RT Journal Article
SR Electronic
T1 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
JF Journal of Clinical Pathology
JO J Clin Pathol
FD BMJ Publishing Group Ltd and Association of Clinical Pathologists
SP 335
OP 342
DO 10.1136/jclinpath-2012-201213
VO 66
IS 4
A1 John E M Midgley
A1 Rudolf Hoermann
A1 Rolf Larisch
A1 Johannes W Dietrich
YR 2013
UL http://jcp.bmj.com/content/66/4/335.abstract
AB 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.