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Cited by 11Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentThyroid and Parathyroid Surgery

Type 2 deiodinase Thr92Ala polymorphism and aging are associated with a decreased pituitary sensitivity to thyroid hormone

Luongo, Cristina, De Stefano, Maria Angela, Ambrosio, Raffaele, Volpe, Fabio, Porcelli, Tommaso, Golia, Valeria, Bellevicine, Claudio, Troncone, Giancarlo +6 more·2023·Thyroid
DOI 10.1089/thy.2022.0472
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Abstract

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15–30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = −0.45, p = 0.0002, 95% confidence interval [CI] −0.63 to −0.23; Ala/Thr r = −0.39, p = 0.0012, CI −0.60 to −0.67; and Ala/Ala r = −0.30, p = 0.2347; CI −0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients ( p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO 2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

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Authors
Luongo, C., De Stefano, M. A., Ambrosio, R., Volpe, F., Porcelli, T., Golia, V., Bellevicine, C., Troncone, G., Masone, S., Damiano, V., Matano, E., Klain, M., Schlumberger, M., & Salvatore, D.
Affiliations
  • University of Naples Federico II (IT)
  • Department of Public Health, University of Naples “Federico II,” Naples, Italy.
  • Istituti di Ricovero e Cura a Carattere Scientifico, Synlab, SDN, Naples, Italy.
  • Federico II University Hospital (IT)
  • Université Paris-Saclay (FR)
Corresponding author
  • Luongo, Cristina
  • Salvatore, Domenico
ORCID
Venue
Thyroid
Publisher
SAGE Publications
Published
2023-03
Volume
33
Issue
3
Pages
294-300
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/thy.2022.0472
OpenAlex
W4317666726
Cited by
11
References
34
Citations by year
2026: 3 · 2025: 4 · 2024: 2 · 2023: 2
FWCI
2.24
Type
journal article
Language
en
Open access
closed
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Thyroid (publishedVersion)
  • PubMed (publishedVersion)
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, aging, thyroid-stimulating hormone, hypothyroidism, thyroidectomy, radioiodine therapy, levothyroxine withdrawal, genetic polymorphism, thyroid cancer, mouse model
MeSH terms
Iodothyronine Deiodinase Type II, Animals, Hypothyroidism, Iodide Peroxidase, Iodine Radioisotopes, Prospective Studies, RNA, Messenger, Thyroid Hormones, Thyrotropin, Thyroxine, Mice

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