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D2 Deiodinase (DIO2), Genetic Testing

D2 deiodinase enzymes are produced in cells to enable the conversion of T4 to the much stronger form of thyroid hormone, T3. A mutation in the DIO2 gene can cause a deficiency of T3 within the cells, but the usual thyroid hormone function tests will not show up as a problem. This means that TSH, T4, and T3 blood tests will look normal.

Most of the biological effects of thyroid hormone in the body are due to the action of T3. The most common forms of thyroid hormone replacement involve giving T4. Due to polymorphism of the deiodinase 2 gene, the peripheral conversion of T4 to T3 is impaired, and the addition of T3 might be needed to compensate for reduced intracellular T3 levels which cannot be detected on blood tests.

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Carriers of the Thr92Ala-DIO2 polymorphism exhibited a strong association with insulin resistance. Population-based studies have suggested associations between Thr92Ala-DIO2 with hypertension, insulin resistance, type 2 diabetes, bipolar disorder, mental retardation, low intelligence quotient (IQ), recovery from a lung injury, osteoarthritis, and increased bone turnover. A recent study of autoimmune thyroid diseases such as Graves’ and Hashimoto’s diseases revealed that the Thr92-DIO2 genotype is less frequent in these patients, especially in Hashimoto’s disease, when compared with controls.

The Thr92Ala-DIO2 polymorphism is relatively common, present in 12−36% of the population. Given the role of DIO2 in the tissue-specific determination of local thyroid hormone levels, it is particularly intriguing that the Thr92Ala-DIO2 polymorphism has been linked to altered responsiveness of hypothyroid patients to thyroid hormone replacement therapy. Although most patients do well on replacement therapy with levothyroxine (LT4), a minority (about 15%) remain symptomatic despite achieving normal thyroid-stimulating hormone (TSH) levels. Residual clinical manifestations of hypothyroidism include objective parameters, that is, higher BMI, greater use of beta-blockers, statins, or antidepressant medication, and lower energy expenditure, as well as subjective aspects, that is, difficulty in weight management, fatigue, or low energy levels, and problems with mood and memory.

DIO2 is expressed in the pituitary gland, central nervous system (CNS), brown adipose tissue, uterus, placenta, thyroid gland, and the heart. The highest levels of expression in the brain are found in a specialized type of glial cell called tanycytes, which line the walls of the third ventricle and extend processes to the hypothalamus and median eminence. Astrocytes also express DΙΟ2 and supply T3 to neurons and other neural cells.

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