Jacqueline Jonklaas, Antonio C. Bianco, Andrew J. Bauer, Kenneth D. Burman, Anne R. Cappola, Francesco S. Celi, David S. Cooper, Brian W. Kim, Robin P. Peeters, M. Sara Rosenthal, and Anna M. Sawka THYROID 24 (12), 2014


Background: A number of recent advances in our understanding of thyroid physiology may shed light on whysome patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to reviewthe goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sourcesof dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowl-edge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies toprovide reason to pursue such therapies and change the current standard of care. This document is intended toinform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for indi-vidualized clinical judgment.

Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinicalliterature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, withrelated mechanistic and bench research literature reviews, performed by our team of translational scientists.Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, whenpossible, in the form of a formal clinical recommendation statement. When responses were not suitable for aformal clinical recommendation, a summary response statement without a formal clinical recommendation wasdeveloped. For clinical recommendations, the supporting evidence was appraised, and the strength of theclinical recommendations was assessed, using the American College of Physicians system. The final documentwas organized so that each topic is introduced with a question, followed by a formal clinical recommendation.Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questionsaddressed in the document. Consensus was achieved for all recommendations by the task force.

Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non–levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category includedthyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.

Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism.We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine–liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, inimproving health outcomes. Some examples of future research needs include the development of superior bio-markers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potentialtherapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (in-cluding subgroup effects) Additional research is also needed to develop thyroid hormone analogs with a favorablebenefit to risk profile.

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