Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis
Abstract
OBJECTIVE: The type 2 deiodinase (D2)-Thr92Ala polymorphism has been associated with decreased D2 activity in some in vitro experiments but not in others. So far no association between the D2-Thr92Ala polymorphism and serum thyroid hormone levels has been observed in humans, but in a recent study in athyroid patients, it was suggested that patients homozygous for the Ala(92) allele needed higher T4 doses to achieve TSH suppression. We studied the association between the D2-Thr92Ala polymorphism with thyroid hormone levels and T4 dosage, in patients treated for differentiated thyroid carcinoma (DTC) and in a group of patients treated for Hashimoto thyroiditis. DESIGN: Cross-sectional study. PATIENTS: We studied 154 patients with DTC treated with TSH suppressive thyroid hormone replacement therapy for longer than 3 years and 141 patients with Hashimoto thyroiditis treated for at least 6 months with T4. MEASUREMENTS: In all patients, serum levels of TSH, free T4, T3 and reverse T3 were measured and genotypes of the D2-Thr92Ala polymorphism were determined by Taqman assay. Univariate regression analysis was performed to determine the relation between T4 dosages and the D2-Thr92Ala polymorphism corrected for age, gender, BMI and serum TSH levels. RESULTS: Both in DTC patients and Hashimoto patients, no association was observed between serum thyroid hormone levels or T4 dosages in presence of the D2-Thr92Ala polymorphism. Categorization of DTC patients according to degree of TSH suppression did not change these results. CONCLUSION: The D2-Thr92Ala polymorphism is not associated with thyroid hormone levels or T4 dose in patients treated for DTC or Hashimoto thyroiditis.
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Studies examining the effect of sex, menopausal status, and the DIO2 Thr92Ala polymorphism on LT4 dose requirement have produced inconsistent findings.
“In contrast to consistency of the findings reported in the above studies, studies examining the effect of sex (214,215, 221), menopausal status (214,215,221), and the presence of the type 2 deiodinase gene ( DIO2 ) Thr92Ala polymorphism (222,224) have produced inconsistent findings.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [222]
The common Thr92Ala polymorphism has been associated with insulin resistance, obesity, hypertension, and altered responses to T4 replacement therapy predicting the need for a higher T4 dosage, although only in thyroidectomized subjects but not in patients with autoimmune hypothyroidism.
“One common Thr92Ala polymorphism has been associated with insulin resistance, obesity, hypertension and importantly, altered responses to T4 replacement therapy that predicted the need for a higher T4 dosage, although only in thyroidectomized subjects but not in patients with autoimmune hypothyroidism (14–16).”
From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [15]
Deiodinase polymorphism studies shed doubt on the validity of relying on TSH levels and TSH normalization during L-T4 therapy to reflect euthyroidism in all tissues.
“Thus, while endocrinologists traditionally rely on TSH levels and TSH “normalization” during L-T4 therapy to reflect euthyroidism in all tissues, these deiodinase polymorphism studies shed some doubt on the validity of this practice for all patients in view of some clinical evidence supporting a role for combination T4/T3 treatment.”
From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [15]
Another larger study found no effect of DIO2-Thr92Ala polymorphism on LT4 dose required to achieve TSH suppression in thyroid cancer patients or TSH within reference intervals in patients with autoimmune hypothyroidism.
“Another larger study, in contrast, found no effect of this polymorphism on the LT4 dose required to achieve TSH suppression in thyroid cancer patients or TSH within the reference intervals in patients with autoimmune hypothyroidism (70).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [70]
These results were not confirmed in another study reporting no association between D2 Thr92Ala and serum thyroid hormone levels or L-T4 dosage in patients with thyroid cancer or Hashimoto's thyroiditis.
“These results were not confirmed in another study reporting no association between D2 Thr92Ala and serum thyroid hormone levels or L-T4 dosage in patients with thyroid cancer or Hashimoto's thyroiditis [62] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [62]
The absence of an association between DIO2 genotype and thyroid hormone level was confirmed in many other studies.
“Indeed, the absence of an association between the genotype and thyroid hormone level was confirmed in many other studies [ 93 , 97 – 99 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [98]
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- Authors
- Heemstra, K. A., Hoftijzer, H. C., Van Der Deure, W. M., Peeters, R. P., Fliers, E., Appelhof, B. C., Wiersinga, W. M., Corssmit, E. P. M., Visser, T. J., & Smit, J. W. A.
- Affiliations
- Leiden University Medical Center (NL)
- Erasmus MC (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Smit, J. W. A.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2009-07-06
- Volume
- 71
- Issue
- 2
- Pages
- 279-283
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2102605635
- Cited by
- 51
- References
- 11
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 4
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- type 2 deiodinase, thyroid hormone levels, levothyroxine dose, TSH suppression, differentiated thyroid cancer, Hashimoto's thyroiditis, genetic association, free thyroxine, reverse T3
- MeSH terms
- Iodothyronine Deiodinase Type II, Adult, Cross-Sectional Studies, Dose-Response Relationship, Drug, Female, Humans, Iodide Peroxidase, Male, Middle Aged, Polymorphism, Genetic, Thyroid Hormones, Thyroxine, Mutation, Missense, Hashimoto Disease
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