Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients
Abstract
CONTEXT: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity. OBJECTIVE: Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients. SETTING: Ambulatory patients were included in the study. PATIENTS: A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n=117, <0.1 mU/liter) or near-supp (n=74, >or=0.1<0.5 mU/liter) serum TSH levels. MAIN OUTCOME MEASURES: DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (microg/kg) needed to obtain target TSH levels were determined. RESULTS: Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08+/-0.43 vs. 1.90+/-0.35 microg/kg; P<0.05). This difference was observable in the near-supp group (P=0.002), but not in the supp group (P=0.4). CONCLUSIONS: D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.
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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 [224]
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 [14]
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 [14]
One study showed that individuals with thyroid cancer with DIO2-Thr92Ala polymorphism required a higher dose of LT4 to achieve near suppression of serum TSH levels.
“With regards to the effect of deiodinase polymorphisms on the LT4 dose required to reach a target TSH concentration, one study showed that individuals with thyroid cancer with the DIO2-Thr92Ala polymorphism required a higher dose of LT4 in order to achieve near suppression of their serum TSH levels (69).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [69]
The need for a higher L-T4 dose to obtain target serum TSH levels in thyroidectomised patients was higher in carriers of the DIO2 Thr92Ala SNP.
“Indeed, the need for a higher L-T4 dose to obtain target serum TSH levels in thyroidectomised patients was higher in carriers of this SNP [61] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [61]
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References 15 · Cited by 92
- Authors
- Torlontano, M., Durante, C., Torrente, I., Crocetti, U., Augello, G., Ronga, G., Montesano, T., Travascio, L., Verrienti, A., Bruno, R., Santini, S., D’Arcangelo, P., Dallapiccola, B., Filetti, S., & Trischitta, V.
- Affiliations
- Casa Sollievo della Sofferenza (IT)
- Sapienza University of Rome (IT)
- Unit of Endocrinology (R.B.), Tinchi-Pisticci Hospital, 75020 Matera, Italy
- Departments of Clinical Sciences (C.D., G.R., T.M., L.T., A.V., S.F., V.T.), “La Sapienza” University, 00161 Rome, Italy
- Corresponding author
- Torlontano, Massimo
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-03-01
- Volume
- 93
- Issue
- 3
- Pages
- 910-913
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2035160565
- Cited by
- 92
- References
- 15
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 9 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 7 · 2014: 6 · 2013: 4 · 2012: 8
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (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, TSH suppression, thyroidectomy, thyroid cancer, genetic variation, radioiodine ablation
- MeSH terms
- Iodothyronine Deiodinase Type II, Adult, Aged, Female, Humans, Iodide Peroxidase, Male, Middle Aged, Polymorphism, Genetic, Thyroidectomy, Thyrotropin, Thyroxine
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