Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome

M., Wolff, Tobias; Veil, C; Dietrich, Johannes W.; Müller, Matthias A.

doi:10.3389/fendo.2022.882788

Front. Endocrinol.

2022

DOI: 10.3389/fendo.2022.882788

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Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome

Wolff, Tobias M.

C Veil

Johannes W. Dietrich

et al.

Abstract: IntroductionA 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 … Show more

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2023

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Cited by 4 publications

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Hyperthyroidism therapy: What can decision support systems already achieve?

Benninger,

Theiler-Schwetz,

Pilz

et al. 2023

J. Klin. Endokrinol. Stoffw.

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Currently, only a few theoretical support systems exist for the treatment of hyperthyroidism. They are typically not practically applicable and solely focus on Graves’ disease. The recently developed DigiThy software framework can be used to assist physicians for methimazole dose titration during the treatment of Graves’ disease. In this study, a pool of 60 virtual patients was created to compare physicians’ individual treatment approaches by 8 different physicians and students (including three colleagues, unexperienced with care of Graves’ disease) with the decision support system DigiThy in terms of already defined performance indices. These indices are used to assess the deviation of FT4 from the reference range throughout the treatment. The computer aided treatment algorithms outperformed the usual care approach according to different prespecified criteria for treatment success. Two out of the three unexperienced colleagues improved their treatment success over time, i.e. with more patients treated. In conclusion, our findings suggest that the DigiThy software may be a useful tool for use as a decision support system in routine care of patients with Graves’ disease, while also serving as an effective training tool for the education of physicians. Randomized controlled studies are required before implementation of DigiThy in daily clinical practice.

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Hyperthyroidism therapy: What can decision support systems already achieve?

Benninger,

Theiler-Schwetz,

Pilz

et al. 2023

J. Klin. Endokrinol. Stoffw.

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The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic–pituitary–thyroid axis

Hoermann

Pekker

Midgley

et al. 2023

Therapeutic Advances in Endocrinology

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Background: Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood. Objective: We used mathematical modelling to further examine mechanisms that exist in the HPT axis regulation for protecting circulating FT3 levels. Methods: A mathematical model consisting of a system of four coupled first-order parameterized non-linear ordinary differential equations (ODEs) was developed, accounting for the interdependencies between the hormones in the HPT axis regulation. While TRH and TSH feed forward to the pituitary and thyroid, respectively, FT4 and FT3 feed backward to both the pituitary and hypothalamus. Stable equilibrium solutions of the ODE system express homeostasis for a particular variable, such as FT3, if this variable stays in a narrow range while certain other parameter(s) and system variable(s) may vary substantially. Results: The model predicts that (1) TSH-feedforward protects FT3 levels if the FT4 production rate declines and (2) combined negative feedback by FT4 and FT3 on both TSH and TRH production rates keeps FT3 levels insensitive to moderate changes in FT4 production rates and FT4 levels. The optimum FT4 and FT3 feedback and TRH and TSH-feedforward ranges that preserve FT3 homeostasis were found by numerical continuation analysis. Model predictions were in close agreement with clinical studies and individual patient examples of hypothyroidism and hyperthyroidism. Conclusions: These findings further extend the concept of HPT axis regulation beyond TSH and FT4 to integrate the more active sister hormone FT3 and mechanisms of FT3 homeostasis. Disruption of homeostatic mechanisms leads to disease. This provides a perspective for novel testable concepts in clinical studies to therapeutically target the disruptive mechanisms.

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Automatic Levothyroxine Dosing Algorithm for Patients Suffering from Hashimoto’s Thyroiditis

et al. 2023

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Hypothyroidism is a condition where the patient’s thyroid gland cannot produce sufficient thyroid hormones (mainly triiodothyronine and thyroxine). The primary cause of hypothyroidism is autoimmune-mediated destruction of the thyroid gland, referred to as Hashimoto’s thyroiditis. A patient’s desired thyroid hormone concentration is achieved by oral administration of thyroid hormone, usually levothyroxine. Establishing individual levothyroxine doses to achieve desired thyroid hormone concentrations requires several patient visits. Additionally, clear guidance for the dosing regimen is lacking, and significant inter-individual differences exist. This study aims to design a digital automatic dosing algorithm for patients suffering from Hashimoto’s thyroiditis. The dynamic behaviour of the relevant thyroid function is mathematically modelled. Methods of automatic control are exploited for the design of the proposed robust model-based levothyroxine dosing algorithm. Numerical simulations are performed to evaluate the mathematical model and the dosing algorithm. With the help of the developed controller thyroid hormone concentrations of patients, emulated using Thyrosim, have been regulated under the euthyroid state. The proposed concept demonstrates reliable responses amidst varying patient parameters. Our developed model provides a useful basis for the design of automatic levothyroxine dosing algorithms. The proposed robust feedback loop contributes to the first results for computer-assisted thyroid dosing algorithms.

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Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome

Cited by 4 publications

References 26 publications

Hyperthyroidism therapy: What can decision support systems already achieve?

Hyperthyroidism therapy: What can decision support systems already achieve?

The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic–pituitary–thyroid axis

Automatic Levothyroxine Dosing Algorithm for Patients Suffering from Hashimoto’s Thyroiditis

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