1. Graves’ Disease
Devin Brooker 5 2

2. Graves’ Disease causes an increase in thyroid hormones2
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

3. Thyroid Stimulating Hormone stimulation versus auto-antibody binding3

4. 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

5. An increase of thyroid hormones leads to hypothyroidism4

6. An increase of thyroid hormones leads to hypothyroidism4

7. 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

8. 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

9. 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

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. 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

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

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

19. Image References
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20. Image References Continued
5. content/uploads/2014/08/Graves-Disease-Before-After-Surgery.jpg