Graves’ Disease Devin Brooker 5 2

Graves’ Disease causes an increase in thyroid hormones 2 An autoimmune condition that uses antibody-mediated antibodies to target the thyrotropin- TSH receptor (TSHR) Results in hyperthyroidism The result of of a breakdown in the Thyroid-Stimulating Hormone Receptor (TSHR) tolerance This causes the thyroid gland to produce to many thyroid hormones 1

Thyroid Stimulating Hormone stimulation versus auto-antibody binding 3

Thyroid hormones T3 and T4 stimulate the production of TSH 7 Thyroid hormone levels decrease: Pituitary gland produces TSH TSH stimulates thyroid to produce more hormones (T3 and T4) T3 and T4 regulate vital body functions and controls metabolism 1

An increase of thyroid hormones leads to hypothyroidism 4

An increase of thyroid hormones leads to hypothyroidism 4

What are the symptoms of Graves’ Disease? Graves orbitopathy Autoimmune inflammatory disorder of the eyes Swelling of the eyes and eye lid Proptosis Reduced vital and mental quality of life for several years Cardiomyopathy Heart muscle thickens and becomes weaker If left untreated: Leads to significantly increased morbidity and mortality 2

The connection between hypothyroidism and the symptoms 6 Increased size of extraocular muscles and ocular fat: Orbital fibroblast Cytokines Immune cells Autoantibodies Environmental factors Genetic factors The antigen involved is still unknown Hypothesize that the orbital and thyroid tissues share a common antigen Cardiomyopathy occurs, but is unknown as to why it occurs

What is the Epidemiology of Graves’ Disease? Epidemiology: the study of the distribution and the determinants of the distribution of the disease About 14 people out of 100,000 are diagnosed with Graves disease per year 88% female Generally diagnosed between the ages of 30 and 50 3

What are the risk factors of Graves’ Disease? Genetics Hypothyroidism can be elicited in about 50% of families that has a history of Graves’ Disease People with gene locus HLA-B8 are more at risk Not just that gene alone causes GD When the HLA-B8 are in linkage dysequilibrium (close enough) to another gene Environmental determinants Smoking People who have Down’s Syndrome More than just genetic predisposition 4

What triggers Graves’ Disease? 8 Stressful life events Infection Exposure to high doses of iodine Genetic susceptibility coupled with environmental factors

What is the Thyroid-Stimulating Hormone Receptor (TSHR)? Pituitary gland produces TSH TSHR is the main autoantigen Expressed mainly in thyroid but also in adipocytes, fibroblasts, bone cells, and other places Regulates thyroid growth, production and secretion 1

Molecular and cellular pathophysiology of Graves’ Disease TSHR-reactive B cells survive deletion Potentially present thyroid autoantigen to T cells Induces proinflammatory cytokines B cells in thyroid gland are hyperactive TSHR blocking antibodies also prevent TSH binding to the receptor T3 and T4 hormones are produced uncontrollably in thyroid Graves’ Disease is now underway Hyperthyroidism will more than likely occur 1

Factors contributing to the development of Graves’ Disease Simplified Outline of the Development of Graves’ Disease 1 Thyrocytes: cells in thyroid gland that are responsible for the production and secretion of thyroid hormones

What is the role of molecular mimicry in Graves’ Disease? (Friedman and Fialkow) A failure to respond to a pathogenic agent which cross-reacts with the persons antigens Immune system releases TSHR blocking antibodies that mimic TSH Binds directly to the natural TSHR conformational epitopes in ectodomain 4

What are the treatments for Graves’ Disease?7 Initially treated by giving thyreostatic drugs Carbimazol Blocks synthesis of thyroid hormone Then followed by radioiodine therapy if carbimazol did not work Radioactive iodine processed and destroys the precursor for TSH Fewer amounts of hormones being produced Leads to decreased hormones in thyroid Surgical removal of the thyroid gland

References 1. Morshed, S. A., Davies, T. F. 2015. Graves' disease mechanisms: the role of stimulating, blocking, and cleavage region TSH receptor antibodies. Horm Metab Res. 47(10): 727-734. 2. Ungerer, Martin, FaBbender, Julia, Li, Zhongmin, Münch, Götz, Holthoff, Hans-Peter. 2017. Review of mouse models of graves’ disease and orbitopathy—novel treatment by induction of tolerance. Clinic Rev Allerg Immunol. 52: 182-193. 3. Cooper, Glinda S., Stroehla, Berrit C. 2003. The epidemiology of autoimmune diseases. Autoimmunity Reviews. 2(2003): 119-125. 4. Friedman, J. M and Fialkow, Philip J. 1978. The genetics of graves’ disease. Clinics in Endocrinology and Metabolsim. 7(1): 47-65.

References Continued… 5. DeGroot, Leslie J. Graves’ disease and the manifestations of thyrotoxicosis. National Library of Medicine. 2015. 6. Maheshwari, Rajat and Weis, Ezekiel. 2012. Thyroid associated orbitopathy. Indian Journal of Ophthalmology. 60(2): 87-93. 7. Brady, Bridget. “Thyroid Gland, How it Functions, Symptoms of Hyperthyroidism and Hypothyroidism.” EndocrineWeb, Vertical Health LLC, 7 Apr. 2017. 8. Girgis, Christian M., Champion, Bernard L., and Wall, Jack R. 2011. Current concepts in graves’ disease. Endocrinol and Metabolism. 2(3): 135-144.

Image References 1. https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact =8&ved=0ahUKEwi2t72zms_XAhWGRyYKHcjkDAIQjRwIBw&url=https%3A%2F%2Fwww.e ndocrineweb.com%2Fconditions%2Fthyroid%2Fhow-your-thyroid- works&psig=AOvVaw14MxHe-D2W6nGG1SpwQDUZ&ust=1511337808040245 2. http://davemontgomerymd.com/graves-disease/ 3.https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&ua ct=8&ved=0ahUKEwjp6Z7Pis_XAhUS3YMKHYGxC9YQjRwIBw&url=https%3A%2F%2Fww w.slideshare.net%2Fyassinalsaleh1%2Fgraves-disease-in-children-and- adolscent&psig=AOvVaw3VzXpT676qZl1Mlo1LVQkM&ust=1511333608955696 4. https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact =8&ved=0ahUKEwj8_qm6i8_XAhXj4IMKHVpHD94QjRwIBw&url=http%3A%2F%2Fcmaps public3.ihmc.us%2Frid%3D1209675116453_740248024_47097%2F04b.%2520Thyroid%2 520Hormone%2520Diseases.cmap&psig=AOvVaw1vEGWttBtV8k5tGzOJ56nm&ust=1511 333823001709

Image References Continued 5. https://tabanmd-6dce.kxcdn.com/wp- content/uploads/2014/08/Graves-Disease-Before-After-Surgery.jpg