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
TSH
- Thyroid Stimulation
Blocking Ab (TSBAb)
Receptor
Autoimmune
Thyroid peroxidase Hypothyroidism
Thyroglobulin Ab (Hashimotos)
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 (Hashimotos) painless, often post partum
subacute (de Quervains) 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
Its 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 Hashimotos
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):27082716
Uptodate Online Disorders that Cause Hyperthyroidism, Diagnosis of
Hyperthyroidism, Cardiovascular Effects of Hyperthyroidism, Treatment
of Graves Ophthalmopathy