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
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

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

4. Functions of Selenium Cofactor for glutathione peroxidase
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

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 immunomodulatory effects

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

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

9. 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

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 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

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
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:
Ginsberg J. Diagnosis and management of Graves’ disease. Canadian Medical Association Journal. 2003:168:
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):
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:
Duntas LH. The Evolving Role of Selenium in the Treatment of Graves’ Disease and Ophthalmopathy. Journal of Thyroid Research :2012:1-6