Graves’ disease

What is Graves' disease?

Graves’ disease occurs when your child’s immune system develops antibodies that attach to the thyroid cells, causing them to produce too much thyroid hormone. This antibody— called thyroid-stimulating immunoglobulin (TSI) — binds to the thyroid-stimulating hormone (TSH) receptor and causes unregulated production and release of thyroid hormone.

Graves’ disease affects 1 in 10,000 children in the United States and is much less common than Hashiomoto’s thyroiditis (autoimmune hypothyroidism). It is more common in girls than in boys and more common in adolescents than in children under 5; however, boys and young children may be diagnosed with Graves’ disease.

Graves’ disease was named after an Irish doctor, Sir Robert Graves, who first described the condition in the early 19th century.

What are the signs and symptoms of Graves’ disease?

Symptoms of Graves’ disease may be mild or severe. Some children may have significant complaints with slightly elevated thyroid hormone levels; however, the severity of symptoms is not always predicted by the level of thyroid hormone elevation.

Signs and symptoms of Graves’ disease may include:

  • Irritated and/or bulging eyes (called proptosis) with redness or visible blood vessels on the white part of the eye, pain when moving the eyes and inability to fully open the eyelid (known as Graves’ ophthalmopathy or thyroid eye disease). May also have swelling of the eyelids, most noticeable in the morning and decreasing throughout the day.
  • Enlarged thyroid (called a goiter), visible when the person looks up.
  • Increased heart rate or palpitations (feeling that the heart is beating quickly).
  • Hand tremors.
  • Mood changes, most commonly anxiety.
  • Difficulty concentrating. May be diagnosed with "late-onset" attention deficit disorder (ADD) with decreased school performance despite trying to do well.
  • Increased fidgetiness, hyperactivity, restlessness, and constant, disorganized small body movements.
  • Fatigue with decreased muscle strength at the hips and shoulders, leading to increased clumsiness, decreased coordination and decreased stamina.
  • Increased appetite — with or without weight loss.
  • Increased number of bowel movements per day.
  • Heat intolerance (always feeling warm).
  • Lighter and less frequent menstrual cycles in young women.

What causes Graves’ disease?

Graves’ disease is an autoimmune disorder. While we do not know why patients develop autoimmune thyroid disorders, it is common for other family members to have been diagnosed with the same or a different autoimmune disorder.

In Graves’ disease, the immune system develops an antibody — TSI — that  attaches to the thyroid cells, leading to an unregulated, increased production of thyroid hormone, both T3 and T4. This over-stimulation and inflammation causes the thyroid to enlarge and to have increased blood flow that is detectable on an ultrasound exam. The TSI antibody can also attach to cells behind the eye, causing these tissues to enlarge and push the eye forward.

In the majority of patients with Graves’ disease, the autoimmune disease is limited to the thyroid. However, once a patient has one autoimmune disease, it is possible to develop a second. In pediatrics, the most common second autoimmune disease is celiac disease, an intolerance to gluten.

How is Graves’ disease diagnosed?

In the Pediatric Thyroid Center at Children’s Hospital of Philadelphia (CHOP), clinical experts use a variety of diagnostic tests to diagnosis Graves’ disease.

These tests include:

  • A physical exam, during which clinicians check for elevated resting heart rate, restlessness/fidgetiness, tremor of hands when the arm is extended, goiter, decreased proximal muscle strength and prominent bulging eyes (only found in 30% of patients).
  • A thyroid function screening, a group of blood tests that measure thyroid hormone levels. Hyperthyroidism is associated with a low TSH level and elevated T3 and T4 levels. In early Graves’ disease, the T3 may be elevated before the T4. The TSI antibody or TSH receptor antibody (TRAb) levels are also elevated.
  • A thyroid ultrasound, which uses ultrasonic waves to image your child’s thyroid gland. Classic findings of Graves’ disease include an enlarged thyroid gland and tissue irregularity with increased blood flow throughout the gland.
  • A nuclear medicine uptake and scan, which helps determine how well your child’s thyroid tissue absorbs iodine, a key ingredient in making thyroid hormone. Classic findings of Graves’ disease include increased absorption of the radioiodine (greater than 30% of thyroid hormone production at 24 hours) that is uniformly distributed throughout the thyroid tissue. This scan is typically not required if a physical exam and laboratory tests can confirm the diagnosis.

What are the treatment options for patients with Graves’ disease?

CHOP’s Pediatric Thyroid Center takes a team approach to treating children with Graves’ disease.

Treatment options include:

  • Anti-thyroid medication (methimazole)
  • Radioactive iodine ablation
  • Total thyroidectomy (surgical removal of the thyroid) or lobectomy (removal of half of the thyroid gland)

Anti-thyroid medication

Most children and adolescents with hyperthyroidism will be started on methimazole (MMI), anti-thyroid medication also known as Tapazole, at the time of diagnosis. For patients with severe symptoms, including an elevated heart rate, heart palpitations and anxiety, a medicine called a beta-blocker will be added to help decrease symptoms. Once thyroid hormone levels normalize, the beta-blocker can be stopped. Anti-thyroid medication should not be stopped unless the TSI level (the antibody causing the Graves’ disease) is normal.

Up to 50% of patients treated with medication achieve remission, which is defined as resolution of hyperthyroidism for at least 6-12 months after medication is stopped. Unfortunately, 30-40% of these patients — who appear to have their hyperthyroidism resolve — will eventually experience a relapse. Thus, the overall percentage of patients that achieve stable, long-lasting remission is only 20-25%. In general, if a patient has not achieved remission within 5 years of diagnosis, it is unlikely that they will.

Some patients (up to 30%) treated with methimazole may experience side effects. The most common side effect of methimazole is hives and joint pain. Dose reduction and the use of an antihistamine or ibuprofen may reduce side effects and allow for the continuation of anti-thyroid medication.

Rarely, a patient may experience an adverse reaction to methimazole. In 1% of patients, anti-thyroid medication may lower white blood cell (WBC) count, specifically neutrophils — the cells that help fight infection. Signs and symptoms of this adverse reaction include:

  • Fever
  • Sore throat
  • Appearance of illness

Any patient being treated with methimazole who develops a fever greater than 101o should stop taking the medication and receive a medical evaluation, which should include a CBC blood test. Stopping anti-thyroid medication results in the recovery of WBC.

For patients who do not achieve remission on medication, experience side effects or adverse reactions, or experience a disruption in normal activities due to the unpredictable course of their disease, definitive (permanent) therapy with either surgery or radioactive iodine ablation should be pursued.

In contrast, patients who are doing well, even if they have not achieved remission within 5 years of their diagnosis, may continue anti-thyroid medication if they are not interested in definitive therapy.

Radioactive iodine ablation (oral medication)

Radioactive iodine (RAI) ablation is one of two ways to permanently treat hyperthyroidism. Permanent treatment of Graves’ disease is referred to as definitive therapy. The goal of definitive therapy is to permanently convert the hyperthyroidism to hypothyroidism. Hypothyroidism is more stable and the medication used to treat it does not have side-effects. 

The advantage of RAI ablation is that it is an oral medication and does not require surgery. The disadvantage of RAI ablation is that it usually takes 1-3 months for hyperthyroidism to convert to hypothyroidism.

Thyroidectomy (surgery)

Thyroidectomy is the second way to permanently treat hyperthyroidism. The removal of the thyroid gland immediately resolves Graves’ disease, and there is no risk of worsening thyroid eye disease. However, there are disadvantages to surgical removal of the thyroid. After a thyroidectomy, your child will have a scar. In addition, the risk of surgical complications includes hypoparathyroidism (damage to the parathyroid glands that control calcium) and recurrent laryngeal nerve damage (damage to the nerves that control the voice and help protect the airway so food, liquid or other items do not enter the lungs).

At the Pediatric Thyroid Center, the risk of a permanent complication from surgery is less than 1% over more than 700 thyroid surgeries.

Which treatment option is best for my child?

If you are interested in definitive therapy, your child’s endocrinologist should review which option may be best for your child’s disease status as well as clinical and social situation. Both RAI ablation and thyroidectomy are highly effective, and when performed in a high-volume pediatric thyroid center, both have a low rate of complications.

Surgery may be more favorable than RAI ablation if:

  • The patient is younger than 10.
  • The patient has thyroid eye disease.
  • The patient’s thyroid gland is more than three times enlarged.
  • A thyroid nodule is present.
  • There is a short window of time in a patient’s schedule to achieve hypothyroidism.

While definitive therapy may sound frightening, our team has never had a patient regret pursuing definitive therapy; we have only had patients wish they had considered definitive therapy sooner.

What is the follow-up care for patients with Graves’ disease?

Once your child has been diagnosed with Graves’ disease and has started on medication, their hormone levels will be checked monthly until the T3 and T4 levels have normalized. Once this occurs, bloodwork can occur less often, usually every 2-3 months.

In general, a higher dose of anti-thyroid medication will be needed to stabilize thyroid hormone levels, but lower doses will be needed to maintain normal levels. The average time frame from diagnosis to normalization of thyroid hormone levels is 3-6 months. Anti-thyroid medication should not be stopped unless your endocrinologist confirms that the TSI level is normal for at least two blood draws. Patients are typically evaluated in clinic every 3-6 months until thyroid hormone levels are stable and then every 6-12 months once the disease is under control.

At each clinic visit, your provider will review the course of your child’s disease, including their heart rate, growth and development. Your child will receive a physical exam, and the results of their lab tests will be reviewed along with their medication dosage. Clinic visits also provide an opportunity to discuss definitive therapy options as opposed to continued medication usage.

Follow-up care and ongoing support for Graves’ disease is available in our Pediatric Thyroid Center at our Main Campus or at the CHOP Specialty Care and Surgery Center in Voorhees, N.J. Patients are also treated by our general pediatric endocrinologists throughout our CHOP Care Network. Our team is committed to partnering with you to provide the most current, comprehensive and specialized care possible for your child.

What are the outcomes for patients with Graves’ disease?

The majority of children with Graves’ disease can return to normal activities — including sports — once thyroid hormone levels are improving or have normalized, depending on the individual patient. However, even after thyroid hormone levels normalize, it can take weeks, or even months, for a patient to regain strength, coordination and endurance. Compliance with the treatment plan — including medication, labwork and clinic visits — is critically important to optimizing the timing of thyroid hormone level normalization.