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=<sec><title>Introduction</title><p>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 <italic>SLC16A2</italic> 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 (<italic>T</italic><sub>4</sub>) is partially retained in thyroid cells.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>In dynamic simulations, damaged membrane transporters result in a retention of <italic>T</italic><sub>4</sub> 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.</p></sec><sec><title>Discussion</title><p>The results support the hypothesis that a partial retention of <italic>T</italic><sub>4</sub> in thyroid cells represents one mechanism responsible for the unusual hormone concentrations of AHDS patients. Moreover, our results suggest that the retention of <italic>T</italic><sub>4</sub> in thyroid cells could be the main reason for the unusual hormone concentrations of AHDS patients.</p></sec>