REVIEW: Treatment of Hypothyroidism with Combinations of Levothyroxine Plus Liothyronine

Context: Combined infusion of levothyroxine plus liothyronine, as opposed to levothyroxine alone, is the only way of restoring the concentrations of circulating TSH, T4, and T3 as well as those of both T4 and T3 in all tissues of thyroidectomized rats. Considering the substantial differences in thyroid hormone secretion, transport, and metabolism between rats and humans, whether or not combined levothyroxine plus liothyronine replacement therapy has advantages over treatment with levothyroxine alone in hypothyroid patients is still questioned.

Evidence Acquisition: We conducted a systematic review of all the published controlled studies comparing treatment with levothyroxine alone with combinations of levothyroxine plus liothyronine in hypothyroid patients, identified through the Entrez-PubMed search engine.

Evidence Synthesis: Nine controlled clinical trials were identified that compared treatment with levothyroxine alone and treatment with combinations of levothyroxine plus liothyronine and included a sufficient number of adult hypothyroid patients to yield meaningful results. In only one study did the combined therapy appear to have beneficial effects on the mood, quality of life, and psychometric performance of the patients over levothyroxine alone. These results have not been confirmed by later studies using either T3 substitution protocols or approaches with fixed combinations of levothyroxine plus liothyronine, including those based on the physiological proportion in which T3 and T4 are secreted by the human thyroid. However, in some of these studies the patients preferred levothyroxine plus liothyronine combinations, for reasons not explained by changes in the psychological and psychometric tests employed. Yet patients' preference should be balanced against the possibility of adverse events resulting from the addition of liothyronine to levothyroxine, even in the small doses used in these studies.

Conclusions: Until clear advantages of levothyroxine plus liothyronine are demonstrated, the administration of levothyroxine alone should remain the treatment of choice for replacement therapy of hypothyroidism.