SPINATHYR: A NOVEL SYSTEMS THEORETIC APPROACH TO DETERMINE THE SECRETION CAPACITY OF THE THYROID GLA - PowerPoint PPT Presentation

Title: SPINATHYR: A NOVEL SYSTEMS THEORETIC APPROACH TO DETERMINE THE SECRETION CAPACITY OF THE THYROID GLA


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SPINA-THYR A NOVEL SYSTEMS THEORETIC APPROACH
TO DETERMINE THE SECRETION CAPACITY OF THE
THYROID GLAND

• J. W. Dietrich, M. R. Fischer, J. Jauch, E.
  Pantke,
• R. Gärtner and C. R. Pickardt
• Medizinische Klinik, Klinikum Innenstadt,
  University of Munich, F. R. Germany

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Current Situation
TSH has poor positive predictive value in
diagnosing hyperthyroid disorders Hidden
physiological parameters determining the
feedback controls behaviour are inaccessible
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Information Processing Structure
Cybernetic model of the feedback
control
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Steady State Prognosis
Steady State Prognosis 1
Inner Loop 5 (ultrashort feedback of TSH)
All hormone levels and transfer parameters
are positive, therefore
gt There is one positive and one negative solution
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Steady State Prognosis
Steady State Prognosis 2
Overall system (all 5 feedback loops)
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Steady State Prognosis
Steady State Prognosis 3
Overall system (continued)
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Steady State Prognosis
Steady State Prognosis 4
Overall system (continued)
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Steady State Prognosis
Steady State Prognosis 5
Overall system (continued)
If
If
Cardanos equation
Casus irreducibilis
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Computer Simulations
Computer Simulations
SimThyr
Parameter settings result output
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Clinical Application
SPINA Thyr
Clinical Application
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SPINA Thyr
SPINA Thyr
Strukture Parameter Inference-Approach to
calculate constant parameters of the feedback
loop from hormone levels determined only
once A The thyroids secretion capacity for
T4 ?T Dilution factor for T4 (0,1 /
l) ?T Clearance exponent for T4 (1,1 10-6
sec-1) DT EC50 for TSH (2,75 mU/l) K41 Dissocia
tion constant T4-TBG (2 1010 l/mol) K42
Dissociation constant T4-TBPA (2 108 l/mol)
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SPINA Thyr
SPINA Thyr
B Sum activity of the peripheral
5-Deiodinase ?31 Dilution factor for T3
(0,026 / l) ?31 Clearance exponent for T3 (8
10-6 sec-1) KM1 Dissociation constant of the
Type-I-DI (5 10-7 mol/l) K30 Dissociation
constant T3-TBG (2 109 l/mol)
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SPINA Thyr
SPINA Thyr
Preliminary reference regions GT 1,41 8,67
pmol/s GD 19,7 38,9 nmol/s Determined from
86 healthy volunteers
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Biological Relevance
SPINA Thyr
Biological relevance? First evaluation with 108
healthy volunteers and 43 patients with diffuse
goiter
1,40E-11
1,20E-11
1,00E-11
GT mol/s
8,00E-12
6,00E-12
4,00E-12
2,00E-12
0
plt0,05 n151
0
5
10
15
20
25
30
35
40
45
50
Volumen ml
Y 3E-12 5,6E-14 X R2 4,6E-2
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Epidemiology
SPINA Thyr
Epidemiology / normal variants 1 Influence of
gender
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Epidemiology
SPINA Thyr
Epidemiology / normal variants 2 Dependency of
age
1,80E-11
3,50E-12
1,60E-11
3,00E-12
1,40E-11
2,50E-12
1,20E-11
2,00E-12
1,00E-11
spez. GT (pmol/(sml)
GT
8,00E-12
1,50E-12
6,00E-12
1,00E-12
4,00E-12
5,00E-13
2,00E-12
0
0
1,00E1
2,00E1
3,00E1
4,00E1
5,00E1
6,00E1
7,00E1
1,00E1
2,00E1
3,00E1
4,00E1
5,00E1
6,00E1
7,00E1
Alter
Alter
Y 3,94E-12 8,79E-15 X R2 2,4E-3
Y 4,78E-13 - 3,92E-15 X R2 ,02
GT (mol/s) spec. GT (mol/(mls)
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Pathophysiology
SPINA Thyr
Pathophysiology 1 Effect of iodide substitution
2,40E-11
2,00E-11
1,60E-11
0
mol/s
I
1,20E-11
8,00E-12
n152 plt0,05
4,00E-12
0
GT
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Pathophysiology
SPINA Thyr
Pathophysiology 2 GT among several thyroid
disorders
Struma diffusa diffuse goiter Struma nodosa
nodular goiter Autonomie toxic adenoma Basedow
Graves disease
1,00E-7
1,00E-8







n. s.




Kontrolle
Kontrolle
1,00E-8
1,00E-9
Struma diffusa
Struma diffusa
1,00E-9
1,00E-10
Autonomie
Autonomie
de Quervain
de Quervain
1,00E-10
1,00E-11
mol/l
mol/l
Struma nodosa
Struma nodosa
1,00E-11
1,00E-12
Basedow
Basedow
1,00E-12
1,00E-13
Hashimoto
Hashimoto
1,00E-13
1,00E-14
GT
spez. GT
n. s. not significant compared with the control
group plt0,05 plt0,001
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Pathophysiology
SPINA Thyr
Pathophysiology 3
Struma diffusa diffuse goiter Struma nodosa
nodular goiter Autonomie toxic adenoma Basedow
Graves disease
n. s. not significant compared with the control
group plt0,05 plt0,001
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Clinical Appraisal
SPINA Thyr
Clinical appraisal 1
Sensitivity TSH FT4 FT3
GT Diffuse goiter 8,9 4,4
7,0 4,5 Nodular goiter 31,6
0,0 5,6 31,6 Toxic adenoma
79,2 8,3 21,7
66,7 Graves disease 58,3 50,0
33,3 58,3 de Quervain 25,0
12,5 25,0 12,5 Hashimoto
50,0 12,5 25,0 37,5
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Clinical Appraisal
SPINA Thyr
Clinical appraisal 2
Specificity TSH FT4 FT3
GT Diffuse goiter 77,3 94,3
89,7 80,7 Nodular goiter 81,2
94,1 89,9 85,1 Toxic adenoma
87,3 94,9 91,8
89,8 Graves disease 81,2 94,1
89,9 85,1 de Quervain 80,3
94,8 90,9 83,5 Hashimoto
81,2 94,8 90,9 84,4
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Clinical Appraisal
SPINA Thyr
Clinical appraisal 3
Pos. pred. value TSH FT4 FT3
GT Diffuse goiter 9,1 16,7
14,3 5,6 Nodular goiter 13,6
0,0 4,8 16,7 Toxic adenoma
43,2 16,7 23,8
44,4 Graves disease 15,9 50,0
19,0 19,4 de Quervain 4,5
8,3 9,5 2,8 Hashimoto
9,1 8,3 9,5 8,3
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Conclusions
SPINA Thyr
Conclusions The secretion capacity GT seems
to mirror the thyroids biology. TSH ideal
for sreening. GT suitable for confirmations
of some hyperthyroidism disorders.
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Outlook
SPINA Thyr
Outlook Prospective study to
asses edidemiological data for
GT Evaluation of GT for therapy
planning Evaluation of deiodinase activity
(GD) Application on other biological signal
transfer systems