Graves’ Disease: An Overview

Matthew Volk

Morning Report

November 17th, 2009

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)

Pathogenesis

An autoimmune phenomenon – presentation determined by ratio of antibodies

TSHReceptor

Thyroid Stimulating Ab (TSAb)

Thyroid Stimulation Blocking Ab (TSBAb)

Thyroid+

-

Graves’ Disease

AutoimmuneHypothyroidism(Hashimoto’s)Thyroglobulin Ab

Thyroid peroxidase Ab (anti TPO)

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)

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

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

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

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

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

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

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

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

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

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%

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%

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

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