Pediatric Hyperthyroidism Medication

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

The antithyroid medication currently used in the United States is methimazole. Carbimazole is similar in action to methimazole but is primarily used in Europe and Asia. PTU is used in increasingly limited circumstances. All 3 antithyroid medications belong to the class of compounds known as thionamides and have been used for more than 60 years.

These medications inhibit thyroid hormone biosynthesis by decreasing the oxidation of iodide and iodination of tyrosine. In addition, PTU diminishes the peripheral conversion of T₄ into T₃. Some evidence suggests that antithyroid drugs modify the immune response and decrease circulating levels of thyroid autoantibodies; however, whether this is a direct effect of these medications or simply a fortuitous side effect of the reduction of circulating thyroid hormone levels is unclear.

Dosage and administration

Dosage and frequency of administration for these medications have not been well established. The initial pediatric dose of methimazole is administered at 0.4-0.7 mg/kg/d. Its half-life is 4-6 hours. The usual pediatric dose of PTU is 5-7 mg/kg/d; its serum half-life is 75 minutes. Pharmacokinetically, it would seem that neither of these should be effective as once-daily therapy; yet, because the thyroid accumulates the drugs, methimazole given once daily is clinically effective. However, PTU should be administered 3 times a day.

Lower per-kilogram doses of methimazole (< 0.5 mg/kg/d) have been shown to prolong the free T ₄ 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) is added to the regimen until hyperthyroidism is under control.

Dosage of PTU or methimazole is titrated to maintain T ₄ concentration 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 alternative approach is to give a larger dose of medication to induce hypothyroidism, and exogenous T ₄ is added to the regimen to correct the hypothyroidism. The addition of T ₄ has been suggested to result in a higher rate of remission, although studies are conflicting. This approach requires administration of 2 drugs and, because of the higher dose of antithyroid drugs, may 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; however, patients can generally continue on the medication, provided that the white blood cell (WBC) 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, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients using this agent.^[6] 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.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil (PTU). Among adults, 12 deaths and 5 liver transplantations occurred; among the pediatric patients, 1 death and 6 liver transplantations occurred. PTU is indicated for hyperthyroidism due to Graves disease.

These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

For more information, see the FDA Safety Alert.^[6] The FDA recommends the following criteria be considered for prescribing PTU^[6] :

• Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole
• 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

Neonatal Graves disease

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 PTU, because it is bound mostly to plasma proteins and does not cross the blood-milk barrier to a significant degree.

Class Summary

Thionamide agents block the synthesis of thyroid hormone.

Propylthiouracil (PTU)

In addition to inhibiting thyroid hormone biosynthesis by decreasing the oxidation of iodide and iodination of tyrosine, propylthiouracil diminishes peripheral conversion of T4 into T3.

Methimazole (Tapazole)

Methimazole is the treatment of choice for fetal hyperthyroidism.

Class Summary

Iodide agents block iodide uptake by the thyroid, thereby transiently decreasing T₄ synthesis. This effect lasts for about 2 weeks. Various iodide preparations, including strong iodine solution (ie, Lugol iodine solution, first made in 1829), saturated solution of potassium iodine (SSKI), and iodinated radiographic contrast agents (sodium ipodate) have been used.

Radiographic contrast agents are effective, not only because they release iodide, but also because they inhibit conversion of T₄ to T₃. Sodium iodide may be administered intravenously (IV) if oral (PO) intake is compromised. Damaged or immature thyroid glands (eg, after treatment with radioactive iodine or neonatal thyrotoxicosis) are particularly susceptible to the suppressive effects of iodides and are less likely to rebound from these effects.

Potassium Iodide and Iodine (Lugol Solution, SSKI)

Lugol iodine solution contains about 6.3 mg elemental iodine per drop (gtt). Saturated solution of potassium iodide (SSKI) contains about 38 mg of potassium iodide per drop.

Sodium ipodate and sodium iopanoic acid are iodinated contrast agents that act by liberating iodide. Sodium ipodate contains 308 mg iodine/capsule, whereas sodium iopanoic acid contains 333 mg iodine/capsule. This is advantageous, because these agents are also thought to inhibit extrathyroidal conversion of T4 to T3.

Class Summary

Beta-adrenergic blocking agents are used for symptomatic treatment of cardiac complications of hyperthyroidism.

Propranolol (Inderal, InnoPran XL)

Cardiac symptoms can be alleviated with propranolol.

Class Summary

Radioiodide (iodide I 131) is used for radioablation as an alternative to medical or surgical therapy.

Sodium Iodide I-131 (Hicon, Iodotope)

One to 2 doses of radioiodide is sufficient for radioablation. Some physicians give the standard dose, but others calculate the dose based on measured radioiodine uptake.

Class Summary

Stress doses of glucocorticoid agents are used primarily to treat thyroid storm. Their effects are thought to be due to reduction in conversion of T ₄ to T ₃ , reduction in autoantibody formation, and protection from adrenal insufficiency. High-dose glucocorticoids may also be used for severe sight-threatening ophthalmopathy.

Hydrocortisone (A-Hydrocort, Solu-Cortef, Cortef)

Hydrocortisone elicits anti-inflammatory properties and causes profound and varied metabolic effects. This agent modifies the body's immune response to diverse stimuli.