AUTHOR=Wolff Tobias M. , Veil Carina , Dietrich Johannes W. , Müller Matthias A. TITLE=Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome JOURNAL=Frontiers in Endocrinology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.882788 DOI=10.3389/fendo.2022.882788 ISSN=1664-2392 ABSTRACT=Introduction

A mathematical model of the pituitary-thyroid feedback loop is extended to deepen the understanding of the Allan-Herndon-Dudley syndrome (AHDS). 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. A nonlinear modeling approach based on the Michaelis-Menten kinetics and its linear approximation are employed to consider the membrane transporters. The unknown parameters are estimated 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 Michaelis-Menten modeling approach and its linear approximation lead to similar results.

Discussion

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.