Conditions: Graves’ Disease

Graves’ disease, also known as toxic diffuse goiter, is an autoimmune condition in which antibodies stimulate the thyroid gland to make too much thyroid hormone and can also affect the eyes.

What is Graves’ disease?

Graves’ disease, also known as toxic diffuse goiter, is the most common cause of an overactive thyroid gland (hyperthyroidism) in the United States. The thyroid is a butterfly-shaped gland in the front of the neck that makes hormones controlling how fast the body’s systems work. In Graves’ disease, the immune system mistakenly makes antibodies that switch the thyroid “on” constantly, so it produces too much thyroid hormone and often becomes enlarged (a diffuse goiter). Because it is caused by the immune system attacking the body’s own tissue, it is called an autoimmune disease.

Graves’ disease can also affect the eyes (thyroid eye disease, also called Graves’ ophthalmopathy or orbitopathy) and, rarely, the skin of the shins (pretibial dermopathy) and the fingers (acropachy).

Who gets Graves’ disease?

Graves’ disease is fairly common, occurring in about 0.5% of males and 3% of females. It is far more common in women than in men and most often appears between ages 30 and 60, though it can develop at any age. Several factors raise the risk:

• Genetics and family history. Persons are more likely to be affected if they have a family member with the disease, and about half of people with Graves’ disease have a relative with an autoimmune thyroid condition. If one twin is affected, a 30% chance exists that the other twin will also have the disease.

• Autoimmunity. Those with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected.

• Smoking. Smoking increases the risk of getting the disease and is the strongest known modifiable risk factor for developing and worsening thyroid eye disease. More smoke exposure correlates with greater severity of eye problems, and the risk falls after quitting.

• Other triggers. Physical or emotional stress, infection, pregnancy and the period after giving birth, large changes in iodine intake, and certain medications (including some cancer and multiple sclerosis drugs) have been linked to the onset of the disease.

What problems does Graves’ disease cause?

Symptoms of an overactive thyroid (hyperthyroidism) can include:

• Fast or irregular heartbeat and palpitations

• Unintended weight loss despite a normal or increased appetite

• Feeling hot, sweating easily, and sensitivity to warm temperatures

• Nervousness, anxiety, irritability, and trouble sleeping

• Trembling hands, muscle weakness, and fatigue

• More frequent bowel movements

• Lighter or irregular menstrual periods

Goiter. The thyroid is often smoothly and diffusely enlarged (a goiter), which may be visible or felt as fullness in the neck. A very large goiter can compress the airway or esophagus (swallowing tube).

Serious complications of untreated or poorly controlled hyperthyroidism include:

• Thyroid storm. A rare, life-threatening surge of thyroid hormone causing high fever, very fast or irregular heart rate, confusion or agitation, and vomiting or diarrhea. It is a medical emergency, often triggered by infection, surgery, or suddenly stopping medication.

• Atrial fibrillation. An irregular heart rhythm that raises the risk of stroke.

• Osteoporosis. Thinning of the bones from prolonged excess thyroid hormone, increasing fracture risk.

Thyroid eye disease. Graves’ disease also causes eye problems (Graves’ ophthalmopathy or thyroid eye disease) associated with swelling of the muscles that move the eyeballs and of the tissues behind the eyes. It affects a meaningful minority of people with Graves’ disease and ranges from mild to severe. The swelling leads to a bulging forward of the eyeballs, called exophthalmos or proptosis, creating an unnatural appearance to the eyes and also promoting dry eyes, chemosis, eye discomfort, swelling of eyelids, a staring appearance from eyelid retraction, tearing, light sensitivity, double vision, and redness. The optic nerve can also become stretched and compressed, causing difficulty seeing colors, decreased vision, and/or visual field defects. Rarely, blindness may result from stretch on the optic nerve or from dryness and exposure of the cornea.

Thyroid eye disease tends to have an “active” inflammatory phase lasting months to a couple of years, followed by a stable phase. The swelling of the eye muscles may progress over time, and the changes may not fully reverse even after control of the thyroid problem itself.

What causes Graves’ Disease?

An autoimmune disease, such as Graves’ disease, occurs when an individual’s immune system attacks normal tissues. In Graves’ disease, the immune system produces antibodies that bind to the TSH receptor on thyroid cells. These antibody molecules, called “thyrotropin receptor antibody” (TRAb), “TSH receptor binding antibody,” or “thyroid stimulating immunoglobulins” (TSI), inappropriately over-activate the TSH receptor.

Normally, thyroid stimulating hormone (TSH) from the pituitary gland tells the thyroid how much hormone to make. In Graves’ disease, the antibodies act like a stuck accelerator: they bind to the same receptor as TSH and drive the thyroid to make hormone nonstop, regardless of the body’s actual needs. The antibodies attached to the TSH receptor also attract additional inflammation of the gland. Because the same antibodies can affect tissues behind the eyes, eye disease is part of the condition.

How is Graves’ disease diagnosed?

Graves’ disease may be diagnosed when hyperthyroidism (a low TSH with elevated free T4 and/or T3 blood levels) is present together with a diffuse enlargement of the thyroid gland (goiter). An ultrasound may be very helpful in demonstrating the diffuse aspect of thyroid enlargement, differentiating it from a thyroid with one or more enlarged nodules, and assessing blood flow.

To clarify any remaining diagnostic uncertainty, one or more of these methods may be utilized:

• Thyrotropin receptor antibody (TRAb) testing. Also called TSH receptor binding antibody testing, this methodology detects both thyroid stimulating and thyroid blocking antibodies and cannot distinguish between them. Modern antibody testing has high sensitivity and specificity for the diagnosis of Graves’, on the order of 97% and 99%, respectively.

• Thyroid receptor stimulating immunoglobulin (TSI) testing. This specifically detects stimulating antibodies and differentiates them from other TSH receptor antibody types.

• Radioactive iodine uptake scan. Uptake is typically increased evenly across the whole thyroid gland in Graves’ disease, helping distinguish it from other causes of hyperthyroidism such as a toxic hyperfunctioning nodule. This test is not used during pregnancy or breastfeeding.

• Doppler flow ultrasonography. Demonstration of evenly and diffusely increased vascularity supports the diagnosis.

Both TRAb and TSI tests are accurate for the diagnosis of Graves’ and some argue that performing both tests is redundant. Antibody testing is also especially useful during pregnancy.

How is Graves’ disease treated?

Essentially, there are three treatment options for Graves’ disease:

• Radioiodine therapy

• Medications (antithyroid drugs)

• Thyroid surgery (thyroidectomy)

The choice among these depends on age, disease severity, goiter size, eye involvement, pregnancy plans, other health conditions, and personal preference. Beta blockers (such as propranolol) are often used early with any approach to quickly ease palpitations, tremor, and anxiety while other treatments take effect. These treatments are detailed below.

Eye problems may require additional treatment, and avoiding tobacco smoke entirely is a key element in minimizing thyroid eye disease.

Radioactive iodine ablation therapy

Radioiodine ablation therapy involves taking a one-time radioactive iodine-131 pill by mouth, which is then concentrated in the thyroid and gradually shrinks and disables it over weeks to months. Hypothyroidism commonly results, and most people become underactive and are treated with synthetic thyroid hormone replacement. Radioiodine is effective, convenient, generally well tolerated, and avoids surgery, but treatment does carry a risk of creating or worsening eye disease. It is not used in pregnancy or breastfeeding, and pregnancy is avoided for at least 6–12 months afterward.

Patient factors that favor use of radioactive iodine include:

• When a patient is unable to take antithyroid drugs due to liver disease or a prior severe adverse reaction

• Women who are willing to avoid pregnancy for at least 6–12 months after radioiodine therapy

• Patients with increased surgical risk (comorbidities, prior neck surgery or neck radiation)

• Lack of access to a high-volume thyroid surgeon

Situations in which radioactive iodine is generally avoided include:

• Moderate to severe thyroid eye disease, due to the risk of worsening eye disease. This is especially true in smokers with high TSH receptor antibody (TRAb) levels.

• Potential to become pregnant within 4–6 months, because radioactive iodine crosses the placenta and can damage the fetal thyroid.

• Breastfeeding, including continued lactation even if not feeding the baby with the breast milk, because the radioactivity is concentrated in breast milk and poses an exposure risk.

• Inability to comply with radiation safety precautions, as patients must maintain appropriate distance from others (especially pregnant women and children) for several days to weeks after treatment.

Note that iodine allergy is not a contraindication to RAI therapy.

Medications for Graves’ disease hyperthyroidism

Antithyroid drugs (methimazole and propylthiouracil) reduce the thyroid’s hormone production, usually over a 12–18 month course. They do not involve surgery or radiation, can be adjusted or stopped, are relatively inexpensive, and appear less likely to result in hypothyroidism than treatment with radioactive iodine. They may lead to lasting remission (resolution of the disease) in roughly 40–50% of people, but the disease returns after stopping in about half.

Common minor side effects include rash, itching, and joint aches. Rarely, antithyroid drugs may cause liver toxicity or a dangerous condition in which the bone marrow stops making infection-fighting white blood cells (agranulocytosis). A sudden fever or sore throat while taking these drugs is a reason for urgent medical attention. Monitoring for these toxicities does require periodic blood testing.

In patients found to be very hyperthyroid, a category of medicines called beta blockers (such as propranolol) may be used to control some of the symptoms of hyperthyroidism while antithyroid medications are taking effect.

Patient factors that favor use of medications for Graves’ disease include:

• Patients with high likelihood of remission (resolution of the disease), including women, mild disease, small goiter, and negative or low titers of thyrotropin receptor antibody

• Elderly patients or those with comorbidities and increased surgical risk or short life expectancy

• Patients with moderate to severe active Graves’ eye disease (ophthalmopathy)

Medications for Graves’ thyroid eye disease

Care is often shared between an endocrinologist and an eye specialist, and keeping thyroid hormone levels normal and avoiding smoking are considered essential. The approach to medical therapy depends on disease severity and activity.

For mild thyroid eye disease, conservative measures are typically sufficient. These include artificial tears, gels, and ointments for dryness and grittiness, dark glasses for light sensitivity, sleeping with the head elevated to reduce morning swelling, selenium supplementation (for disease of less than 6 months duration), and observation.

For moderate-to-severe active thyroid eye disease, first-line medical therapy consists of intravenous glucocorticoids (such as methylprednisolone), often combined with mycophenolate according to EUGOGO guidelines. However, glucocorticoids primarily reduce inflammation and may not reliably improve eye protrusion (proptosis) or double vision (diplopia).

Teprotumumab (Tepezza®), an infused medication that targets the IGF-1 receptor, has emerged as the most effective medical therapy for Graves’ thyroid eye disease. The standard treatment duration is 24 weeks (8 infusions given every 3 weeks). A little more than half of patients who respond to treatment with this medication will maintain the response for up to 51 weeks, and repeat treatment may be necessary in people who initially respond but then regress. Possible side effects include high blood sugar and hearing changes. The retail cost of one complete course of teprotumumab (8 infusions) is approximately $300,000, depending on patient weight.

Thyroid surgery for Graves’ disease

Total thyroidectomy treats Graves’ disease by removing the driver of the autoimmune process. Once completed, hyperthyroidism is cured, with the lowest chance of recurrence of the three treatment options, and the individual will need to take a thyroid hormone pill daily long-term to avoid hypothyroidism. Patients are usually made euthyroid (normal thyroid hormone levels) with medication before surgery. Surgical risks of thyroidectomy include those of anesthesia, permanent hypoparathyroidism (low calcium from injury to the nearby parathyroid glands), and vocal cord weakness (hoarseness from injury to the nerves to the voice box).

Surgical thyroidectomy is especially useful when:

• The thyroid is very large with compression of the airway or esophagus.

• Patients have a low radioactive iodine uptake, as radioiodine therapy would not be very effective in that situation.

• A patient has another (simultaneous) reason to undergo surgery involving the thyroid (thyroid cancer, hyperparathyroidism, or suspicious thyroid nodules).

• Patients have moderate to severe active thyroid eye disease. Data on this specific reason for thyroid surgery is evolving. The standard approach for patients with active moderate-to-severe thyroid eye disease remains antithyroid drugs as first-line, with thyroidectomy as a valid alternative, while radioactive iodine (without prior total thyroidectomy) is generally avoided in this setting. Some evidence suggests thyroidectomy may lead to improvement or stabilization of eye disease in 60–100% of patients. Total thyroidectomy reduces the problematic TSH receptor antibodies over 1–1.5 years. A technique called total thyroid ablation, which is total thyroidectomy followed by radioactive iodine remnant ablation, has received attention with some promising results reported.

• A woman is planning pregnancy in less than 6 months, a setting in which antithyroid drugs are generally avoided.

• A patient has a preference for surgery or intolerance to antithyroid drugs.

For surgical management of Graves’ disease, total thyroidectomy is preferred over subtotal thyroidectomy as it removes the target tissue for TSH receptor antibodies and is associated with lower recurrence rates (see extent of thyroid surgery). Information about what follows surgery is available on the thyroidectomy recovery page.

Eye decompression surgery for Graves’ eye disease

Surgical decompression of the bony walls of the orbit (eye socket) may be undertaken to make more space for the eyeball, muscles, and fat within the orbit.

The primary reasons for orbital decompression in thyroid eye disease are severe conditions such as impairment of the optic nerve (dysthyroid optic neuropathy), disfiguring eye bulging (proptosis, exophthalmos), inability to close the eyes with dryness of the cornea (exposure keratopathy), when the eyeball has moved more than halfway out of its socket (globe subluxation), and long-standing lack of blood outflow (chronic orbital congestion). The timing and urgency of surgery depend on whether the disease is in the active or inactive phase. Orbital decompression and other surgeries (including eyelid and eye-muscle surgery) are typically performed once the disease is stable to correct bulging, double vision, or appearance, and urgently if vision is threatened.

Graves’ disease in pregnancy

Graves’ disease requires special care before and during pregnancy because both uncontrolled hyperthyroidism and the medications used carry risks. Poorly controlled disease is linked to miscarriage, high blood pressure, poor fetal growth, premature birth, and thyroid storm.

• Thyroid levels are ideally normal and stable before conception.

• Propylthiouracil is generally preferred in early pregnancy (the first trimester), with a switch strategy afterward, because methimazole carries a small risk of birth defects when used early in pregnancy. The lowest effective dose is used.

• Radioactive iodine is not given during pregnancy or breastfeeding.

• Because the antibodies can cross the placenta and affect the baby’s thyroid, antibody levels are monitored, and the baby may need extra ultrasound and heart-rate monitoring. Care is coordinated with an obstetrician or maternal-fetal medicine specialist.

What is expected after treatment?

Many people do very well, and long-term quality of life is generally good across all treatment approaches. Key points include:

• Lifelong thyroid hormone replacement. After radioactive iodine or surgery, and in many cases even after drug treatment over time, the thyroid becomes underactive, requiring a daily levothyroxine tablet. The dose is adjusted by blood tests to keep levels normal (see hypothyroidism treatment).

• Ongoing monitoring. Regular blood tests are needed to fine-tune the dose and to watch for relapse in those treated with antithyroid drugs. Recurrence is most common after stopping antithyroid drugs and least common after surgery.

• Bone and heart health. Once thyroid levels are controlled, risks such as irregular heartbeat and bone loss improve.

• Eye follow-up. Eye disease can appear or change independently of the thyroid, so new eye symptoms warrant prompt evaluation.

• Lifestyle. Not smoking is one of the most important protective factors for both the thyroid and the eyes.

Key points

• Graves’ disease is an autoimmune condition in which TSH receptor antibodies drive the thyroid to make excess hormone, and it is the most common cause of hyperthyroidism.

• It can also cause thyroid eye disease, with higher risk and greater severity in smokers.

• Diagnosis relies on thyroid blood tests, antibody tests, and sometimes ultrasound or a radioactive iodine uptake scan.

• Treatment options include antithyroid drugs, radioactive iodine, and total thyroidectomy, each with different advantages and risks. Thyroid eye disease has its own treatments.

• Lifelong thyroid hormone replacement is common after definitive treatment, and pregnancy requires special coordination of care.

This information is for general education and is not medical care or a recommendation for any individual. Decisions about testing and treatment are made with a personal physician. See the site disclaimer.