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

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 B cells produce autoantibodies against the TSH receptor Treatment drawbacks: -Antithyroid = common relapse into hyperthyroidism -radioiodine = hypothyroidism in more than 50% of pt within 10 yrs, and worsens symptoms of graves orbitopathy -surgery = hypothyroidism in 50% of pt within 25 yrs of treatment 7

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

Functions of Selenium Cofactor for glutathione peroxidase http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/GSH.html Cofactor for glutathione peroxidase Catalyzed the removal of H2O2 or lipid peroxide Cofactor for thioredoxin reductase 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 3 Hypermetabolic state in GD = increased oxygen consumption = mitochondrial dysfunction = generates ROS and disrupts oxidant/antioxidant balance = oxidative stress = tissue injury Selenium regenerates Glutathione and Thioredoxin for antioxidant function

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 immunomodulatory effects

Methods 159 Randomized 50 Placebo bid 54 Selenium 100μg bid 48 pentoxifylline 600mg bid 15 Discontinued

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

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 thyrotropin receptor All side effects of treatments were recorded File:Diplopia.jpg From Wikipedia, the free encyclopedia

Results GO-QOL 6 months: Overall Eye Evaluation 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 6 points is the minimum increase that qualifies as clinical improvement in QOL 7 patients experienced adverse side effects to the treatment during the study all were in the pentoxifylline group

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

Limitations Lack of data on serum selenium levels before and after sodium selenite administration Lack of measuring patient compliance Did not assess diets of the participants before or during the study Smokers were not excluded Different ophthalmologists per center Review article by Duntas LH stated that smoking was either linked to the development or worsening of Graves’ orbitopathy patients.about.com

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

References Marcocci C 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. Prabhakar BS, Bahn RS, Smith TJ. Current Perspective on the Pathogenesis of Graves’ Disease and Ophthamopathy. Endocrine Reviews 2003;24(6):802-835. Bartalana L, 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