In vertebrates, the thyroid gland synthesizes hormones that act on almost all tissues and are essential for normal growth and metabolism. Thyroid hormone production relies on iodination of thyroglobulin and requires H2O2, which contributes to a relatively high basal oxidative stress in the thyroid that must be tightly controlled to prevent cellular damage. The thyroid has efficient antioxidant and detoxifying enzymes that help it resist H2O2-induced oxidative stress maintaining the homeostasis necessary for hormone synthesis. By regulating the expression of genes involved in cellular detoxification, NRF2 acts as a master regulator of the cellular defense against oxidative stress. Using zebrafish embryos and mouse ESC-derived thyroid organoids, we generated nrf2a/Nrf2 loss-of-function and identified a common dyshormonogenesis phenotype. Although in zebrafish, the driving mechanisms are possibly related to thyroglobulin iodination defects, in thyroid organoids, it is likely due to a reduction in Tg production, consequently affecting folliculogenesis and thyroid hormone production.

To facilitate shared decision-making, patients increasingly rely on online platforms for health-related information. While thyroid diseases are common, the quality of available thyroid-related information varies. This study comprehensively evaluated a new audiovisual information material developed by Medtronic for patients with surgical thyroid disease in English and French. Data were collected from patients at baseline (t1), after accessing the French version of Medtronic’s Butterfly platform but before surgery (t2), and three weeks post-surgery (t3). Patients assessed the material’s usefulness (USE), impact (eHIQ) and quality (Brief DISCERN), provided feedback on its content using a custom debriefing questionnaire, and self-reported on their anxiety (GAD-7), depression (PHQ-9) and stress (PSS-14). We assessed both versions for readability (FRES, FKGL, SMOG, GFI, and Scolarius); understandability and actionability (PEMAT-A/V); linguistic aspects (LIWC-22) and tone style (YesChat Tone Analyzer). In addition to quantitative and qualitative analyses of the respective datasets, triangulation was used to integrate both approaches. Of 26 patients enrolled, 24 participated at t2 and 22 at t3; both benign and malignant/potentially malignant surgical indications were represented. The material’s usefulness and impact scores at t2 were significantly above respective predefined thresholds. Consistently, qualitative analysis showed that most participants found the material useful/ very useful. Whereas anxiety and depression scores were low across t1-t3, levels of stress were consistently high; PSS-14 scores at t1 correlated positively with eHIQ-Part 2 scores at t3 (r = 0.495, p = 0.019), suggesting that patients with higher stress may experience a greater impact. Even though readability scores for both languages indicated higher complexity than the generally recommended 6th -8th grade level, neither the quantitative nor the qualitative patient feedback indicated challenges with the material’s language. Assessment of the material by five investigators showed very good understandability and excellent actionability. Linguistic analysis showed a somewhat higher complexity of the French version; for both versions, tone analysis reported a clear, approachable, and professional style, with direct and informative content, using generally simple language. Finally, participants suggested slight improvements, especially regarding online navigation. These findings provide preliminary evidence that the Butterfly platform may serve as a useful educational resource for patients undergoing thyroid surgery; further validation in larger and more diverse populations is warranted.

BackgroundFibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) has emerged as a promising molecular imaging modality with favorable lesion-to-background contrast across several malignancies. In radioiodine-refractory thyroid carcinoma (RAIR-TC) and thyroglobulin-elevated negative iodine scintigraphy (TENIS) syndrome, conventional radioiodine imaging and fluorodeoxyglucose (FDG) PET/CT may be limited in selected clinical scenarios. This systematic review evaluated the diagnostic utility, comparative performance, and potential clinical impact of FAPI PET/CT in this patient population.MethodsPubMed, Embase, and Scopus were searched from inception to 6 August 2025 according to PRISMA 2020 guidelines. Eligible studies included original clinical studies and case reports evaluating FAPI PET/CT in RAIR-TC or TENIS syndrome. Non-original, non-human, in vitro, conference abstract, and non-English publications were excluded. Two reviewers independently performed study selection, data extraction, and quality assessment. QUADAS-2 was applied to eligible cohort studies.ResultsEight studies comprising 167 patients were included: three prospective studies, one retrospective study, and four case reports. FAPI PET/CT showed promising complementary diagnostic value in selected clinical scenarios, particularly for lesions with low FDG conspicuity or high physiologic FDG background. In one prospective cohort of 24 patients, [68Ga]Ga-DOTA-FAPI-04 PET/CT detected disease in 87.5% of patients. In the largest retrospective cohort (n = 117), [68Ga]Ga-DOTA.SA.FAPi showed higher detection than FDG PET/CT for selected metastatic sites, including lymph nodes, liver, and brain. However, comparative performance varied across tracers, lesion sites, and study designs; one prospective [18F]FAPI-74 study reported lower lesion detection than FDG PET/CT.ConclusionFAPI PET/CT demonstrates promising but preliminary diagnostic utility in RAIR-TC and TENIS syndrome. Current evidence supports a complementary role in selected patients, but remains insufficient to establish routine diagnostic superiority over FDG PET/CT. Larger prospective multicenter studies with standardized protocols and robust reference validation are required.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251123809.

This article reviews a selection of recent developments in various fields of endocrinology. Advances in the diagnosis and management of endocrine disorders of general interest are highlighted, focusing on the following areas: a) new recommendations for the diagnosis and management of primary hyperaldosteronism; b) confirmation of the validity of therapeutic deescalation in low-risk differentiated thyroid cancer and c) the expansion of indications for genetic testing in multiple endocrine neoplasia syndromes.

Background: The health-related quality of life (HRQoL) of patients with differentiated thyroid carcinoma (DTC), especially their mental health, can be compromised by various factors beyond disease prognosis and treatment stage. However, predictors of poor emotional functioning (EF) in DTC patients have not been thoroughly studied. To inform targeted interventions that could improve or preserve HRQoL in patients with DTC, this study aimed to identify predictors of impaired EF, and particularly modifiable factors. Methods: Data analyzed were from the phase IV international validation study of the European Organization for Research and Treatment of Cancer thyroid cancer-specific HRQoL questionnaire (QLQ-THY34). Patients (n = 196) were assessed at three timepoints before treatment (t1), 6 weeks after the start of treatment (t2), and 6 months after t2 (t3). Multilevel, multivariable logistic regression models were used to assess the likelihood of impaired EF at t3 according to predefined potential predictors at t1 and t2. Results: Impaired EF at t1 or t2 predicted impaired EF at t3. Exhaustion, head and neck discomfort and body image issues were significantly associated with poor EF at t3. More specifically, temporal changes of these three variables from t1 to t2 were independent predictors of poor EF at t3 with an odds ratio of 1.04 (p < 0.001), 1.01 (p = 0.04), and 1.01 (p = 0.001) per score point, respectively. There was no evidence that worry about important others, lacking social support, sex, stage, or Karnofsky performance score are associated with EF at t3. Conclusions: Exhaustion, head and neck discomfort, and body image concerns emerged as modifiable factors that predict future impaired EF in patients with DTC undergoing treatment. These factors could be targeted in prehabilitation, rehabilitation or other interventional programs to potentially improve or preserve patients' EF.

We screened 424 natural compounds, including many marketed as dietary supplements, to assess their antioxidant and thyroidal effects. In rat PCCL3 thyroid follicular cells, we performed parallel primary screens for antioxidant response element (ARE) activation, thyroglobulin (Tg) promoter activity, sodium/iodide symporter (NIS) promoter activity and iodide uptake. Hits were tested in downstream analyses, including ARE activation in Nrf2-knockout cells, an Nrf1 stabilization reporter, endogenous Nqo1, Tg and NIS mRNA and protein levels, and relationships between these readouts. Of 424 compounds, 69 induced ARE activity in wild-type cells; most also activated the ARE in Nrf2-knockout cells, and only 8 showed a profile consistent with predominantly Nrf2-dependent ARE activation. Several Nrf2-independent ARE inducers also stabilized an Nrf1-based reporter. Thirty compounds activated the Tg promoter and 26 significantly modulated iodide uptake, with only partial concordance between promoter activity, mRNA/protein expression and iodide uptake. Notable hits included genistein and apigenin, which showed balanced ARE and Tg induction together with NIS upregulation, supporting further evaluation in hypothyroidism and redifferentiation; luteolin, chrysin and diosmetin, which enhanced NIS expression and/or iodide uptake, highlighting potential as redifferentiation or adjunctive agents in thyroid cancer; emodin and gamma-oryzanol, which increased iodide uptake, suggesting utility in hypothyroidism or iodine deficiency; and bavachin, which showed the strongest iodide uptake induction without markedly increasing NIS protein, warranting mechanistic follow-up. Thyroid-relevant bioactivity was enriched among dietary supplements. Many compounds displayed complex Nrf2-dependent and -independent actions that can confer indication-specific thyroid benefits or risks, emphasizing the need for thyroid-focused evaluation of antioxidant and natural supplements.

OBJECTIVES:Patient education can improve patients' health literacy, participation in shared decision-making, and quality of life. Contemporary guidelines, including the 2025 American Thyroid Association Guidelines for differentiated thyroid cancer (DTC), emphasize high-quality, accessible written information, and survivorship-focused counseling as core components of care. This exploratory cross-sectional study performed a multimodal evaluation of DTC patient information booklets (PIBs). METHODS:Ten PIBs (5 in English, 5 in French) were assessed by 6 healthcare professionals for (i) information content across 7 themes from a systematic review of unmet patient needs; (ii) quality of treatment information using DISCERN; (iii) understandability and actionability using the Patient Education Materials Assessment Tool for Printable materials (PEMAT-P); and (iv) readability using 4 standard indices (Flesch-Kincaid Grade Level, Gunning Fog Index, Simple Measure of Gobbledygook and Flesch Reading Ease formulas). RESULTS:Interrater agreement was excellent. Global content scores ranged from 25% to 70%. General information, diagnosis, treatment, and follow-up were mostly addressed, whereas psychosocial concerns, care coordination, and complementary medicine were consistently underrepresented. Three PIBs scored "excellent," 4 "good," and 3 "fair" on DISCERN. Eight PIBs were sufficiently understandable and 5 sufficiently actionable on PEMAT-P. Readability levels were systematically higher than recommended. Content scores correlated positively with booklet length, DISCERN scores, and PEMAT-P actionability. CONCLUSIONS:Assessed DTC PIBs show a persistent mismatch with patient-identified needs, particularly in psychosocial, care-coordination, and complementary-medicine domains, alongside variable quality of treatment information, understandability, and actionability. Readability remains uniformly more complex than recommended. These findings are useful for the development and clinical use of patient information materials.

Aims: Thyroid hormones (TH) are major regulators of cell differentiation, growth, and metabolic rate. TH synthesis in the thyroid gland requires high amounts of H2O2 to oxidize iodide for the iodination of thyroglobulin (TG). Retinol Saturase (RetSat) is an oxidoreductase implicated in dihydroretinol formation and cellular sensitivity toward peroxides and ferroptosis. RetSat is highly expressed in metabolically active organs where it regulates lipid metabolism and the production of reactive oxygen species. Due to the high expression of RetSat in the thyroid gland and its role in peroxide sensitivity, we investigated the regulation and function of RetSat in the thyroid gland in appropriate mouse models. Results: RetSat is strongly expressed in thyrocytes, induced by hypothyroidism, and decreased by iodide overload in mice. Thyrocyte-specific deletion of RetSat increased circulating thyroid-stimulating hormone levels, altered thyroid morphology, and disturbed metabolic homeostasis in a diet- and sex-dependent manner without major effects on the concentrations of circulating TH. Moreover, deletion of RetSat increased TG protein levels but lowered TG iodination upon iodide overload. In cultured thyrocytes, acute RetSat depletion altered the expression of genes involved in TH biosynthesis and the response to endoplasmic reticulum stress. Innovation: This is the first report that specifically dissects the regulation and function of the oxidoreductase RetSat in the thyroid gland. Conclusion: Deletion of RetSat in thyrocytes induces compensatory feedback mechanisms to maintain TH homeostasis in mice. We conclude that RetSat in the thyroid gland is required for TH biosynthesis and secretion and metabolic homeostasis in mice. Antioxid. Redox Signal. 42, 463-479.

Thyroid nodules affect up to 70% of adults undergoing ultrasonography. The European Thyroid Association (ETA) recently issued high-quality guidelines outlining management options. However, their implementation in routine practice remains uncertain. This study examined guideline adoption and barriers, focusing on nodules with atypia of undetermined significance (AUS), a particularly challenging cytological category. From November 2023 to April 2024, members of the Hellenic Endocrine Society (HES) participated in a web-based survey concerning management of a 2.5 cm thyroid nodule with fine-needle aspiration (FNA) cytology results of AUS. The scenario varied based on the nodule's sonographic risk, namely, as intermediate (EU-TIRADS 4) or high (EU-TIRADS 5). The questionnaire also collected demographic information and inquired about reasons for non-adherence to the guidelines. The response rate was 25%. For an EU-TIRADS 4 nodule, 61% chose to repeat FNA, whereas only 23% would repeat FNA for an EU-TIRADS 5 nodule, despite the 2023 ETA guidelines recommending this approach as the next step in both cases. More experienced endocrinologists were less likely to opt for repeat FNA and more likely to choose total thyroidectomy in the first scenario, whereas experience did not influence preferences in the second scenario. Reasons for non-compliance were skepticism regarding the recommendations, limited access to reliable neck ultrasonography, and molecular testing, and a shortage of high-volume surgeons. Greek endocrinologists deviate from the 2023 ETA guidelines for the management of thyroid nodules with AUS cytology in daily clinical practice. These findings highlight the need for targeted educational strategies and enhancement of clinical infrastructure in Greece.

Technetium-99m sestamibi single-photon emission computed tomography/computed tomography (99mTc-sestamibi SPECT/CT) is a mainstay of the pre-operative localization of parathyroid lesions. We report here the case of a 30 year-old woman with a fortuitously discovered 2 cm cervical mass for which a parathyroid origin was originally suspected due to its retro-thyroidal localization and a personal history of nephrolithiasis. Normal serum calcium and parathyroid hormone (PTH) levels excluded primary hyperparathyroidism, raising suspicion of a non-functional parathyroid adenoma, and SPECT/CT imaging showed that the mass was 99mTc-sestamibi-avid. Fine-needle aspiration (FNA) was performed; cytology was non-diagnostic but the needle washout was negative for thyroglobulin, calcitonin and PTH, arguing against a thyroidal or parathyroidal origin of the mass. Core needle biopsy revealed a schwannoma, ostensibly originating from the recurrent laryngeal nerve; upon surgical resection, it was finally found to arise from the esophageal submucosa. This case illustrates the fact that endocrinologists, radiologists, nuclear medicine, head and neck, and other specialists investigating patients with cervical masses should be aware that schwannomas need to be considered in the differential diagnosis of focal 99mTc-sestamibi uptake in the neck region.

Hashimoto’s thyroiditis (HT) is not only the most frequent autoimmune thyroid disease (AITD), but it also has a significant impact on patients’ health-related quality of life (HRQoL), and it has been variably associated with differentiated thyroid carcinoma. Even though its pathogenesis is still incompletely understood, oxidative stress is believed to play an important role. Hypothyroidism related to later stages of HT can be treated with levothyroxine substitution therapy; various approaches such as selenium supplementation and iodine-restricted diets have been proposed as disease-modifying treatments for earlier stages, and even thyroidectomy has been suggested for refractory cases of painful HT. Nevertheless, many patients still report suboptimal HRQoL, highlighting an unmet medical need in this area. The concepts and approaches of traditional Chinese medicine (TCM) in treating HT are not broadly known in the West. Here, we provide an overview of TCM for HT, including combinations of TCM with selenium. We encompass evidence from clinical trials and other studies related to complex TCM prescriptions, single herbs used in TCM, and phytochemicals; wherever possible, we delineate the probable underlying molecular mechanisms. The findings show that the main active components of TCM for HT have commonly known or presumed antioxidant and anti-inflammatory activities, which may account for their potential utility in HT. Further exploring the practices of TCM for HT and combining them with evidence- and mechanism-based approaches according to Western standards may help to identify new strategies to alter the clinical course of the disease and/or to treat patients’ symptoms better and improve their HRQoL.

Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1KD) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1KD mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1KD mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs.

BackgroundThe incidence of thyroid cancer is on the rise worldwide, with childhood exposure to radiation being the sole acknowledged catalyst for its emergence. Nonetheless, numerous other factors that may pose risks are awaiting thorough examination and validation. This retrospective study aims to explore the malignancies linked to thyroid cancer and contrast the survival rates of those afflicted with a solitary tumor versus those with multiple primary neoplasms (MPN).MethodsThis retrospective study examined data from King Hussein Cancer Center (KHCC), Jordan. Among 563 patients diagnosed with thyroid cancer, 30 patients had thyroid malignancy as part of MPN. For a 1:3 propensity score-matched analysis, 90 patients with only a primary thyroid malignancy were also enrolled.ResultsHematologic and breast malignancies were among the most frequent observed cancers alongside thyroid neoplasm. Patients who had MPN were diagnosed at older age, had higher body mass index and presented with higher thyroglobulin antibody levels (p < 0.05 for each). Additionally, MPN patient displayed a stronger family history for cancers (p= 0.002). A median follow-up duration of 135 months unveiled that MPN patients faced a worse 5-year survival compared to their counterparts with a singular neoplasm (87% vs 100% respectively; p < 0.01). However, no distinction emerged in the 5-year event-free survival between these two groups.ConclusionMPN correlates with a significantly altered survival outcome of thyroid cancer patients. The diagnosis of thyroid carcinoma at an older age, accompanied by elevated initial thyroglobulin antibody levels and a notable familial predisposition, may raise concerns about the potential occurrence of synchronous or metachronous tumors.

Background: 18F-FDG PET/CT is performed for the assessment of radioactive iodine non-avid disease in patients with DTC. In patients prepared by THW, increased pituitary uptake of 18F-FDG in the absence of pituitary disease may reflect the physiological activation of pituitary thyrotroph cells by hypothyroidism. This study aimed to compare pituitary 18F-FDG uptake in patients with DTC under THW vs. rhTSH stimulation. Methods: A total of 57 patients with DTC undergoing 18F-FDG PET/CT (40 under THW and 17 under rhTSH stimulation) were retrospectively analyzed. Pituitary metabolism was expressed as maximum standardized uptake value (SUVmax) and as SUVratio using the right cerebellum as reference. Results: Pituitary hypermetabolism (SUVmax ≥ 4.1) was present in more patients in the THW group compared to the rhTSH group (62.5% vs. 23.5%; p = 0.01). Pituitary metabolism was significantly higher in the THW group compared to the rhTSH group, as assessed by either SUVmax (mean ± SD: 4.61 ± 1.22, 95%CI: 4.22–5.00 vs. 3.34 ± 0.86, 95%CI: 2.9–3.8; p < 0.001) or SUVratio (0.52 ± 0.11, 95%CI: 0.49–0.56 vs. 0.42 ± 0.07, 95%CI: 0.38–0.46; p < 0.001). Serum TSH levels correlated positively with SUVmax (r = 0.41, p < 0.01) and SUVratio (r = 0.44, p < 0.01) in the THW group only. Conclusions: The present findings support the hypothesis that pituitary hypermetabolism on 18F-FDG PET/CT in patients with DTC undergoing THW is a common physiological response to hypothyroidism. Awareness of this physiological hypermetabolism is important to avoid potential pitfalls in image interpretation.

Background: Health economic appraisals often rely on the assessment of health utilities using preference-based measures (PBM). The cancer-specific PBM, European Organisation for Research and Treatment of Cancer Quality of Life Utility - Core 10 Dimensions (EORTC QLU-C10D), was developed recently, and now needs to be validated in various clinical populations.Methods: In a multicenter, multinational prospective cohort study, we longitudinally collected EORTC QLQ-C30 and EQ-5D-5L data from patients with thyroid cancer. We applied seven country-specific value sets to the QLQ-C30 data to derive country-specific utility values and used the EQ-5D-5L as a comparator PBM. Criterion validity was assessed by correlating index scores and Bland-Altman plots. Construct validity was investigated by correlating domain scores. Known-group comparisons and responsiveness were assessed using external clinical criteria.Results: A total of 181 patients with thyroid cancer from nine countries (three continents) provided analyzable data. Patients were included if they had differentiated, medullary, or anaplastic thyroid cancer. Mean utility values of both instruments were generally lower compared to general population norms. No floor or ceiling effects were present for the QLU-C10D. The intra-class correlation for EQ-5D-5L and QLU-C10D index values ranged from 0.761 to 0.901 across the measurement timepoints, supporting criterion validity. Spearman's correlation coefficients ranged from 0.289 to 0.716 for theoretically corresponding domain pairs. The QLU-C10D detected differences in 9 of 15 known-group comparisons, supporting sensitivity. Clinically important changes were detected by all QLU-C10D country specific value sets, supporting responsiveness. Further, the QLU-C10D had higher statistical efficiency than the EQ-5D-5L in 74.7% of comparisons.Conclusions: The QLU-C10D is a valid PBM for health economic evaluations in thyroid cancer studies. We recommend its use to estimate health utilities in economic evaluations of thyroid cancer therapies.

Graves’ disease is the most common form of hyperthyroidism, especially in younger people. Current European guidelines recommend antithyroid drugs as initial treatment for a period limited to 12–18 months. Definitive treatment such as surgery or radioactive iodine is proposed in the case of contraindication to antithyroid drugs or in the case of recurrence after medical treatment. However, more recent studies show that long-term antithyroid treatment is associated with reduced risk of recurrence without an increase in adverse effects. Such data support the option of long-term treatment of Graves’ disease with antithyroid drugs and suggest the necessity for a change to long-standing practices in the field. Herein, after reviewing some general knowledge on Graves’ disease treatment, we discuss the evidence regarding long-term treatment of Graves’ disease with antithyroid drugs for endocrinologists, internists, and other specialists involved in the management of these patients. We consider the main studies in the field, outline their respective strengths and limitations, and, finally, present our opinion on when, in the light of this new evidence, endocrinologists should consider long-term treatment with antithyroid drugs.