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.
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.
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.
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.
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. 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.
Diagnosis of Graves disease starts with a thorough history and physical examination. History should include a family history of Graves’ disease. 
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. 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 Graves disease and can be used to differentiate Graves’ disease from thyroiditis induced thyrotoxicosis.
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.
There are three options to reduce thyroid hormone synthesis. These options are:
- Antithyroid drugs which block thyroid hormone synthesis and release
- Radioactive iodine (RAI) treatment of the thyroid gland
- 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 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.
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 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.
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.
- 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
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.
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 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. Other options include orbital irradiation, rituximab, and emergency orbital decompression.
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.