Search Results

You are looking at 1 - 3 of 3 items for

  • Author: Heike Heuer x
Clear All Modify Search
Julia Müller Leibniz Institute for Age Research/Fritz Lipmann Institute, Jena, Germany

Search for other papers by Julia Müller in
Google Scholar
PubMed
Close
and
Heike Heuer Leibniz Institute for Age Research/Fritz Lipmann Institute, Jena, Germany

Search for other papers by Heike Heuer in
Google Scholar
PubMed
Close

Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain. In humans, inactivating mutations of the MCT8 gene (SLC16A2) are associated with severe forms of psychomotor retardation and abnormal TH serum levels (Allan-Herndon-Dudley syndrome). Surprisingly, Mct8 knockout (ko) mice do not exhibit overt neurological symptoms but fully replicate the unusual serum TH profile with highly increased serum T<sub>3</sub> in the presence of low serum T<sub>4</sub>. In order to evaluate the underlying mechanisms for these abnormalities, TH transport and metabolism have been intensively studied in different tissues of Mct8 ko mice. Here, we summarize the observed changes within the hypothalamus-pituitary-thyroid axis that result in altered TH production and secretion. Although analysis of Mct8 ko mice has greatly expanded our knowledge, many open questions still remain to be addressed in order to define the tissue- and cell-specific role of this important TH transporter.

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

Search for other papers by Jacqueline Jonklaas in
Google Scholar
PubMed
Close
,
Antonio C. Bianco Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, Illinois, USA

Search for other papers by Antonio C. Bianco in
Google Scholar
PubMed
Close
,
Anne R. Cappola Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Search for other papers by Anne R. Cappola in
Google Scholar
PubMed
Close
,
Francesco S. Celi Division of Endocrinology, Diabetes and Metabolism, Virginia Commonwealth University, Richmond, Virginia, USA

Search for other papers by Francesco S. Celi in
Google Scholar
PubMed
Close
,
Eric Fliers Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center, Amsterdam, The Netherlands

Search for other papers by Eric Fliers in
Google Scholar
PubMed
Close
,
Heike Heuer Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

Search for other papers by Heike Heuer in
Google Scholar
PubMed
Close
,
Elizabeth A. McAninch Division of Endocrinology, Rush University, Chicago, Illinois, USA

Search for other papers by Elizabeth A. McAninch in
Google Scholar
PubMed
Close
,
Lars C. Moeller Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

Search for other papers by Lars C. Moeller in
Google Scholar
PubMed
Close
,
Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

Search for other papers by Birte Nygaard in
Google Scholar
PubMed
Close
,
Anna M. Sawka Division of Endocrinology, University Health Network and University of Toronto, Toronto, Ontario, Canada

Search for other papers by Anna M. Sawka in
Google Scholar
PubMed
Close
,
Torquil Watt Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

Search for other papers by Torquil Watt in
Google Scholar
PubMed
Close
, and
Colin M. Dayan Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

Search for other papers by Colin M. Dayan in
Google Scholar
PubMed
Close

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.

Free access
Kathrin A. Schmohl Department of Internal Medicine II, Germany

Search for other papers by Kathrin A. Schmohl in
Google Scholar
PubMed
Close
,
Andrea M. Müller Department of Internal Medicine II, Germany

Search for other papers by Andrea M. Müller in
Google Scholar
PubMed
Close
,
Nathalie Schwenk Department of Internal Medicine II, Germany

Search for other papers by Nathalie Schwenk in
Google Scholar
PubMed
Close
,
Kerstin Knoop Department of Internal Medicine II, Germany

Search for other papers by Kerstin Knoop in
Google Scholar
PubMed
Close
,
Eddy Rijntjes Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Eddy Rijntjes in
Google Scholar
PubMed
Close
,
Josef Köhrle Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Josef Köhrle in
Google Scholar
PubMed
Close
,
Heike Heuer Leibniz Institute for Environmental Medicine, Düsseldorf, Germany

Search for other papers by Heike Heuer in
Google Scholar
PubMed
Close
,
Peter Bartenstein Department of Nuclear Medicine, Germany

Search for other papers by Peter Bartenstein in
Google Scholar
PubMed
Close
,
Burkhard Göke Department of Internal Medicine II, Germany

Search for other papers by Burkhard Göke in
Google Scholar
PubMed
Close
,
Peter J. Nelson Medical Policlinic IV, University Hospital of Munich, Munich, Germany

Search for other papers by Peter J. Nelson in
Google Scholar
PubMed
Close
, and
Christine Spitzweg Department of Internal Medicine II, Germany

Search for other papers by Christine Spitzweg in
Google Scholar
PubMed
Close

Due to the high variance in available protocols on iodide-131 (<sup>131</sup>I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of <sup>131</sup>I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T<sub>4</sub> concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and <sup>99m</sup>Tc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) <sup>131</sup>I alone was not sufficient to abolish thyroidal T<sub>4</sub> production, 500 µCi (18.5 MBq) <sup>131</sup>I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high <sup>131</sup>I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) <sup>131</sup>I decreased serum T<sub>4</sub> concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. <sup>99m</sup>Tc-pertechnetate scintigraphy revealed absence of thyroidal <sup>99m</sup>Tc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene.

Free access