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Cited by 146Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentThyroid and Parathyroid Surgery

Scope and limitations of iodothyronine deiodinases in hypothyroidism

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Gereben, Balázs, McAninch, Elizabeth A., Ribeiro, Miriam O., Bianco, Antonio C.·2015·Nature Reviews Endocrinology
DOI 10.1038/nrendo.2015.155PMC PMC5003781
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Abstract

The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition.

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  • Maintaining normal plasma T3 levels is the main directive of the hypothalamus-pituitary-thyroid axis.

    “The first discovery was that maintaining normal plasma T3 levels is the main directive of the hypothalamus-pituitary-thyroid (HPT) axis (17).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [17]

    In 'Limitations of levothyroxine monotherapy' (page unavailable), the paper describes T4 and T3 feedback on the hypothalamus and pituitary. It does not say that maintaining normal plasma T3 is the axis’s main directive; 'Normalization of T3 levels in hypothyroidism' also reports that normal TSH can coexist with low serum T3 during levothyroxine treatment. (LLM, conf=0.78)

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References 137 · Cited by 146

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Authors
Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C.
Affiliations
  • HUN-REN Institute of Experimental Medicine (HU)
  • Rush University Medical Center (US)
  • Universidade Presbiteriana Mackenzie (BR)
Corresponding author
Bianco, Antonio C.
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2015-09-29
Volume
11
Issue
11
Pages
642-652
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/nrendo.2015.155
PMC
PMC5003781
OpenAlex
W2201239534
Cited by
146
References
137
Citations by year
2026: 3 · 2025: 14 · 2024: 13 · 2023: 17 · 2022: 13 · 2021: 18 · 2020: 12 · 2019: 16 · 2018: 13 · 2017: 13 · 2016: 9 · 2015: 3 · 2013: 1
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058538, R01DK065055, R01DK077148)
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
iodothyronine deiodinase, hypothyroidism, type 2 deiodinase, DIO2, levothyroxine monotherapy, triiodothyronine, thyroid hormone replacement, neurodegenerative disease risk
MeSH terms
Iodothyronine Deiodinase Type II, Animals, Brain Diseases, Humans, Hypothyroidism, Iodide Peroxidase, Thyroid Hormones

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