Endocrine Abstracts

The adequacy of thyroid hormone replacement in hypothyroid subjects has long been debated. A proportion of subjects on thyroxine report not achieving their pre-disease level of well-being and evidence from community studies suggest impaired well-being in subjects on thyroxine compared to the general population. Our work on the large HUNT 2 cohort from Norway confirms this and furthermore revealed that subjects on thyroxine have a different relationship between TSH and well-being. Despite this, ten randomised controlled studies (and meta-analysis) of combination T₄/T₃ replacement compared to T₄ alone did not confirm findings from an initial study which showed a benefit of combination therapy.

We explored a genetic basis for these findings in light of greater understanding of the human genome and common variation within it. These methods have already shown us that single nucleotide changes in genes may be associated with serum levels, for example a SNP in the deiodinase 1 gene (DIO1) and one in the phosphodiesterase 8B gene (PDE8B) have been shown to be associated with T₃/T₄ and TSH levels respectively. Although they have only a small effect on hormone levels, they are important findings as they further our understanding of thyroid physiology and can be used to confirm associations via Mendelian Randomisation. There is also evidence of an effect of these polymorphisms beyond serum hormone levels, with SNPs in DIO2 increasing risk for osteoarthritis.

Therefore, we investigated the effect of common variation in the three deiodinase genes on response to combination T₄/T₃ versus T₄ only therapy in the largest trial – WATTS. We found that subjects with a polymorphism in DIO2 had impaired well-being at baseline on T₄ and furthermore improved significantly when put on combination therapy. Whilst this result requires replication, it suggests that there may be a proportion of the population on thyroxine who required combination therapy.