Diffuse Toxic Goiter Medication

No standard treatment protocols exist; individualization of treatment based on clinical experience is protocol. Patient preference after informed consent affects all therapeutic decisions.

Beta-blockers

Beta-blockers are used if symptomatic tremor or palpitations require their use. They may be used even as investigation is ongoing because they have no effect on thyroid gland function, but they block the beta-adrenergic peripheral manifestations of the hyperthyroid state. Propranolol has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown clinical significance with the usual doses. The dose may be decreased and then stopped when the euthyroid state occurs. They should not be used in the presence of bronchospasm, even the beta1-selective agents. Calcium channel blockers may be substituted.

Thionamides

Thionamide drugs, propylthiouracil (PTU) and methimazole (MTZ), inhibit hormonogenesis within the thyroid gland. PTU has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown added clinical significance. Other than in pregnancy and breastfeeding, MTZ has advantages over PTU by a longer half-life with once-a-day dosing, and possibly more rapid return to the euthyroid state. Although rare, agranulocytosis, lupuslike vasculitis, and hepatitis are more commonly associated with PTU than with MTZ. Agranulocytosis occurs in less that 0.1% of cases but is unpredictable; it may occur at any time. Routine monitoring of WBC count is not useful. Should any infection occur, such as a sore throat, the WBC count should then be measured. Discontinuation of the drug results in a rise of WBC within a few days.

Granulocyte colony-stimulating factor may need to be administered. Skin rash may perhaps be more common with MTZ; incidence is about 3%, and it usually occurs within the first few weeks of therapy. Methimazole is the drug of choice.^[2]

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. The boxed warning also states that PTU should be reserved for use in patients 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 on 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 PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants 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 to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert)^[3] :

• 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, evaluate the patient 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 health care 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.

Monitor the serum thyroid indices monthly until euthyroid, and then the dose of the drug may be decreased for maintenance. The lowest dose needed to maintain the euthyroid state is then used for long-term therapy.

Normalization of thyroid function with these drugs must occur for some time, at least 6 months and perhaps for 1-2 years, to maximize the remission rate after drug discontinuation. Despite this, the relapse rate is 50-70%, usually within the first few weeks or months, but occasionally after a few years. Remission is weakly predicted by a short duration of symptoms, age younger than 40 years, minimal enlargement of the thyroid gland, and concomitant presence of Hashimoto thyroiditis.

Relapse after discontinuation of the drug requires a decision regarding radioiodine therapy or surgery for more definitive therapy, or return to the antithyroid drug. Although general practice is not to use these drugs long-term, there is no reason why this cannot occur, if that is what the patient chooses.

Iodine

In severe cases, such as thyroid storm, iodine in the form of potassium iodide (SSKI) 10 drops twice a day or iopanoic acid 1-3 g/d may be given. They inhibit the release of thyroxin from the gland and inhibit peripheral conversion of T4 to T3. They help render a euthyroid state more rapidly in response to antithyroid drugs, or prepare for surgery, but will eliminate the use of radioiodine for many months due to expansion of the iodine pool and thus decrease the delivery of radioiodine to the thyroid gland.

Radioiodine

Oral administration of I 131 is incorporated into the thyroid follicular cells, and the beta emission results in cell destruction and glandular fibrosis. The effect is seen in 1 and a half to 4 months. Off medications, the thyroid hormone levels become normal (requiring continued monitoring), fall below normal (requiring thyroid hormone replacement therapy, likely for life), or remain elevated (requiring another administration of radioiodine). In those becoming euthyroid, the chance every year of becoming hypothyroid due to ongoing disease in the gland is 5%; occasionally, hyperthyroidism may reoccur. The usual dose is 6-8 mCi. The dose is adjusted based on size of the thyroid gland, age of the patient, and severity of the clinical picture. Resistance is increased by age older than 40 years, large goiters, prior therapy with PTU, and nodularity (not seen with diffuse toxic goiter). Recent reviews confirm the safety of the use of radioiodine.^[4]

Radioiodine therapy is not used in clinically severe hyperthyroidism or thyroid storm until the hyperthyroid state is medically controlled.

Because of transplacental transfer and lactation transfer, it is contraindicated in women who are pregnant or breastfeeding. For the theoretical ovarian exposure, conception in treated women is empirically discouraged for 3-6 months.

It may be administered to children, if clinically indicated. Long-term safety data in children are not available.

Worsening of the hyperthyroid state may occur after radioiodine therapy due to release of prestored hormone. Gland tenderness and swelling is uncommon and may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (not aspirin), and they rarely require steroid administration.

Radioiodine administration has been associated with worsening or progression of symptomatic ophthalmopathy. Either radioiodine is avoided in very symptomatic individuals or corticosteroids (prednisone 0.5 mg/kg) are used beginning the day after the radioiodine administration for 1-3 months, or they are administered if any worsening of the ophthalmopathy occurs after radioiodine administration. Cessation of smoking and avoidance of hypothyroidism also help the course of ophthalmopathy.

The return to the euthyroid state, regardless of therapy, is best monitored by serum free thyroxin, or its equivalent, because the pituitary is suppressed and TSH secretion may remain low for some time after a normal or hypothyroid state occurs. Relapse from a euthyroid state to hyperthyroidism is first monitored by new suppression of the serum TSH, and often the serum T3 then increases above normal before the serum T4 increases above normal.

Pregnancy and breastfeeding

Pregnancy often has an effect on improving the immunologic disease state during the pregnancy and then often relapses following delivery. The treatment of choice is PTU, which has less placental transfer than MTZ. Rare congenital anomalies reported with MTX (eg, aplasia cutis) are even less associated with PTU. Overall, the congenital abnormality rate with these drugs is similar to background normal rate. MTZ may be used if a problem exists with PTU.

The goal is to keep the free thyroxin in the upper part of normal to minimize fetal drug exposure. Monthly monitoring of serum free thyroxin usually allows the dose of PTU to be decreased and often discontinued in the third trimester. Both PTU and MTZ may be used in breastfeeding mothers. A small amount of drug does enter the milk, but neonatal thyroid levels generally remain normal. PTU and MTZ are not contraindicated in pregnancy or lactation.

Class Summary

These agents may either inhibit hormonogenesis within the thyroid gland or inhibit release of thyroid hormone from the gland.

Propylthiouracil (PTU)

Actively transported into the thyroid gland and inhibits incorporation of iodine to thyroid hormones, and inhibits peripheral conversion of T4 to T3. Drug recommended in pregnancy and lactation with dose adjustment to minimum needed. Laboratory monitoring of free T4 to adjust dose therapy. The serum TSH may lag behind the changes in free T4. Long-term experience with this drug.

Methimazole (Tapazole)

Actively transported in thyroid gland and inhibits thyroid synthesis by preventing oxidation of trapped iodine. Ten times more potent than PTU, and once-a-day dose is effective. Euthyroid state is achieved in 4-6 wk, and maintenance treatment continued for 12-24 mo. Relapse may be observed 1-6 mo after stopping therapy, occasionally later.

Less desirable than propylthiouracil in pregnancy and lactation but may be used if propylthiouracil cannot be used.

Potassium iodide (Pima, Thyro-Block)

Inhibits thyroid hormone secretion. Contains 8 mg of iodide per gtt. May be mixed with juice or water for intake.

May decrease thyroid gland secretion and vascularity for a short time, such as 2 wk; may be used in severe cases of hyperthyroidism, such as thyroid storm, or to prepare patient for thyroidectomy

Supersaturated potassium iodide (SSKI)

Contains 50 mg of iodide per drop. May be mixed with juice or water for ingestion. Inhibits thyroid hormone release.

Class Summary

These agents have profound and varied metabolic effects.

Dexamethasone (Decadron)

Steroids block peripheral conversion of T4 to T3. Used as adjunct in management of thyroid storm and symptomatic progressive Graves ophthalmopathy.

Class Summary

These agents are used to destroy thyroid cells.

Radioiodine (I-131)

Agent of choice because it is selectively taken up by the thyroid gland. Causes dysfunction or death of thyroid cells over time. Long-term experience suggests good safety profile.

Class Summary

Relief of adrenergic symptoms, especially cardiac and neurologic. Propranolol blocks peripheral conversion of T4 to T3, but this is of unknown clinical significance.

Propanolol (Inderal)

Nonselective beta-adrenergic receptor blocker. Also blocks peripheral conversion of T4 to T3. Used along with antithyroid drugs, before and after radioiodine treatment. Useful in thyroid crisis/storm, or in cardiac complications such as atrial fibrillation. Oral or intravenous use controls cardiac and psychomotor manifestations within minutes. Continue until euthyroid state is achieved.