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Combination L-T3 and L-T4 therapy for hypothyroidism

Wartofsky, Leonard

Current Opinion in Endocrinology & Diabetes and Obesity: October 2013 - Volume 20 - Issue 5 - p 460–466
doi: 10.1097/
THYROID: Edited by Lewis E. Braverman and Angela M. Leung

Purpose of review Because of the longstanding controversy regarding whether hypothyroid patients can be optimally replaced by treatment with levothyroxine (L-T4) alone, numerous studies have addressed potential benefits of combined therapy of triiodothyronine (T3) with L-T4. Results of these studies have failed to support a potential benefit of combined therapy. A strong argument for the addition of L-T3 to L-T4 monotherapy has been lacking until recent genetic studies indicated a rationale for such therapy among a small fraction of the hypothyroid patient population.

Recent findings Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid state and the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormone concentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associated with reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroid-pituitary feedback, and in responses to thyroid hormone treatment.

Summary Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients. Future well controlled clinical trials will be required to more fully resolve the controversy.

Department of Medicine, Washington Hospital Center, Georgetown University, Washington, District of Columbia, USA

Correspondence to Leonard Wartofsky, MD, 110 Irving Street, NW, Washington, DC 20010-2975, USA. Tel: +1 202 877 3109; fax: +1 202 877 6292; e-mail:

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins