Måned: oktober 2022

How hypothyroid can it be

Af

I would like to know how hypothyroid the model can get when the different parameters from fig. 6. A in Principles, Hoermann et al 2022.

Recap text from fig. 6. A: FT4 levels (blue curve) decline, but the mechanisms in system (sys. 10) protect FT3 levels (green curve), keeping them in a range close to the original level, as the percentage of the estimate of FT4 production rate constant (k32 = 0.4 to 1.1) decreases – as typical at the onset of hypothyroidism in patients suffering from autoimmune thyroiditis and progressive thyroid destruction. Other parameters are chosen within ranges, k423 = 0.2-0.3, k43 = 0.7-0.8 and k42 = 0.1-0.2, to approximate the relative contributions to FT3 production according to (32).

The figures shows the most hypothyroid state the model can achieve under the given conditions.

Trying to change the k42 parameter which results in a slight decrease of TSH

Adding drug4 = 0.8 to the most hypothyroid state. We see FT3 is not returning to the level in the perfect homeostasis. See sys1 below. Apart from that FT3 drops with lower k32.

Here I have tried to show the pattern following perfect homeostasis plus drug4. Mimicing the situation where a patient gets unnecessary LT-4 treatment. Will it be possible to identify the pattern and use it to get the patient off LT-4? Is the pattern disguised by the transformation to real hormone values?

Rethinking Hypothyroidism + Principles of Endocrine Regulation

Af

These plots are based on a theoretical model developed by Hoerman et al 2022. The changes in the figures are mine and not discussed with the creators – so I and not the authors are to blame for any error. I would like to show two citations from Rethinking Hypothyroidism, written by A. Bianco.

1.a
1.b

These two plots illustrate perfect homeostasis

2.a
2.b

Here I have added L-T4 to the perfect homeostasis illustrating the hormone pattern in a situation where there is no need for L-T4. The gap between TSH/FT4 widens. (~1/3 is getting unnecessary L-T4 treatment. From Rethinking Hypothyroidism, A. Bianco 2022)

  • TSH decreases
  • FT4 increases
  • FT3 increases
3.a
3.b

Introducing a hypothyroid pattern – TSH increases

4.a
4.b

L-T4 is added to the hypothyroid pattern and we see that L-T4 treatment is not restoring FT3 although TSH is normalized. ( “Once TSH had normalized, the metabolic rate had not,” from Rethinking Hypothyroidism, A. Bianco 2022)

Is it possible to identify those patients who are not hypothyroid but is treated with L-T4 by the changed hormone pattern? In the perfect homeostasis scenario, the ratio FT4/TSH is close to one whereas in the perfect homeostasis with added LT4 the ratio looks close to 1.5. In the L-T4-treated hypothyroid pattern, the ratio is a little above one.

Will converting the hormone figures to standard values obscure the pattern?

Perfect homeostasis

Af

In the article: “Principles of Endocrine Regulation: Reconciling Tensions Between Robustness in Performance and Adaptation to Change.” (Ref.1) the authors describe how their mathematical model can describe perfect homeostasis. The patterns of TRH, TSH, FT3 and FT4 are plotted. The FT3 value is preserved whatever changes in the other hormones.

k32* = 1

In the next two plots, the K32* is changed to 0.3 and 3. Changes in the patterns between the three hormones TSH, FT4 and TRH.

k32* = 0.3
k32* = 3.0

Redefinition of FT3 reference ranges?

k32

The FT4 production rate parameter k32 is the proportionality constant,
positive feedforward of TSH onto FT4 (downstream, activating (short red arrow)).
FT4 increases as k32 increases and TRH-TSH decreases (due to the negative feedback k134 and k234 (green and blue bars)
Thyroid follicular cell (F), deiodinases (D), hypothalamus (H), pituitary (P), thyroid gland (T).
  1. Hoermann R, Pekker MJ, Midgley JEM, Larisch R and Dietrich JW (2022) Principles of Endocrine Regulation: Reconciling Tensions Between Robustness in Performance and Adaptation to Change. Front. Endocrinol. 13:825107. doi: 10.3389/fendo.2022.825107 https://www.frontiersin.org/articles/10.3389/fendo.2022.825107/full