This review will address the following questions i) what is the evidence that levothyroxine replacement alone is insufficient to deal with the treatment of hypothyroidism; ii) what is the evidence form randomised control studies that combinations of tri-iodothyronine and levothyroxine are superior to levothyroxine alone in replacement treatment for hypothyroidism; iii) what other factors may be involved in the optimal replacement of thyroid hormone deficiency and iv) what conclusions may we draw and what future directions are likely in this area?
There is accumulating evidence that around 10% of patients feel dissatisfied with levothyroxine replacement although it is not clear whether these results in part stem from selection or treatment biases. There is no evidence so far that animal studies showing inadequate tissue levels of T3 on T4-only replacement are replicated in man. A meta-analysis of 11 trials of T3 and T4 combination treatment up to 2006 concluded that this was not superior to T4 alone although three subsequent trials have found some weak evidence for benefit.
Amongst the factors that must be taken into account in judging these trials are the heterogeneity of the causes of hypothyroidism, different durations of disease and treatment, variation in T4:T3 dose ratio (by weight) of 20:11:1 and the use of differing outcome measures. Liothyronine is so far available only as a 20 μg tablet: unavoidable supraphysiological peaks of T3 are inevitable. Moreover T3 displays a circadian rhythm and this is not mimicked with current preparations. Variability in deiodinase enzyme and thyroid hormone transporter distribution, including genetic polymorphism, might mean that some tissues are underexposed to sufficient T3 without the endogenous T3 secreted by thyroid gland. There is also preliminary evidence that a SNP in DIO2 may be associated with a greater improvement on combination T3 and T4 treatment.
Although combination T3 and T4 treatment cannot be recommended for routine use, there is still a need physiological replacement trials, stratified by genotype and with meticulous, dynamic TSH monitoring.
30 Apr - 04 May 2011
European Society of Endocrinology