american thyroid association corporate leadership council may 14, 2010 minneapolis, minnesota
TRANSCRIPT
American Thyroid AssociationCorporate Leadership Council
May 14, 2010Minneapolis, Minnesota
"..I have seen societies come and go..I recognize a harmonious and understanding
attitude between those who are interested in almost pure science, bordering on its relation to clinical medicine, and the rest of us...Even
if we often do not possess the fundamental training and experience to understand them
fully, we listened with profit to these scientific papers that have been presented to us..."
1. Mayo Clinic, Rochester, Minn.3. Johns Hopkins Hospital, Baltimore7. Brigham and Women's Hospital, Boston10. Hospital of the University of Pennsylvania14. University of Chicago16. Washington Hospital Center17. University of Michigan19. Cedars-Sinai Hospital23. Baystate Medical Center24. Methodist Hospital
• National Academy of Sciences-1• Institute of Medicine-2• Medical School Deans and Associate Deans-
Northwestern, UCLA, Georgetown, Harvard, former-Yale, Univ of Alabama, UC San Diego
• Scientific Director NIDDK (Natl Institutes of Health)• Department Chairs; Medicine, Pediatrics, Surgery,
ENT, Genetics-12• University/Major Medical Center Division Chiefs-20• NIH Molecular and Cellular Endocrinology Study
Section-3 of 15 regular members, current chair and 2 past chairs
Condition Reported Prevalence in Adult Population (%)
Hypothyroidism 2Mild (subclinical) hypothyroidism
5-17
Hyperthyroidism 0.2Mild (subclinical) hyperthyroidism
0.1-6
Prevalence of Mild Thyroid Failure Prevalence of Mild Thyroid Failure Across Studies: Women by DecadeAcross Studies: Women by Decade
1. Tunbridge W, et al. Clin Endocrinol. 1977;7:481-493. 2. Canaris G. Arch Intern Med. 2000;160:526-534. 3. Hollowell J. J Clin Endocr Metab. 2002;87:489-499.
0
5
10
15
20
25
30s 50s 80s
% o
f Wom
en
Colorado2 (N=25,862) NHANES3 (N=17,353)
Whickham1 (N=2779)
Decade of Age
http://seer.cancer.gov/cgi-bin/csr/1975_2006
Smith, et al., J Clin Oncol 2009
• Thyroid autoimmunity -prevalent disease, familial, identify triggers, genetic susceptibility, antigen-antibody interactions, antagonists, application to other autoimmune conditions (eg. Type 1 diabetes).
• Thyroid hormone action -development in mammals and amphibians, tissue specificity, analogs, metabolic regulation, neural development, adult brain function, bone growth and remodeling, crystal structure-function, central regulation of TRH/TSH, environmental toxicants.
• Thyroid hormone metabolism -developmental role, deiodinase enzyme structure/function/regulation, regulation in tissues (tumors, skeletal muscle, brain), interface with adrenergic system, role in metabolic regulation.
• Thyroid cancer-mechanism of onset, mechanism of spread, iodine transport and regulation, molecular diagnostics, targeted therapy.
• Thyroid and the heart-mechanism of action, role in atrial fibrillation and heart failure, therapy for heart failure, vascular action to reduce resistance.
• Thyroid Clinical-thyroid disease in pregnancy, iodine intake and influence on thyroid function, thyroid and brain development, psychiatric disease, cardiovascular effects, bone effects, thyroid nodule evaluation, impact of mild thyroid disease, epidemiology, thyroid and aging (bone loss, frailty), thyroid function testing, .
• “Related” Areas-Sodium/iodide symporter (NIS) regulation in tumors and NIS gene therapy, pharmacological treatment in psychiatric disease, interaction with feeding behavior, sleep, circadian rhythms.
Potential Applications of Thyroid Hormone Analogs
Brenta G et al, Nature Clin Pract Endocrin Metab 3:632, 2007
Thyroid hormones T4 and T3
Thyroid hormone analogs
Pituitary GlandCardiovascular System
Liver
All Organ Systems
TSH suppression(negative regulation of
TSH -subunit
Cardiac OutputHeart Rate (HCN2)
Contractility (SERCA2, MHCs)Systemic Vascular Resistance
Cholesterol Metabolism(SERBP-2 sterol regulatoryelement binding protein-stimulatesLDL-R gene, CYP7A-cholesterol7 hydroxylase-bile acid syn/cholesterolClearance, CETP-cholesterol estertransfer protein)
Thermogenesis and V02
(ATP turnover, muscle mass,facultative thermogenesis)
100%
87%
DBD Hinge LDB
TR1
TR1
N-terminal
410
461
P448H
P398H
cofactor interaction interface
Activation
Thyroid Hormone Receptors and Functional Domains
Liu and Brent Trends Endo Metab 2010; 21:166
SERBP-2 sterol regulatory element binding proteinCYP7A-cholesterol 7 hydroxylaseCETP-cholesterol ester transfer protein
Rulon Rawson, MDPresident, American Goiter Association
Presidential Address, 1956
Side effects
• Cardiac
• CNS
• Bone
• Muscle
Metabolic effects
• Metabolic rate
• Cholesterol
• Triglycerides
• Lipoprotein(a)
• Reverse cholesterol transport
Metabolic effects
• Metabolic rate
• Cholesterol
• Triglycerides
•
•
Selective Thyromimetics
Baxter and Webb Nature Drug Discovery 8:308, 2009
Cable et al Hepatology 49:407, 2009
Liver-Activated Thyroid Hormone Receptor Analog
MB07811 is a phosphonate containing derivative of MB07344with high first-pass extraction in the liver and activated byCytochrome P450 3A
Cable et al Hepatology 49:407, 2009
Vehicle MB07811 10mg MB07811 30mg
Baxter and Webb Nature Drug Discovery 8:308, 2009
Ladenson et al N Engl J Med 2010 362:906
Lichtenbelt N Engl J Med 360:1500, 2009
LeanHighBAT
LeanModBAT
Obese
2 hoursExposure16ºC
Brown Adipose Tissue in Humans
Klein I, Danzi S. Circulation 2007; 116:1725
Thyroid Hormone Actions on the Cardiovascular System
Goldman et al Circulation 119:3093, 2009
End Diastolic Diameter Cardiac Index
DITPA
Thyroid Hormone Analogs
Thyroid Hormone Synthesis
Coupling ReactionsDIT+DIT=T4MIT+DIT=T3
NIS-Sodium Iodide Symporter, TPO-thyroid peroxidase, D1/D2-5’-deiodinase 1 and 2
Coupling ReactionsMIT+DIT=T3DIT+DIT=T4
Kondo, et al., Nat Rev Cancer 2006
Neumann et al Endocrinology 149:5945, 2008
Neumann et al Endocrinology 149:5945, 2008
Low Molecular Weight Compound 52 Antagonizes TSHStimulation of the TSH-Receptor
Thyroid Salivary Gland
Stomach Lactating Breast
Transactions of the American Goiter Association 1951
Xing, et al., J Clin Oncol, 2009
Bauer et al J Clin Endocrinol Metab 94:2922, 2009PCC-posterior cingulate cortexACC-anterior cingulate cortex
P13, ~ onset of hearing
P0, birth P20, weaning
Dio2 activating
amplify hormone
conception
Thyroid hormone and the senses: the example of hearing
Multiple genes determine the nature, cell-specificity and timing of the response to T3
• Adequate amounts of thyroid hormone in the circulation are necessary
• The cochlea auto-regulates its hormonal response: Dio2 and Dio3, double control over timing
• “Critical period” of maturation of auditory function, depends upon T3
Dio3 inactivating
limit hormone
TR~ E12
“critical period”
MCT8-Thyroid Hormone Transporter
Hierarchy of ligand preference T3>T4>rT3~T2
Visser et al Best Prac Res Clin Endo Metab 21:223, 2007
Model of the role of astrocytes expressing D2 to convert
T4 to T3 and neurons expressing the MCT8
transporter to take up T3.
• Mutations in the monocarboxylase transporter 8 (MCT8) gene located on X chromosome.
• Neurologic and thyroid function test abnormalities in males carrying the mutation
• Neurologic abnormalities include dystonia, developmental delay, and progressing to quadriplegia
• Inactivating mutations of the MCT8 gene identified
Alan-Herndon-Dudley Syndrome-X Linked Mental Retardation
Schwartz and Stevenons, Best Prac Res Clin Endo Metab 21:307, 2007
DITPA
Thyroid Hormone Analogs