Abstract
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.
Highlights
In recent years, the mathematical modeling of human thyroid hormone homeostasis via the hypothalamic–pituitary–thyroid feedback loop has received an increasing amount of attention
TSH-T3-Shunt in Thyroid Homeostasis parameter values have to be estimated), it does not consider any dynamic phenomena in the HPT axis, which are, of great importance for a deepened understanding of the HPT axis and the development of personalized optimal medication strategies
The inclusion of the TSH-T3-shunt into the model significantly reduces the delay of FT3 w.r.t
Summary
The mathematical modeling of human thyroid hormone homeostasis via the hypothalamic–pituitary–thyroid feedback loop has received an increasing amount of attention. TSH-T3-Shunt in Thyroid Homeostasis parameter values have to be estimated), it does not consider any dynamic phenomena in the HPT axis, which are, of great importance for a deepened understanding of the HPT axis and the development of personalized optimal medication strategies Another drawback is the absence of any consideration of T3, which has been shown to be significant as a key actor in the hypothalamic–pituitary–thyroid feedback loop [4, 9] and in maintaining a good quality of life [5]. The (first-order) sensitivities are a measure for how “sensitive” certain system states (i.e., TSH or hormone concentrations) are with respect to changes in certain parameters (such as, e.g., the thyroid’s secretory capacity GT) These sensitivities reveal structural insight into the functionality of the hypothalamic–pituitary–thyroid axis and can provide explanations for certain clinical observations.
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