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

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 In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease

“…Technically, the interrelationships can be approximately represented by the T 3 -T 4 ratio reflecting conversion efficiency and the FT 4 -TSH ratio estimating the standardized amount of FT 4 released per unit of TSH. The equilibrated levels measured can also be mathematically deconstructed into estimates of the maximum thyroidal capacity (SPINA-GT or abbreviated GT, see Methods) and the pituitary response curve using a validated model of thyroid hormone homeostasis [6,7,8,9,10,11]. In this study we confirmed a strong correlation between functional and sonographically determined anatomical capacity.…”

“…The theoretical background including methodological aspects and reliability of the calculated parameters has recently been reviewed [6,8]. Measurement of thyroid parameters is affected by several types of variation including assay performance, high interindividual variation compared to other laboratory parameters, considerable biological (intraindividual) variation, and variation from circadian and circannual rhythms [33,34].…”

“…In addition to these crude ratios, more refined measures on global deiodinase activity (SPINA-GD) and maximum thyroid capacity (SPINA-GT) were derived according to a mathematical model of thyroid hormone homeostasis, as has been previously described [6,7] and recently reviewed [8]. The SPINA parameters have been validated in a number of studies in different populations comprising together more than 10,000 subjects [6,7,8,9,10,11].…”

“…The SPINA parameters have been validated in a number of studies in different populations comprising together more than 10,000 subjects [6,7,8,9,10,11]. They can be calculated with free open source software (SPINA Thyr 4.0), available from sourceforge.net (RRID:SCR_014352, http://spina.sf.net).…”

“…For further background information and additional methodological details including a Monte Carlo evaluation in comparison with conventional hormone measurements, we refer to recent review articles [6,8]. As for biological variation, when remeasuring the parameters after an average of 8 months in 108 euthyroid subjects, the intraindividual coefficient of variation for GT was only 16%, compared to 20% for TSH in the same subjects.…”