[Simthyr-announce] Recent paper suggests hypothyroidism, euthyroidism and hyperthyroidism to be different homeostatic conditions

[Johannes W. D. <joh...@ru...>]

Recently, a new paper using SPINA has been published in the Journal of  
Clinical Pathology. By combining in-silico modelling using SimThyr  
with an observation study in a large clinical sample (n=6641) it could  
be demonstrated that TSH levels are not unambiguously coupled to FT4  
levels. To add even more complexity, GT values in different ranges  
were associated with a different influence of structure parameters on  
TSH levels in sensitivity analysis.

These observations question the log-linear standard model of thyroid  
homeostasis and suggest that a hierarchically structured model of the  
hypothalamic pituitary thyroid interaction may be a more appropriate  
description of pituitary thyrotroph physiology.

The results of this study are of considerable importance for  
diagnostic evaluation of thyroid homeostasis, since they demonstrate  
that a pure TSH-centric approach may be inadequate for diagnosis of  
thyroid function in some, if not most, affected patients.


Abstract:
Aims: Understanding the exact relationship between serum thyrotropin/ 
thyroid stimulating hormone (TSH) and free thyroxine (FT4) is a  
prerequisite for improving diagnostic reliability and clinical  
decision making.

Methods: We (1) retrospectively studied the relationship between TSH  
and FT4 in a large unselected clinical sample (n=6641) of primary  
hypothyroid, euthyroid and hyperthyroid subjects, and (2) applied a  
mathematical model of thyroid hormone feedback control to assess the  
relation between structural parameters and TSH levels in the different  
functional states.

Results: When separately analysing total sample and untreated  
subjects, the correlation slope for logTSH versus FT4 for hypothyroid  
subjects was significantly different from that of the euthyroid panel  
and hyperthyroid subjects (the latter being compromised by reaching  
the TSH assay's lower detection limit). As trends between functional  
states changed, each functional segment appeared to become differently  
regulated. Theoretical modelling and sensitivity analysis revealed  
that the influence of various structural parameters on TSH levels also  
depends on the overall function of the feedback loop.

Conclusions: Our data suggest that the states of hypothyroidism,  
euthyroidism and hyperthyroidism can be regarded as differently  
regulated entities. The apparent complexity could be replicated by  
mathematical modelling suggesting a hierarchical type of feedback  
regulation involving patterns of operative mechanisms unique to each  
condition. For clinical purposes and assay evaluation, neither the  
standard model relating logTSH with FT4, nor an alternative model  
based on non-competitive inhibition can be reliably represented by a  
single correlation comparing all samples for both hormones in one all- 
inclusive group.

Citation and Access:
Midgley JE, Hoermann R, Larisch R, Dietrich JW. [Physiological states  
and functional relation between thyrotropin and free thyroxine in  
thyroid health and disease: in vivo and in silico data suggest a  
hierarchical model.](http://jcp.bmj.com/content/66/4/335.abstract) J  
Clin Pathol. 2013 Apr;66(4):335-342. Epub 2013 Feb 19. [PMID 23423518](http://www.ncbi.nlm.nih.gov/pubmed/23423518 
), [doi 10.1136/jclinpath-2012-201213](http://dx.doi.org/10.1136/jclinpath-2012-201213 
).




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-- Dr. Johannes W. Dietrich, M.D.
-- Laboratory XU44, Endocrine Research
-- Medical Hospital I, Bergmannsheil University Hospitals
-- Ruhr University of Bochum
-- Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, NRW, Germany
-- Phone: +49:234:302-6400, Fax: +49:234:302-6403
-- eMail: "j.w...@me..."
-- WWW: http://medical-cybernetics.de
-- WWW: http://www.bergmannsheil.de
-- Researcher ID: C-3498-2009
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