Relational Stability in the Expression of Normality, Variation, and Control of Thyroid Function

Abstract

Thyroid hormone concentrations only become sufficient to maintain a euthyroid state through appropriate stimulation by pituitary thyroid-stimulating hormone (TSH). In such a dynamic system under constant high pressure, guarding against overstimulation becomes vital. Therefore, several defensive mechanisms protect against accidental overstimulation, such as plasma protein binding, conversion of T4 into the more active T3, active transmembrane transport, counter-regulatory activities of reverse T3 and thyronamines, and negative hypothalamic-pituitary-thyroid feedback control of TSH. TSH has gained a dominant but misguided role in interpreting thyroid function testing in assuming that its exceptional sensitivity thereby translates into superior diagnostic performance. However, TSH-dependent thyroid disease classification is heavily influenced by statistical analytic techniques such as uni- or multivariate-defined normality. This demands a separation of its conjoint roles as a sensitive screening test and accurate diagnostic tool. Homeostatic equilibria (set points) in healthy subjects are less variable and do not follow a pattern of random variation, rather indicating signs of early and progressive homeostatic control across the euthyroid range. In the event of imminent thyroid failure with a reduced FT4 output per unit TSH, conversion efficiency increases in order to maintain FT3 stability. In such situations, T3 stability takes priority over set point maintenance. This suggests a concept of relational stability. These findings have important implications for both TSH reference limits and treatment targets for patients on levothyroxine. The use of archival markers is proposed to facilitate the homeostatic interpretation of all parameters.

Keywords: TSH; TSH feedback control; set point; thyroid homeostasis; thyroid hormones.

Figure 1

Relationship between FT3 and TSH in healthy controls and LT4-treated patients. While stable and uncorrelated with logarithmic TSH levels in controls, serum FT3 concentrations were unstably associated with TSH in LT4-treated patients. Data are from a published trial (88). The regression lines shown and their 95% confidence interval (shaded area) were fitted by a linear model in 207 controls or locally weighted scatterplot smoothing in 353 patients on LT4.