Relationship between population T4/TSH setpoint data and T4/TSH physiology

Graag met vermelding van de bron
Plaats reactie
ineke
Berichten: 396
Lid geworden op: 08 nov 2014, 17:53

Relationship between population T4/TSH setpoint data and T4/TSH physiology

Bericht door ineke » 01 mei 2016, 11:32

The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology

Stephen Paul Fitzgerald en Nigel Geoffrey Bean

Abstract
Context.
Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies.
The reasons for the similarities and differences between the curves describing these relationships are unresolved.

Methods.
We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation.
The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a “population curve”) were generated and compared to the empiric population curve.
The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis.

Conclusions.
Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4.
The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4.
The population curve in the dysthyroid states is consistent with known physiological responses to these states.

Figure 1:
Comparison of 2 representations of the population distribution of T4/TSH (the population curve) with the T4/TSH physiological relationship as described in individuals (the TSH curve).
http://www.hindawi.com/journals/jtr/2016/6351473/fig1/

Figure 2:
(a) The TSH curve, (b, c) the T4 curve (on different axes, approx. 41), and (d) the location of the T4/TSH set point.
http://www.hindawi.com/journals/jtr/2016/6351473/fig2/

Figure 3:
The generation of the T4/TSH set points in a population. The circles represent the different potential set points of different individuals (generated as per Figure 2) that are lying on the intersection points of their individual T4 and TSH curves.
http://www.hindawi.com/journals/jtr/2016/6351473/fig3/

Figure 4:
(a) shows a population in which interindividual T4 curve variation is greater than interindividual TSH curve variation (the extreme example of only one TSH curve intersecting with multiple T4 curves is shown), (b) shows the converse, one T4 curve intersecting with multiple TSH curves, and (c) shows a population in which T4 and TSH curve variation are similar (there are multiple T4 and multiple TSH curves and more intersection points).
In these graphs the intersection points are marked by circles of different sizes to indicate a typical distribution of the curves and the larger circles indicate that more individuals are expected to lie in the centre of the range as compared to the extremities. The lines of best fit (thick red lines) are drawn such that the differences in the possible slopes of the lines of best fit (the different population curves) are apparent.
http://www.hindawi.com/journals/jtr/2016/6351473/fig4/

Figure 5:
The generation of a population T4/TSH relationship by nonrandom associations between the physiological curves.
In this example there is a hypothetical association between insensitive thyroids and sensitive pituitaries (this might occur by evolution to minimise T4 variation).
The sizes of the circles, as in Figure 4, are proportionate to the number of individuals in the population with T4/TSH levels at that point. The line of best fit has a small negative slope.
http://www.hindawi.com/journals/jtr/2016/6351473/fig5/

Figure 6:
The effect of vertical shifts in the TSH curves, induced by primary thyroid dysfunction, on the points of intersection of the physiological curves.
On account of these changes the T4 curves in the hypothyroid and hyperthyroid ranges do not intersect with the extensions of the TSH curves of the normal range (these extensions are shown as dashed lines) and therefore the slope of the population curve increases.
The extensions of the TSH curves into the normal range from the regions of thyroid dysfunction are also shown as dashed lines to indicate that they do not normally exist in this range. The red line is the population curve as per Hadlow et al. [4].
http://www.hindawi.com/journals/jtr/2016/6351473/fig6/


5. Conclusion
In summary, this work offers a resynthesis of the empiric data concerning the T4/TSH relationship, demonstrating that the previously derived individual physiological data and population set point data refer to different relationships, which are compatible with each other, and that therefore the former needs no revision on account of the latter.
The similarities and differences previously noted are readily explained by population variations in physiology and by the known physiological responses to primary thyroid dysfunction.
In turn the population data imply a particular pattern of interindividual variation of thyroid and pituitary physiology.
This clarification and simplification of the T4/TSH relationship, apart from having intrinsic value, may contribute to the further understanding of thyroid physiology and in particular the understanding of thyroid regulation.

Gebruikersavatar
laura
Berichten: 2995
Lid geworden op: 11 sep 2013, 22:42
Contacteer:

Re: The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology

Bericht door laura » 01 mei 2016, 11:41

Een population curve?
Het interessante en belangrijke is juist dat het bij de tsh-fT4 setpoint gaat om het individuele setpoint.
Hoe is dat voor jou en voor mij.
Maar niet hoe ons gemiddelde is.
laura

Kijk voor meer informatie ook eens op Schildkliertje.

Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.

ineke
Berichten: 396
Lid geworden op: 08 nov 2014, 17:53

Over schildklierregulatie / setpointmodel / fysiologie

Bericht door ineke » 30 jun 2017, 12:50

Volledig artikel.


Taylor and Francis Online - Open Access
Temperature Volume 4, 2017 - Issue 2 - Pages 114-116
Accepted author version posted online: 19 Jan 2017, Published online: 19 Jan 2017
FRONT MATTER: DISCOVERY


Eigen commentaar op eerder artikel van deze auteurs: Fitzgerald SP, Bean NG.
Population data indicate that thyroid regulation is consistent with an equilibrium-point model, but not with a set-point model

Although it is believed that normal thyroid hormone levels are set points, representing individually pre-determined reference levels, in this paper, we discuss how analysis of the population distribution of Free Thyroxine/ Thyroid Simulating Hormone (FT4/TSH) levels supports a model of homeostasis in which these levels represent the equilibrium points of the physiologic processes of homeostasis alone.

This discussion follows on from our previous work1 in which we differentiated the curve describing the population distribution of FT4/TSH levels (the ‘population curve’) from the curve describing the physiologic relationship of TSH suppression by FT4 (the ‘TSH curve’).
We demonstrated1 that the population curve theoretically could have a positive, neutral or negative slope depending on the pattern of population inter-individual variation in the TSH curve and the ‘T4 curve’ (the curve describing the stimulation of FT4 by TSH).

The fact that the empiric population curve resembles the TSH curve, in also having a negative slope, indicates that in the population inter-individual variation in TSH curves is less than the inter-individual variation in T4 curves.
We discuss here how the negative slope of the population curve also provides evidence as to the nature of FT4 homeostasis.

The prevailing model of homeostasis,2 and particularly as it applies to FT4 levels,3 is a ‘set point’ model.
All set-point models require an obvious set point (a physical/physiologic reference signal) or a hidden set point (a “mathematical” reference signal based on some internal property of the system).
Apart from the means to specify such a set point, such physiology also requires that the body has the means to identify the desired level of the parameter to be so specified, a means to sense an ‘error signal’ (a deviation from this set point), and a linked ‘corrective’ process.2

Thus there has arisen a conception that the body aims for a particular but variable FT4 value,3 and that hypothalamus-pituitary function is controlled to attain and maintain this target level.3
Research has been directed at identifying individuals’ personal set points, rather than relying on population ranges, so that thyroid disorders may be better diagnosed and treated.4

In contrast, an equilibrium or balance model requires no reference level; the level of a parameter in this model reflects the balance point of the physiologic processes acting on the parameter.
In the case of FT4 levels the balance point is that which results from the closed control-loop of FT4 and TSH, i.e. the TSH and T4 curves, each based on proportional control.
In the set point model of FT4 regulation, given that the set point is a reference point set independently of the thyroid, it must be possible for 2 individuals to be identical in terms of thyroid gland sensitivity to TSH (i.e., to have identical T4 curves) but have different FT4 set points.

The prevailing set point model of regulation model requires that the hypothalamus/pituitary attains the appropriate different set point levels by maintaining the different appropriate levels of TSH.
As the T4 curve has a positive slope, the individual with the higher FT4 set point must have the higher prevailing TSH level. If we extend this to a population with inter-individual variation in FT4 set points and T4 curves, we can divide this population into different groups.

For the purposes of this analysis we compare the half with higher set points with the half with lower set points.
Because of the independence of each individual’s T4 set point from his/her T4 curve, these 2 halves must be identical in terms of their T4 curve distributions.
Therefore the half with the higher FT4 set points must, by the same logic as above, have (on average) higher prevailing TSH levels.
However, the population curve has a negative slope reflecting the fact that in the population individuals with higher FT4 have (on average) lower TSH levels. Therefore the set point model cannot be valid.

By contrast an equilibrium point model of FT4 regulation, on account of not requiring independence of the FT4 level and the T4 curve, can generate a population in which higher FT4 values are associated with (on average) lower TSH values.
A mathematical representation of the above argument is shown in Figure 1.

We show a representation of the population distribution of normal T4 curves. The panel representing the set point model shows the FT4 levels being driven by TSH curves, adjusted by mechanisms unimportant to this discussion, to match the set point levels.
In contrast the panel representing the equilibrium point model shows the FT4 values lying at the intersection of the given T4 and TSH curves.
The set point model implies that the FT4 level is set externally to thyroid gland physiology and thus is independent of the T4 curve. Therefore the distribution of FT4 levels on each of the T4 curves is identical to the population distribution.

On each of the T4 curves, higher FT4 levels are accompanied by and driven by higher TSH levels. The population curve in this situation must have a positive slope (Fig. 1.)
In an equilibrium model of FT4 regulation it is not necessary that the distribution of FT4 levels be identical on each T4 curve. If the distribution of TSH curves is restricted as compared with the distribution of T4 curves a negatively sloped population curve is generated (Fig. 1).

To maintain the set point model one could propose that the dominant controller of FT4 levels is not TSH, or that the 2 halves of the population are sufficiently different in terms of the T4 curve distribution that a negative population curve is generated. Both proposals are implausible.
There is no described physiology whereby the FT4 /TSH feedback loop is not the major controller of thyroid physiology, and any putative discrepancy in T4 curve distribution would have to go beyond merely compensating for the different set points, as such compensation would result in a population curve with zero rather than a negative slope.

Triiodothyronine (T3) physiology does not save the thyroid set point model. The physiologic T3/TSH relationships are similar but not as tight as the T4/TSH relationships,4 and the population T3 correlation with TSH is similar to the population T4 correlation in being negative.5

Thus T3 homeostasis also behaves as an equilibrium. The validity of all of the previously described physiologic processes concerning FT4 homeostasis, the hereditary nature of FT4 levels,3 their intra-individual stability3 as compared with the population range, and their variation in response to physiologic and pathological stimuli,3 as well as the importance of deiodinases, hormone transporters, transcription factors, and other processes of thyroid hormone metabolism are not challenged by this paper- they are equally valid in set point and equilibrium point models.

Other work regarding the physiologic effects of different hormone levels within the normal range, the effects of genetic polymorphisms of genes controlling physiologic processes,4 and the effects of changing the mass of the thyroid or pituitary on FT4 levels4 also suggest that thyroid hormone levels are equilibrium points.

In summary we have shown that the analysis of statistical population data can provide information, not available from empiric experimentation, concerning fundamental physiologic processes.
The equilibrium model of thyroid regulation is simple, consistent with evolutionary principles, and consistent in the most parsimonious way with all of the data from physiologic and population studies. The principles of this analysis are applicable to the analysis of other physiologic processes.

Stephen Paul Fitzgerald Department of Internal Medicine, Department of Endocrinology The Royal Adelaide Hospital, Adelaide 5000, South Australia School of Medicine, The University of Adelaide, SA 5005, Australia

http://www.tandfonline.com/doi/abs/10.1 ... RydWVAQEAw



Bovenvermeld commentaar betreft op hun eerder geplaatst artikel:
Research Article
The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology
StephenPaulFitzgerald1,2 andNigelGeoffreyBean3,4

Abstract
Context.
Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies. The reasons for the similarities and differences between the curves describing these relationships are unresolved. Methods. We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation. The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a “population curve”) were generated and compared to the empiric population curve. The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis. Conclusions. Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4. The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4. The population curve in the dysthyroid states is consistent with known physiological responses to these states

Volledig:
https://www.hindawi.com/journals/jtr/2016/6351473/


.

Gast1
Berichten: 524
Lid geworden op: 28 jun 2015, 13:18

Re: Over schildklierregulatie / setpointmodel / fysiologie

Bericht door Gast1 » 09 jul 2017, 22:07

Interessant leesvoer!

Gebruikersavatar
laura
Berichten: 2995
Lid geworden op: 11 sep 2013, 22:42
Contacteer:

Nieuw onderzoek van Fitzgerald

Bericht door laura » 22 okt 2018, 14:01

Population correlations do not support the existence of set points for blood levels of calcium or glucose – a new model for homeostasis


Meer over het onderzoek vind je hier: viewtopic.php?f=17&t=3126&start=10#p24430

The further exposition of the above and the clinical implications of our analysis are the subjects of future planned work.
laura

Kijk voor meer informatie ook eens op Schildkliertje.

Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.

Plaats reactie