The homeostatic set point of the hypothalamus-pituitary-thyroid axis--maximum curvature theory for personalized euthyroid targets

Abstract

Background: Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual.

Methods: We have previously shown that the dose-response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the 'knee' region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic.

Results: The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals.

Conclusions: In this treatise, we provide evidence supporting a set point-based approach in tailoring euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.

Figure 1

HP function (f1), curvature function (f2) and derivative of f2 (f3). For illustrative purposes, [FT4]sp (set point) and [TSH]sp (set point) which respectively represent the values of [FT4] and [TSH] where the euthyroid set point occurs are 15 pmol/L and 1.6 mIU/L respectively. These set point values correspond to $\phi =\frac{1}{\left[\mathit{TSH}\right]\sqrt{2}}=0.442$ and S = [TSH]exp(φ[FT4]) = 1211.

Figure 2

Plot of loop gain as a function of TSH (solid line). This shows a maximum loop gain at the set point while the first derivative of the loop gain is illustrated by the dotted line.

Figure 3

The homeostatic euthyroid equilibrium point. The set point occurs at the intersection of the HP (black) and the inverted thyroid (blue) functions coinciding with the maximum curvature of the HP function.

Figure 4

Sensitivity analysis of S and φ A) Parameter variations as a function of [FT4] and B) Parameter variations as a function of [TSH].

Figure 5

Multi-level regression model of the dataset in Table1(gamma distribution and log link; random intercept and slope model). TFTs are level 1 while subjects are level 2. Rectangles represent observed variables and ovals represent latent variables. Numbers represent variance, covariance, regression coefficient and constant.

Figure 6

Set point tracing of patient P11 (LMC).

Figure 7

Set point tracing of patient P53 (AL).

Figure 8

Set point tracing of patient P31 (SSPG).

Figure 9

Set point tracing of patient P68 (KST).

Figure 10

Set point tracing of patient P45 (LBH).

Figure 11

Set point tracing of patient P19 (NWC).

Figure 12

Set point tracing of patient P22 (LBG).

Figure 13

Set point tracing of patient P20 (LPB).

Figure 14

Scatter plots and associated HP curves A) TSH vs. FT4 (N=70) B) log TSH vs. FT4 (N=70) C) HP curves (N=20) and D) HP curves with individual set points (N=70).

Figure 15

Graph showing the scatter-plot of the computed set points of all cases (N = 70).

Figure 16

Computation of set point using a C57BL/6 healthy mouse model.