Pediatric Hyperthyroidism Treatment & Management

Updated: Nov 03, 2015
  • Author: Sunil Kumar Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
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Treatment

Approach Considerations

The treatment administered for pediatric hyperthyroidism depends on the child's age and severity of their disease. Treatment approaches include antithyroid medications, radioiodine ablation, and thyroidectomy [6] ; because each of these treatments has advantages and disadvantages, the therapeutic choice must be individualized.

Once treatment is initiated, careful monitoring is essential because patients are at risk for either recurrent thyrotoxic symptoms or hypothyroidism. Patients who receive inadequate treatment may have bone demineralization and subsequently be at increased risk for osteoporosis and fractures.

Inpatient care is rarely required in children with hyperthyroidism, and serious complications of medical therapy (eg, agranulocytosis, hepatitis, lupuslike syndrome) are quite rare. Nonetheless, patients should be carefully monitored for complications.

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Surgical Intervention

Surgery is the oldest treatment for Graves disease and is quite effective. [7] Generally, patients are initially treated with antithyroid medications. Iodide then is added before surgery to decrease the vascularity of the thyroid gland. To minimize risk of recurrence, most of the gland is removed. Consequently, the risk of permanent hypothyroidism is high. Patients may require lifelong T4 replacement.

Surgical complications can include hypoparathyroidism and damage to the recurrent laryngeal nerve. In a recent study, incidental parathyroid excision was reported in 19.4% of pediatric thyroidectomies. [8]  Transient hypocalcemia is another potential complication, even without incidental parathyroid excision. In the hands of an experienced surgeon, these risks are 1-3%. The surgical mortality rate is very low, but referring patients to experienced surgeons who report both their case volumes and complication rates is prudent.

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Remission

Remission, which can takes months to years, is defined as persistent euthyroidism after discontinuation of therapy. The reported remission rate with medical therapy is 34-64% within 5 years of diagnosis. In the first 24-48 months of therapy, the remission rate increases with the duration of therapy. After the first few years, however, spontaneous remission is less likely. Patients may have a relapse weeks or years after discontinuation of therapy. Variation in the reported relapse rate is, in part, related to differences in the length of follow-up.

Attempts to define positive prognostic indicators of long-term remission have not been successful thus far.

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Long-Term Monitoring

Patients treated medically should have thyroid function tests (T 4 , T 3 , thyroid-stimulating hormone [TSH]) every 2-3 months. TSH levels are suppressed for several months after the initiation of therapy; therefore, T 3 and T 4 levels are better initial chemical markers of the euthyroid state.

Besides thyroid function tests, routine laboratory evaluation is generally not required. Although hepatitis, thrombocytopenia, and agranulocytosis are known side effects of propylthiouracil (PTU) and methimazole, they are rare enough and of such sudden onset that routine laboratory screening is rarely helpful.

Ghrelin and insulinlike growth factor – binding protein-1 (IGFBP-1) levels may have a role in the hunger-satiety signal pathway in patients with Graves thyrotoxicosis. Ghrelin levels in untreated patients are low and increase with medical therapy, whereas fasting IGFBP-1 levels, which are initially elevated, fall.

Glucocorticoid therapy should be considered in patients (both adults and children) with severe ophthalmopathy. Pulse therapy may provide a favorable response in up to 88% of patients.

Patients treated with radioiodine or surgery should have thyroid function tests annually.

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Symptomatic Treatment

Self-limited causes of hyperthyroidism, such as subacute thyroiditis, iodine-induced hyperthyroidism, and exogenous administration of T 4 , can be treated symptomatically. For more significant cardiovascular symptoms, beta-adrenergic blockade with propranolol can be helpful.

Initial response to antithyroid medications depends on the level of preformed thyroid hormone. Because antithyroid medications do not block the release of preformed hormone, patients may need 3-12 weeks on therapy before they become clinically and chemically euthyroid. Propranolol can be a useful adjunct during this period. See Antithyroid Agents.

Neonatal Graves disease

To date, no treatments can correct the underlying immune dysfunction in Graves disease. Treatment is directed at correcting the clinical and biochemical abnormalities.

For neonatal Graves disease, various approaches may be used. In mild cases, symptomatic treatment with a beta-blocker (eg, propranolol) may be tried. In some cases, this is adequate, because the disease is usually transient. In more severe cases, antithyroid medications are necessary. In very severe cases, iodides in the form of Lugol iodine solution or saturated solution of potassium iodide (SSKI) are used.

Iodide inhibits the release of preformed T 4 and T 3 from the thyroid gland and therefore has a more rapid onset of action than the thionamides. Glucocorticoids may be necessary in severe cases. These inhibit the peripheral conversion of T 4 to T 3 and protect the infant against adrenal insufficiency, which can occur because T 4 increases the metabolism of cortisol. Note that iodide or thionamide therapy may render the neonate hypothyroid, which is clearly not desirable. Therefore, thyroid function tests must be monitored very closely, and the dose of thionamide reduced or T 4 must be added if the infant becomes hypothyroid. In rare cases of congestive heart failure (CHF), digoxin is a useful adjunct.

Maternal hyperthyroidism and breastfeeding

Medical treatment of maternal hyperthyroidism is not a contraindication to breastfeeding. In this case, the drug of choice is propylthiouracil (PTU), because it is bound mostly to plasma proteins and does not cross the blood-milk barrier to a significant degree.

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Antithyroid Agents

Treatment with antithyroid medications is considered to be the treatment of choice in children and adolescents. This treatment is a relatively safe option, provided that patients are willing to participate in prolonged therapy.

In the United States, methimazole is the only antithyroid medication currently used. [9] A third medication, carbimazole, is similar in action to methimazole and is primarily used in Europe and Asia. PTU has been discouraged as routine practice due to its more adverse risk profile. These antithyroid medications belong to the thionamides class and have been used for more than 60 years.

Dosage and administration

Dosage and frequency of administration for these medications have not been well established. The usual pediatric dose of methimazole is 0.4-0.7 mg/kg/d, with a lower maintenance dose (one third to one half the starting dose). Its half-life is 4-6 hours. Pharmacokinetically, it would seem that neither methimazole nor PTU should be effective as once-daily therapy; yet, because the thyroid accumulates these drugs, methimazole given once daily is clinically effective. However, PTU is administered 3 times a day.

Lower per-kilogram doses of methimazole (< 0.5 mg/kg/d) have been shown to prolong the free T4 elevations for almost 3 times as long as the higher per-kilogram doses (> 0.5 mg/kg/d).

Because antithyroid medications affect the thyroid principally at the level of hormone biosynthesis, patients may continue to secrete preformed hormone for 6-12 weeks after initiation of therapy. In patients with marked cardiac manifestations of hyperthyroidism, a beta-blocker (eg, propranolol, 80 mg/m2/d given once in the morning) is added to the regimen until hyperthyroidism is under control.

Titration

The dosage of PTU or methimazole is titrated to maintain free T4 and total T3 concentrations within the normal range. As the disease comes under control and thyroid-stimulating hormone (TSH) levels rise, the dose is decreased and eventually discontinued. An obsolete approach was to give a larger dose of medication to induce hypothyroidism, then to add exogenous T4 to correct the hypothyroidism. Such rest of the thyroid by an addition of T4 appeared to result in a higher rate of remission, although the preponderance of evidence does not support this conclusion. Moreover, this complex approach requires administration of 2 drugs and, because of the higher dose of antithyroid drugs, could increase the risk of adverse effects.

Adverse effects

Adverse effects of these medications are relatively common and may be dose-related. Approximately 1-9% of patients develop a drug-induced rash that resolves with discontinuation of therapy. Drug cross-reactivity between PTU and methimazole may be as high as 50%. Other minor adverse effects include a bitter taste, nausea, and headache. An asymptomatic, mild, transient granulocytopenia is observed in as many as 12% of patients receiving methimazole or PTU. However, these patients can generally continue on the medication, provided that the WBC count is closely monitored.

More severe adverse effects are less common. Arthritis, fever, and mucosal ulcerations are observed in a small number of patients. Other serious adverse effects include agranulocytosis, hepatitis, glomerulonephritis, arthritis, and a lupuslike syndrome. These effects, thought to be idiosyncratic reactions, can occur at any time during the course of therapy. Medication should be stopped immediately. Reactions usually resolve within a few weeks.

Boxed warning for PTU

On April 21, 2010, the US Food and Drug Administration (FDA) added a boxed warning to the prescribing information for PTU that emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients receiving PTU. [10] The boxed warning also states that PTU should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

For more information, see the FDA Safety Alert [10] as well as the Medication section. The FDA recommends the following criteria be considered for prescribing PTU [10] :

  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole; the dose of PTU is 5-7 mg/kg/d, divided 3 times daily.

  • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

  • For suspected liver injury, promptly discontinue PTU therapy, and evaluate for evidence of liver injury and provide supportive care.

  • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.

  • Counsel patients to promptly contact their healthcare provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

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Radioactive Iodine Ablation of the Thyroid Gland

Ablation of the thyroid gland with radioiodine is the treatment of choice for most adults. Pregnancy is the sole contraindication to this therapy. After more than 50 years of widespread use, no evidence of an increased risk of malignancy or genetic damage is noted. Nonetheless, because of the theoretic risk, frequency of radioiodine therapy is much lower in pediatric patients.

131 I is administered orally in 1-2 doses by mouth in a controlled setting (ie, the hospital). Ablation may take about 2-3 months to achieve hypothyroid state, and hyperthyroid symptoms may continue until that time. Propranolol may be used to ameliorate these symptoms.

The major undesirable effect of radioiodine ablation is hypothyroidism. Most patients eventually become hypothyroid regardless of the radiation dose. Patients treated with this method should expect to require lifelong thyroid replacement with T4.

Long-term follow-up (36 y) of over 100 children who were treated with radioactive iodine before age 20 years revealed no increase in the rates of thyroid cancer or birth defects in offspring of these children. [11]

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Consultations

Consultations with the following specialists may be necessary:

  • A pediatric endocrinologist should monitor patients with hyperthyroidism

  • Ophthalmologic evaluation is necessary in patients with significant ophthalmopathy

  • A nuclear radiologist should be consulted for radionuclide studies or radioactive iodine therapy

  • Consultation with a competent neck surgeon is required if a subtotal thyroidectomy is contemplated

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Activity

Patients with symptomatic hyperthyroidism may present with restlessness or fatigue and decreased exercise tolerance. Generally, these symptoms resolve with therapy. Activity may be guided by tolerance and should be limited until the hyperthyroidism is controlled.

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