Art. over T3/T4 waarden in schildklierpatienten

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Lid geworden op: 08 nov 2014, 17:53

Art. over T3/T4 waarden in schildklierpatienten

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Endocrine Society > Journal of Clinical Endocrinology & Metabolism
DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients
1 Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy;
2 Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy;
3 Istituto Di Ricovero e Cura a Carattere Scientifico SDN, 80143 Naples, Italy;
4 Dipartimento di Medicina Molecolare e Biotecnologie Mediche University Federico II, 80131 Naples, Italy;
and 5 CEINGE–Biotecnologie Avanzate Scarl, 80145 Naples, Italy

Abstract
Context:
A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience
hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4.
The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions.

Objectives:
To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis.

Design:
We compared the presurgical hormonal status of thyroidectomized LT4-treated patients
who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and
analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients.
We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models.

Subjects and methods:
A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohistochemistry and immunoblotting were performed for D2 protein.

Results:
The DIO2 genotyping revealed an association between low FT3 values and Thr92Ala.
Specifically, the mean postsurgery FT3 levels were significantly lower in patients carrying the
mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to
presurgery levels.
The 2258 G/A variation was not associated with hormonal alteration. We found that endogenous wild-type D2 and Thr92Ala share the same subcellular localization but differ in protein stability. Importantly, Thr92Ala reduced D2-mediated thyroxine to T3 conversion.

Conclusions:
Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular
and serum T3 concentrations that are not adequately compensated for by LT4, thus
providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.
(J Clin Endocrinol Metab 102: 1623–1630, 2017)


Figure 1.
Thyroid hormone levels before and after surgery and correlation with DIO2 gene polymorphisms. Presurgical and postsurgical thyroid hormone parameters (a). Presurgical and postsurgical FT3 levels in the “reduced FT3” group (b, panel A) and in the “unchanged FT3” (b, panel B) group. Presurgical and postsurgical FT3 levels in relation to the DIO2 genotype (c). Differences between presurgical and postsurgical serum FT3 levels in the three genotype groups (d). SD, standard deviation; WT, wild-type.

Table 1.Clinical, Demographical, and Biochemical Data in “Reduced FT3” and “Unchanged FT3” Patients

Figure 2. D2 localizes etc.

Figure 3. Wild-type D2 and D2-Ala proteins share the same localization, but etc.


These findings support our hypothesize that lower postsurgical levels of FT3 in Thr/Ala and Ala/Ala subjects could be related to the presence of the D2 polymorphism rather than to lower FT4 levels in Ala/Ala and Thr/Ala patients vs Thr/ Thr patients.
The strength of our study is that it was conducted in patients that had similar presurgical and postsurgery TSH levels, thus enabling us to evaluate putative changes in circulating TH levels with the same feedback set point.

A limitation of our study is that, being unable to perform a replicative study of the deiodinase gene mutations in an independent cohort, we cannot exclude the presence of false-positive results.
In conclusion, we demonstrate that a lower plasmatic T3 level is associated with the X/Ala D2 genotype, which suggests that a segment of these patients do not respond optimally to standard LT4 therapy.

It is reasonable to speculate that in the “FT3-reduced” group of patients, restoration of presurgery FT3 values would be obtained by increasing the LT4 dose at the expense of a higher
plasmatic LT4 level and a lower TSH level (in the range of subclinical hypothyroidism) or by adding T3.
In this context, our study might support the use of combined T4+T3 therapy in the subgroup with low serum T3 that carries D2-Ala mutants.

Volledig artikel:
https://academic.oup.com/jcem/article/1 ... ntary-data




Abstract > vervolg
Copyright © 2017 Endocrine Society
J Clin Endocrinol Metab (2017) 102 (5): 1775-1778 Published: 04 May 2017
Marco Medici, Layal Chaker, Robin P. Peeters
This article involves the study by Castagna et al. published in this issue of the Journal of Clinical Endocrinology & Metabolism on the association and functional analyses of genetic variation in DIO2.

A Step Forward in Understanding the Relevance of Genetic Variation in Type 2 Deiodinase
Up to 20% of treated hypothyroid patients have residual hypothyroid complaints despite normalized thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels.
The pathophysiological mechanism behind these persistent complaints is one of the major unresolved questions in thyroidology.

In euthyroid individuals, ~20% of serum triiodothyronine (T3) results from direct thyroidal secretion, with the remainder derived from extrathyroidal conversion of T4 to T3 by type 1 and 2 deiodinase (D1 and D2).

The vast majority of hypothyroid patients are treated with levothyroxine (LT4) monotherapy, and their serum T3 levels are therefore fully dependent on extrathyroidal T3 production.

Thus, patients receiving LT4 monotherapy generally have higher T4/T3 ratios than euthyroid individuals.
Some patients with normalized TSH levels will have serum T3 levels at the lower end or even less than the reference range, with high FT4 levels.

D2 accounts for ∼70% of circulating serum T3 levels in humans,...


Link:
https://academic.oup.com/jcem/article-a ... m=fulltext


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