Download Cholesterol - American Thyroid Association

American Thyroid Association
Corporate Leadership Council
May 14, 2010
Minneapolis, 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, Baltimore
7. Brigham and Women's Hospital, Boston
10. Hospital of the University of Pennsylvania
14. University of Chicago
16. Washington Hospital Center
17. University of Michigan
19. Cedars-Sinai Hospital
23. Baystate Medical Center
24. Methodist Hospital
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National Academy of Sciences-1
Institute of Medicine-2
Medical School Deans and Associate DeansNorthwestern, 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
Hypothyroidism
Mild (subclinical)
hypothyroidism
Hyperthyroidism
Mild (subclinical)
hyperthyroidism
Reported Prevalence in
Adult Population (%)
2
5-17
0.2
0.1-6
Prevalence of Mild Thyroid Failure Across
Studies: Women by Decade
25
% of Women
20
Whickham1 (N=2779)
Colorado2
(N=25,862)
3
NHANES
(N=17,353)
15
10
5
0
30s
50s
Decade of Age
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.
80s
http://seer.cancer.gov/cgi-bin/csr/1975_2006
Smith, et al., J Clin Oncol 2009
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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 structurefunction, central regulation of TRH/TSH,
environmental toxicants.
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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.
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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
Cardiovascular System
Pituitary Gland
Cardiac Output
Heart Rate (HCN2)
Contractility (SERCA2, MHCs)
Systemic Vascular Resistance
TSH suppression
(negative regulation of
TSH -subunit
Thyroid hormones T4 and T3
Thyroid hormone analogs
Liver
Cholesterol Metabolism
(SERBP-2 sterol regulatory
All Organ Systems
element binding protein-stimulates
LDL-R gene, CYP7A-cholesterol
7 hydroxylase-bile acid syn/cholesterol
Clearance, CETP-cholesterol ester
transfer protein)
Thermogenesis and V02
(ATP turnover, muscle mass,
facultative thermogenesis)
Brenta G et al, Nature Clin Pract Endocrin Metab 3:632, 2007
Thyroid Hormone Receptors and Functional Domains
Activation
N-terminal
TR1
DBD Hinge
LDB
P448H
461
100%
cofactor interaction interface
TR1
87%
410
P398H
SERBP-2 sterol regulatory element binding protein
CYP7A-cholesterol 7 hydroxylase
CETP-cholesterol ester transfer protein
Liu and Brent Trends Endo Metab 2010; 21:166
Rulon Rawson, MD
President, American Goiter Association
Presidential Address, 1956
Selective Thyromimetics
Side effects
• Cardiac
• CNS
• Bone
• Muscle
Metabolic effects
• Metabolic rate
• Cholesterol
• Triglycerides
• Lipoprotein(a)
• Reverse cholesterol transport
Baxter and Webb Nature Drug Discovery 8:308, 2009
Liver-Activated Thyroid Hormone Receptor Analog
MB07811 is a phosphonate containing derivative of MB07344
with high first-pass extraction in the liver and activated by
Cytochrome P450 3A
Cable et al Hepatology 49:407, 2009
Vehicle
MB07811 10mg
MB07811 30mg
Cable et al Hepatology 49:407, 2009
Baxter and Webb Nature Drug Discovery 8:308, 2009
Ladenson et al
N Engl J Med
2010 362:906
Brown Adipose Tissue in Humans
Lean
High
BAT
Lean
Mod
BAT
Obese
2 hours
Exposure
16ºC
Lichtenbelt N Engl J Med 360:1500, 2009
Thyroid Hormone Actions on the Cardiovascular System
Klein I, Danzi S. Circulation 2007; 116:1725
End Diastolic Diameter
Cardiac Index
Goldman et al Circulation 119:3093, 2009
Thyroid Hormone Analogs
DITPA
Thyroid Hormone Synthesis
Coupling Reactions
MIT+DIT=T3
DIT+DIT=T4
Coupling Reactions
DIT+DIT=T4
MIT+DIT=T3
NIS-Sodium Iodide Symporter, TPO-thyroid peroxidase, D1/D2-5’-deiodinase 1 and 2
Kondo, et al., Nat Rev Cancer 2006
Neumann et al Endocrinology 149:5945, 2008
Low Molecular Weight Compound 52 Antagonizes TSH
Stimulation of the TSH-Receptor
Neumann et al Endocrinology 149:5945, 2008
Thyroid
Salivary Gland
Stomach
Lactating Breast
Transactions of the American Goiter Association 1951
Xing, et al., J Clin Oncol, 2009
ACC-anterior cingulate cortex
PCC-posterior cingulate cortex
Bauer et al J Clin Endocrinol Metab 94:2922, 2009
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
P13, ~ onset
of hearing
P0, birth
conception
P20, weaning
~ E12
TR
Dio3
Dio2
inactivating
activating
limit hormone
amplify hormone
“critical period”
MCT8-Thyroid Hormone Transporter
Hierarchy of ligand preference
T3>T4>rT3~T2
Model of the role of astrocytes
expressing D2 to convert
T4 to T3 and neurons
expressing the MCT8
transporter to take up T3.
Visser et al Best Prac Res Clin Endo Metab 21:223, 2007
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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
Thyroid Hormone Analogs
DITPA