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      2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism

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          Abstract

          Background

          Data suggest symptoms of hypothyroidism persist in 5–10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area.

          Methods

          Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large.

          Results

          Suggested explanations for persisting symptoms include: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.

          Conclusion

          L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

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          Most cited references83

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          Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

          The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.
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            Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.

            Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This article describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspeciality physicians and others providing care for patients with this condition. The development of these guidelines was commissioned by the American Thyroid Association in association with the American Association of Clinical Endocrinologists. The American Thyroid Association and American Association of Clinical Endocrinologists assembled a task force of expert clinicians who authored this report. The task force examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to develop the text and a series of specific recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' ophthalmopathy; and management of other miscellaneous causes of thyrotoxicosis. One hundred evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
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              Grading strength of recommendations and quality of evidence in clinical guidelines: report from an american college of chest physicians task force.

              While grading the strength of recommendations and the quality of underlying evidence enhances the usefulness of clinical guidelines, the profusion of guideline grading systems undermines the value of the grading exercise. An American College of Chest Physicians (ACCP) task force formulated the criteria for a grading system to be utilized in all ACCP guidelines that included simplicity and transparency, explicitness of methodology, and consistency with current methodological approaches to the grading process. The working group examined currently available systems, and ultimately modified an approach formulated by the international GRADE group. The grading scheme classifies recommendations as strong (grade 1) or weak (grade 2), according to the balance among benefits, risks, burdens, and possibly cost, and the degree of confidence in estimates of benefits, risks, and burdens. The system classifies quality of evidence as high (grade A), moderate (grade B), or low (grade C) according to factors that include the study design, the consistency of the results, and the directness of the evidence. For all future ACCP guidelines, The College has adopted a simple, transparent approach to grading recommendations that is consistent with current developments in the field. The trend toward uniformity of approaches to grading will enhance the usefulness of practice guidelines for clinicians.

                Author and article information

                Journal
                Eur Thyroid J
                Eur Thyroid J
                ETJ
                European Thyroid Journal
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch )
                2235-0640
                2235-0802
                July 2012
                13 June 2012
                13 June 2012
                : 1
                : 2
                : 55-71
                Affiliations
                [1] aDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
                [2] bEndocrine Unit, Evgenidion Hospital, University of Athens Medical School, Athens, Greece
                [3] cFederal Endocrinological Scientific Center, Moscow, Russia
                [4] dDepartment of Endocrinology, Herlev Hospital, Herlev, Denmark
                [5] eDepartment of Endocrinology, Royal Free Hampstead NHS Trust, London, UK
                Author notes
                *Wilmar M. Wiersinga, Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL–1105 AZ Amsterdam (The Netherlands), E-Mail w.m.wiersinga@ 123456amc.uva.nl

                Authors represent the task force for these guidelines, instituted by the ETA Executive Committee and Guidelines Board.

                Article
                etj-0001-0055
                10.1159/000339444
                3821467
                24782999
                a21c8f85-ad35-49fe-8145-d3f282af069f
                Copyright © 2012 European Thyroid Association Published by S. Karger AG, Basel
                History
                : 30 March 2012
                : 7 May 2012
                Page count
                Tables: 6, References: 79, Pages: 17
                Categories
                Guidelines

                hypothyroidism,treatment,thyroxine,triiodothyronine,combination therapy,guidelines

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