Hyperthyroidism.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

3,3',5-Triiodothyroacetic Acid Transporters.

Introduction: 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. Materials and Methods: 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 in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 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. Conclusions: 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.

2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action.

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

Thyroid and adrenal incidentalomas on chest CT: Prevalence, diagnostic work-up and outcomes in a cohort of COVID-19 suspected patients.

OBJECTIVE: Due to increased use of computed tomography (CT), prevalence of thyroid and adrenal incidentalomas is rising. Yet, previous studies on the outcomes of diagnostic work-up of incidentalomas are subjected to inclusion bias. Therefore, we aimed to investigate prevalence and outcomes of diagnostic work-up of thyroid and adrenal incidentalomas detected on chest CT in a less selected population of COVID-19 suspected patients. DESIGN: A retrospective, observational cohort study. METHODS: We included all COVID-19 suspected patients who underwent chest CT between March 2020 and March 2021. Radiology reports and medical records were reviewed for the presence and subsequent diagnostic work-up of thyroid and adrenal incidentalomas. RESULTS: A total of 1,992 consecutive COVID-19 patients were included (59.4% male, median age 71 years [IQR: 71-80]). Thyroid and adrenal incidentalomas were identified in 95 (4.8%) and 133 (6.7%) patients, respectively. Higher prevalence was observed with increasing age, among female patients and in patients with malignancy. Forty-four incidentalomas were further analyzed, but no malignancies were found. Only three lesions were hormonally active (1 thyrotoxicosis and 2 mild autonomous cortisol secretion). Diagnostic work-up did not lead to any change in clinical management in 97.7% of the analyzed patients. CONCLUSION: Prevalence rates of thyroid and adrenal incidentalomas on chest CT in a less selected COVID-19 cohort were 4.8% and 6.7%, respectively. Yet, as all incidentalomas turned out to be benign and only three lesions were (mildly) hormonally active, this raises the question whether intensive diagnostic work-up of incidentalomas is necessary in all patients.

Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.

Background: Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods: In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results: Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC50: 2.5 ± 1.5 µM) or thyroxine (T4) (IC50: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions: Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines in vivo.

Clinical and Histopathological Risk Factors for Radioactive Iodine Refractory Follicular and Oncocytic Thyroid Carcinoma.

INTRODUCTION: Risk factors for radioactive iodine (RAI)-refractory disease in follicular (FTC) and oncocytic thyroid carcinoma (OTC) are unknown. Therefore, the aim of this study is to identify clinical and histopathological risk factors for RAI-refractory disease in FTC and OTC patients, facilitated by an extensive histopathological revision. METHODS: All adult FTC and OTC patients treated at Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. 2015 ATA Guidelines were used to define RAI-refractory disease. An extensive histopathological revision was performed applying the 2022 WHO Classification using Palga: Dutch Pathology Databank. Logistic regression was used to identify risk factors for RAI-refractory disease, stratified for histological subtype. RESULTS: Ninety FTC and 52 OTC patients were included, of which 14 FTC (15.6%) and 22 OTC (42.3%) developed RAI-refractory disease over a follow-up time of 8.5 years. RAI-refractory disease occurred in OTC after fewer cycles than in FTC (2.0 [IQR: 1.0-2.0] vs 2.5 [IQR: 2.0-3.75]), and it substantially decreased the 10-year disease specific survival, especially in OTC (46.4%; FTC 85.7%). In FTC, risk factors were higher age at diagnosis, pT3/pT4-stage, N1-stage, widely invasive tumors and extra-thyroidal extension. N1-stage and M1-stage were the strongest risk factors in OTC, rather than histopathological characteristics of the primary tumor. CONCLUSION: To our knowledge, this is the first study that correlates clinical and histopathological risk factors with RAI-refractory disease in FTC and OTC, facilitated by a histopathological revision. In FTC, risk factors for RAI-refractory disease were foremost histopathological characteristics of the primary tumor, whereas in OTC presentation with lymph node and distant metastasis was associated with RAI-refractory disease. Our data can help clinical decision making, particularly in patients at risk for RAI-refractory disease.

Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.

Background: 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. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (n = 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 (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132). Results: 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, Pfor trend =1.7 × 10-8). Conclusions: 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.

Management of patients with rare adult solid cancers: objectives and evaluation of European reference networks (ERN) EURACAN.

About 500,000 patients with rare adult solid cancers (RASC) are diagnosed yearly in Europe. Delays and unequal quality of management impact negatively their survival. Since 2017, European reference networks (ERN) aim to improve the quality of care of patients with rare disease. The steering committee of EURACAN, including physicians, researchers and patients review here the previous actions, present objectives of the ERN EURACAN dedicated to RASC. EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training session were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required. In this Health Policy, evaluation criteria of the performances of the network and of health care providers are proposed.

Replication studies in the Netherlands: Lessons learned and recommendations for funders, publishers and editors, and universities.

Drawing on our experiences conducting replications we describe the lessons we learned about replication studies and formulate recommendations for researchers, policy makers, and funders about the role of replication in science and how it should be supported and funded. We first identify a variety of benefits of doing replication studies. Next, we argue that it is often necessary to improve aspects of the original study, even if that means deviating from the original protocol. Thirdly, we argue that replication studies highlight the importance of and need for more transparency of the research process, but also make clear how difficult that is. Fourthly, we underline that it is worth trying out replication in the humanities. We finish by formulating recommendations regarding reproduction and replication research, aimed specifically at funders, editors and publishers, and universities and other research institutes.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Defining gestational thyroid dysfunction through modified non-pregnancy reference intervals: an individual participant meta-analysis.

BACKGROUND: Establishing local trimester-specific reference intervals for gestational TSH and FT4 is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific non-pregnancy reference intervals as compared to trimester-specific reference intervals. METHODS: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the non-pregnancy reference intervals included an absolute modification (per 0.1 mU/L TSH or 1 pmol/L FT4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 to 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity and positive predictive value (PPV) of aforementioned methodologies with population-based trimester-specific reference intervals. RESULTS: The final study population comprised 52,496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity 0.70, confidence interval [CI] 0.47-0.86; PPV 0.64, CI 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity 0.91, CI 0.67-0.98; PPV 0.71, CI 0.58-0.80). Absolute and fixed modifications yielded similar results. Confidence intervals were wide, limiting generalizability. CONCLUSION: We could not identify modifications of non-pregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned towards studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Comparison of two different TSH-receptor antibody assays: A clinical practice study.

Background: Graves' disease (GD) is caused by the production of TSH-receptor (TSHR) stimulating auto-antibodies. Over the years various TSHR-antibody (TRAb) detection assays have been developed. Most clinical laboratories use competitive TSH-binding inhibitory immunoglobulin (TBII) assays, which measure the total amount of stimulating and blocking auto-antibodies. Selective detection of TSHR stimulating auto-antibodies (TSI) was previously only possible with functional cell-based bioassays. However, more recently an automated bridge-based binding assay to more specifically measure TSI has become available. The aim of our study was to compare the third-generation automated competitive immunoassay (TBII) with the automated bridge immunoassay (TSI) in clinical practice in an academic thyroid expert center. Methods: A retrospective study in 356 patients with Graves' disease, Graves orbitopathy (GO), and other (thyroid) disease treated in an academic thyroid center was performed. All samples were analyzed for TBII and TSI. For both assays, sensitivity, specificity, positive predictive value (PVV), negative predictive value (NPV) and diagnostic odds ratios were calculated using different cut-offs for negativity. Results: Using the provided cut-off, the overall sensitivity appeared similar between TBII and TSI, but TSI showed higher overall specificity, PPV, NPV and diagnostic odds ratio. Using two or three times the cut-off for negativity resulted in a decrease in sensitivity, but an increase in specificity and PPV, which was most pronounced for the TBII-assay. Analysis in a subgroup of newly diagnosed treatment naïve GD/GO patients also revealed overall favorable results for the TSI-assay. Increasing the cut-off for negativity resulted in increased specificity for both assays, with similar results using two or three times the cut-off. Most patients with concordant positive results for TBII and TSI suffered from GD or GD + GO (n = 110, 95.6 %), while patients negative for both TBII and TSI mostly suffered from other (thyroid) disease (n = 143, 77.3 %). From patients with positive TBII but negative TSI only 42.1 % had GD/GO (n = 16), whereas 57.9 % (n = 22) had other (thyroid) disease. In contrast, 88.9 % of patients with positive TSI but negative TBII had GD/GO (n = 16), whereas 11.1 % (n = 2) had other (thyroid) disease. Conclusion: In our academic thyroid center, the diagnostic performance of the TSI-assay outperformed the TBII-assay. Using a higher cut-off value for negativity can be helpful in assessing clinical relevance.

Stress-Induced Graves Disease: Spontaneous Recovery After Stress Relief.

Purpose: Emotional stress is a precipitating factor for Graves disease (GD). However, the influence of stress relief on the course of GD is unknown. Here, we present a series of patients diagnosed with stress-induced GD in whom stress relief alone led to remission of GD. Cases: We report on 11 patients in whom hyperthyroid symptoms started just after severe emotional stress. All patients had suppressed thyroid-stimulating hormone (TSH) levels and elevated free thyroxine (FT4; 22.2-49.5 pmol/L) and TSH-receptor antibody (TRAb; 0.57-40 U/L) levels and were subsequently diagnosed with stress-induced GD. However, all patients declined antithyroid drug treatment. Surprisingly, clinical and biochemical remission was observed in 9 out of 11 patients after 1 to 3 and 2 to 7 months of self-reported stress relief, respectively. Five patients showed long-lasting remission (median follow-up 2.3 years). In 4 patients, remission was initially achieved, but GD relapsed 1 to 4 years afterwards. In 2 patients, treatment with antithyroid drugs was initiated because of rapidly increasing FT4 levels. Baseline FT4 and TRAb levels tended to be higher in patients who did not achieve remission. Furthermore, patients without long-lasting remission were more frequently known to have prior thyroid disease. Conclusion: We report on a series of patients with stress-induced GD in whom stress relief alone led to remission of GD (thus without antithyroid drugs). This may indicate that clinicians could consider stopping antithyroid drug treatment or at least shortening the treatment period after stress relief in patients with stress-induced GD.