The conundrum of "syndrome T": Is the solution in cybernetic modelling?

Authors

Johannes W. Dietrich

Abstract

Thyroid homeostasis results from a complex multi-loop feedback control that involves the pituitary, the thyroid and peripheral organs. Although this system was believed to be completely understood in 2000, it remained enigmatic why 10% of hypothyroid patients report a poor quality of life, although normal plasma concentrations of the controlling hormone TSH suggest a sufficient substitution dose.

This obvious contradiction acted as a stimulus for intensified research in pituitary-thyroid interaction. We developed a parametrically isomorphic model, which integrates top-down and bottom-up approaches. The resulting description is nearly parameter-free, since its functional relations were based on standard biochemical motifs like Michaelis-Menten kinetics and non-competitive inhibition, which could be calibrated to results of physiological and biochemical research [1].

This form of biological linkage delivers simulation results that are meaningful in a physiological context. Therefore, it was possible to compare different potential processing structures for pituitary function. Analysis on the basis of fractal geometry facilitated the selection of a model that predicted the existence of ultrashort loop feedback control of TSH secretion [2], which is today regarded as an integral part of thyroid homeostasis.

Since the model is based on physiological data even its limits are valuable. Comparing results of in silico simulations with in vivo observations in more than 1000 patients delivered subtle differences that lead to the discovery of a functional TSH-T3 shunt, which links deiodinase activity to TSH signalling and which is mainly mediated via the thyroid [3-5]. This mechanism might compensate for decreasing thyroid function in commencing hypothyroidism, and it may explain, why a subgroup of hypothyroid patients benefits from a combination therapy of levothyroxine (L-T4) and liothyronine (L-T3), while others are better under L-T4 monotherapy.

Combining computer simulations with in-vivo data helps to unveil new motifs of biological processing structures, and it also delivers valuable hypotheses for future biochemical and clinical research.

References

1. Dietrich JW 2002 Der Hypophysen-Schilddrüsen-Regelkreis. Entwicklung und klinische Anwendung eines nichtlinearen Modells. Berlin: Logos-Verlag

2. Dietrich JW, Tesche A, Pickardt CR, Mitzdorf U 2004 Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis. Cybernetics and Systems 35:315-331

3. Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R 2014 Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clinical endocrinology 81:907-915

4. Hoermann R, Midgley JE, Larisch R, Dietrich JW 2015 Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 47:674-680

5. Midgley JE, Larisch R, Dietrich JW, Hoermann R 2015 Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine connections 4:196-205

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