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Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
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Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
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Introduction
Thyroid hormones have systemic effects on the human body and play a key role in the development and function of virtually all tissues. They are regulated via the hypothalamic–pituitary–thyroid (HPT) axis and have a heritable component. Using genetic information, we applied tissue-specific transcriptome-wide association studies (TWAS) and plasma proteome-wide association studies (PWAS) to elucidate gene products related to thyrotropin (TSH) and free thyroxine (FT4) levels.
Results
TWAS identified 297 and 113 transcripts associated with TSH and FT4 levels, respectively (25 shared), including transcripts not identified by genome-wide association studies (GWAS) of these traits, demonstrating the increased power of this approach. Testing for genetic colocalization revealed a shared genetic basis of 158 transcripts with TSH and 45 transcripts with FT4, including independent, FT4-associated genetic signals within the CAPZB locus that were differentially associated with CAPZB expression in different tissues. PWAS identified 18 and ten proteins associated with TSH and FT4, respectively (HEXIM1 and QSOX2 with both). Among these, the cognate genes of five TSH- and 7 FT4-associated proteins mapped outside significant GWAS loci. Colocalization was observed for five plasma proteins each with TSH and FT4. There were ten TSH and one FT4-related gene(s) significant in both TWAS and PWAS. Of these, ANXA5 expression and plasma annexin A5 levels were inversely associated with TSH (PWAS: P = 1.18 × 10−13, TWAS: P = 7.61 × 10−12 (whole blood), P = 6.40 × 10−13 (hypothalamus), P = 1.57 × 10−15 (pituitary), P = 4.27 × 10−15 (thyroid)), supported by colocalizations.
Conclusion
Our analyses revealed new thyroid function-associated genes and prioritized candidates in known GWAS loci, contributing to a better understanding of transcriptional regulation and protein levels relevant to thyroid function.
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Context
Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported.
Case presentation and results
We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of −0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of −0.060.
Conclusion
As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Background
Radiofrequency ablation (RFA) is effective in the treatment of thyroid nodules, leading to a 50–90% reduction with respect to baseline. Current guidelines indicate the need for a benign cytology prior to RFA, though, on the other side, this procedure is also successfully used for the treatment of papillary microcarcinomas. No specific indications are available for nodules with an indeterminate cytology (Bethesda III/IV).
Aim
To evaluate the efficacy of RFA in Bethesda III nodules without genetic alterations as verified by means of a custom panel.
Methods
We have treated 33 patients (mean delivered energy 1069 ± 1201 J/mL of basal volume) with Bethesda III cytology, EU-TIRADS 3-4, and negative genetic panel. The mean basal nodular volume was 17.3 ± 10.7 mL.
Results
Considering the whole series, the mean volume reduction rate (VRR) was 36.8 ± 16.5% at 1 month, 59.9 ± 15.5% at 6 months, and 62 ± 15.7% at 1-year follow-up. The sub-analysis done in patients with 1 and 2 years follow-up data available (n = 20 and n = 5, respectively) confirmed a progressive nodular volume decrease. At all-time points, the rate of reduction was statistically significant (P < 0.0001), without significant correlation between the VRR and the basal volume. Neither cytological changes nor complications were observed after the procedure.
Conclusion
RFA is effective in Bethesda III, oncogene-negative nodules, with reduction rates similar to those obtained in confirmed benign lesions. This procedure represents a good alternative to surgery or active surveillance in this particular class of nodules, regardless of their initial volume. A longer follow-up will allow to evaluate further reduction or possible regrowth.
Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
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Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
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Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
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Department of Endocrinology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Department of Endocrinology and Diabetes Care and Prevention Unit, IRCCS Sant’Orsola-Malpighi Polyclinic, Bologna, Italy
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Department of Endocrinology and Diabetes Care and Prevention Unit, IRCCS Sant’Orsola-Malpighi Polyclinic, Bologna, Italy
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Department of Endocrinology and Diabetes Care and Prevention Unit, IRCCS Sant’Orsola-Malpighi Polyclinic, Bologna, Italy
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Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
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Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
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Objective
Many cases of subacute thyroiditis (SAT) have been described related to SARS-CoV-2 infection, but no prospective data about follow-up are known. This prospective, longitudinal, 3-year, multicentre study aims to explore the clinical peculiarities and outcome of SAT in relation to SARS-CoV-2 infection, ascertained with antibody dosage.
Methods
All patients receiving SAT diagnosis from November 2020 to May 2022 were enrolled. Data on anamnesis, physical examination, blood tests (TSH, freeT4, freeT3, thyroglobulin, anti-thyroid antibodies, C-reactive protein, erythrocyte sedimentation rate, complete blood count), and thyroid ultrasound were collected. At baseline, the presence of IgG against the SARS-CoV-2 spike protein or nucleocapsid was investigated. Patients were evaluated after 1, 3, 6, and 12 months.
Results
Sixty-six subjects were enrolled. At baseline, 54 presented with pain, 36 (67%) for at least 15 days. Serum SARS-CoV-2 IgG measurements documented that 7 out of 52 subjects (13.5%) had infection before SAT diagnosis (COVID+). No significant differences between the COVID+ and COVID− groups were found at baseline, except for respiratory symptoms and fever, which were more common in COVID+ (P = 0.039 and P = 0.021, respectively). Among the 41 subjects who completed follow-up, COVID+ and COVID− did not differ for therapeutic approach to SAT or outcome, all having an improvement in neck pain, inflammation parameters, and ultrasound features.
Conclusion
This is the first prospective study investigating any difference both at diagnosis and at follow-up between SAT presentation in patients with previous SARS-CoV-2 infection and those without. Our data demonstrate that SARS-CoV-2 does not impact on SAT onset, evolution, and outcome.
Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
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Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands
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Amsterdam Public Health Research Institute, Amsterdam UMC, The Netherlands
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Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
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Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
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Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands
Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC Location Vrije Universiteit Amsterdam, Boelelaan, Amsterdam, The Netherlands
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Laboratory Specialized Diagnostics & Research, Department of Laboratory Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
Amsterdam Public Health Research Institute, Meibergdreef, Amsterdam, The Netherlands
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Background
Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up recommendations.
Methods
Following the PRISMA guidelines, we searched PubMed, Embase, and guideline-specific databases and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument.
Results
Of the 2624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from 3 to 12 months.
Conclusion
This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There isa need for clear recommendations in guidelines considering diagnostic workup, treatment, and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Objective
Maternal thyroid autoimmunity and thyroid function in early pregnancy may impact fetal neurodevelopment. We aimed to investigate how thyroid autoimmunity and thyroid function in early pregnancy were associated with language acquisition in offspring at 12–36 months of age.
Methods
This study was embedded in the prospective Odense child cohort. Mother–child dyads were excluded in case of maternal intake of thyroid medication during pregnancy. The parents completed MacArthur–Bates Communicative Development Inventories (MB-CDI) every third month to assess their offspring’s productive vocabulary. All completed reports for each child were included in the analyses. Logistic growth curve models evaluated associations between MB-CDI scores and levels of maternal thyroid peroxidase antibodies (TPOAb), free thyroxine (FT4), and thyrotropin, respectively, measured in early pregnancy (median gestational week 12). All models were stratified by offspring sex and adjusted for maternal age, education, pre-pregnancy body mass index, parity, breastfeeding, and offspring age.
Results
The study included 735 mother–child dyads. Children born to mothers with TPOAb ≥11 kIU/L, opposed to TPOAb <11 kIU/L, had a lower probability of producing words at age 18–36 months for girls (OR = 0.78, P < 0.001) and 33–36 months for boys (OR = 0.83, P < 0.001). The probability of producing words was higher in girls at 30–36 months of age with low-normal maternal FT4 vs high-normal FT4 (OR = 0.60, P < 0.001), and a similar trend was seen in boys. Results were ambiguous for thyrotropin.
Conclusion
In women without known thyroid disease, TPOAb positivity in early pregnancy was negatively associated with productive vocabulary acquisition in girls and boys. This association was not mediated by a decreased thyroid function, as low-normal maternal FT4, unexpectedly, indicated better vocabulary acquisition. Our results support that maternal thyroid autoimmunity per se may affect fetal neurodevelopment.
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Center for Interdisciplinary Research on Medicines (C.I.R.M.), University of Liege (ULiège), CHU (B35), Liege, Belgium
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Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Center for Interdisciplinary Research on Medicines (C.I.R.M.), University of Liege (ULiège), CHU (B35), Liege, Belgium
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Center for Interdisciplinary Research on Medicines (C.I.R.M.), University of Liege (ULiège), CHU (B35), Liege, Belgium
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Objective
The aim was to evaluate the possible association between some endocrine disruptive chemicals and thyroid cancer (TC) in an Italian case–control cohort.
Methods
We enrolled 112 TC patients and 112 sex- and age-matched controls without known thyroid diseases. Per- and poly-fluoroalkyl substances (PFAS), poly-chlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (4,4′-DDT and 4,4′-DDE) were measured in the serum by liquid or gas chromatography–mass spectrometry. Unconditional logistic regression, Bayesan kernel machine regression and weighted quantile sum models were used to estimate the association between TC and pollutants’ levels, considered individually or as mixture. BRAF V600E mutation was assessed by standard methods.
Results
The detection of perfluorodecanoic acid (PFDA) was positively correlated to TC (OR = 2.03, 95% CI: 1.10–3.75, P = 0.02), while a negative association was found with perfluorohexanesulfonic acid (PFHxS) levels (OR = 0.63, 95% CI: 0.41–0.98, P = 0.04). Moreover, perfluorononanoic acid (PFNA) was positively associated with the presence of thyroiditis, while PFHxS and perfluorooctane sulfonic acid (PFOS) with higher levels of presurgical thyroid-stimulating hormone (TSH). PFHxS, PFOS, PFNA, and PFDA were correlated with less aggressive TC, while poly-chlorinated biphenyls (PCB-105 and PCB-118) with larger and more aggressive tumors. Statistical models showed a negative association between pollutants’ mixture and TC. BRAF V600E mutations were associated with PCB-153, PCB-138, and PCB-180.
Conclusion
Our study suggests, for the first time in a case–control population, that exposure to some PFAS and PCBs associates with TC and some clinical and molecular features. On the contrary, an inverse correlation was found with both PFHxS and pollutants’ mixture, likely due to a potential reverse causality.
Endocrinology Unit, Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Ophthalmology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Department of Specialistic Surgical Sciences, Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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National Institute of Molecular Genetics (INGM) “Romeo and Enrica Invernizzi”, Milan, Italy
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Introduction
Secondary thyroid autoimmunity, especially Graves’ disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment.
Case presentation
A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy.
Conclusion
RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.
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Global warming is now universally acknowledged as being responsible for dramatic climate changes with rising sea levels, unprecedented temperatures, resulting fires and threatened widespread species loss. While these effects are extremely damaging, threatening the future of life on our planet, one unexpected and paradoxically beneficial consequence could be a significant contribution to global iodine supply. Climate change and associated global warming are not the primary causes of increased iodine supply, which results from the reaction of ozone (O3) arising from both natural and anthropogenic pollution sources with iodide (I−) present in the oceans and in seaweeds (macro- and microalgae) in coastal waters, producing gaseous iodine (I2). The reaction serves as negative feedback, serving a dual purpose, both diminishing ozone pollution in the lower atmosphere and thereby increasing I2. The potential of this I2 to significantly contribute to human iodine intake is examined in the context of I2 released in a seaweed-abundant coastal area. The bioavailability of the generated I2 offers a long-term possibility of increasing global iodine status and thereby promoting thyroidal health. It is hoped that highlighting possible changes in iodine bioavailability might encourage the health community to address this issue.
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Atrial fibrillation (AF) is a common condition with a global estimated prevalence of 60 million cases, and the most common cardiac complication of hyperthyroidism, occurring in 5–15% of overtly hyperthyroid patients. Additionally, subclinical hyperthyroidism and high-normal free T4 have been associated with an increased risk in the development of AF. Hyperthyroidism-related AF is a reversible cause of AF, and the majority of patients spontaneously revert to sinus rhythm in 4–6 months during or after restoration of euthyroidism. Therefore, restoring thyroid function is an indispensable element in hyperthyroidism-related AF management. Rate control with beta-blockers consists another first-line therapy, reserving rhythm control in cases of persistent hyperthyroidism-related AF. It is still controversial whether hyperthyroidism is an independent risk factor of stroke in nonvalvular AF. As a result, initiating anticoagulation should be guided by the clinical thromboembolic risk score CHA2DS2-VASc score in the same way it is applied in patients with non-hyperthyroidism-related AF. Treatment with the novel direct oral anticoagulants appears to be as beneficial and may be safer than warfarin in patients with hyperthyroidism-related AF. In this review, we address the epidemiology, prognosis, and diagnosis of hyperthyroidism-related AF, and we discuss the management strategies and controversies in patients with hyperthyroidism-related AF.
