Graves’ Disease: An Overview

1. Graves’ Disease: An Overview Matthew Volk Morning Report November 17th, 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 Graves’ Disease Thyroid Stimulating Ab (TSAb) + Thyroid - Thyroid Stimulation Blocking Ab (TSBAb) TSH Receptor Autoimmune Hypothyroidism (Hashimoto’s) Thyroid peroxidase Ab (anti TPO) Thyroglobulin Ab

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