Graves Disease - StatPearls - NCBI Bookshelf https://www.ncbi.nlm.nih.

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Graves Disease
Binod Pokhrel; Kamal Bhusal.

Author Information and Affiliations

Last Update: June 22, 2022.

Continuing Education Activity

Graves' disease is the most common cause of hyperthyroidism. It is a disorder with systemic
manifestations that primarily affect heart, skeletal muscle, eyes, skin, bone, and liver. Failure to
diagnose Graves' disease in a timely manner can predispose thyroid storm which carries high
morbidity and mortality. Clinicians ought to be aware of systemic manifestations of Graves'
disease and the different modalities available for treatment. Early diagnosis and management of
Graves' disease can also prevent severe cardiac complications such as atrial flutter, atrial
fibrillation, and high output cardiac failure. This activity reviews the evaluation and treatment of
Graves' disease and highlights the role of the interprofessional team in reducing morbidity and
improving care for affected patients.

Objectives:

• Identify the etiology of Graves' disease.

• Describe the proper evaluation of Graves' disease.

• Summarize the treatment options for Graves' disease.

• Review interprofessional team strategies for improving care coordination to improve

outcomes for patients with Graves' disease.

Access free multiple choice questions on this topic.

Introduction
Graves' disease is an autoimmune disease which primarily affects the thyroid gland. It may also
affect multiple other organs including eyes and skin. It is the most common cause of
hyperthyroidism.[1] In this chapter, we attempt to review different aspects of Graves’ disease.

Etiology
Like all autoimmune diseases, it occurs more commonly in patients with a positive family
history. It is more common in monozygotic twins than in dizygotic twins. It is precipitated by
environmental factors like stress, smoking, infection, iodine exposure, and postpartum, as well as
after highly active antiretroviral therapy (HAART) due to immune reconstitution.[2]

Epidemiology
Graves’ disease is the most common cause of hyperthyroidism accounting for 60% to 80% of
hyperthyroid cases. The overall prevalence of hyperthyroidism in the United States is 1.2% with
an incidence of 20/100,000 to 50/100,000. It is most common in people ages 20 to 50 years.
Graves’ disease is more common in women than men. Some data suggest its lifetime risk in

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women and men are 3% and 0.5%, respectively. As per the data from Nurses’ Health Study II
(NHSII), the 12-year incidence among women ages 25 to 42 years was as high as 4.6/1000.[2]

Pathophysiology
Graves' disease is caused by thyroid stimulating immunoglobulin (TSI), also known as thyroid
stimulating antibody (TSAb). B lymphocytes primarily synthesize Thyroid stimulating
immunoglobulin within the thyroid cells, but it can also be synthesized in lymph nodes and bone
marrow. B lymphocytes are stimulated by T lymphocytes which get sensitized by antigen in the
thyroid gland. Thyroid stimulating immunoglobulin binds with thyroid-stimulating hormone
(TSH) receptor on the thyroid cell membrane and stimulates the action of the thyroid-stimulating
hormone. It stimulates both, thyroid hormone synthesis and thyroid gland growth, causing
hyperthyroidism and thyromegaly.[3]

Several environmental factors including pregnancy (mainly postpartum), iodine excess,

infections, emotional stress, smoking, and interferon alfa trigger immune responses on
susceptible genes to eventually cause Graves’ disease.

Graves' orbitopathy (ophthalmopathy) is caused by inflammation, cellular proliferation and

increased growth of extraocular muscles and retro-orbital connective and adipose tissues due to
the actions of thyroid stimulating antibodies and cytokines released by cytotoxic T lymphocytes
(killer cells). These cytokines and thyroid stimulating antibodies activate periorbital fibroblasts
and preadipocytes, causing synthesis of excess hydrophilic glycosaminoglycans (GAG) and retro-
orbital fat growth. Glycosaminoglycans cause muscle swelling by trapping water. These changes
give rise to proptosis, diplopia, congestion, and periorbital edema. If left untreated, it eventually
leads to irreversible fibrosis of the muscles.[4]

Pathogenesis of other rare manifestations of Graves disease like pretibial myxedema and thyroid
acropachy are poorly understood and are believed to be due to cytokines mediated stimulation of
fibroblasts. Many symptoms of hyperthyroidism like tachycardia, sweating, tremors, lid lag, and
stare are thought to be related to increased sensitivity to catecholamine.

History and Physical

Most patients with Graves disease present with classic signs and symptoms of hyperthyroidism.
Initial presentation of Graves disease with only Graves orbitopathy or pretibial myxedema is rare.
Presentation depends on the age of onset, severity, and duration of hyperthyroidism. In the elderly
population, symptoms may be subtle or masked, and they may present with non-specific signs
and symptoms like fatigue, weight loss, and new onset atrial fibrillation. Atypical presentation of
hyperthyroidism in elderly is also referred as apathetic thyrotoxicosis.

In younger patients, common presentations include heat intolerance, sweating, fatigue, weight
loss, palpitation, hyper defecation, and tremors. Other features include insomnia, anxiety,
nervousness, hyperkinesia, dyspnea, muscle weakness, pruritus, polyuria, oligomenorrhea or
amenorrhea in the female, loss of libido, and neck fullness. Eye symptoms include lids swelling,
ocular pain, conjunctival redness, double vision. Palpable goiter is more common in the younger
population, age younger than 60 years. Up to 10 % of patients may have weight gain.[1]

Physical signs of hyperthyroidism include tachycardia, systolic hypertension with increased pulse
pressure, signs of heart failure (like edema, rales, jugular venous distension, tachypnea), atrial
fibrillation, fine tremors, hyperkinesia, hyperreflexia, warm and moist skin, palmar erythema and
onycholysis, hair loss, diffuse palpable goiter with thyroid bruit and altered mental status.

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Signs of extrathyroidal manifestations of Graves’ disease include ophthalmopathy like eyelid

retraction, proptosis, periorbital edema, chemosis, scleral injection, exposure keratitis. Thyroid
dermopathy causes marked thickening of the skin, mainly over tibia which is rare, seen in 2% to
3% of cases.[1] The thickened skin has peau d’orange appearance and is difficult to pinch. Bone
involvement includes subperiosteal bone formation and swelling in the metacarpal bones which is
called osteopathy or thyroid acropachy. Onycholysis (Plummer nails) and clubbing are very rare.

Evaluation
Diagnosis of Graves disease starts with a thorough history and physical examination. History
should include a family history of Graves’ disease. [5][6]

Thyroid function tests to diagnose hyperthyroidism:

The initial test for diagnosis of hyperthyroidism is the thyroid-stimulating hormone (TSH) test. If
TSH is suppressed, one needs to order Free T4 (FT4) and Free T3 (FT3). If free hormone assays
are not available, total T4 (Thyroxine) and total T3 (Triiodothyronine) can be ordered.
Suppressed TSH with high FT4 or FT3 or both will confirm the diagnosis of hyperthyroidism. In
subclinical hyperthyroidism, only TSH is suppressed, but FT4 and FT3 are normal.

Tests to differentiate Graves from other causes of hyperthyroidism:

Graves diagnosis can be obvious with a careful history and physical examination. Features
suggestive of Graves disease include a positive family history of Graves disease, the presence
of orbitopathy, diffusely enlarged thyroid with or without bruit and pretibial myxedema.
However, if the diagnosis is in question due to lack of one or more of these features, following
tests can be ordered:

1. Measurement of TSH receptor antibody (TRAb): There are two available assays, the thyroid
stimulating immunoglobulin (TSI) and thyrotropin-binding inhibiting (TBI) immunoglobulin or
thyrotropin-binding inhibitory immunoglobulin (TBII). Measurement of TRAb with third
generation assay has sensitivity and specificity of 97% and 99% for the diagnosis of Graves
disease.[7] TRAb measurement is indicated in following conditions:

• Hyperthyroidism during pregnancy when thyroid uptake scan is contraindicated

• Pregnant women with h/o Graves disease to determine possible fetal and neonatal
hyperthyroidism as these antibodies cross placenta

• Patients with possible Graves’ orbitopathy without biochemical hyperthyroidism

• Patients with recent h/o large iodine load where thyroid uptake scan cannot be reliable, e.g.,
recent amiodarone use, recent imaging studies with iodinated contrast

• To determine the prognosis of hyperthyroidism who are being treated.

2. Radioactive iodine uptake scan with I-123 or I-131: In Graves disease, the uptake will be high
and diffuse whereas, in a toxic nodule, the uptake will be focal known as a hot nodule. Toxic
multinodular goiter will have heterogeneous uptake. The radioactive iodine uptake in subacute or
silent thyroiditis, factitious hyperthyroidism, and recent iodine load will be low.

3. Thyroid Ultrasonogram with Doppler: The thyroid gland in Graves disease is usually
hypervascular.

4. T3/T4 ratio greater than20 (ng/mcg) or FT3/FT4 ratio greater than 0.3 (SI unit) suggests

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Graves disease and can be used to differentiate Graves’ disease from thyroiditis induced
thyrotoxicosis.

Other Tests:

CT or MRI of orbits can be performed to diagnose Graves orbitopathy in patients who present
with orbitopathy without hyperthyroidism.

Patient with hyperthyroidism can have microcytic anemia, thrombocytopenia, bilirubinemia, high
transaminases, hypercalcemia, high alkaline phosphatase, low LDL and HDL cholesterol.

Treatment / Management
Treatment for Graves' disease depends on its presentation. Treatment consists of rapid symptoms
control and reduction of thyroid hormone secretion.

A beta-adrenergic blocker should be started for symptomatic patients, specifically for patients
with heart rate more than 90 beats/min, patients with a history of cardiovascular disease, and
elderly patients. Atenolol 25 mg to 50 mg orally once daily may be considered the preferred beta
blocker due to its convenience of daily dosing, and it is cardioselective (beta-1 selective). Some
prescribers recommend Propranolol 10 mg to 40 mg orally every six to eight hours, due to its
potential effect to block peripheral conversion of T4 to T3. If a beta blocker after that, calcium
channel blockers like diltiazem and verapamil can be used to control heart rate.[6][8][9]

There are three options to reduce thyroid hormone synthesis. These options are:

1. Antithyroid drugs which block thyroid hormone synthesis and release

2. Radioactive iodine (RAI) treatment of the thyroid gland

3. Total or subtotal thyroidectomy.

All three options have pros and cons, and there is no consensus on which one is the best option. It
is very important to discuss all three options in detail with the patients and make an
individualized decision.

Anti-thyroid Drugs (Thionamides)

Methimazole (MMI) and propylthiouracil (PTU) are two anti-thyroid drugs available in the USA.
Outside USA, carbimazole, a derivative of methimazole which is rapidly metabolized to
methimazole, is also available. These thioamides inhibit Thyroid Peroxidase (TPO) mediated
iodination of thyroglobulin in the thyroid gland, blocking the synthesis of T4 and T3. To some
extent, Propylthiouracil also blocks peripheral conversion of T4 to T3.

In nonpregnant patients, methimazole is the drug of choice due to its less frequent side effects
(especially hepatotoxicity), once-daily dosing, and more rapid achievement of normal thyroid
function. During the first trimester of pregnancy, propylthiouracil must be used due to its less
teratogenic side effects. We can start methimazole from the second trimester of pregnancy.
American Thyroid Association (ATA) recommends propylthiouracil for patients with thyroid
storm and for patients with minor reactions to methimazole therapy who refuses surgery or
RAIA.

Before starting thionamide treatment, patients should be informed about possible side effects
including allergic reactions, neutropenia, and hepatotoxicity. A complete blood count with
differentials and liver function test should be obtained. Thionamide should not be started if

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baseline transaminase level is more than five times the upper limit of normal or if absolute
neutrophil count (ANC) is less than 1000/ml.

Dosage: Initiate methimazole 5 mg to 10 mg oral daily if FT4 is 1 to 1.5 times the upper limit of
normal (ULN), 10 mg to 20 mg oral daily if FT4 is 1.5 to 2 times ULN, 30 mg to 40 mg oral
daily if FT4 is more than two to three times ULN. Start PTU 50 mg t0 150 mg oral three times
daily based on the severity of hyperthyroidism. Once thyroid function improves,
the thioamide dose can be tapered and continued at maintenance doses once TFTs become
euthyroid. Methimazole is usually maintained at 5 mg to 10 mg daily, and propylthiouracil is
maintained at 50 mg two to three times a day.

Adverse effects: Minor side-effects include pruritus and rash (3% to 6%), and major side effects
include hepatocellular injury (2.7% propylthiouracil, 0.4% Methimazole), agranulocytosis (0.7%,
ANC less than 500/ml) and vasculitis (rarely lupus and pANCA-positive small vessel vasculitis;
more with propylthiouracil than methimazole). Rarely hypoglycemia has been reported
with methimazole therapy.

Follow-up and monitoring: Monitor thyroid function tests (TFTs) every four to six weeks for
the thionamide dose adjustment. Once TFTs improve, we can reduce the thionamide dose by 30%
to 50% until a maintenance dose is achieved. Once on a maintenance dose, TFTs can be checked
every three months for up to 18 months, thereafter every six months is acceptable. Monitor for
adverse effects and perform blood tests as needed based on clinical information. Stop
the thionamide if transaminase level is more than three times of ULN. Routine monitoring of
liver function tests and complete blood count is not necessary. Thionamides can be continued for
minor cutaneous reactions with or without concurrent use of antihistamines, but if the problem
persists, alternative treatment options including surgery or RAI therapy should be considered.

Duration of treatment: For patients on long-term, thionamide therapy who are on maintenance
doses, we can consider stopping the therapy after 12 to 8 months, if TSH and TRAb levels
normalize during follow-up. If patients remain clinically and biochemically euthyroid, we can
repeat TFTs every two to three months during the first six months after stopping the treatment,
then every four to six months for another six months, then every six to 12 months. If TSH
remains normal for one year without treatment, annual monitoring with TSH is enough.

RAI Therapy

It is preferred for non-pregnant adult patients older than 21 years, patients not planning to get
pregnant within the next six to 12 months after treatment, patients with risky comorbid conditions
for surgery, and patients with contraindications for thioamides. It is contraindicated during
pregnancy, lactation, coexisting thyroid cancer, in patients with moderate to severe Graves
orbitopathy, and for individuals who cannot follow radiation safety guidelines.

Preparation: Beta-adrenergic blockade and pretreatment

with methimazole (propylthiouracil pretreatment has a high failure rate for RAI treatment) should
be considered for patients with an increased risk of complications from hyperthyroidism and
patients with very high thyroid hormone levels. If methimazole is started, it should be stopped
three to five days before RAI treatment. It can be restarted for high-risk patients three to seven
days after treatment. A pregnancy test is required before RAI treatment.

Dosage: I-131 is administered as a capsule or liquid. The I-131 dose can be calculated or one may
use a fixed dose. Calculated dose is based on thyroid volume, uptake of RAI and local factors. A
fixed dose can be 10 to 25 mCi of I-131. The patient should be provided with a written radiation

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safety precautions after RAI treatment to avoid exposure to household members or community
members, especially children, and pregnant women.

Follow-up and monitoring: TFTs should be monitored every four to six weeks for six months or
until the patient becomes hypothyroid. Once the patient is on a stable levothyroxine dose, TFTs
can be repeated every six to 12 months. If hyperthyroidism persists after six months of RAI
therapy, it can be considered as treatment failure, and a repeat treatment with RAI may be
needed.[10]

Thyroidectomy

Thyroidectomy is preferred for patients with very large goiter (more than 80 grams), anterior
neck compressive symptoms, co-existing suspicious thyroid cancer, large thyroid nodules (greater
than 4 cm), cold nodules, co-existing parathyroid adenoma, very high TRAb, and moderate to
severe Graves orbitopathy.

Preparation:

• Use thionamides to achieve near or complete euthyroid state before surgery

• Use Beta-blockers as needed

• Use potassium iodide, five to seven drops of Lugol’s solution or one to two drops of SSKI,
mixed in water or juices three times a day, starting seven to ten days before surgery to
reduce vascularity

• Assess calcium and Vitamin D levels and replace if needed

Post-op follow-up:

Thionamides should be stopped after surgery and beta-blocker should be weaned off.
Levothyroxine is started at 1.6 micrograms per kg body weight, and the dose is adjusted based on
TSH level every six to eight weeks.[11][12]

Other Adjunct Treatment for Graves Hyperthyroidism

Iodinated contrast agents, sodium ipodate, and iopanoic acid inhibit peripheral conversion of T4
to T3. They are used with methimazole but not as a solo agent as they can cause resistant
hyperthyroidism. They are not available in the United States. Iodide (SSKI drops) can be used for
mild hyperthyroidism especially after RAI treatment. Glucocorticoid, cholestyramine, lithium,
carnitine are other agents have also been tried. Rituximab may induce remission in patients with
Graves disease, but it is costly.

Treatment of Graves Orbitopathy (GO)

Rapid achievement of euthyroid level should be sought in patients with Graves orbitopathy.
Patients should be advised to quit smoking if they do. Treatment depends on the severity of
orbitopathy. For patients with mild orbitopathy who undergo RAI treatment, prednisone
0.4 mg/kg/day to 0.5 mg/kg/day should be started one to three days after treatment and continued
for one month. It should be tapered slowly over two months. Mild active Graves
orbitopathy should be treated with artificial tears, and glucocorticoid therapy can be considered.
Elevation of the head during sleep reduces orbital congestion. Selenium treatment has doubtful
benefits. Prompt ophthalmology referral should be considered for all cases of Graves orbitopathy.

Treatment of moderate to severe active Graves orbitopathy requires up to 100 mg of oral

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prednisone daily for one to two weeks, then tapered over six to 12 weeks or intravenous (IV)
methylprednisolone 500 mg/wk for six weeks followed by 250 mg/wk for six weeks. If
glucocorticoids is in effective, tepretumumab is FDA approved for use in moderate to severe
active graves orbitopathy. [13]Other options include orbital irradiation, rituximab, and emergency
orbital decompression.[14]

Treatment of inactive Graves orbitopathy involves interval close clinical monitoring, elective
orbital decompression, strabismus repair and eyelid repair depending upon severity.

Treatment of Dermopathy and Acropachy

Graves dermopathy usually does not need treatment. If treatment is considered, topical high
potency glucocorticoid with occlusive dressing can be considered. Rituximab treatment to reduce
B-cell may be beneficial, but it remains experimental. There is no treatment available for
acropachy.

Differential Diagnosis

• Exogenous thyroid hormone

• Hashimoto thyroiditis

• Hyperemesis gravidarum

• Papillary Thyroid carcinoma

• Pheochromocytoma

• Pituitary resistance to thyroid hormone

• Postpartum thyroiditis

• Radiation-induced thyroiditis

• Silent thyroiditis

• Struma ovarii

• Subacute thyroiditis

• Thyrotropin producing pituitary adenomas

• Toxic multinodular goiter

Complications

• Agranulocytosis related to the thionamides

• Exacerbation of hyperthyroidism

Enhancing Healthcare Team Outcomes

Graves disease is a systemic disorder that affects numerous organs; it's presentations are diverse
and hence the disorder is best managed by an interprofessional team. The natural history of
Graves disease is well documented and eventually, all patients become hypothyroid and require

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hormone replacement therapy. Similarly, the ocular features of the disorder also become
quiescent with time. Some patients may develop recurrence of hyperthyroidism after ablation and
further therapy with radioactive iodine is needed. While the antithyroid drugs do control the
symptoms, they do not cure the disease and hence relapses are common. The condition is best
addressed with radioactive iodine. All patients need to be educated about the symptoms and signs
of hyper-and hypothyroidism, as well as the side effects of the medications. More importantly, the
patient should be urged to avoid over-the-counter medications that contain pseudoephedrine or
ephedrine during treatment.

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References
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Disclosure: Binod Pokhrel declares no relevant financial relationships with ineligible companies.

Disclosure: Kamal Bhusal declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

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