The  TRHR  Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

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Abstract

Background: Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated. Objectives: We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback. Methods: We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT4 resulting in TSH levels detectable but <0.5 μIU/ml. The two SNPs rs3134105 and rs3110040 were identified as informative markers of the TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls. Results: The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT4)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT3) and fT4, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT3/TSH (p = 0.01) and fT4/TSH ratios (p < 0.01). Conclusions: We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT4 therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT4.

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Most cited references 29

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Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis.

Lucilla Gargano, Mark A Franchi, Gianluca Canettieri … (2006)

Malabsorption of thyroxine has been described in patients treated with drugs that modify an acidic environment. We determined whether there is an increased need for thyroxine in patients with euthyroid multinodular goiter and impaired secretion of gastric acid. We assessed the dose of thyroxine required to obtain a low level of thyrotropin (0.05 to 0.20 mU per liter) in 248 patients with multinodular goiter. Of these 248 patients, 53 also had Helicobacter pylori-related gastritis and 60 had atrophic gastritis of the body of the stomach (31 with evidence of H. pylori infection and 29 without such evidence). The reference group comprised 135 patients with multinodular goiter and no gastric disorders. In addition, variation in the level of serum thyrotropin was prospectively studied in 11 patients treated with thyroxine before and after H. pylori infection and both before and during treatment with omeprazole in 10 patients treated with thyroxine who had gastroesophageal reflux. The daily requirement of thyroxine was higher (by 22 to 34 percent) in patients with H. pylori-related gastritis, atrophic gastritis, or both conditions than in the reference group. In prospective studies, the occurrence of H. pylori infection in the 11 patients treated with thyroxine led to an increase in the level of serum thyrotropin (P=0.002), an effect that was nearly reversed on eradication of H. pylori infection. In a similar way, omeprazole treatment was associated with an increase in the level of serum thyrotropin in all 10 patients treated with thyroxine, an effect that was reversed by an increase in the thyroxine dose by 37 percent. Patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine. Copyright 2006 Massachusetts Medical Society.

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Timing of levothyroxine administration affects serum thyrotropin concentration.

Madhabika B Nayak, Thien Huynh-The, Jacqueline Jonklaas … (2009)

Patients treated with levothyroxine typically ingest it in a fasting state to prevent food impairing its absorption. The serum thyrotropin concentration is the therapeutic index of levothyroxine action. The study objective was to determine the effect of the timing of levothyroxine administration in relationship to food on serum thyrotropin levels. Participants were randomized to one of six sequences, each consisting of three 8-wk regimens in a three-period crossover design. These regimens were in a fasting state, at bedtime, and with breakfast. The concentrations of TSH, free T(4), and total T(3) during each of the three timing regimens were documented. The primary outcome was the difference between serum TSH concentrations under fasting conditions compared with concentrations during the other 8-wk regimens. The study was conducted in an academic medical center. Study participants were receiving levothyroxine for treatment of hypothyroidism or thyroid cancer. Sixty-five patients completed the study. The mean thyrotropin concentration was 1.06 +/- 1.23 mIU/liter when levothyroxine was administered in the fasting state. When levothyroxine was taken with breakfast, the serum thyrotropin concentration was significantly higher (2.93 +/- 3.29 mIU/liter). When levothyroxine was taken at bedtime, the serum TSH concentration was also significantly higher (2.19 +/- 2.66 mIU/liter). Nonfasting regimens of levothyroxine administration are associated with higher and more variable serum TSH concentrations. If a specific serum TSH goal is desired, thereby avoiding iatrogenic subclinical thyroid disease, then fasting ingestion of levothyroxine ensures that TSH concentrations remain within the narrowest target range.

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Altered intestinal absorption of L-thyroxine caused by coffee.

Salvatore Benvenga, Luigi Bartolone, Maria Angela Pappalardo … (2008)

To report eight case histories, and in vivo and in vitro studies showing coffee's potential to impair thyroxine (T4) intestinal absorption. Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.

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Author and article information

Journal

Journal ID (publisher-id): ETJ

Journal ID (pmc): ETJ

Journal ID (doi): 10.1159/issn.2235-0640

Title: European Thyroid Journal

Publisher: S. Karger AG

ISSN (Print): 2235-0640

ISSN (Electronic): 2235-0802

Publication date Subscription-year: 2014

Publication date (Print): June 2014

Publication date (Electronic): 07 June 2014

Volume: 3

Issue: 2

Pages: 101-108

Affiliations

^aUnit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences and ^bCenter of Genomic Research, University of Modena and Reggio Emilia, and ^cAzienda USL, Modena, Italy; ^dInstitute of Human Genetics, University of Munster, Munster, Germany

Author notes

*Manuela Simoni, MD, PhD, Unit of Endocrinology and Metabolism, Nuovo Ospedale S. Agostino Estense, Via Giardini 1355, IT-41125 Modena (Italy), E-Mail manuela.simoni@unimore.it

Article

Publisher ID: 358590 Pmcid ID: PMC4109513 Other ID: Eur Thyroid J 2014;3:101-108

DOI: 10.1159/000358590

PMC ID: PMC4109513

PubMed ID: 25114873

SO-VID: 657b44ba-445f-44ea-82c3-25cc0e059505

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 21 October 2013

Date accepted : 13 January 2014

Page count

Figures: 5, Tables: 1, Pages: 8

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The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

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Karger: Endocrinology

Most cited references 29

Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis.

Timing of levothyroxine administration affects serum thyrotropin concentration.

Altered intestinal absorption of L-thyroxine caused by coffee.

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