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Emerging Clinical and Scientific Trends in Thyroidology. American Thyroid Association Corporate Leadership Council May 14, 2010 Minneapolis, Minnesota. Dr. Frank Lahey on Receiving the American Thyroid Association Award for Meritorious Service, 1953.
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Emerging Clinical and Scientific Trends in Thyroidology American Thyroid AssociationCorporate Leadership CouncilMay 14, 2010Minneapolis, Minnesota
Dr. Frank Lahey on Receiving the American Thyroid Association Award for Meritorious Service, 1953 "..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..."
Taken From The Top 25 Endocrinology Divisions US News and World Report 2010 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
Membership Profile • 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
Prevalence of Mild Thyroid Failure Across Studies: Women by Decade 25 Whickham1 (N=2779) Colorado2 (N=25,862) 20 NHANES3 (N=17,353) 15 % of Women 10 5 0 30s 50s 80s 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.
Trends in Cancer Incidence and Mortality, 1997-2006 http://seer.cancer.gov/cgi-bin/csr/1975_2006
“Graying” of the US Population Smith, et al.,J Clin Oncol 2009
Current Areas of Thyroid-Related Research • 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.
Current Areas of Thyroid-Related Research • 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.
Current Areas of Thyroid-Related Research • 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 element binding protein-stimulates LDL-R gene, CYP7A-cholesterol 7 hydroxylase-bile acid syn/cholesterol Clearance, CETP-cholesterol ester transfer protein) All Organ Systems 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 P448H DBD Hinge LDB N-terminal TRb1 461 100% cofactor interaction interface 410 TRa1 87% P398H
Thyroid Hormone Receptor Crosstalk With Metabolic Regulators 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
Metabolic effects Metabolic effects Side effects Metabolic rate Metabolic rate • • Cardiac • Cholesterol Cholesterol • • CNS • Triglycerides Triglycerides • • Bone • Lipoprotein(a) • • Muscle • Reverse cholesterol transport • • SelectiveThyromimetics Provide New TreatmentOpportunities Selective Thyromimetics
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
Liver Histology of Diet-Induced Obesity Mice After 10 Weeks Treatment with Vehicle or MBO7811 (10 or 30 mg/Kg/day) Vehicle MB07811 10mg MB07811 30mg Cable et al Hepatology 49:407, 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
DITPA (3,5-Diiodothyropropionic Acid) to Treat Heart Failure 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
TSH Receptor as a “Target” for Therapy Kondo, et al.,Nat Rev Cancer 2006
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
Signaling Pathways in Differentiated Thyroid Cancer C-MET EGFR VEGFR RET/PTC PLC-g P Endothelial cell RAS PKC Y1062 BRAF VEGF Tumor cell PI3K MEK AKT ERK
Significance of BRAF Mutations in Papillary Thyroid Cancer Xing, et al.,J Clin Oncol, 2009
Changes in Regional Cerebral Activity Before and After Thyroxine Treatment of Hypothyroidism: Areas Where Uptake Decreased After Treatment 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 inactivating Dio2activating 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
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