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 (1813 1878) 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 (1871 1945) GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 2 The Concept of Homeostasis Regelungstechnik. Die technische Aufgabe und ihre wirtschaftliche, sozialpolitische und kulturpolitische Auswirkung. Hermann Schmidt (1894 1968) Cerebral Inhibition Meeting 1942 Macy-Conferences 1946 1953 Cybernetics Group and Norbert Wiener GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 3 1
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, 38 40. 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, 13 67. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 4 Homeostasis in Endocrinology Hohlweg, W. & Junkmann, K. (1932) Die hormonal-nervöse Regulierung des Hypophysenvorderlappens. Klinische Wochenschrift, 11, 321 323 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 5 Discovery of Thyroid Homeostasis Roy Graham Hoskins (1880 1964) E. B. Astwood (1936) Treatment of Hyperthyroidism with Thiourea and Thiouracil. JAMA 122;2: 78 81 Edwin Bennett Astwood (1909 1976) GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 6 2
Discovery of Thyroid Homeostasis Roy Graham Hoskins (1880 1964) Edwin Bennett Astwood (1909 1976) R. G. Hoskins (1949) The Thyroid-Pituitary Apparatus as a Servo (Feed-Back) Mechanism. JCEM 9: 1429 31 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 7 Publications with PubMed search term "pituitary AND thyroid AND (feedback OR homeostasis)" GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 8 Early models GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 9 3
Early models GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 10 Early models GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 11 Early models GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 12 4
Early models GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 13 Thyroid Homeostasis GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 14 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 04.04.2016 15 5
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 04.04.2016 16 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 04.04.2016 17 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 04.04.2016 18 6
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 04.04.2016 19 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 04.04.2016 20 MiMe-NoCoDI Platform Iterative equation: Equifinal solution: Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 21 7
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 2006. 269-74. DOI: 10.13140/2.1.2400.2568 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 22 Simulations with CyberUnits www.cyberunits.sf.net GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 23 Simulations with CyberUnits www.cyberunits.sf.net GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 24 8
Simulations with CyberUnits www.cyberunits.sf.net GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 25 Simulations with CyberUnits www.cyberunits.sf.net GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 26 MiMe-NoCoDI Platform Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 27 9
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: 335 42 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 28 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: 335 42 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 29 MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 30 10
MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 31 MiMe-NoCoDI Model Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 32 Pulsatile TSH Secretion Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion of thyrotropin in man. J Clin Endocrinol Metab. 1986 Sep;63(3):661-8. PMID 3734036. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 33 11
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. 315 331, 2004. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 34 T3 Dissociation Hoermann, Midgley, Larisch and Dietrich, Is Pituitary TSH and adequate measure of thyroid hormone-controlled homeostasis during thyroxine treatment? EJE 2013: 168 271 80 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 35 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 351864, 29 pages, 2012. doi:10.1155/2012/351864 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 36 12
GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 37 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: 335 42 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 38 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 * 10 10 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. 2008 Oct 13;8:13. doi:10.1186/1472-6823-8-13. PMID 18851740 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 39 13
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 04.04.2016 40 Patients Characteristics Sex 26 female, 68 male Age 16 92 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 04.04.2016 41 Results * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 1e-4 Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 42 14
Results Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 43 Results GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 44 Diagnostic Utility : Optimal Parameter Jeyabalan et al. unpublished GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 45 15
Algorithm GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 46 GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s 20 40 nmol/s 1,3 4,1 2 +2 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 47 GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s 20 40 nmol/s 1,3 4,1 2 +2 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 48 16
GT 25,56 GD 8,5 TSHI 1,27 stshi 2,11 1,41 8,67 pmol/s 20 40 nmol/s 1,3 4,1 2 +2 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 49 The TSH Reference Range War GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 50 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. 2002 Mar;87(3):1068-72. PMID 11889165. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 51 17
GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 52 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. 2014 Jun;76(6):1270-87. doi: 10.1007/s11538-014-9955-5. PMID 24789568. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 53 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. 2014 Mar;249:1-7 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 54 18
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. 2014 Mar;249:1-7. doi: 10.1016/j.mbs.2014.01.001. PMID 24480737 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 55 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. 2014 Mar;249:1-7. doi: 10.1016/j.mbs.2014.01.001. PMID 24480737 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 56 M. Leow, S. Goede, J. W. Dietrich. SYSTEM AND METHOD FOR DERIVING PARAMETERS FOR HOMEOSTATIC FEEDBACK CONTROL OF AN INDIVIDUAL 12/2012; Patent: 201208940-5 (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. 2014 Aug 8;11:35. doi: 10.1186/1742-4682-11-35. PMID: 25102854 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 57 19
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. 2014 Mar;249:1-7. doi: 10.1016/j.mbs.2014.01.001. PMID 24480737 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 58 MiMe-Log Model # Pre-Surgery TSH (miu/l) Pre-Surgery FT4 (pmol/l) Setpoint TSH Setpoint FT4 Delta TSH Delta FT4 1 0.23 14.2 1.22 14.7 0.99 0.4 2 1.15 10.3 0.91 11.2 0.24 0.7 3 0.04 10.3 1.09 6.3 1.05 3.1 4 1.42 10.3 4.94 9.3 3.52 0.8 5 1.16 10.3 1.64 12.6 0.48 1.8 6 1.29 11.6 1.63 10.9 0.34 0.5 Mean 1.10 1.22 Cases from NOMOTHETICOS trial (clinicaltrials.gov NCT01145040) GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 59 Reconstruction of Set Point GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 60 20
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. 2015 Aug;47(9):674-80. doi: 10.1055/s-0034-1398616. PMID 25750078. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 61 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: 335 42 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 62 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. 2015 Aug;47(9):674-80. doi: 10.1055/s-0034-1398616. PMID 25750078. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 63 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. 2015 Aug;47(9):674-80. doi: 10.1055/s-0034-1398616. PMID 25750078. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 64 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: 335 42 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 65 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). 2014 Dec;81(6):907-15. doi: 10.1111/cen.12527. PMID 24953754. GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 66 22
Discovering the TSH-T3 shunt GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 67 Discovering the TSH-T3 shunt GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 68 Systems Endocrinology: Advanced Methodology and Clinical Application in Hormonal Feedback GeneSEES 2015 J. W. Dietrich 20150907 GeneSEES 2015 Modelling Hormonal Feedback 04.04.2016 69 23