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Zhi Zhang Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Anita Boelen Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Andries Kalsbeek Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Thyroid hormone (TH) plays a key role in regulating body temperature in mammals. Cold exposure stimulates the hypothalamus-pituitary-thyroid (HPT) axis at the hypothalamic level by activating hypophysiotropic thyrotropin-releasing hormone (TRH)-producing neurons, ultimately resulting in increased plasma TH concentrations. Importantly, the local TH metabolism within various cold-responsive organs enables tissue-specific action of TH on heat production and adaption to cold independently of the circulating TH levels. In addition to these neuroendocrine effects, TRH neurons in the hypothalamus also have neural connections with brown adipose tissue (BAT), probably contributing to regulation of thermogenesis by the autonomic nervous system. Recent studies have demonstrated that intrahypothalamic TH has profound metabolic effects on BAT, the liver, and the heart that are mediated via the autonomic nervous system. These effects originate in various hypothalamic nuclei, including the paraventricular nucleus (PVN), the ventromedial nucleus, and recently reported neurons in the anterior hypothalamic area, indicating a potential central function for TH on thermoregulation. Finally, although robust stimulation of the thermogenic program in BAT was shown upon TH administration in the ventromedial hypothalamus, the physiological relevance of these neurally mediated effects of TH is unclear at present. This review provides an overview of studies reporting the role of TH in cold defense, with a focus on recent literature evidencing the centrally mediated effects of TRH and TH.

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands

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Barbara Demeneix Evolution des Régulations Endocriniennes, Département “Adaptation du Vivant”, UMR 7221 Muséum National d’Histoire Naturelle/CNRS, Paris, France

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Ashok Bhaseen , Montreal, Québec, Canada

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Thomas H. Brix Department of Endocrinology and Metabolism, Odense University Hospital, Odense C, Denmark

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Several European countries have seen major health issues after a switch from one levothyroxine brand to another, as well as following the introduction of several levothyroxine formulation changes. While the relationship between these health issues and brand or formulation changes merits further investigation, the current position statement on behalf of both health-care providers and patients summarizes recent events in several European countries and provides a number of recommendations to limit the burden for patients, so as to prevent increased health-care consumption and health-care expenses in this context.

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Christiaan F. Mooij Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Nitash Zwaveling-Soonawala Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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A.S. Paul van Trotsenburg Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Yalan Hu Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands

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Kim Falize Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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A S Paul van Trotsenburg Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands

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Raoul Hennekam Department of Pediatrics, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Eric Fliers Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Eveline Bruinstroop Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Anita Boelen Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands

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Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.

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Luca Persani Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Georg Brabant Experimental and Clinical Endocrinology Medical Clinic I – University of Lübeck, Lübeck, Germany

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Mehul Dattani Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London, United Kingdom

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Marco Bonomi Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Ulla Feldt-Rasmussen Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

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Eric Fliers Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Annette Gruters Department for Pediatric Endocrinology and Diabetes, Charité University Medicine, Berlin, Germany
University Hospital Heidelberg, Heidelberg, Germany

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Dominique Maiter Department of Endocrinology and Nutrition, UCL Cliniques Saint-Luc, Brussels, Belgium

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Nadia Schoenmakers University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, United Kingdom

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A.S. Paul van Trotsenburg Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Objectives: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. Study Design: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH. Results: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years). Conclusions: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.

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Jacqueline Jonklaas Division of Endocrinology, Georgetown University, Washington, District of Columbia, USA

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Antonio C. Bianco Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, Illinois, USA

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Anne R. Cappola Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Francesco S. Celi Division of Endocrinology, Diabetes and Metabolism, Virginia Commonwealth University, Richmond, Virginia, USA

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center, Amsterdam, The Netherlands

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Heike Heuer Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Elizabeth A. McAninch Division of Endocrinology, Rush University, Chicago, Illinois, USA

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Lars C. Moeller Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Anna M. Sawka Division of Endocrinology, University Health Network and University of Toronto, Toronto, Ontario, Canada

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Torquil Watt Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

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Colin M. Dayan Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

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Laura P.B. Elbers Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam
Departments of Vascular Medicine, University of Amsterdam, Amsterdam

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Hjalmar A. Boon Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam

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Maaike I. Moes Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam

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Bregje van Zaane Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam
Departments of Vascular Medicine, University of Amsterdam, Amsterdam

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Dees P.M. Brandjes Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam
Departments of Vascular Medicine, University of Amsterdam, Amsterdam

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Eric Fliers Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam

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Harry R. Büller Departments of Vascular Medicine, University of Amsterdam, Amsterdam

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Suzanne Cannegieter Department of Clinical Epidemiology, Leiden University Medical Center
Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Victor E.A. Gerdes Department of Internal Medicine, Medical Center Slotervaart, University of Amsterdam, Amsterdam
Departments of Vascular Medicine, University of Amsterdam, Amsterdam

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Background: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT<sub>4</sub>) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT<sub>4</sub> within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. Methods: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1:4. We evaluated the association between preoperative FT<sub>4</sub> levels and the risk of major bleeding by logistic regression. Results: Seventy-two cases (2.5%) with major bleeding were identified and 288 controls were selected. The median plasma level of FT<sub>4</sub> was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT<sub>4</sub> on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT<sub>4</sub> level <11 pmol/l, 1.03 (0.49-2.18) for patients with an FT<sub>4</sub> level <12 pmol/l, and 1.12 (0.65-1.94) for patients with an FT<sub>4</sub> level <13 pmol/l as compared to patients with FT<sub>4</sub> values greater than or equal to these cutoff levels. Interpretation: We did not observe an increased risk of major bleeding with low levels of FT<sub>4</sub> in patients undergoing bariatric surgery.

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