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  • Author: Lars C. Moeller x
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Denise Zwanziger Department of Endocrinology and Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany

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Helena Rakov Department of Endocrinology and Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany

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Kathrin Engels Department of Endocrinology and Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany

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Lars C. Moeller Department of Endocrinology and Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany

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Dagmar Führer Department of Endocrinology and Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany

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Background: In the liver the tight junction protein claudin-1 plays an important role in bile secretion by maintaining the paracellular barrier of bile canaliculi and the bile duct. A diminished bile excretion has been found in hypothyroid patients, and the prevalence of gallstones is increased in hypothyroidism. This association, however, only applies for men and is in contrast to the well-established female preponderance of biliary disease in the general population. Objectives: We hypothesized that hypothyroidism could lead to altered claudin-1 expression in the liver, and that this effect may be sex specific. Methods: We characterized claudin-1 expression and localization in livers of euthyroid and hypothyroid male and female C57BL/6NTac mice by real-time PCR, Western blot and immunofluorescence. Results: Claudin-1 is expressed in canalicular regions and the bile ducts of the murine liver. Livers of female mice showed lower claudin-1 expression than male livers. In hypothyroid livers, female animals showed an elevated claudin-1 expression, whereas reduced claudin-1 expression was found in male animals compared to the euthyroid controls. Conclusion: We demonstrate a correlation between claudin-1 expression and hypothyroidism in the murine liver. Furthermore, a sex-dependent alteration of claudin-1 expression was found.

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Theodora Pappa Departments of Medicine, Chicago, IL, USA

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Lars C. Moeller Department of Endocrinology and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Deborah V. Edidin Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA

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Silvana Pannain Departments of Medicine, Chicago, IL, USA

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Samuel Refetoff Departments of Medicine, Chicago, IL, USA
Departments of Pediatrics, Chicago, IL, USA
Departments of Committee on Genetics, The University of Chicago, Chicago, IL, USA

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Background: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). Objective: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. Methods: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T<sub>4</sub>. Although her serum TSH normalized, her serum T<sub>4</sub> remained low. Affected family members had low total T<sub>4</sub> and T<sub>3</sub>, but a normal free T<sub>4</sub> index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T<sub>4</sub> and T<sub>3</sub>. His brother had a similar thyroid phenotype. Results: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T<sub>4</sub>. Conclusions: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T<sub>4</sub> resulting in low serum T<sub>4</sub>. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

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Kathrin Engels Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany

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Helena Rakov Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany

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Denise Zwanziger Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany

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Lars C. Moeller Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany

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Georg Homuth Department of Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany

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Josef Köhrle Institute of Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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Klaudia Brix Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany

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Dagmar Führer Department of Endocrinology and Metabolism, University Hospital Essen, Essen, Germany

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Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight <smlcap>L</smlcap>-thyroxine (T<sub>4</sub>) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T<sub>4</sub> (fT<sub>4</sub>) concentrations were significantly higher in euthyroid young compared to old mice. T<sub>4</sub> treatment increased total T<sub>4</sub>, fT<sub>4</sub> and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ.

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

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Yaw Appiagyei-Dankah Medical University of South Carolina, Charleston, S.C., USA

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Birgit Köhler Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

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Heike Biebermann Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

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Onno E. Janssen Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Dagmar Führer Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Background: Thyroxine-binding globulin (TBG) is the main transport protein for T<sub>4</sub> in blood. Until now, 22 mutations leading to complete TBG deficiency (TBG-CD) have been reported. Objective: We report two mutations associated with TBG-CD found in patients from Andrews, S.C., USA (TBG-CD-Andrews), and Berlin, Germany (TBG-CD-Berlin). Methods: Automated chemiluminescence immunoassays were used for the determination of TSH, free and total T<sub>4</sub> and T<sub>3</sub> (fT<sub>4</sub>, TT<sub>4</sub>, TT<sub>3</sub>) and TBG. Direct DNA sequencing was used to identify the TBG mutations in the propositi. Results: TBG-CD-Andrews was found in a 1-month-old boy who was euthyroid with normal TSH and fT<sub>4</sub>, but reduced TT<sub>4</sub>, indicating TBG deficiency. TBG was not detectable, confirming TBG-CD. No mutation in the coding region and the promoter of the TBG gene was found, but a single nucleotide substitution in intron 1 disrupts the donor splice site of exon 0 (IVS1+2T>C). Another mutation was found in an 11-year-old boy. He was also euthyroid with normal fT<sub>4</sub> and TSH. However, TT<sub>4</sub> and TT<sub>3</sub> were low, suggesting TBG-CD. Sequencing revealed a 79-nucleotide deletion, ranging from intron 3 into exon 3. Conclusion: We report two novel mutations of the TBG gene associated with TBG-CD. Whereas most TBG-CDs are caused by small deletions, in TBG-CD-Andrews the disruption of a donor splice site was detected, whilst in TBG-CD-Berlin the largest deletion in the Serpina7 gene to date was found.

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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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Kerstin Krause Division of Endocrinology and Nephrology, Department of Medicine, Germany

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Juliane Weiner Division of Endocrinology and Nephrology, Department of Medicine, Germany

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Sebastian Hönes Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Nora Klöting Division of Endocrinology and Nephrology, Department of Medicine, Germany
IFB Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany

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Eddy Rijntjes Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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John T. Heiker Division of Endocrinology and Nephrology, Department of Medicine, Germany

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Claudia Gebhardt Division of Endocrinology and Nephrology, Department of Medicine, Germany

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Josef Köhrle Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany

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Dagmar Führer Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany

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Karen Steinhoff Department of Nuclear Medicine, University of Leipzig, Germany

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Swen Hesse Department of Nuclear Medicine, University of Leipzig, Germany
IFB Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany

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

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Anke Tönjes Division of Endocrinology and Nephrology, Department of Medicine, Germany

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Background: Thyroid hormones (TH) exert pleiotropic effects on glucose and lipid homeostasis. However, it is as yet unclear how TH regulate lipid storage and utilization in order to adapt to metabolic needs. Acyl-CoA thioesterases (ACOTs) have been proposed to play a regulatory role in the metabolism of fatty acids. Objectives: We investigated the interaction between thyroid dysfunction and Acot expression in adipose tissues and livers of thyrotoxic and hypothyroid mice. Methods: Ten-week-old female C57BL/6NTac mice (n = 10/group) were made hyperthyroid by the application of <smlcap>L</smlcap>-thyroxine (2 µg/ml in drinking water) for 4 weeks. Hypothyroidism was induced in 10-week-old mice by feeding an iodine-free chow supplemented with 0.15% PTU for 4 weeks. We measured mRNA expression levels of Acot8, 11 and 13 in the liver and epididymal and inguinal white and brown adipose tissues (BAT). Furthermore, we investigated hepatic Acot gene expression in TRα- and TRβ-deficient mice. Results: We showed that the expression of Acot8, 11 and 13 is predominantly stimulated by a thyrotoxic state in the epididymal white adipose tissue. In contrast, hypothyroidism predominantly induces the expression of Acot8 in BAT in comparison with BAT of thyrotoxic and euthyroid mice (p < 0.01). However, no significant changes in Acot expression were observed in inguinal white adipose tissue. In liver, Acot gene expression is collectively elicited by a thyrotoxic state. Conclusions: These data suggest that ACOTs are targets of TH and are likely to influence 3,5,3′-triiodo-<smlcap>L</smlcap>-thyronine-orchestrated mechanisms of lipid uptake, storage and utilization to adapt the regulation of metabolic demands.

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