TY - JOUR

T1 - Mathematical modeling and simulation of thyroid homeostasis

T2 - Implications for the Allan-Herndon-Dudley syndrome

AU - Wolff, Tobias M.

AU - Veil, Carina

AU - Dietrich, Johannes W.

AU - Müller, Matthias A.

N1 - Funding Information: This work is supported by grants from the National Natural Science Foundation of China (No. 81974382), the Major Scientific and Technological Innovation Projects in Hubei Province (No. 2018ACA136), and the Innovative Team for Human Major Diseases Program, Tongji Medical College, Huazhong University of Science and Technology. Funding Information: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 948679).

PY - 2022/12/8

Y1 - 2022/12/8

N2 - 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.

AB - 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.

KW - Allan-Herndon-Dudley syndrome

KW - mathematical modeling

KW - MCT8 deficiency

KW - pituitary-thyroid feedback loop

KW - thyroid hormone transport

UR - http://www.scopus.com/inward/record.url?scp=85144490074&partnerID=8YFLogxK

U2 - 10.3389/fendo.2022.882788

DO - 10.3389/fendo.2022.882788

M3 - Article

AN - SCOPUS:85144490074

VL - 13

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 882788

ER -