Mathematical modeling and simulation of thyroid homeostasis

Implications for the Allan-Herndon-Dudley syndrome

authored by

Tobias M. Wolff, Carina Veil, Johannes W. Dietrich, Matthias A. Müller

Abstract

Objective A mathematical model of the pituitary-thyroid feedback loop is extended to deepen the understanding of the Allan-Herndon-Dudley syndrome (AHDS).

Background The AHDS is characterized by unusual thyroid hormone concentrations and a mutation in the SLC16A2 gene encoding for the monocarboxylate transporter 8 (MCT8). This mutation leads to a loss of thyroid hormone transport activity. One hypothesis to explain the unusual hormone concentrations of AHDS patients is that due to the loss of thyroid hormone transport activity, thyroxine (T4) is partially retained in thyroid cells.

Methods This hypothesis is investigated by extending a mathematical model of the pituitary-thyroid feedback loop to include a model of the net effects of membrane transporters such that the thyroid hormone transport activity can be considered. Two modeling approaches of the membrane transporters are employed: on the one hand a nonlinear approach based on the Michaelis-Menten kinetics and on the other hand its linear approximation. The unknown parameters are identified through a constrained parameter optimization.

Results In dynamic simulations, damaged membrane transporters result in a retention of T4 in thyroid cells and ultimately in the unusual hormone concentrations of AHDS patients. The two different modeling approaches lead to similar results.

Conclusion The results support the hypothesis that a partial retention of T4 in thyroid cells represents one mechanism responsible for the unusual hormone concentrations of AHDS patients. Moreover, our results suggest that the retention of T4 in thyroid cells could be the main reason for the unusual hormone concentrations of AHDS patients.

Organisation(s)

Institute of Automatic Control

External Organisation(s)

University of Stuttgart
Ruhr-Universität Bochum
Klinik Blankenstein - Katholisches Klinikum Bochum
Centrum für Seltene Erkrankungen Ruhr (CeSER)

Type

Article

Journal

Frontiers in Endocrinology

Volume

13

No. of pages

12

ISSN

1664-2392

Publication date

08.12.2022

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://www.biorxiv.org/content/10.1101/2022.01.24.476744v1 (Access: Open)
https://doi.org/10.3389/fendo.2022.882788 (Access: Open)