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Jingyue Chen Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Chenyan Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Weiping Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Zhongyan Shan Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Jun Jin Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yining Wei Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Jing Sun Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yushu Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Huifang Zhou Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Objective

The management of thyroid eye disease (TED) has undergone significant changes for decades. The study sought to investigate current clinical practice on the management of TED in China.

Methods

An online questionnaire survey was conducted from April to May 2023. The questionnaire involved diagnostic criteria for TED, multidisciplinary treatment (MDT) collaboration, and treatment preference for mild, moderate, and severe TED.

Results

A total of 289 questionnaires were collected, with 165 from endocrinologists and 124 from ophthalmologists. Only 36.7% of participants claimed there was an MDT clinical pattern for TED in their institutions. The coverage of biological agents was around 10% or lower. These were distinctly lower than in Western countries. About 62.6% of participants believed the incidence of TED has increased in recent years. Imaging techniques were used widely to assist in the diagnosis of TED. However, there was still controversy regarding the definition of proptosis in the Chinese population. Most doctors managed risk factors and provided orbital supportive treatments of artificial tears and glasses. For mild active TED, endocrinologists (39.4%) were inclined to recommend therapy for hyperthyroidism alone, while ophthalmologists (43.6%) preferred orbital corticosteroid injections. Currently, the most widely used treatment for moderate to severe active TED was high-dose intravenous corticosteroid (94.8%), while orbital radiotherapy combined with immunosuppressive agents was the most recognized second-line therapy (43.6%).

Conclusion

The study documented the consistency and differences between current clinical practices in the management of TED in China and the recently updated guidelines. There was a remarkable difference between ophthalmology and endocrinology departments, warranting management optimization.

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Line Tang Møllehave Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Nils Knudsen Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Allan Linneberg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Inge Bülow Pedersen Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Gitte Ravn-Haren Research Group for Risk Benefit, National Food Institute, Technical University of Denmark, Lyngby, Denmark

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Anja Lykke Madsen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Allan Carlé Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Charlotte Cerqueira The Danish Clinical Quality Program – National Clinical Registries (RKKP), Denmark

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Anne Krejbjerg Department of Oncology, Aalborg University Hospital, Aalborg, Denmark

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Lone Banke Rasmussen Independent researcher, Klemensker, Denmark

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Lars Ovesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Hans Perrild Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Lena Bjergved Sigurd Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Internal Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark

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Betina Heinsbæk Thuesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Pernille Vejbjerg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Torben Jørgensen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild–moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program – as IF – is initiated.

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Kenneth Ka Hei Lai K Lai, Department of Ophthalmology and Visual Sciences, PWH, Hong Kong, Hong Kong

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Fatema Mohamed Ali Abdulla Aljufairi F Aljufairi , Hong Kong, Hong Kong

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Jake Uy Sebastian J Sebastian , Department of Ophthalmology and Visual Sciences, PWH, Hong Kong, Hong Kong

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Yingying Wei Y Wei, Statistics, CUHK, Hong Kong, Hong Kong

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Ruofan Jia R Jia, Statistics, CUHK, Hong Kong, Hong Kong

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Karen Kar Wun Chan K Chan, Hong Kong, Hong Kong

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Elaine Yuen Ling Au E Au , Pathology, Queen Mary Hospital, Hong Kong, Hong Kong

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Alan Chun Hong Lee A Lee, Medicine , The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong

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Chiu Ming Ng C Ng, Medicine , Queen Elizabeth Hospital, Hong Kong, Hong Kong, Hong Kong

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Hunter Kwok Lai Yuen H Yuen , Department of Ophthalmology and Visual Sciences, Hong Kong Eye Hospital, Hong Kong, Hong Kong

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Wilson Wai Kuen Yip W Yip, Department of Ophthalmology and Visual Sciences, PWH, Hong Kong, Hong Kong

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Alvin Lerrmann Young A Young, Department of Ophthalmology and Visual Sciences, PWH, Hong Kong, Hong Kong

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George Pak Man Cheng G Cheng, Department of Ophthalmology and Visual Sciences, CUHK, Hong Kong, Hong Kong

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Clement Chee Yung Tham C Tham, Department of Ophthalmology and Visual Sciences, CUHK, Hong Kong, Hong Kong

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Chi Pui Pang C Pang, Department of Ophthalmology and Visual Sciences, CUHK, Hong Kong, Hong Kong

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Kelvin Kam Lung Chong K Chong, Department of Ophthalmology and Visual Sciences, CUHK, Hong Kong, Hong Kong

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Purpose:

This study aims to report correlations between thyroid-stimulating immunoglobulin(TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease(TED) patients.

Methods:

A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the clinical activity score(CAS), marginal reflex distance1(MRD1), extraocular muscle motility restriction(EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI.

Results:

A total of 255(197female) treatment-naïve patients, with an average onset age of 50±14 years, were included. Elevated pre-treatment TSI level was observed in 223(88%) patients. There was a weak positive correlation between TSI and CAS(r=0.28, P=0.000031), MRD1(r=0.17, P=0.0080), and the size of the levator palpebrae superioris/superior rectus complex(r=0.25, P=0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67(95% confidence interval:0.60-0.75) and 284%(Specificity:50%, sensitivity:85%). 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP(P=0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level(P<0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and non-responded to the first course of IVMP.

Conclusion:

TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be further warranted.

Open access
Ana Isabel Álvarez-Mancha Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, General University Hospital of Ciudad Real, Ciudad Real, Spain

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Isabel Mancha-Doblas Department of Medicine, University of Malaga, Malaga, Spain
Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain

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María Molina-Vega Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Diego Fernández-García Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain

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Ana María Gómez-Pérez Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Elena Gallego-Domínguez Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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María Victoria Ortega-Jiménez Department of Medicine, University of Malaga, Malaga, Spain
Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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Isabel Hierro-Martín Department of Pathology, Virgen de la Victoria University Hospital, Málaga, Spain

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Francisco J Tinahones Department of Medicine, University of Malaga, Malaga, Spain
Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain
The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA-BIONAND Platform), University of Malaga, Malaga, Spain

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Graphical abstract

Abstract

Objective

The objective of this study was to analyze the evolution in the diagnosis and management of indeterminate thyroid nodules over three time periods.

Methods

In total, 3020 patients with thyroid nodules underwent cytological evaluation during three periods (2006–2008, 2012–2014, 2017–2019). The distribution of diagnostic cytology, risk of malignancy, diagnostic performance indices of fine needle aspiration (FNA), and cytologic–histologic correlation in indeterminate cytology were analyzed.

Results

Only 2.2% of cytology tests were insufficient for a diagnosis. About 86.9% cytology was benign, 1.7% malignant, and 11.4% indeterminate. Indeterminate cytology rates were 15.9% (2006–2008), 10.1% (2012–2014), and 10% (2017–2019). Surgery was performed in 13% of benign cytology, resulting in malignant histology in 2.7%. All malignant and suspicious cytology underwent surgery, with malignancy confirmed in 98% and 77% of cases, respectively.

All ‘indeterminate with atypia’ cytology (2006–2008) and Bethesda IV (2012–2014; 2017–2019) underwent surgery, with malignancy confirmed in 19.6%, 43.8%, and 25.7%, respectively. In the ‘indeterminate without atypia’ category (2006–2008) and Bethesda III (2012–2014; 2017–2019), diagnostic surgery was performed in 57.7%, 78.6%, and 59.4%, respectively, with malignancy confirmed in 3.3%, 20.5%, and 31.6%. The FNA sensitivity was 91.6%, with a negative predictive value greater than 96% in all periods. The specificity exceeded 75% in the last two periods.

Conclusion

The Bethesda system reduces indeterminate cytology and improves the accuracy of FNA diagnosis. We reported a higher proportion of malignancy than expected in Bethesda III, underscoring the importance of having institution-specific data to guide decision-making. However, there is a need for risk stratification tools that allow for conservative management in low-risk cases.

Open access
Carla Colombo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Daniele Ceruti Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Massimiliano Succi Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Simone De Leo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy

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Matteo Trevisan Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Claudia Moneta Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Laura Fugazzola Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Background

Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI).

Aim

The objective was to assess the entire adrenal function in patients on systemic treatments.

Methods

ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases.

Results

After a median treatment period of 7 months, we observed an increase in ACTH values in 80–100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI.

Conclusion

Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Open access
Maria Mavromati Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Verdiana Caironi Department of Internal Medicine, Lugano Regional Hospital, Ente Ospedaliero Cantonale, Via Tesserete Lugano, Switzerland

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Essia Saiji Department of Pathology, Geneva University Hospitals, University of Geneva, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Maria-Isabel Vargas Department of Neuroradiology, Geneva University Hospitals, University of Geneva, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Shahan Momjian Department of Neurosurgery, Geneva University Hospitals, University of Geneva, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Stephanie Andrade-Lopes Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland

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Capucine Gubert Department of Internal Medicine, Geneva University Hospitals, University of Geneva, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland

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Marco Stefano Demarchi Department of Thoracic and Endocrine Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland

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Ismini Mainta Department of Nuclear Medicine, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland

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François R Jornayvaz Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Kaveh Samii Department of Hematology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Grégoire Stalder Service and Central Laboratory of Hematology, Lausanne University Hospital, rue du Bugnon Lausanne, Switzerland.
Service of Hematology and Laboratory of Hematology, Institut Central des Hôpitaux, Hôpital du Valais, Av. du Grand-Champsec, Sion, Switzerland

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Sophie Leboulleux Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, Geneva, Switzerland
University of Geneva, Faculty of Medicine, Rue Michel Servet, Geneva, Switzerland

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Langerhans cell histiocytosis (LCH) may present as unifocal disease of the suprasellar region, with symptoms and signs of hypopituitarism, arginine vasopressin deficiency (AVP-D), and weight gain. Transcranial biopsy is necessary to define diagnosis and guide treatment decisions, but it is associated with significant morbidity. We describe a patient with Hashimoto thyroiditis and a single hypothalamic mass in whom LCH diagnosis was made by thyroid fine-needle aspiration cytology (FNAC) performed despite nonspecific findings in thyroid imaging, on the basis of a slightly elevated [18F]-fluorodeoxyglucose (FDG) avidity on PET/CT and volume increase during follow-up.

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Sophie Demartin Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Stefan Matei Constantinescu Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Kris G Poppe Endocrine Unit, Centre Hospitalier Universitaire Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Dominique Maiter Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Raluca Maria Furnica Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Orsalia Alexopoulou Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Chantal Daumerie Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Frederic Debiève Department of Obstetrics, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Maria-Cristina Burlacu Department of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

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Background

Current guidelines recommend different postpartum approaches for patients started on levothyroxine (LT4) during pregnancy.

Objective

We studied the postpartum management of these patients and determined factors associated with long-term hypothyroidism.

Methods

A retrospective study was conducted at a tertiary center between 2014 and 2020, with LT4 initiation according to 2014 ETA recommendations. We performed multivariate logistic regression (MVR) and a receiver operating characteristic curve analysis to determine variables associated with long-term hypothyroidism and their optimal cutoffs.

Results

LT4 was initiated in 177 pregnant women, and 106/177 (60%) were followed at long-term (at least 6 months post partum) (28.5 (9.0–81.9) months). LT4 could have been stopped in 45% of patients who continued it immediately after delivery. Thirty-six out of 106 (34%) patients were long-term hypothyroid. In them, LT4 was initiated earlier during pregnancy than in euthyroid women (11.7 ± 4.7 vs 13.7 ± 6.5 weeks, P = 0.077), at a higher thyroid-stimulating hormone (TSH) level (4.1 (2.2–10.1) vs 3.5 (0.9–6.9) mU/L, P = 0.005), and reached a higher dose during pregnancy (62.8 ± 22.2 vs 50.7 ± 13.9 µg/day, P = 0.005). In the MVR, only the maximal LT4 dose during pregnancy was associated with long-term hypothyroidism (odds ratio (OR) = 1.03, 95% CI: 1.00–1.05, P = 0.003). The optimal cutoffs for predicting long-term hypothyroidism were an LT4 dose of 68.75 µg/day (87% specificity, 42% sensitivity; P = 0.013) and a TSH level ≥ 3.8 mU/L (68.5% specificity, 77% sensitivity; P = 0.019).

Conclusion

One-third of the patients who started on LT4 during pregnancy had long-term hypothyroidism. The TSH level at treatment initiation and the LT4 dose during pregnancy could guide the decision for continuing long-term LT4.

Open access
Véronique Raverot Hospices Civils de Lyon, Groupement Hospitalier Est, LBMMS, Centre de biologie et de pathologie Est, Lyon, France

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Stéphanie Metrat Hospices Civils de Lyon, Groupement Hospitalier Est, LBMMS, Centre de biologie et de pathologie Est, Lyon, France

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Pauline Perrin Hospices Civils de Lyon, Groupement Hospitalier Est, LBMMS, Centre de biologie et de pathologie Est, Lyon, France

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Juliette Abeillon Hospices Civils de Lyon, Groupement Hospitalier Est, Fédération d’Endocrinologie, Lyon, France

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Hélène Lasolle Hospices Civils de Lyon, Groupement Hospitalier Est, Fédération d’Endocrinologie, Lyon, France

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MacroTSH still interferes with TSH assays. We present here a case report illustrating the difficulties that can arise in such conditions and attempt to discuss the steps involved in diagnosis.

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Sara Monteiro-Martins Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany

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Rosalie B T M Sterenborg Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Oleg Borisov Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany

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Nora Scherer Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany
Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany

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Yurong Cheng Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany

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Marco Medici Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Anna Köttgen Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

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Alexander Teumer Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
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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Abdul Rehman Syed University of Calgary, Calgary, Alberta, Canada

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Aakash Gorana Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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Erik Nohr Alberta Precision Laboratories, Molecular Pathology Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Xiaoli-Kat Yuan Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Parthiv Amin MASc Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada

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Sana Ghaznavi Arnie Charbonneau Cancer Institute, Department of Medicine, Section of Endocrinology, University of Calgary, Calgary, Alberta, Canada

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Debbie Lamb Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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John McIntyre Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Markus Eszlinger Department of Oncology, Cumming School of Medicine, and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada

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Ralf Paschke Departments of Medicine, Section of Endocrinology, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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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.

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