Introduction: There remains considerable debate over combination T4/T3 therapy for thyroid hormone replacement. Whilst large randomised-controlled studies have failed to show benefit over T4 only, there remain patients who feel better on the combination. Animal studies suggest that up to 80% of intracellular T3 in the brain is derived from circulating T4 by local deiodination. We hypothesized that in patients on thyroxine common variants in the deiodinase genes might influence response to each therapy.
Methods: We analysed common variants in the 3 deiodinase genes versus baseline psychological morbidity and response to T4/T3 in 552 subjects on thyroxine from a trial of combination therapy. Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).
Results: The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on thyroxine (CC versus TT genotype: 14.1 vs 12.8, P=0.03). In addition this genotype showed greater improvement on T4/T3 therapy compared to T4 only by 2.3 GHQ points at 3 months and 1.4 at 12 months, P=0.04 for repeated measures ANOVA. This polymorphism had no impact on circulating thyroid hormone levels. None of the polymorphisms in DIO1 or DIO3 had an effect on psychological well-being.
Conclusions: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on thyroxine and enhanced response to combination T4/T3 therapy, whilst not affecting serum thyroid hormone levels. This suggests there is a small subgroup of patients on thyroid hormone replacement who may benefit from combination therapy.