@article {919, title = {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.}, journal = {J Clin Pathol}, volume = {66}, year = {2013}, month = {2013 Apr}, pages = {335-42}, abstract = {

AIMS: Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making.

METHODS: We (1) retrospectively studied the relationship between TSH and FT(4) 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 FT(4) for hypothyroid subjects was significantly different from that of the euthyroid panel and hyperthyroid subjects (the latter being compromised by reaching the TSH assay{\textquoteright}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 FT(4), 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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Autoantibodies, Autoantigens, Biological Markers, Computer Simulation, Feedback, Physiological, Humans, Hyperthyroidism, Hypothyroidism, Iodide Peroxidase, Iron-Binding Proteins, Linear Models, Middle Aged, Models, Biological, Multivariate Analysis, Nonlinear Dynamics, Predictive Value of Tests, Retrospective Studies, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Young Adult}, issn = {1472-4146}, doi = {10.1136/jclinpath-2012-201213}, author = {Midgley, John E M and Hoermann, Rudolf and Larisch, Rolf and Dietrich, Johannes W} } @article {918, title = {Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?}, journal = {Eur J Endocrinol}, volume = {168}, year = {2013}, month = {2013 Feb}, pages = {271-80}, abstract = {

OBJECTIVE: In recognition of its primary role in pituitary-thyroid feedback, TSH determination has become a key parameter for clinical decision-making. This study examines the value of TSH as a measure of thyroid hormone homoeostasis under thyroxine (T(4)) therapy.

DESIGN AND METHODS: We have examined the interrelationships between free triiodothyronine (FT(3)), free T(4) (FT(4)) and pituitary TSH by means of i) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of l-T(4) and ii) independent mathematical simulation applying a model of thyroid homoeostasis, together with a sensitivity analysis.

RESULTS: Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH vs FT(3) and FT(4) between untreated patients and l-T(4) groups. Total deiodinase activity (G(D)) was positively correlated with TSH in untreated subjects. However, G(D) was significantly altered and the correlation was lost under increasing l-T(4) doses. Ninety-five per cent confidence intervals for FT(3) and FT(4), when assessed in defined TSH concentration bands, differed significantly for l-T(4)-treated compared with untreated patients. Higher doses were often needed to restore FT(3) levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including an important role of pituitary deiodinase type 2.

CONCLUSION: The data reveal disjoints between FT(4)-TSH feedback and T(3) production that persist even when sufficient T(4) apparently restores euthyroidism. T(4) treatment displays a compensatory adaptation but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.

}, keywords = {Adult, Female, Homeostasis, Humans, Hypothyroidism, Male, Pituitary Gland, Retrospective Studies, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1479-683X}, doi = {10.1530/EJE-12-0819}, author = {Hoermann, Rudolf and Midgley, John E M and Larisch, Rolf and Dietrich, Johannes W} } @article {917, title = {TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis.}, journal = {J Thyroid Res}, volume = {2012}, year = {2012}, month = {2012}, pages = {351864}, abstract = {

This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range.

}, issn = {2042-0072}, doi = {10.1155/2012/351864}, author = {Dietrich, Johannes W and Landgrafe, Gabi and Fotiadou, Elisavet H} } @article {920, title = {The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome.}, journal = {BMC Endocr Disord}, volume = {8}, year = {2008}, month = {2008}, pages = {13}, abstract = {

BACKGROUND: Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies.

OBJECTIVES: Primary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis.Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication.

DESIGN: The approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes.The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00591032.

}, issn = {1472-6823}, doi = {10.1186/1472-6823-8-13}, author = {Dietrich, Johannes W and Stachon, Axel and Antic, Biljana and Klein, Harald H and Hering, Steffen} }