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Emerging Clinical and Scientific Trends in Thyroidology

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

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  1. Emerging Clinical and Scientific Trends in Thyroidology American Thyroid AssociationCorporate Leadership CouncilMay 14, 2010Minneapolis, Minnesota

  2. 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..."

  3. 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

  4. 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

  5. Prevalence of Thyroid Diseases

  6. 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.

  7. Trends in Cancer Incidence and Mortality, 1997-2006 http://seer.cancer.gov/cgi-bin/csr/1975_2006

  8. “Graying” of the US Population Smith, et al.,J Clin Oncol 2009

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Thyroid Hormone Receptors and Functional Domains Activation P448H DBD Hinge LDB N-terminal TRb1 461 100% cofactor interaction interface 410 TRa1 87% P398H

  14. 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

  15. Rulon Rawson, MD President, American Goiter Association Presidential Address, 1956

  16. 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

  17. Baxter and Webb Nature Drug Discovery 8:308, 2009

  18. 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

  19. 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

  20. Baxter and Webb Nature Drug Discovery 8:308, 2009

  21. Ladenson et al N Engl J Med 2010 362:906

  22. Brown Adipose Tissue in Humans Lean High BAT Lean Mod BAT Obese 2 hours Exposure 16ºC Lichtenbelt N Engl J Med 360:1500, 2009

  23. Thyroid Hormone Actions on the Cardiovascular System Klein I, Danzi S. Circulation 2007; 116:1725

  24. DITPA (3,5-Diiodothyropropionic Acid) to Treat Heart Failure End Diastolic Diameter Cardiac Index Goldman et al Circulation 119:3093, 2009

  25. Thyroid Hormone Analogs DITPA

  26. 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

  27. TSH Receptor as a “Target” for Therapy Kondo, et al.,Nat Rev Cancer 2006

  28. Neumann et al Endocrinology 149:5945, 2008

  29. Low Molecular Weight Compound 52 Antagonizes TSH Stimulation of the TSH-Receptor Neumann et al Endocrinology 149:5945, 2008

  30. Thyroid Salivary Gland Stomach Lactating Breast

  31. Transactions of the American Goiter Association 1951

  32. 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

  33. Significance of BRAF Mutations in Papillary Thyroid Cancer Xing, et al.,J Clin Oncol, 2009

  34. 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

  35. 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”

  36. 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

  37. 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

  38. Alan-Herndon-Dudley Syndrome-X Linked Mental Retardation Schwartz and Stevenons, Best Prac Res Clin Endo Metab 21:307, 2007

  39. Thyroid Hormone Analogs DITPA

  40. Thank-you

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