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
Graves’ Disease
Thyroid Stimulating
Ab (TSAb)
+
Thyroid
Thyroid Stimulation
TSH -
Blocking Ab (TSBAb)
Receptor
Autoimmune
Thyroid peroxidase Hypothyroidism
Thyroglobulin Ab (Hashimoto’s)
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