hypothyroidism is one of the most common endocrine disorders , affecting about 4% of the adult us population , and is caused primarily by autoimmune thyroiditis . even though it is recognized that 3,5,3-triiodothyronine ( t3 ) is the biologically active form of thyroid hormone , for decades replacement therapy has been based on levothyroxine ( l - t4 ) monotherapy . this rationale stems from the existence of iodothyronine deiodinases , enzymes that activate thyroxine ( t4 ) to t3 outside of the thyroid parenchyma and generate most of the circulating t3 . however , large community - based studies have reported that a subset ( about 10% ) of hypothyroid patients on l - t4 monotherapy exhibit significant impairment in psychological well - being , even when serum thyroid function tests are within the normal range . this suggests that these important neurocognitive parameters may not be completely restored in these hypothyroid patients when kept on l - t4 monotherapy . these findings create the need for alternative therapeutic approaches for hypothyroid patients that do not do well on l - t4 monotherapy , including the use of desiccated animal thyroid or combined therapy with l - t4 and 3,5,3-l - triiodothyronine ( l - t3 ) ( t4/t3 ) . in the latter case , studies have been hampered due to formulation issues , given that t4 has a much longer half - life and the current lack of a long acting preparation of l - t3 . t3 and t4 are found at a ratio of approximately 1:15 in the human thyroglobulin molecule , and this is unlikely to be markedly affected by the intrathyroidal conversion of t4 to t3 . thus , one would think that in order to mimic normal thyroidal secretion , thyroid hormone replacement therapy should be based on the combination of l - t4 and l - t3 at similar ratios as found in human thyroglobulin . however , for decades it has been known that t4 can be activated outside the thyroid gland to t3 via iodothyronine deiodinases d1 and d2 . these are highly homeostatic enzymes that adjust their catalytic activities according to the plasma levels of t4 and t3 . in fact , this paradigm is supported by extensive literature that has served as the basis for the guidelines set forth by the american thyroid association recommending l - t4 monotherapy as the primary choice for thyroid hormone replacement in patients with hypothyroidism . a meta - analysis of 11 randomized controlled trials with a total of 1216 patients indicated that t4/t3 combination therapy provided no advantage when compared with standard l - t4 monotherapy in any of the following parameters : bodily pain , depression , anxiety , fatigue , quality of life , body weight , total serum cholesterol and triglycerides , serum low - density lipoprotein , and high - density lipoprotein , and demonstrated no difference in adverse events . a second meta - analysis including a total of 1243 patients suggested that t4/t3 combination therapy is beneficial for the psychological and physical well - being of patients previously on l - t4 monotherapy , but there was no statistically significant difference in the other variables . only one trial found a significant benefit of t4/t3 combination therapy compared with l - t4 monotherapy , but it is not clear whether these findings were related to the cause of hypothyroidism , as was later suggested . it is well accepted that , in humans , most circulating t3 is derived from extrathyroidal deiodination of t4 via d2 ; thus , it makes sense to hypothesize that defects in d2 expression / activity could interfere with the efficacy of l - t4 monotherapy . in recent years , several polymorphisms have been reported for the gene encoding d2 ( dio2 ) , including some associated with insulin resistance , obesity , and hypertension , to name but a few . however , these findings have been restricted to specific populations and a more universal corollary is still missing . central to this problem is whether any of the dio2 polymorphisms reported to date affect the activity and/or kinetic properties of d2 . the single nucleotide polymorphism a / g in dio2 predicts a threonine to alanine substitution at codon 92 ( thr92ala ) and , in subjects homozygous for the ala allele , d2 velocity was reported to be decreased in an early study , but this may have been the result of an artifact . with this in mind , asked whether common variants in dio2 could explain differences in psychological morbidity and response to thyroid hormone replacement therapy in 552 patients of the weston area t4/t3 study ( watts ) in the uk . their results indicated that the thr92ala polymorphism in dio2 is associated with both impaired baseline psychological well - being in patients on l - t4 monotherapy and enhanced response to combination t4/t3 therapy , which could explain the biological mechanism of the t3 requirement . however , what could be the mechanistic basis for such findings given that the dio2 polymorphism did not affect thyrotropin , t4 , or t3 serum levels in the panicker et al . a rationale could be based on the fact that d2 activity increases the intracellular t3 concentration relatively independently of the serum concentration of t3 . accordingly , dio2 knockout mice have normal serum t3 concentrations but only half as much t3 in their brains as wild type . although not as severe as in hypothyroid mice , the dio2 knockout mice exhibited clear defects in certain agility tasks when evaluated for locomotion and agility , learning and memory , reflexes , anxiety , and exploratory levels . furthermore , these animals are also known for exhibiting defects in adaptive thermogenesis and thermal homeostasis because of the role played by d2 in brown adipose tissue . whether these findings could serve as the basis for the improved psychological well - being and quality of life reported in patients receiving combination t4/t3 therapy remains to be determined . the overwhelming evidence available in the literature supports the notion that l - t4 monotherapy provides adequate thyroid hormone replacement in patients with hypothyroidism . a small subset of hypothyroid patients does seem to have a better quality of life and perform better on cognitive tests when placed on combination t4/t3 therapy . according to one large study , this could be explained by the thr92ala polymorphism in the dio2 gene , which is present in about 15% of the general population . while a prospective trial studying the effect of the thr92ala polymorphism on the neuropsychiatric response to combined t3/t4 versus l - t4 monotherapy has yet to be carried out , it is fascinating to contemplate the notion that personalized medicine is rapidly catching up with modern thyroidology .
it is widely accepted that thyroid hormone replacement for patients with hypothyroidism can be fully accomplished with levothyroxine monotherapy , as assessed by serum thyroid function tests 
 . however , approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine monotherapy , and physicians continue to report benefits from combined levothyroxine - triidothyronine therapy for some hypothyroid patients . 
 recently , a large prospective study reported that the benefit of the combined levothyroxine - triidothyronine therapy is associated with the thr92ala polymorphism in the type 2 deiodinase gene , which is present in about 15% of the general population . 
 if confirmed , these findings indicate that personalized medicine is rapidly catching up with modern thyroidology .