Levothyroxine Substitution Depending on Patient Genotype
Careful titration of hormone dose leads to optimal dosing of replacement therapy for hypothyroidism. The authors of a cross-sectional study published in the Endocrine Journal examined the impact of polymorphisms in genes for proteins involved in thyroid hormone metabolism on the response to levothyroxine treatment in patients after thyroidectomy.
Regulation of Thyroid Hormone Levels
The production of thyroid hormones is regulated by hypothalamic thyrotropin-releasing hormone (TRH), which binds to TRH-α and β receptors in the adenohypophysis. This is followed by the release of thyrotropin (TSH), which binds to TSHR receptors located on the membrane of thyrocytes. TSH affects their biosynthetic activity and the secretion of thyroxine (T4) and triiodothyronine (T3).
The concentration of thyroid hormones in plasma and within the cells of peripheral tissues, as well as in the hypothalamus and pituitary, are regulated by deiodinases. These enzymes transform the prohormone T4 into biologically active T3 (DIO1, 2 isoforms) or biologically inactive rT3 (DIO3). Liver UDP-glucuronyltransferases (UGT1A1 and A3) also participate in the elimination of T4. Hormone concentrations feedback to influence the entire hormonal axis.
The above receptors and enzymes were the focus of research by scientists from Istanbul University.
Study Methodology
Ninety-four adult patients (mean age 51.3 ± 1.5 years, 83% female) with secondary hypothyroidism due to total thyroidectomy were included in the cross-sectional study. All the patients took levothyroxine once daily and were stratified into groups with a low (< 1.7 μg/kg) or high (≥ 1.7 μg/kg) daily dose.
The patients' free T3 and T4 (fT3, fT4) and TSH levels were measured. Additionally, DNA was isolated from blood samples followed by analysis of 13 single nucleotide polymorphisms (SNPs) in the DIO1, DIO2, THRA, TSHR, UGT1A3, and UGT1A1*28 genes.
Results and Discussion
No significant correlation was found between genotypes and the dose of levothyroxine, thyroid function biochemical markers (TSH, fT3, and fT4), or body mass index.
Polymorphism rs225014 in the DIO2 gene correlated with TSH levels. The homozygous non-mutated genotype (TT) was associated with higher TSH levels (p < 0.05). The GG genotype at the rs225015 position was associated with higher TSH levels compared to the AA genotype (p < 0.05). However, these higher levels were still within the normal range (i.e., < 4.0 mIU/l). Although it is plausible that the TT and GG genotypes could be linked to a lower conversion of T4 to T3 in cells, this is likely not a clinically significant phenomenon.
Homozygous mutants of TSHR rs4903957 (AA), rs1991517 (CC), rs2239610 (CC), and rs2268458 (CC) were also associated with higher TSH levels. Conversely, homozygous variants of THRA rs939348 (TT) and UGT1A3 rs1983023 (CC) were associated with lower TSH levels. However, these differences were only numerically different and did not reach statistical significance in the studied population sample.
Conclusion
To some extent, it is considered physiological that individuals are equipped with slightly more or fewer functional or sensitive receptors and enzymes. Turkish researchers attempted to evaluate how differences in patients' genetic backgrounds might affect levothyroxine replacement therapy. The statistically significant differences described cannot be considered clinically significant. Pharmacogenetic testing is therefore unlikely to revolutionize the choice of the correct dose of levothyroxine. Dose management based on TSH response and the patient's clinical condition remains irreplaceable.
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Source: Arici M., Oztas E., Yanar F. et al. Association between genetic polymorphism and levothyroxine bioavailability in hypothyroid patients. Endocr J 2018; 65 (3): 317−323, doi: 10.1507/endocrj.EJ17-0162.
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