Thyroid最新文献

{"title":"First Report of SPECC1L::ALK Fusion in Medullary Thyroid Carcinoma with Remarkable Response to Alectinib.","authors":"Hervé Bischoff, Antonin Fattori, Fabien Moinard-Butot, Olivier Schneegans, Pablo Diaz, Damien Reita, Valérie Rimelen, Anne-Claire Voegeli, Laura Bender","doi":"10.1089/thy.2025.0017","DOIUrl":"https://doi.org/10.1089/thy.2025.0017","url":null,"abstract":"<p><p><b><i>Background:</i></b> Rearrangements of the <i>ALK</i> gene are rare in medullary thyroid carcinoma (MTC), with limited data on the efficacy of ALK inhibitors in this context. Novel fusions, such as SPECC1L::ALK, have not been extensively studied. <b><i>Methods:</i></b> We present a case of a 33-year-old woman with metastatic MTC, in whom molecular profiling using next-generation sequencing (Archer FusionPlex®) identified a SPECC1L::ALK gene fusion. Treatment with the ALK inhibitor alectinib was initiated at 600 mg twice daily. <b><i>Results:</i></b> The patient demonstrated a dramatic partial to near-complete response after 6 days of treatment, as shown by positron emission tomography-computed tomography. At 6 weeks, a complete response was confirmed. Treatment was generally well tolerated, aside from grade 3 myalgia with elevated creatine phosphokinase, managed with temporary cessation and dose adjustment. As of the latest follow-up (8 months), the patient remains on alectinib with sustained complete response. <b><i>Conclusions:</i></b> This is the first report of a SPECC1L::ALK fusion in MTC. The dramatic response to alectinib highlights the importance of molecular profiling and suggests that ALK inhibitors may benefit patients with rare <i>ALK</i> fusions in thyroid cancers.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079810","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":"Long Noncoding RNAs Papillary Thyroid Carcinoma Susceptibility Candidate 3 Antisense 1 and Papillary Thyroid Carcinoma Susceptibility Candidate 3 Synergistically Regulate ZC3H12A mRNA Stability via Vimentin at 14q13.3 Thyroid Cancer Locus.","authors":"Yutong Zhang, Xiuzhi Shi, Shengqi Cheng, Jing Liu, Jianyun Shi, Zhekun An, Jiali Yao, Binbin Zou, Ming Gao, Xiaolong Cheng, Yanqiang Wang","doi":"10.1089/thy.2024.0674","DOIUrl":"https://doi.org/10.1089/thy.2024.0674","url":null,"abstract":"<p><p><b><i>Background:</i></b> The 14q13.3 has been identified as a genetic locus associated with a genetically increased risk of papillary thyroid cancer (PTC) in several cohorts, yet its underlying regulatory mechanisms remain poorly understood. <b><i>Methods:</i></b> The full-length sequence of expressed sequence tag fragment AA632637 in the thyroid was obtained by rapid amplification of complementary DNA ends assay. Quantitative Reverse Transcription PCR (qRT-PCR) assays were utilized to examine the expression levels of the long noncoding RNA (lncRNA) in clinical thyroid tissues and cell lines. Functional assays, including cell proliferation, migration, invasion, and apoptosis assays, were conducted both <i>in vitro</i> and <i>in vivo</i>. Furthermore, RNA-seq analysis, actinomycin D assay, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays were performed to identify the long noncoding RNA (lncRNA) binding targets and reveal the underlying regulatory mechanism. <b><i>Results:</i></b> We identified a previously unannotated lncRNA gene, named papillary thyroid carcinoma susceptibility candidate 3 antisense 1 (<i>PTCSC3-AS1</i>), within 14q13.3. The expression of <i>PTCSC3-AS1</i> was strongly downregulated in PTC tumor tissues, and restoration of <i>PTCSC3-AS1</i> expression in PTC cells inhibited tumorigenesis and promoted cell apoptosis. Moreover, <i>PTCSC3-AS1</i> and <i>PTCSC3</i>, two lncRNAs located on the opposite strands at 14q13.3, were revealed to synergistically interact with their shared binding protein vimentin. Forced overexpression of <i>PTCSC3</i> and <i>PTCSC3-AS1</i> revealed that <i>ZC3H12A</i>, a gene validated as a PTC suppressor, was the shared downstream target of the two lncRNAs. Vimentin significantly reduced the mRNA stability of <i>ZC3H12A</i>, while the upregulation of <i>PTCSC3</i> and <i>PTCSC3-AS1</i> suppressed the mRNA degradation of <i>ZC3H12A</i>. In addition, rs944289 and rs116909374 were identified as two potential causative variants with distinct regulatory roles in the 14q13.3 locus. Mechanistically, <i>PTCSC3-AS1</i> and <i>PTCSC3</i> protected <i>ZC3H12A</i> from vimentin-mediated mRNA degradation by targeting the <i>ZC3H12A</i> 3' untranslated region (3'UTR) during PTC initiation and progression. <b><i>Conclusion:</i></b> Our results suggest a novel dual-lncRNA regulatory model in the 14q13.3 risk locus and provide a comprehensive annotation of the <i>PTCSC3-AS1</i>/<i>PTCSC3</i>-vimentin-<i>ZC3H12A</i> signaling network in PTC genetic predisposition.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080006","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":"<i>Letter:</i> \"High Rates of Unnecessary Surgery for Indeterminate Thyroid Nodules in the Absence of Molecular Test and the Cost-Effectiveness of Utilizing Molecular Test in an Asian Population: A Decision Analysis\" by Fung et al.","authors":"Kennichi Kakudo, Andrey Bychkov, Jen-Fan Hang, Mitsuyoshi Hirokawa, Somboon Keelawat, Zhiyan Liu, Radhika Srinivasan, Chan Kwon Jung","doi":"10.1089/thy.2025.0072","DOIUrl":"10.1089/thy.2025.0072","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"595-596"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701640","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":"Development of a Nomogram to Integrate Molecular Testing and Clinical Variables to Improve Malignancy Risk Assessment Among Cytologically Indeterminate Thyroid Nodules.","authors":"Jiahui Wu, Paul Stewardson, Markus Eszlinger, Moosa Khalil, Sana Ghaznavi, Erik Nohr, Adrian Box, Ralf Paschke","doi":"10.1089/thy.2024.0481","DOIUrl":"10.1089/thy.2024.0481","url":null,"abstract":"<p><p><b><i>Background:</i></b> The introduction of molecular testing (MT) of cytologically indeterminate thyroid nodules (ITNs) alone has not impacted thyroidectomy rates. Due to this, we evaluated the incremental diagnostic value of various clinical variables in addition to MT results, in predicting the risk of malignancy (ROM) among ITNs. <b><i>Methods:</i></b> This prospective observational study included 1024 consecutive ITNs that underwent reflexive ThyroSPEC MT between Jul 30, 2020, and Oct 30, 2023. A multivariable logistic regression model was built to assess the relationship between histology outcomes and clinical variables, including nodule discovery by palpation, ultrasound risk categories, maximum nodule size, Bethesda category, Bethesda atypia, and ThyroSPEC categories. A total of 332 out of 1024 patients who underwent surgery and had complete data for all variables were included in the model. A nomogram was subsequently developed based on the model. <b><i>Results:</i></b> The model achieved a cross-validated AUC of 0.831 (95% confidence intervals: 0.787-0.874). Patients with high-risk mutations or malignant molecular markers exhibited significantly higher odds (152.79 times) of malignancy compared to those with mutation-negative or benign molecular marker results. Patients with maximum nodule size >5 cm have 4.34 times higher odds of malignancy than those 0-2 cm. The presence of nuclear atypia increased the odds of malignancy by 4.26 times, while ultrasound malignancy risk category 5 increased the odds of malignancy by 2.89 times compared to categories 1-3. Positive palpation discovery increased the odds by 1.83 times. The integrated ROM estimated from the regression model is significantly associated with the surgery type (<i>p</i> < 0.001). In the low (0-30%) and intermediate ROM (31-70%) categories, lobectomy alone is the most common surgery (61% and 70%, respectively), while in the high ROM (>70%) category, total thyroidectomy dominates (62%). <b><i>Conclusions:</i></b> Although MT alone played an important role in decision-making regarding surveillance versus surgery in our study population, integrating MT results with additional clinical variables improved the malignancy risk prediction for ITNs. Our results highlight the importance of contextualizing MT results within an integrated interdisciplinary thyroid nodule diagnostic pathway.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"508-515"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557359","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":"The 2024 World Medical Association Declaration of Helsinki and Its Importance for Thyroidology.","authors":"Joseph Tobias, Megan K Applewhite, Peter Angelos","doi":"10.1089/thy.2025.0181","DOIUrl":"10.1089/thy.2025.0181","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"457-459"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015458","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":"Evaluation of the Current State of Thyroid Hormone Testing in Human Serum-Results of the Free Thyroxine and Thyrotropin Interlaboratory Comparison Study.","authors":"Ashley Ribera, Otoe Sugahara, Tatiana Buchannan, Norma Vazquez, Alicia N Lyle, Li Zhang, Uliana I Danilenko, Hubert W Vesper","doi":"10.1089/thy.2024.0728","DOIUrl":"10.1089/thy.2024.0728","url":null,"abstract":"<p><p><b><i>Background:</i></b> Performance of thyroid function assays can vary significantly. To address this issue, the Centers for Disease Control and Prevention (CDC) Clinical Standardization Programs conducted an interlaboratory comparison of free thyroxine (fT4) immunoassays (IAs) and laboratory-developed tests (LDTs). This assessment aimed to determine the current performance characteristics of these assays as a first step toward measurement standardization. Thyrotropin (TSH) IAs were also evaluated. <b><i>Methods:</i></b> Assays measured 41 blinded individual-donor sera, including a sample from a pregnant woman (for fT4 analysis only) and three serum pools, with 11.3-32.1 pmol/L (0.881-2.49 ng/dL) fT4 and 0.337-21.6 mIU/L TSH in duplicate over 2 days. Passing-Bablok regression analysis performed pre-recalibration compared assays performance to the CDC fT4 reference measurement procedure (RMP) or TSH all-lab mean (ALM). Additionally, the impact of linear regression-based recalibration of assays to the CDC fT4 RMP or TSH ALM was estimated. Inter-assay agreement of sample classification according to the assay-specific reference interval (RI) was assessed pre- and post-recalibration. <b><i>Results:</i></b> A total of 21 fT4 and 17 TSH assays participated. Pre-recalibration, median biases of TSH measurements to the ALM were -1.2% [confidence interval or CI -1.8% to -0.4%], and good classification agreement among TSH assays was observed. fT4 assays all showed a negative median bias to the RMP, with higher bias among IAs (median: -20.3%, CI [-21.5% to -19.4%]) than LDTs (median: -4.5%, [CI -6.1% to -3.2%]). Of the individual-donor sera, only 21 out of 40 samples were classified uniformly by all fT4 assays, indicating poor inter-assay agreement. Post-recalibration, agreement improved to 33 out of 40 individual-donor sera correctly classified by all tested IAs and LDTs. Similar improvement in post-recalibration median percent bias was observed for fT4 IAs (median: -0.2, [CI -1.2% to 0.6%]) and LDTs (median: -0.3%, [CI -2.5% to 1.4%]). <b><i>Conclusions:</i></b> The comparison among fT4 assays emphasizes the need for measurement standardization to improve accuracy and comparability. This and previous studies demonstrate the possibility to develop common fT4 RIs via standardization, enabling the use of evidence-based clinical guidelines universally in patient care. Recalibration can effectively address high variability in fT4 assays, ensuring consistent diagnostic classification.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"471-484"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998713","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":"Response to Kakudo et al.: \"High Rates of Unnecessary Surgery for Indeterminate Thyroid Nodules in the Absence of Molecular Test and the Cost-Effectiveness of Utilizing Molecular Test in an Asian Population: A Decision Analysis\".","authors":"Man Him Matrix Fung, Ching Tang, Gin Wai Kwok, Tin Ho Chan, Yan Luk, David Tak Wai Lui, Carlos King Ho Wong, Brian Hung Hin Lang","doi":"10.1089/thy.2025.0150","DOIUrl":"10.1089/thy.2025.0150","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"597-598"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027994","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":"Reimagining the Therapeutic Approach for Anaplastic Thyroid Cancer: The Roadmap to a Cure.","authors":"Maria E Cabanillas, Neal Akhave, Victoria Banuchi, Naifa Busaidy, Ramona Dadu, Renata Ferrarotto, Gary B Gunn, Sarah Hamidi, Marie-Claude Hofmann, S Mohsen Hosseini, Priyanka C Iyer, Stephen Y Lai, Anna Lee, Anastasios Maniakas, Matthew S Ning, Michael Spiotto, Jennifer R Wang, Michelle D Williams, Mark Zafereo","doi":"10.1089/thy.2025.0044","DOIUrl":"https://doi.org/10.1089/thy.2025.0044","url":null,"abstract":"<p><p><b><i>Background:</i></b> Anaplastic thyroid cancer (ATC) is an aggressive cancer that leads to rapid death if left untreated. However, recent advances in ATC treatment have dramatically changed the prognosis in a select group of patients with BRAF^V600E mutations. In these patients, BRAF/MEK inhibitors have been shown to dramatically and rapidly shrink tumors. Yet, these responses are short-lived unless additional treatment modalities are applied. In patients without a BRAF^V600E mutation, the current available therapies are far less effective. <b><i>Summary:</i></b> In this article, we review the relevant literature and propose applying the \"Total Therapy\" approach used since the 1960s for another deadly but curable disease, acute lymphocytic leukemia, to ATC. We have adapted the concepts of Induction, Consolidation, and Maintenance, applying them to ATC. This regimen integrates the treatments we have found to be successful in ATC: combination systemic therapy using targeted therapy plus immunotherapy, surgery, radiation, and continuation of the systemic therapy for several years, thereby attempting to eradicate all residual ATC cells. <b><i>Conclusions:</i></b> There has been a renewed interest in understanding the genomics of ATC and treating these patients with urgency rather than just providing palliative care. This shift has led to significant improvements in the prognosis of ATC. With the right tools and a clear roadmap to guide us, we now aim to take on the challenge of curing these patients.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":"35 5","pages":"462-470"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102077","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":"DNA Methylation Dynamics and Prognostic Implications in Metastatic Differentiated Thyroid Cancer.","authors":"Helena Rodríguez-Lloveras, Carles Zafon, Carmela Iglesias, Jennifer Marcos-Ruiz, Joan Gil, Anna Rueda-Pujol, Lorena González, Regina Mayor, Esther N Klein Hesselink, Bettien M van Hemel, Cristina Carrato, Cecília Perelló-Fabregat, Javier Hernández-Losa, Rosa Somoza, Raquel Pluvinet, Jose F Sánchez-Herrero, Lauro Sumoy, Joan Seoane, Garcilaso Riesco-Eizaguirre, Cristina Montero-Conde, Mercedes Robledo, Jorge Hernando, Jaume Capdevila, Jordi L Reverter, Manel Puig-Domingo, Thera P Links, Mireia Jordà","doi":"10.1089/thy.2024.0303","DOIUrl":"10.1089/thy.2024.0303","url":null,"abstract":"<p><p><b><i>Background:</i></b> 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. <b><i>Materials and Methods:</i></b> 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. <b><i>Results:</i></b> 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 <i>de novo</i> 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. <b><i>Conclusions:</i></b> 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.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"494-507"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568191","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":"Sex Differences in Risk for Iatrogenic Thyrotoxicosis Among Older Adults: An Analysis from Real-World Clinical Data.","authors":"Roy Adams, Jennifer Sophie Mammen","doi":"10.1089/thy.2024.0604","DOIUrl":"10.1089/thy.2024.0604","url":null,"abstract":"<p><p><b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 (<i>p</i> < 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 (<i>p</i> = 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]; <i>p</i> < 0.001) and was fully mediated by dose calculated using lean body mass (HR = 1.06 [CI: 0.95-1.19]; <i>p</i> < 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. <b><i>Conclusions:</i></b> 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.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"485-493"},"PeriodicalIF":5.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674576","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}