Thyroid hormone replacement therapy: three 'simple' questions, complex answers

Current guidelines recommend that hypothyroid patients should be treated with levothyroxine, which in the vast majority of the cases leads to resolution of the symptoms and normalization of serum free T4 (FT4), T3 and TSH levels. However, a small group of hypothyroid patients remain symptomatic for neurocognitive dysfunction despite normal serum FT4 and TSH, which could be explained by localized brain hypothyroidism. More than half of the T3 in the brain is produced locally via the action of the type II deiodinase (D2) and variability/defects in this pathway could explain the residual symptoms. If this rationale is correct, adding liothyronine to the replacement therapy could prove beneficial. However, with a few exceptions, several clinical trials failed to identify any beneficial effects of combined therapy. More recently, the results of a large clinical trial revealed a better neurocognitive outcome with combined therapy only in hypothyroid patients carrying a polymorphism in the DIO2 gene. This obviously needs to be confirmed by other groups but it is tempting to speculate that combined levothyroxine and liothyronine has a place in the treatment of hypothyroidism, for some.