Wilmar M. Wiersinga, Leonidas Duntas, Valentin Fadeyev, Birte Nygaard, Mark P.J. Vanderpump, European Thyroid Journal 2012;1:55–71

Background: Data suggest symptoms of hypothyroidism persist in 5–10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such pa- tients is controversial. The ETA nominated a task force to re- view the topic and formulate guidelines in this area.

Methods: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and com- ments from the European Thyroid Association (ETA) mem- bership at large.

Results: Suggested explanations for per- sisting symptoms include: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid auto- immunity per se, and inadequacy of L-T4 treatment to re- store physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient ev- idence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 mono- therapy remains the standard treatment of hypothyroidism.
L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothy- roid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by ac- credited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio be- tween 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined prep- arations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aim- ing not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.

Conclusions: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

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