<html><body style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><div>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.</div><div><br></div><div>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.</div><div><br></div><div>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.</div><div><br></div><div><br></div><div>Abstract:</div><div>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. </div><div><br></div><div>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. </div><div><br></div><div>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. </div><div><br></div><div>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.</div><div><br></div><div>Citation and Access:</div><div>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.](<a href="http://jcp.bmj.com/content/66/4/335.abstract">http://jcp.bmj.com/content/66/4/335.abstract</a>) J Clin Pathol. 2013 Apr;66(4):335-342. Epub 2013 Feb 19. [PMID 23423518](<a href="http://www.ncbi.nlm.nih.gov/pubmed/23423518">http://www.ncbi.nlm.nih.gov/pubmed/23423518</a>), [doi 10.1136/jclinpath-2012-201213](<a href="http://dx.doi.org/10.1136/jclinpath-2012-201213">http://dx.doi.org/10.1136/jclinpath-2012-201213</a>).</div><div><br></div><div><br></div><div><br></div><div apple-content-edited="true"> <div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div><div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; "><br class="Apple-interchange-newline">-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Dr. Johannes W. Dietrich, M.D.</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Laboratory XU44, Endocrine Research</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Medical Hospital I, Bergmannsheil University Hospitals</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Ruhr University of Bochum</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, NRW, Germany</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Phone: +49:234:302-6400, Fax: +49:234:302-6403</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- eMail: "<a href="mailto:j.w.dietrich@medical-cybernetics.de">j.w.dietrich@medical-cybernetics.de</a>"</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- WWW: <a href="http://medical-cybernetics.de">http://medical-cybernetics.de</a></span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- WWW: <a href="http://www.bergmannsheil.de">http://www.bergmannsheil.de</a></span></font></div></div></div></span></div></span></div></span><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space; "><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div><div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- Researcher ID: C-3498-2009</span></font></div><div><font class="Apple-style-span" size="2"><span class="Apple-style-span" style="font-size: 10px; ">-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --</span></font></div></div></div></span><br><span class="Apple-style-span" style="border-collapse: separate; color: rgb(0, 0, 0); font-family: Helvetica; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-decorations-in-effect: none; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; font-size: medium; "><div><br></div></span></div></span></div></span><br class="Apple-interchange-newline"></div><br class="Apple-interchange-newline"> </div><br></body></html>