07 Fakultät Konstruktions-, Produktions- und Fahrzeugtechnik
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Item Open Access Mathematical modeling of the pituitary-thyroid feedback loop: role of a TSH-T3-shunt and sensitivity analysis(2018) Berberich, Julian; Dietrich, Johannes W.; Hoermann, Rudolf; Müller, Matthias A.Despite significant progress in assay technology, diagnosis of functional thyroid disorders may still be a challenge, as illustrated by the vague upper limit of the reference range for serum thyrotropin (TSH). Diagnostical problems also apply to subjects affected by syndrome T, i.e. those 10% of hypothyroid patients who continue to suffer from poor quality of life despite normal TSH concentrations under substitution therapy with levothyroxine (L-T4 ). In this paper, we extend a mathematical model of the pituitary-thyroid feedback loop in order to improve the understanding of thyroid hormone homeostasis. In particular, we incorporate a TSH-T3 –shunt inside the thyroid, whose existence has recently been demonstrated in several clinical studies. The resulting extended model shows good accordance with various clinical observations, such as a circadian rhythm in free peripheral triiodothyronine (FT3). Furthermore, we perform a sensitivity analysis of the derived model, revealing the dependence of TSH and hormone concentrations on different system parameters. The results have implications for clinical interpretation of thyroid tests, e.g. in the differential diagnosis of subclinical hypothyroidism.Item Open Access Mathematical modeling and simulation of thyroid homeostasis : implications for the Allan-Herndon-Dudley syndrome(2022) Wolff, Tobias M.; Veil, Carina; Dietrich, Johannes W.; Müller, Matthias A.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. 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. 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. 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.