Mathematical modeling of the pituitary-thyroid feedback loop: role of a TSH-T3-shunt and sensitivity analysis

[PR4NOW]

The next paper by the group. PR

frontiersin.org/articles/10...

1Julian Berberich1, Johannes W. Dietrich2, Rudolf Hoermann3 and Matthias A. Müller1*

1Institute for Systems Theory and Automatic Control, University of Stuttgart, Germany

2Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University Bochum, Germany

3Private Consultancy Research & Development, Australia

Despite significant progress in assay technology, diagnosis of functional thyroid disorders may still be a challenge, as illustrated by the vague upper limit of the reference range for serum thyrotropin (TSH). Diagnostical problems also apply to subjects affected by syndrome T, i.e. those 10% of hypothyroid patients who continue to suffer from poor quality of life despite normal $TSH$ concentrations under substitution therapy with levothyroxine (L-T_4).

In this paper, we extend a mathematical model of the pituitary-thyroid feedback loop in order to improve the understanding of thyroid hormone homeostasis.

In particular, we incorporate a TSH-T_3-shunt inside the thyroid, whose existence has recently been demonstrated in several clinical studies. The resulting extended model shows good accordance with various clinical observations, such as a circadian rhythm in free peripheral triiodothyronine (FT_3). Furthermore, we perform a sensitivity analysis of the derived model, revealing the dependence of TSH and hormone concentrations on different system parameters. The results have implications for clinical interpretation of thyroid tests, e.g. in the differential diagnosis of subclinical hypothyroidism.

[diogenes Remembering]

The basic aim of this paper was to include T3 in the story of the control of thyroid function. The TSH-T3 shunt inside the thyroid (a TSH-stimulated T4-T3 conversion) is primarily responsible for the T3 the thyroid produces direct and also produces the circadian rhythm for FT3 lagging that of TSH. But it is even more important than that. First, a paper in review shows that this shunt does its utmost to help maintain "normal" FT3 in the body as the thyroid fails, by promoting more and more conversion in thyroid and body until the thyroid has so degenerated that the whole system collapses both from abolition of control and of supply. In that sense the thyroid gland acts not only as a supplier of T4 and T3 for suitable body conversion, but also controls the whole process. On losing the thyroid, the system is irrevocably altered, and oral T4 therapy cannot make up for the complexity there once was. There is no conductor of the process any more, merely a supplier by mouth. That's why the diagnosis/treatment paradigm is quite different from the healthy situation and needs different concepts to achieve it.

[PR4NOW in reply to diogenes]

Diogenes, a few years ago there was a paper about the change is the glycosylation of TSH late in the evening. They estimated that the bioactivity declined by some 30-40%. We thought that this was the driver for the FT4 + FT3 curves from about 11 PM forward. Hopefully helvella will have a better memory than mine of the paper, I haven't been able to find it. Do you think the change in glycosylation could also be tied to circadian rhythm? How does the shunt produce the rhythm? PR

[diogenes Remembering in reply to PR4NOW]

You are taxing my ability to the limit here. The best way I can visualise the working for the FT3 rhythm is to imagine two rates of T3 production, one by the thyroid (feedforward T3-TSH shunt) and one by feedback TSH-mediated body conversion. Obviously they react in different directions to TSH. This causes an instability in the T3 production so that "waves and troughs" occur regularly over time. If they both worked in the same direction then no rhythm would happen. This is shown if you leave the shunt out of the equation. The two opposing effects create a close control, as one forward tendency is countereacted by a reverse one. Its like a seesaw. The TSH story will be quite different in the details of what happens but the end result will also be a circadian rhythm. Different TSH isoforms may well play a part here.

[PR4NOW in reply to diogenes]

Diogenes, well, I think this may be the only time I have taxed your ability to the limit, whereas you consistently seem to tax mine to the limit. PR

[diogenes Remembering in reply to PR4NOW]

I think this is it:

Changes in the Degree of Sialylation of Carbohydrate Chains Modify the Biological Properties of Circulating Thyrotropin Isoforms in Various Physiological and Pathological States

Luca Persani Stefano Borgato Roberto Romoli Carmela Asteria Alessandro Pizzocaro Paolo Beck-Peccoz

The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 7, 1 July 1998, Pages 2486–2492, doi.org/10.1210/jcem.83.7.4970

[helvella Administrator in reply to diogenes]

I've probably picked a different paper - but did post this four or so years ago:

healthunlocked.com/thyroidu...

Thyroid. 2013 Sep 27. [Epub ahead of print]

THYROTROPIN ISOFORMS - IMPLICATIONS FOR TSH ANALYSIS AND CLINICAL PRACTICE.

Estrada JM, Buckey TM, Burman KD, Soldin OP.

ncbi.nlm.nih.gov/pubmed/240...

[Hillwoman]

Thanks to you and Diogenes for extending my knowledge with your discussion above.

However, when my eyes read the phrase "mathematical modeling", my eye-brain comprehension feedback loop promptly shut down.

[RedApple in reply to Hillwoman]

Hillwoman, mine too Maybe there's a little white pill we can take to remedy that?

[Hillwoman in reply to RedApple]

In my case, the little white pills don't seem to be working.