The deiodinase 2 enzyme (DIO2) in the brain is responsible for converting T4 to T3 in the brain. Sixteen percent of the population carries a variation in the DIO2 gene that may affect how they respond to thyroid therapy after thyroidectomy. These individuals show in genetic testing a “CC” type or rs225014 polymorphism in the DIO2 gene. This single change in nucleotide or SNIP leads to an amino acid change (“Thr92Ala”) or substitutionin the DIO2 enzyme slowing its normal function. The common normal variant is “TT”, those with combination CT or TC have normal function and are not compromised.
Thyroid blood levels do not help to identify who has this genetic variation, genetic tests (such as 23 and me or others) are necessary to find this information. Patients who have this genetic variant may be more vulnerable to being hypothyroid (low T4) because of the impaired ability of this enzyme to increase its activity with low T4 levels or suboptimal replacement. Therefore, for this select group of patients there may be a need to take some T3, in addition to T4, as a source of T3 in the brain. The only way to achieve this is with combination therapy of T4+T3 after thyroidectomy.
I have included the reference and abstract of an important article published in one of my endocrine journals a while back. This is one of the first large studies (552 patients) to document lower psychological health of patients with this DIO2 variant and improvement of psychological wellbeing with combination therapy.
Common Variation in the DIO2Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients. Vijay Panicker, Ponnusamy Saravanan, Bijay Vaidya,Jonathan Evans, Andrew T. Hattersley, Timothy M. Frayling, Colin M. Dayan. The Journal of Clinical Endocrinology & Metabolism, Volume 94, Issue 5, 1 May 2009, Pages 1623–1629, https://doi.org/10.1210/jc.2008-1301
Introduction: Animal studies suggest that up to 80% of intracellular T3in the brain is derived from circulating T4by local deiodination. We hypothesized that in patients on T4common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T4/T3without necessarily affecting serum thyroid hormone levels.
Methods: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T4/T3in 552 subjects on T4from the Weston Area T4T3Study (WATTS). 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 T4(CC vs. TT genotype: 14.1 vs. 12.8, P= 0.03). In addition, this genotype showed greater improvement on T4/T3therapy compared with T4only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P= 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.
Conclusions: Our results require replication but suggest that commonly inherited variation in the DIO2gene is associated both with impaired baseline psychological well-being on T4and enhanced response to combination T4/T3therapy, but did not affect serum thyroid hormone levels.