Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine

  • Rudolf Hoermann, John Edward Maurice Midgley, Rolf Larisch, Johannes Wolfgang Christian Dietrich
  • PLoS ONE, November 2017, Public Library of Science (PLoS)
  • DOI: 10.1371/journal.pone.0187232

TSH – an unreliable diagnostic test of of thyroid function

What is it about?

Up to 15 percent of all hypothyroid patients under therapy suffer from reduced quality of life compared to a healthy condition. Alarmingly, this applies especially to patients receiving substitutive therapy with levothyroxine, even when laboratory results suggest a sufficient substitution dose. The reasons for this „syndrome T“, affecting about 0.5% of the population, are still uncertain. Current research is helping to solve the conundrum of syndrome T. A cooperative project involving two German centres (Klinikum Lüdenscheid and Bergmannsheil University Hospitals) and researchers from Australia and the United Kingdom have devised detailed clinical studies augmented by computer simulation suggesting that today’s diagnostic practice may significantly contribute to poor quality of life in patients with hypothyroidism. According to current guidelines, functional thyroid disorders are principally assessed by means of pituitary thyrotropin (TSH) determination in serum. Since TSH and the so-called “peripheral” thyroid hormones triiodothyronine (T3) and thyroxine (T4) are interconnected in a feedback loop, the supply with thyroid hormones may be assessed by measuring TSH, free T4 (FT4) and free T3 (FT3) in patient serum. This also applies to dose titration in patients receiving substitutive therapy with levothyroxine. For cost efficiency it has repeatedly been suggested to measure TSH only. This practice may be less beneficial than previously assumed. The relevant study included more than 230 patients with different thyroid disorders and a similar sized cohort of thyroid-healthy controls. In this collective they repeatedly measured thyroid hormones and interrelated the clinical findings with a mathematical approach. The results showed that the relationship between the hormones FT4 and TSH is less definite than previously thought. Apart from FT4 concentration TSH levels also depend essentially on the set point of thyroid homeostasis. This observation was confirmed by computer simulation demonstrating that the set point can be modified by multiple biological constants and variables. Based on these results the working group developed a theory of adaptive set points integrating genetic, epigenetic and controlled allostatic effects.

Why is it important?

This study has profound implications for the future care of thyroid patients. It demonstrates that the TSH-centred algorithm commonly used in thyroid diagnostics may not be well-suited for a substantial portion of hypothyroid patients. „The currently prevailing TSH-only approach has been adopted because of its perceived simplicity combined with the advantage of low costs“ says Johannes W. Dietrich from Bergmannsheil University Hospitals. However, the studies have shown that TSH concentration does not precisely mirror thyroid hormone signalling. TSH measurement may be sufficient for screening of asymptomatic subjects. However, in patients presenting with hypothyroid or hyperthyroid symptoms, measurement of FT4 and FT3 appears to be more suited for diagnostic evaluation. This also applies to dose-finding for optimising substitutive therapy with levothyroxine.


PD Dr. med. Johannes W Dietrich
Bergmannsheil University Hospitals Bochum

Precise evaluation of thyroid function must address the complex interrelationships of the whole interactive system. Mathematical methods and computer simulations can aid in assessing the quality of laboratory methods and in increasing the discriminatory power of diagnostics.

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The following have contributed to this page: PD Dr. med. Johannes W Dietrich and Professor Rudolf Hoermann