For Some, l-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale

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Abstract
Although the thyroid gland secretes a very small amount of active thyroid hormone (triiodothyronine or T3), the major circulating form is thyroxine (T4), and it is widely accepted that thyroid hormone replacement in patients with hypothyroidism can be fully accomplished with l-T4 monotherapy [see 1995 American Thyroid Association guidelines (Ref. 1)]. The mechanistic basis for this belief stems from the actions of the iodothyronine deiodinases, enzymes that activate thyroid hormone by conversion of T4 to T3 (or inactivate both forms via further deiodination) (2). Thanks to the actions of the type 2 deiodinase (D2) and to some extent the type 1 deiodinase (D1), both endogenous T4 and l-t4 are converted to T3 at a rate sufficient to maintain normal serum T3 concentration. However, despite the extensive literature demonstrating that patients do well clinically on l-t4 monotherapy, most clinicians have at least anecdotally seen benefits from combined T3/T4 therapy for some patients, prompting a search for the biological mechanism of the T3 requirement. In the current issue of JCEM, Panicker et al. (3) examine this question from a novel perspective, asking whether a polymorphism in the Dio2 gene could explain a differential psychological response to the type of thyroid hormone replacement seen in a subpopulation of the Weston Area T4/T3 Study (WATTS) from the United Kingdom (3, 4).

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