1995 and 2018. <b><i>Results:</i></b> A total of 1416 patients were identified in MTCCoRe, 329 in TCR, 2105 in CCR, and 3820 in SEER. Percentages of patients 20-54 years in MTCCoRe were 58.0%, 50.2% in TCR, 47.2% in CCR, and 44.8% in SEER (<i>p</i> < 0.0001). About half of the patients were female (55.9% in MTCCoRe, 61.4% in TCR, 59% in CCR, and 57.5% in SEER (<i>p =</i> 0.3). Percentages of Hispanic and Black patients differed among cohorts (10.1% and 3.8% for MTCCoRe, 23.7% and 8.2% for TCR, 24.8% and 4.9% in CCR, and 15.9% and 8.2% for SEER, respectively; <i>p</i> < 0.001). MTCCoRe patients presented with more advanced T and N classifications than patients in the other registries (MTCCoRe, 28.6% T3-4 and 49.4% N1; TCR, 12.7% and 32.2%; CCR, 18.6% and 32.4%; and SEER, 24% and 37.8%; <i>p</i> < 0.0001). Prevalence of M1 disease was 10% in MTCCoRe, 11.9% in TCR, 14.1% in CCR, and 9.5% in SEER (<i>p</i> < 0.0001). In the MTCCoRe, 11.4% underwent systemic therapy (compared with 0.3% in TCR and 5.6% in CCR). <b><i>Conclusions:</i></b> The clinicodemographic profile of patients with MTC enrolled in a multi-institutional registry differs from those enrolled in population-based databases, with lower proportions of Hispanic and Black patients but additive data on treatment modalities. Moving forward, MTCCoRe and other registry and clinical trial enrollment efforts should intentionally include underrepresented groups via community engagement techniques, patient stakeholder involvement, and inclusion of languages other than English in study materials to yield more generalizable results and conclusions.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1117-1125"},"PeriodicalIF":8.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3,3',5-Triiodothyroacetic Acid Transporters.","authors":"Zhongli Chen, Sena Yildiz, Boyka Markova, Linda J de Rooij, Selmar Leeuwenburgh, Timo Hamers, Robin P Peeters, Heike Heuer, Marcel E Meima, W Edward Visser","doi":"10.1089/thy.2023.0467","DOIUrl":"10.1089/thy.2023.0467","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. <b><i>Materials and Methods:</i></b> Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent <i>in situ</i> hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. <b><i>Results:</i></b> In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (<i>n</i> = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; <i>n</i> = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. <b><i>Conclusions:</i></b> Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1027-1037"},"PeriodicalIF":5.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reoperation Rates After Initial Thyroid Lobectomy for Patients with Thyroid Cancer: A National Cohort Study.","authors":"Marin Kheng, Alexander Manzella, Joshua C Chao, Amanda M Laird, Toni Beninato","doi":"10.1089/thy.2024.0128","DOIUrl":"10.1089/thy.2024.0128","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> The 2015 American Thyroid Association (ATA) guidelines recommended thyroid lobectomy (TL) as an alternative to total thyroidectomy (TT) for the surgical treatment of low-risk differentiated thyroid cancer. Increasing use of TL has since been reported despite concerns for an increased risk of disease recurrence and need for reoperation. This study sought to compare reoperation rates among patients who underwent initial TL or TT for malignancy, characterize trends at centers based on operative volume, and examine factors associated with reoperation. <b><i>Methods:</i></b> We queried the Vizient Clinical Data Base for TL and TT performed preguideline change (pre-GC = 2013-2015) and postguideline change (post-GC = 2016-2021). Reoperations included reoperative thyroid surgery (RTS) and neck dissection (ND); timing was defined as early (≤180 days), thought to indicate inadequacy of initial operative choice, or late (>180 days), suggesting potential disease recurrence. <b><i>Results:</i></b> Of 65,627 patients, 31.8% underwent initial TL and 68.2% underwent initial TT; TL increased from 21.4% of total cases pre-GC to 37.0% post-GC (<i>p</i> < 0.001). Among TL patients, early RTS declined from 33.9% to 14.2% and ND declined from 0.8% to 0.4% (<i>p</i> < 0.001). Among TT patients, early RTS remained 0.2%, while ND increased from 0.4% to 0.7% (<i>p</i> < 0.001). TL-associated late RTS declined from 2.0% to 1.7%, while ND increased from 0.6% to 0.8% (<i>p</i> = 0.17). In TT patients, both late RTS and ND increased, from 0.2% to 0.3% (<i>p</i> = 0.04) and 1.7% to 2.1% (<i>p</i> < 0.01), respectively. There was no difference in the late reoperation rate for TL compared with TT post-GC (+0.2%, <i>p</i> = 0.18). TL volume grew annually by 12.5% [8.9-16.2%] at high-volume centers (HVCs) and 8.3% [5.6-11.1%] at low-volume centers (LVCs). TL-associated reoperations at HVCs declined annually by 12.6% [5.6-19.0%] and 10.8% [2.7-18.1%] at LVCs. Uninsured status and more recent initial operation were associated with an increased risk of late reoperation (HR = 1.84 [1.06-3.20] and HR = 1.30 [1.24-1.36], respectively). The type of index operation performed, however, was not predictive of late reoperation. <b><i>Conclusions:</i></b> The rate of early reoperations declined for TL after the 2015 ATA guideline release, but late reoperations remained unchanged despite a significant shift in practice patterns towards initial lobectomy. Patients appear to be receiving less aggressive, guideline-concordant care without a significant increase in the late reoperation rate for TL compared with TT.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1007-1016"},"PeriodicalIF":5.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining the <i>In Vivo</i> Role of mTORC1 in Thyrocytes by Studying the TSC2 Conditional Knockout Mouse Model.","authors":"Camila Ludke Rossetti, Bruna Lourençoni Alves, Flavia Leticia Martins Peçanha, Aime T Franco, Vania Nosé, Everardo Magalhaes Carneiro, John Lew, Ernesto Bernal-Mizrachi, Joao Pedro Werneck-de-Castro","doi":"10.1089/thy.2024.0053","DOIUrl":"10.1089/thy.2024.0053","url":null,"abstract":"<p><p><b><i>Background:</i></b> The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathway's overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. <b><i>Methods:</i></b> To elucidate mTORC1's role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting tuberous sclerosis complex 2 (TSC2), an intracellular inhibitor of mTORC1. <b><i>Results:</i></b> The resulting <i>TPO-TSC2^KO</i> mice exhibited a 70-80% reduction in TSC2 levels, leading to a sixfold increase in mTORC1 activity. Thyroid glands of both male and female <i>TPO-TSC2^KO</i> mice displayed rapid enlargement and continued growth throughout life, with larger follicles and increased colloid and epithelium areas. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated cyclin D3 expression in the <i>TPO-TSC2^KO</i> mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone biosynthesis, including <i>thyroglobulin (Tg)</i>, <i>thyroid peroxidase (Tpo)</i>, and <i>sodium-iodide symporter</i> (<i>Nis</i>), while <i>Tff1</i>, <i>Pax8</i>, and <i>Mct8</i> mRNA levels remained unaffected. NIS protein expression was also diminished in <i>TPO-TSC2^KO</i> mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in <i>TPO-TSC2^KO</i> mice. Although total thyroxine (T4), total triiodothyronine (T3), and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in <i>TPO-TSC2^KO</i> compared with littermate control mice. <b><i>Conclusions:</i></b> Our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits thyroid hormone (TH) biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1047-1057"},"PeriodicalIF":5.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.","authors":"Aleksander Kuś, Rosalie B T M Sterenborg, Eirin B Haug, Tessel E Galesloot, W Edward Visser, Johannes W A Smit, Tomasz Bednarczuk, Robin P Peeters, Bjørn O Åsvold, Alexander Teumer, Marco Medici","doi":"10.1089/thy.2024.0045","DOIUrl":"10.1089/thy.2024.0045","url":null,"abstract":"<p><p><b><i>Background:</i></b> Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. <b><i>Methods:</i></b> A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (<i>n</i> = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (<i>n</i> = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (<i>n</i> = 26,321) as well as individuals on levothyroxine (LT4) treatment (<i>n</i> = 1,132). <b><i>Results:</i></b> PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, <i>P_{for trend}</i> =1.7 × 10^-8). <b><i>Conclusions:</i></b> Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"969-979"},"PeriodicalIF":5.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}