GeneSEES 2015 Systems Endocrinology: Advanced Methodology and Clinical Application in Hormonal Feedback J. W. Dietrich

Transcription

1 GeneSEES 2015 Systems Endocrinology: Advanced Methodology and Clinical Application in Hormonal Feedback J. W. Dietrich The Concept of Homeostasis La fixité du milieu intérieur est la condition de la vie libre, indépendante. Claude Bernard ( ) The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings that I have suggested a special designation for these states, homeostasis. It means a condition--a condition which may vary, but which is relatively constant. Walter B. Cannon ( ) GeneSEES 2015 Modelling Hormonal Feedback The Concept of Homeostasis Regelungstechnik. Die technische Aufgabe und ihre wirtschaftliche, sozialpolitische und kulturpolitische Auswirkung. Hermann Schmidt ( ) Cerebral Inhibition Meeting 1942 Macy-Conferences Cybernetics Group and Norbert Wiener GeneSEES 2015 Modelling Hormonal Feedback

2 Homeostasis in Endocrinology Moore, C.R. & Price, D. (1930) The question of sex hormone antagonism. Proceedings of the Society for Experimental Biology and Medicine, 28, Moore, C.R. & Price, D. (1932) Gonadal hormone functions, and the reciprocal influence between gonads and hypophysis with its bearing on the problem of sex hormone antagonism. American Journal of Anatomy, 50, GeneSEES 2015 Modelling Hormonal Feedback Homeostasis in Endocrinology Hohlweg, W. & Junkmann, K. (1932) Die hormonal-nervöse Regulierung des Hypophysenvorderlappens. Klinische Wochenschrift, 11, GeneSEES 2015 Modelling Hormonal Feedback Discovery of Thyroid Homeostasis Roy Graham Hoskins ( ) E. B. Astwood (1936) Treatment of Hyperthyroidism with Thiourea and Thiouracil. JAMA 122;2: Edwin Bennett Astwood ( ) GeneSEES 2015 Modelling Hormonal Feedback

3 Discovery of Thyroid Homeostasis Roy Graham Hoskins ( ) Edwin Bennett Astwood ( ) R. G. Hoskins (1949) The Thyroid-Pituitary Apparatus as a Servo (Feed-Back) Mechanism. JCEM 9: GeneSEES 2015 Modelling Hormonal Feedback Publications with PubMed search term "pituitary AND thyroid AND (feedback OR homeostasis)" GeneSEES 2015 Modelling Hormonal Feedback Early models GeneSEES 2015 Modelling Hormonal Feedback

4 Early models GeneSEES 2015 Modelling Hormonal Feedback Early models GeneSEES 2015 Modelling Hormonal Feedback Early models GeneSEES 2015 Modelling Hormonal Feedback

5 Early models GeneSEES 2015 Modelling Hormonal Feedback Thyroid Homeostasis GeneSEES 2015 Modelling Hormonal Feedback Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition ASIA NoCoDI Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback

6 Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition NoCoDI Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition ASIA NoCoDI Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition ASIA NoCoDI Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback

7 Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition ASIA NoCoDI Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback Modelling Techniques Building Bricks for Parametrically Isomorphic Models Elimination and Distribution Non-competitive Inhibition ASIA Michaelis-Menten Kinetics Plasma Protein Binding GeneSEES 2015 Modelling Hormonal Feedback MiMe-NoCoDI Platform Iterative equation: Equifinal solution: Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems DOI: / GeneSEES 2015 Modelling Hormonal Feedback

8 MiMe-NoCoDI Platform For k parallel loops: Iterative equation: Equifinal solution: Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems DOI: / GeneSEES 2015 Modelling Hormonal Feedback Simulations with CyberUnits GeneSEES 2015 Modelling Hormonal Feedback Simulations with CyberUnits GeneSEES 2015 Modelling Hormonal Feedback

9 Simulations with CyberUnits GeneSEES 2015 Modelling Hormonal Feedback Simulations with CyberUnits GeneSEES 2015 Modelling Hormonal Feedback MiMe-NoCoDI Platform Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems DOI: / GeneSEES 2015 Modelling Hormonal Feedback

10 MiMe-NoCoDI Thyroid Model Midgley, Hoermann,, Larisch and Dietrich (2013) 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 of Clinical Pathology 66;4: GeneSEES 2015 Modelling Hormonal Feedback MiMe-NoCoDI Thyroid Model Midgley, Hoermann,, Larisch and Dietrich (2013) 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 of Clinical Pathology 66;4: GeneSEES 2015 Modelling Hormonal Feedback MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012: doi: /2012/ PMID GeneSEES 2015 Modelling Hormonal Feedback

11 MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012: doi: /2012/ PMID GeneSEES 2015 Modelling Hormonal Feedback MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012: doi: /2012/ PMID GeneSEES 2015 Modelling Hormonal Feedback Pulsatile TSH Secretion Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion of thyrotropin in man. J Clin Endocrinol Metab Sep;63(3): PMID GeneSEES 2015 Modelling Hormonal Feedback

12 Pulsatile TSH Secretion J. W. Dietrich, A. Tesche, C. R. Pickardt, and U. Mitzdorf, Thyrotropic feedback control: evidence for an additional ultrashort feedback loop from fractal analysis, Cybernetics and Systems, vol. 35, no. 4, pp , GeneSEES 2015 Modelling Hormonal Feedback T3 Dissociation Hoermann, Midgley, Larisch and Dietrich, Is Pituitary TSH and adequate measure of thyroid hormone-controlled homeostasis during thyroxine treatment? EJE 2013: GeneSEES 2015 Modelling Hormonal Feedback NTIS / TACITUS Dietrich, J. W., G. Landgrafe, E. H. Fotiadou (2012). TSH and thyrotropic agonists: Key actors in thyroid homeostasis. Journal of Thyroid Research, vol. 2012, Article ID , 29 pages, doi: /2012/ GeneSEES 2015 Modelling Hormonal Feedback

13 GeneSEES 2015 Modelling Hormonal Feedback A Non-linear Model Midgley, Hoermann,, Larisch and Dietrich (2013) 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 of Clinical Pathology 66;4: GeneSEES 2015 Modelling Hormonal Feedback Thyroid s Secretory Capacity Ĝ T = β T (D T + [TSH ])(1+ K 41 [TBG] + K 42 [TBPA])[FT 4 ] α T [TSH ] Symbol Explanation Value T Dilution factor for T4 (reciprocal of apparent volume of distribution) 0.1 l -1 T Clearance exponent for T4 1.1 * 10-6 sec -1 DT EC50 for TSH 2.75 mu/l K41 Dissociation constant T4-TBG 2 * l/mol K42 Dissociation constant T4-TBPA 2 * 10 8 l/mol Dietrich JW, Stachon A, Antic B, Klein HH, Hering S. The AQUA-FONTIS study:protocol of a multidisciplinary, cross-sectional and prospective longitudinalstudy for developing standardized diagnostics and classification of non-thyroidalillness syndrome. BMC Endocr Disord Oct 13;8:13. doi: / PMID GeneSEES 2015 Modelling Hormonal Feedback

14 AQUA FONTIS G Trial 94 Patients Inclusion criteria: ICU treatment 24 hours TSH < 0,5 miu/l Exclusion criteria: Pregnancy Manifest AIDS disease Impossibility to distinguish between hyperthyroidism and NTIS in a retrospective manner Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback Patients Characteristics Sex 26 female, 68 male Age years, median 67 years APACHE II 2 31, median 12 SAPS II 7 71, median 40 Prognosis 12 died 82 survived CPR 15 resuscitated 79 no CPR LOSIH 1 159, median 13 LOSICU 1 89, median 5 Hyperthyroidism 12 with hyperthyroidism 82 with NTIS Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback Results * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 1e-4 Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback

15 Results Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback Results GeneSEES 2015 Modelling Hormonal Feedback Diagnostic Utility : Optimal Parameter Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback

16 Algorithm GeneSEES 2015 Modelling Hormonal Feedback GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s nmol/s 1,3 4, GeneSEES 2015 Modelling Hormonal Feedback GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s nmol/s 1,3 4, GeneSEES 2015 Modelling Hormonal Feedback

17 GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s nmol/s 1,3 4, GeneSEES 2015 Modelling Hormonal Feedback The TSH Reference Range War GeneSEES 2015 Modelling Hormonal Feedback The TSH Reference Range War Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab Mar;87(3): PMID GeneSEES 2015 Modelling Hormonal Feedback

18 GeneSEES 2015 Modelling Hormonal Feedback MiMe-Log Model Goede SL, Leow MK, Smit JW, Klein HH, Dietrich JW. Hypothalamus-pituitary-thyroid feedback control: implications of mathematical modeling and consequences for thyrotropin (TSH) and free thyroxine (FT4) reference ranges. Bull Math Biol Jun;76(6): doi: /s PMID GeneSEES 2015 Modelling Hormonal Feedback Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci Mar;249:1-7 GeneSEES 2015 Modelling Hormonal Feedback

19 MiMe-Log Model Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci Mar;249:1-7. doi: /j.mbs PMID GeneSEES 2015 Modelling Hormonal Feedback MiMe-Log Model Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci Mar;249:1-7. doi: /j.mbs PMID GeneSEES 2015 Modelling Hormonal Feedback M. Leow, S. Goede, J. W. Dietrich. SYSTEM AND METHOD FOR DERIVING PARAMETERS FOR HOMEOSTATIC FEEDBACK CONTROL OF AN INDIVIDUAL 12/2012; Patent: (Intellectual Property Office of Singapore) Leow MK, Goede SL. The homeostatic set point of the hypothalamus-pituitary-thyroid axis--maximum curvature theory for personalized euthyroid targets. Theor Biol Med Model Aug 8;11:35. doi: / PMID: GeneSEES 2015 Modelling Hormonal Feedback

20 MiMe-Log Model = 11,8 pmol/l = 0,97 miu/l Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci Mar;249:1-7. doi: /j.mbs PMID GeneSEES 2015 Modelling Hormonal Feedback MiMe-Log Model # Pre-Surgery TSH (miu/l) Pre-Surgery FT4 (pmol/l) Setpoint TSH Setpoint FT4 Delta TSH Delta FT Mean Cases from NOMOTHETICOS trial (clinicaltrials.gov NCT ) GeneSEES 2015 Modelling Hormonal Feedback Reconstruction of Set Point GeneSEES 2015 Modelling Hormonal Feedback

21 Discovering the TSH-T3 shunt Hoermann R, Midgley JE, Larisch R, Dietrich JW. Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Horm Metab Res Aug;47(9): doi: /s PMID GeneSEES 2015 Modelling Hormonal Feedback A Non-linear Model Midgley, Hoermann,, Larisch and Dietrich (2013) 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 of Clinical Pathology 66;4: GeneSEES 2015 Modelling Hormonal Feedback Discovering the TSH-T3 shunt Hoermann R, Midgley JE, Larisch R, Dietrich JW. Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Horm Metab Res Aug;47(9): doi: /s PMID GeneSEES 2015 Modelling Hormonal Feedback

22 Discovering the TSH-T3 shunt Hoermann R, Midgley JE, Larisch R, Dietrich JW. Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Horm Metab Res Aug;47(9): doi: /s PMID GeneSEES 2015 Modelling Hormonal Feedback A Non-linear Model Midgley, Hoermann,, Larisch and Dietrich (2013) 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 of Clinical Pathology 66;4: GeneSEES 2015 Modelling Hormonal Feedback Discovering the TSH-T3 shunt Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R. Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf) Dec;81(6): doi: /cen PMID GeneSEES 2015 Modelling Hormonal Feedback

23 Discovering the TSH-T3 shunt GeneSEES 2015 Modelling Hormonal Feedback Discovering the TSH-T3 shunt GeneSEES 2015 Modelling Hormonal Feedback Systems Endocrinology: Advanced Methodology and Clinical Application in Hormonal Feedback GeneSEES 2015 J. W. Dietrich GeneSEES 2015 Modelling Hormonal Feedback