Denmark.
Most L-T4 treated hypothyroid patients return to normal health without complaints. However, persistent symptoms such as tiredness, depression, decreased cognitive function, weight increase and musculoskeletal symptoms are described in 25% of L-T4 treated hypothyroid patients compared to 1520% in controls. It has been assumed that all the necessary T3 could be derived from peripheral de-iodination of orally administered L-T4. Nevertheless, data has pointed towards a possible need for supplementary T3 in selected patient groups to fully restore the balance between TSH, TRH, thyroid hormones, de-iodinase and metabolism. Data show a 1520% lower serum FT3/FT4 ratio given a stabile serum TSH after thyroidectomy than before and in thyroidectomized rats it is only possible to restore normal concentrations of FT3 in all tissues by giving a combination of L-T4 as well as L-T3. A meta-analysis in 2006 of data from more than 1200 unselected patients could not confirm an effect of L-T4/L-T3 combination therapy. However, the included studies were heterogeneous, including unselected patients. A minor study in a highly selected patient-group with Hashimoto disease and overt hypothyroidism as well as persistent symptoms demonstrated significant effects in seven out of eleven quality of life scores and preference for L-T3/L-T4 combination therapy in 49% compared to L-T4 monotherapy in 15% (P=0.002). A suggested explanation for a possible need for a T3 substitution as well as T4 has been related to a change in the feedback in the hypothalamic-pituitary- thyroid axis induced by high dose og T4 and a possible relative inactivation of deiodinase 2 and hereby lower values of T3. Another possible suggested explanation is polymorphisms in the deiodinase 2 gene (D2-92 Ala) or to the cellular membrane transporter (MCT10) and by this a potential decrease in the transportation of thyroid hormone from plasma to the intracellular space and a decreased deiodination of T4 to T3. However, extended research is needed to explore the exact effect of these and other polymorphisms.