1. Graves’ Disease: An Overview Matthew Volk Morning Report November 17 th, 2009

2. Epidemiology Prevalence of hyperthyroidism in the general population is 1.2%  0.7% subclinical hyperthyroidism  0.4% Graves’ Disease – most common etiology; note there is overlap with the subclinical group Graves’ Disease is more common in females (7:1 ratio)

3. Pathogenesis An autoimmune phenomenon – presentation determined by ratio of antibodies TSH Receptor Thyroid Stimulating Ab (TSAb) Thyroid Stimulation Blocking Ab (TSBAb) Thyroid + - Graves’ Disease Autoimmune Hypothyroidism (Hashimoto’s) Thyroglobulin Ab Thyroid peroxidase Ab (anti TPO)

4. The Classic Triad of Graves’ Disease Hyperthyroidism (90%) Ophthalmopathy (20-40%)  proptosis, ophthalmoplegia, conjunctival irritation  3-5% of cases require directed treatment Dermopathy (0.5-4.3%)  localized myxedema, usually pretibial  especially common with severe ophthalmopathy There is also a close association with autoimmune findings (e.g. vitiligo) and other autoimmune diseases (e.g. ITP)

5. Syndrome of Hyperthyroidism Weight loss, heat intolerance Thinning of hair, softening of nails Stare and eyelid lag Palpitations, symptoms of heart failure Dyspnea, decreased exercise tolerance Diarrhea Frequency, nocturia Psychosis, agitation, depression

6. Graves’ Ophthalmopathy Antibodies to the TSH receptor also target retroorbital tissues  T-cell inflammatory infiltrate -> fibroblast growth  Severe: exposure keratopathy, diplopia, com- pressive optic neuropathy Strong link with tobacco

7. Myxedema of Graves’ Activation of fibroblasts leads to increased hyaluronic acid and chondroitin sulfate Asymmetric, raised, firm, pink-to-purple, brown plaques of nonpitting edema

8. Hyperthyroidism Differential Graves’ Disease Toxic Multinodular Goiter Toxic Adenoma Thyroiditis  silent (Hashimoto’s) – painless, often post partum  subacute (de Quervain’s) – painful, post viral  drug-induced – amiodarone, lithium, interferon Thyrotoxicosis factitia

9. Laboratory Evaluation Suppressed TSH (<0.05 uU/ml) Elevated Free T4 and/or Free T3 T3:T4 > 20 - Graves’ Disease - Toxic MN Goiter T3:T4 < 20 - Non-thyroid illness - Thyroiditis - Exogenous thyroxine

10. It’s Good to be Free Thyroxin is 99% bound to thyroid binding globulin (TBG), albumin, and transthyretin  Elevated TBG in viral hepatitis, pregnancy, and in patients taking estrogens and opiates  Decreased TBG binding with heparin, dilantin, valium, NSAIDs, lasix, carbamazepine, ASA  Measuring Free T4 instead of total T4 avoids this problem all together

11. Laboratory Evaluation Direct measurement of TSH receptor antibodies (TSAb and TBAb)  Can help with Graves diagnosis in confusing cases (as high as 98% sensitivity)  Can predict new-onset Graves’ in the post-partum period Anti TPO Antibody and anti Tg Antibody  Can be mildly elevated in Graves’  Usually most active in Hashimoto’s

12. Diagnostic Imaging Radioactive Iodine Uptake  Provides quantitative uptake (nl 5-25% after 24h)  Shows distribution of uptake Technetium-99 Pertechnetate Uptake  Distinguishes high-uptake from low-uptake  Faster scan – only 30 minutes Thyroid ultrasonography  Identifies nodules  Doppler can distinguish high from low-uptake

13. Immediate Medical Therapy Thionamides – inhibit central production of T3 and T4; immunosuppressive effect  Methimazole – once daily dosing  PTU – added peripheral block of T4 to T3 conversion; preferred in pregnancy  Side effects: hives, itching; agranulocytosis, hepatotoxicity, vasculitis Beta-blockade – decrease CV effects High-dose iodine – Wolff-Chaikoff effect

14. Long-term Therapeutic Options Continued Medical Management  Low dose (5-10mg/day of methimazole) for 12 to 18 months then withdraw therapy  Lasting remission in 50-60% Radioiodine Ablation  Discontinue any thionamides 3-5 days prior  Overall 1% chance of thyrotoxicosis exacerbation  Hypothyroidism in 10-20% at 1 yr, then 5% per yr  Lasting remission in 85%

15. Long-term Therapeutic Options Total Thyroidectomy  Indications: suspicion for malignant nodule, comorbid need for parathyroidectomy, radioactive ablation contraindicated, compressive goiter  Recent metaanalysis showed this is the most cost effective if surgery is < $19,300.  Prep with 6 weeks thionamides, 2 weeks iodide  Hypoparathyroidism and/or laryngeal nerve damage in <2%  Lasting remission in 90%

16. Treatment of Ophthalmopathy Mild Symptoms  Eye shades, artificial tears Progressive symptoms (injection, pain)  Oral steroids – typical dosage from 30-40mg/day for 4 weeks Impending corneal ulceration, loss of vision  Oral versus IV steroids  Orbital Decompression surgery

17. References Alguire et al. MKSAP14 Endocrinology and Metabolism. 2006. 27-34. Andreoli et al. Cecil Essentials of Medicine. 6th Edition, 2004. 593-7. Nayak, B et al. Hyperthyroidism. Endocrinol Metab Clin N Am. 36 (2007) 617-656. In H et al. Treatment options for Graves disease: a cost-effectiveness analysis. J Am Coll Surg. 2009 Aug;209(2):170-179.e1-2. Stiebel-Kalish H et al. Treatment modalities for Graves' ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab, August 2009, 94(8):2708–2716 Uptodate Online – Disorders that Cause Hyperthyroidism, Diagnosis of Hyperthyroidism, Cardiovascular Effects of Hyperthyroidism, Treatment of Graves Ophthalmopathy