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Thyroid Disorders Editorial The Thr92AlaD2 Polymorphism May Play a Novel Role in Hypothyroidism Elizabeth A McAninch, MD and Antonio C Bianco, MD, PhD Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois, US Abstract The type 2 deiodinase (D2) has an important role in hypothyroidism, where its ability to activate thyroid hormone provides justification for levothyroxine “monotherapy.” A prevalent polymorphism in D2, Thr92AlaD2, has been associated with improved well-being on “combination therapy” with T4+T3; the underlying mechanism is unclear as T4-to-T3 conversion appears normal. Novel studies indicate this might be a risk factor for neurodegenerative disease. If the relationship between Thr92AlaD2-expression and treatment preference is confirmed, personalized medicine may play a role in hypothyroidism. Keywords Hypothyroidism, polymorphism, levothyroxine, deiodinase Disclosure: Elizabeth A McAninch, MD, and Antonio C Bianco, MD, PhD, have no relevant conflicts of interest to declare. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 2, 2015 Published Online: October 25, 2015 Citation: US Endocrinology, 2015;11(2):92–4 Correspondence: Elizabeth A McAninch, MD, Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 W Harrison St, 312 Cohn Building, Chicago, Illinois, 60612, US E: Extrathyroidal production of the active form of thyroid hormone, T3, via deiodination of thyroxine (T4) provides physiologic justification for the treatment of hypothyroidism with levothyroxine ( l -T4) “monotherapy”; 1 T3 production outside of the thyroid gland is mediated largely by the type 2 deiodinase (D2). l -T4-treated patients exhibit stable levels of serum T3 2 and for decades clinicians have attributed this to adequate and consistent peripheral T4-to-T3 conversion. 3,4 Accordingly, the majority of l -T4-treated patients achieve both clinical and biochemical euthyroidism, which is typically defined as normalization of the serum thyroid stimulating hormone (TSH). 5,6 However, it has been recognized in more recent years that despite normalization of serum TSH, some patients suffer from residual hypothyroid symptoms and, in particular, cognitive complaints. 7 Given the high prevalence of hypothyroidism, which afflicts more than eight million Americans alone, 8 that about 12 % of treated individuals remain symptomatic represents a considerable portion of the population. 7 Therefore, optimization of therapeutic response in hypothyroidism represents an important target for the public health. patients would be explained. 12,13 However, superiority of combination therapy has not been demonstrated universally in clinical trials, 5 leaving some to hypothesize that unique individual factors may characterize the subset of patients who do derive benefit from this therapeutic approach. To this effect, a genetic factor has been associated with preference for combination therapy in hypothyroidism; patients with the Thr92Ala polymorphism in DIO2, the gene encoding D2, have demonstrated improved well-being when treated with combination therapy versus l -T4 monotherapy in a large clinical trial. 14 This single nucleotide polymorphism, rs225014, results in a single amino acid substitution within D2’s instability loop. 15 Given that this substitution occurs at a residue that is distant from the catalytic active site, it is not necessarily surprising that Thr92AlaD2 converts T4-to-T3 with normal kinetics when transiently expressed in cells. 16,17 Similarly, these patients do not exhibit gene expression patterns consistent with hypothyroidism at the level of brain tissue, 18 exhibit normal serum thyroid function parameters, 17,19 and require equivalent doses of levothyroxine to normalize serum TSH levels. 20,21 Although l -T4-treated patients typically exhibit serum TSH, T4, and T3 levels within the normal range, this occurs at the cost of an elevated serum T4:T3 ratio. 9 With that being said, a minority of patients fail to achieve normal serum T3 levels. 10,11 One hypothesis to explain residual symptomatology in l -T4-treated patients is localized hypothyroidism within a particular tissue, for example, the brain. D2 is abundantly expressed within this T3-target tissue, and therefore it is logical to consider that a defect in In addition to its association with treatment preference in hypothyroidism, the Thr92AlaD2 polymorphism has been associated with diverse conditions in population-based studies, including hypertension, 22 insulin resistance, 23,24 type 2 diabetes, 25,26 bipolar disorder, 27 mental retardation, 28 low IQ, 29 recovery from lung injury, 30 osteoarthritis, 31–33 and increased bone turnover 34 (see Figure 1). As intact thyroid hormone signaling has been the D2 pathway could result in localized brain hypothyroidism. If this were the case, the ability of “combination” therapy (treatment with T4+T3- containing regimens) to improve psychological parameters in some demonstrated across models, this suggests that mechanisms aside from localized hypothyroidism are likely responsible for the clinical phenotype associated with Thr92AlaD2-expression. 92 TOUCH ME D ICA L ME D IA