Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research.

Johannes W Dietrich,Evelin Wiora,Harald H Klein,Gabi Landgrafe-Mende,Apostolos Chatzitomaris,Rudolf Hoermann,John E M Midgley

doi:10.3389/fendo.2016.00057

Abstract

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thyroid dysfunctions. Advances in mathematical and simulative modeling of pituitary–thyroid feedback control have improved our understanding of physiological mechanisms governing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel’s TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

Highlights

Thanks to the advent of sensitive assays for TSH and free thyroid hormones, the diagnosis of classical forms of overt hypothyroidism and hyperthyroidism has become a straightforward task [1]
A therapeutic challenge arises from the fact that current standard treatment of hypothyroidism with levothyroxine ( -T4) fails to raise the quality of life (QoL) in patients to a level observed in a normal population [7]
They display symptoms that are compatible with either hypothyroidism and hyperthyroidism, and a fraction of 5–15% of hypothyroid patients on -T4 replacement continue to complain about impaired QoL, despite documented biochemical euthyroidism as defined by reference intervals [7, 8]

Summary

Introduction

Thanks to the advent of sensitive assays for TSH and free thyroid hormones, the diagnosis of classical forms of overt hypothyroidism and hyperthyroidism has become a straightforward task [1]. These observations have stimulated a recent debate, whether universal reference ranges for TSH and peripheral thyroid hormones are appropriate [14]. By mathematical modeling and computer simulations, it could be demonstrated that for the majority of hypothyroid patients standard -T4-only therapy should be sufficient to reach normal triiodothyronine tissue concentrations [28, 29], but that substitution with -T3 may be beneficial to reduce the withdrawal period before 131I remnant ablation in patients with thyroid cancer [26].

Results

Conclusion