Selenium and the Course of Mild Graves’ Orbitopathy

1. Selenium and the Course of Mild Graves’ Orbitopathy Marcocci C M.D., Kahaly GJ M.D., Krassas GE M.D., et al The New England Journal of Medicine, 2011 Jessica Seppala and Danielle Taylor

2. Graves’ Disease (GD) • Autoimmune disease • Most common cause of hyperthyroidism in the US, 1-2% of population • 5:1 female to male ratio • 30-50% of those with GD develop Graves’ orbitopathy (GO) • Current Treatment: • Antithyroid drugs • Radioiodine • Surgery 7

3. Graves’ Orbitopathy • Signs/Symptoms • Eyelid retraction • Eye irritation • Dryness • Excessive tearing • Visual blurring • Diplopia (double vision) • Retro-orbital discomfort • Pain on eye movement • Visual loss • Results in decreased quality of life due to decreased visual functioning and altered appearance www.thyroidmanager.org

4. Functions of Selenium • Cofactor for glutathione peroxidase • Catalyzed the removal of H2O2 or lipid peroxide • Cofactor for thioredoxinreductase • Similar to rxn with glutathione peroxidase, involved in oxidation-reduction reaction • Selenoprotein P • Major selenium containing protein in the blood, thought to function as an antioxidant • Selenoprotein W • Thought to function as an antioxidant • Needed for iodine metabolism and regulates thyroid hormone production http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/GSH.html 3

5. Purpose of the Study • Determine if selenium or pentoxifylline are effective treatments for Graves’ orbitopathy. • In vitro studies have shown increased production of free radicals in Graves’ orbitopathy • Superoxide radical production stimulates retroocular fibroblast proliferation. • Pentoxifylline shown in a pilot study to be beneficial • Pentoxifylline is a phosphodiesterase inhibitor • Anti-inflammatory and immunomodulatoryeffects

6. Methods

7. Primary End Points Measured • Evaluated at baseline, 3, 6 and 12 months • Eye examination by an ophthalmologist • eyelid aperture size, soft tissue involvement, exophthalmos, eye-muscle involvement, and visual acuity • Graves’ Orbitopathy-Quality Of Life questionnaire (GO-QOL) • A score of 1, 2, or 3 is assigned to each of the eight questions in each subscale. • 1 = seriously limited • 2 = a little limited • 3 = not at all limited • 0 full limitation to 100 no limitation • An increase in the score of 6+ indicates clinical improvement • A decrease indicates worsening

8. Secondary End Points Measured • 7 item - Clinical Activity Score • Final score is sum of all items present • Gorman diplopia score • Four categories • No diplopia, diplopia at extremes of gaze, diplopia when pt is tired or awakening, continuous diplopia in the primary or reading position • Blood samples • Assessed thyroid function and autoantibodies against thyroid peroxidase and thyrotropinreceptor • All side effects of treatments were recorded File:Diplopia.jpgFrom Wikipedia, the free encyclopedia

9. Results • GO-QOL 6 months: • GO-QOL scores increased 6+ points for 62% and 75% for visual functioning and appearance respectively in selenium group • Selenium group had significantly improved QOL vs placebo group and lower rate of worsening QOL • Overall Eye Evaluation 6 months: • Better in selenium group than placebo group • No significant difference between pentoxifylline and placebo group • Adverse side effects • Beneficial effects of selenium on QOL and eye evaluation persisted after treatment was withdrawn

10. Conclusions • The beneficial effects detected at 6 months persisted for 6 months after selenium therapy was withdrawn • Selenium supplementation for 6 months improves the quality of life and overall eye function in patients with mild Graves’ orbitopathy

11. Limitations • Lack of data on serum selenium levels before and after sodium seleniteadministration • Lack of measuring patient compliance • Did not assess diets of the participantsbefore or duringthe study • Smokers were not excluded • Different ophthalmologists per center patients.about.com

12. Questions • What is one of the main functions of selenium in the body? • Based on this knowledge, can you think of any other nutrients we have discussed in class that could be used in the treatment of Graves’ orbitopathy? An antioxidant

13. References • MarcocciC M.D., Kahaly GJ M.D., Krassas GE M.D., et al. Selenium and the Course of Mild Graves’ Orbitopathy. The New England Journal of Medicine. 2011:364:1920-1931. • Ginsberg J. Diagnosis and management of Graves’ disease. Canadian Medical Association Journal. 2003:168:575-585. • Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. 5th ed. Belmont, CA: Wadsworth; 2009 • Burch HB, Lahiri S, Bahn RS, Barnes S. Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Exp Eye Res 1997; 65:311-6. • PrabhakarBS, Bahn RS, Smith TJ. Current Perspective on the Pathogenesis of Graves’ Disease and Ophthamopathy. Endocrine Reviews 2003;24(6):802-835. • BartalanaL, Baldeschi L, Dickinson A, et al. Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008;158:273-85. • Duntas LH. The Evolving Role of Selenium in the Treatment of Graves’ Disease and Ophthalmopathy. Journal of Thyroid Research. 2012:2012:1-6