Hyperthyroidism occurs when excessive thyroid hormones are produced.5 The majority of cases of hyperthyroidism (50%-80%) occur due to Graves disease, an autoimmune condition in which antibodies form against the thyrotropin receptor and stimulate the production of thyroid hormones.5,6 The remaining cases of hyperthyroidism occur due to a wide variety of reasons.2,5,6,7 (Table 59-3)
TABLE 59-3 Causes of Hyperthyroidism and Hypothyroidism ||Download (.pdf)
TABLE 59-3 Causes of Hyperthyroidism and Hypothyroidism
|Graves disease||Chronic autoimmune thyroiditis (Hashimoto disease)|
|Toxic adenoma||Surgical removal of the thyroid gland|
|Toxic multinodular goiter||Thyroid gland ablation with radioactive iodine|
|Painful subacute thyroiditis||External irradiation|
|Silent thyroiditis||Biosynthetic defect in iodine organification|
|Iodine-induced hyperthyroidism||Replacement of the thyroid gland by tumor|
|Ectopic thyroid tissue||Drugs—amiodarone, lithium, excess antithyroid hormones, interferon-α|
|Excessive pituitary TSH or trophoblastic disease|
|Drugs—excess levothyroxine, amiodarone|
Clinical Presentation/Signs and Symptoms
Patients with hyperthyroidism typically present with nervousness or anxiety, palpitations and tachycardia, weight loss, sleep disturbances, frequent bowel movements, and heat intolerance.5,7 Women can experience irregular menses or decreased fertility, while men may have decreased libido or gynecomastia. Graves disease may induce ophthalmopathies including exophthalmos.6,7 Few patients present with thyroid storm, a rare and life-threatening form of hyperthyroidism.
In order to diagnose hyperthyroidism, patients should undergo a thorough evaluation including a comprehensive history and physical examination and laboratory evaluation of thyroid hormones.5,6 TSH concentrations as determined by a sensitive TSH assay will typically be decreased to less than 0.1 mIU/L, while unbound T3 and T4 concentrations will be elevated. Subclinical hyperthyroidism results when thyroid hormone concentrations remain within the normal reference range but serum TSH is decreased.8 Though rarely needed for diagnosis, the presence of thyrotropin-receptor antibodies or thyroid-stimulating immunoglobulins (TSI) may indicate Graves disease.6,7
Due to the potential for the development of atrial fibrillation and an increase in all-cause mortality associated with subclinical hyperthyroidism, current recommendations suggest that even subclinical hyperthyroidism should be treated.9 Since Graves disease remains the most common cause of hyperthyroidism, treatment recommendations focus on this disease state.5-7,9 Available treatment options include surgery, radioiodine therapy, and antithyroid drugs. Surgical intervention with thyroidectomy remains a last-line option, reserved for treatment-refractory patients or the presence of a large goiter or malignant thyroid nodule.
Radioactive iodine remains the optimal treatment for Graves disease as it reduces the chance of recurrence of Graves disease.5-7,9 This treatment, however, induces permanent hypothyroidism within 4 to 12 months in most cases. Thyroid replacement therapy should begin while patients are euthyroid prior to the development of hypothyroidism and its associated symptoms.7 Less than 20% of patients may need a second dose of radioactive iodine.6 Prior to starting radioiodine therapy, a 24-hour radioiodine-uptake study may be performed to calculate the dose needed, but a fixed-dose of radioiodine may be given. Patients must take several necessary precautions after treatment with radioactive iodine to prevent transference of radioactive iodine to others.7 Pregnant women should avoid treatment with radioiodine as it crosses the placenta and can be taken up by the fetal thyroid hormone with serious consequences. Additionally, women of childbearing age should avoid getting pregnant for 6 to 12 months after treatment. For patients with underlying cardiovascular disease and some elderly patients, pretreatment with antithyroid drugs may reduce the risk of cardiovascular events associated with posttreatment exacerbation of hyperthyroidism. However, recent studies have shown that use of antithyroid drugs may lead to a higher rate of treatment failure after radioiodine therapy.9 These medications must be discontinued 3 to 7 days prior to radioiodine therapy to minimize the risk of treatment failure.6
The thionamides, methimazole, and propylthiouracil are given as monotherapy for hyperthyroidism or in preparation for radioactive iodine therapy.5,6,9.10 These agents block the formation of thyroid hormones by preventing the incorporation of iodine into tyrosine residues by thyroid peroxidase.6,10 Additionally, propylthiouracil blocks the peripheral conversion of T4 to T3. Over the course of therapy, thionamides may provide immunosuppressive effects, including the reduction in the concentrations of thyrotropin-receptor antibodies.
Both methimazole and propylthiouracil are given orally, with rapid gastrointestinal absorption.5,6,10 Due to a longer duration of action, methimazole can be administered once daily, while propylthiouracil requires dosing two to three times daily. Other benefits of methimazole include more rapid clinical effects, with faster reductions in serum concentrations of T4 and T3.
Initial treatment of hyperthyroidism requires higher doses of antithyroid medications (Table 59-4).5,6,10 Inadequate dosing of antithyroid medications may lead to continuation of hyperthyroidism or, conversely, development of hypothyroidism. Symptom and laboratory improvement can be seen about 3 to 4 weeks after initiation of medication. While T4 and T3 normalize quickly, serum concentrations of TSH might take months to normalize. Thyroid function tests should be checked every 4 to 6 weeks during the first 4 to 6 months. As symptoms improve and thyroid function returns to normal, doses of antithyroid medications may be reduced. Monotherapy should be continued for 12 to 18 months to induce remission. However, some patients may require longer durations of therapy.
TABLE 59-4 Antithyroid Medications ||Download (.pdf)
TABLE 59-4 Antithyroid Medications
|Mechanism of action||Blocks formation of T4 and T3|
Blocks formation of T4 and T3
Blocks peripheral conversion of T4 to T3
|Starting dose||10-30 mg daily||200-400 mg divided in 2-3 daily doses|
|Maintenance dose||5-10 mg daily||100-200 mg divided in 2-3 daily doses|
|Half-life||2-28 h||0.9-4.3 h|
|Major side effects||Agranulocytosis, cholestasis, arthralgias||Agranulocytosis, vasculitis, hepatotoxicity (black box warning), arthralgias|
The goal of monotherapy with antithyroid drugs is to achieve remission, defined as the ability to maintain normal thyroid function for 1 year without antithyroid medication.6,10 Remission can be achieved in 30% to 50% of patients, but relapse occurs in more than half of patients treated with antithyroid medications. Most relapses occur within the first 6 months after stopping therapy. Factors such as male sex, older age (>40 years old), a large goiter, higher baseline T4 and T3 concentrations, and higher levels of thyrotropin-receptor antibodies reduce the likelihood of remission. Strategies to improve remission rates, such as longer duration of therapy (>1 year), higher doses of antithyroid medications, and addition of thyroxine, have not proven to be successful. Radioactive iodine therapy remains an alternative for patients who fail antithyroid medications.
Side effects of antithyroid medications occur in about 5% of patients and include cutaneous reactions, gastrointestinal upset, and arthralgias.5,6,10 The occurrence of arthralgias must be taken seriously and antithyroid medication must be stopped as it may signal the development of a severe polyarthritis. Other side effects occur infrequently but produce severe reactions. Agranulocytosis occurs in approximately 0.3% of patients treated with antithyroid medications. Most cases occur within the first 3 months of therapy but may develop after more than a year. Routine monitoring of white blood cells is not recommended as agranulocytosis rarely occurs and usually develops rapidly. Patients should be advised to discontinue antithyroid medications and seek medical attention if they develop fever, sore throat, or mouth ulcers as hospitalization and treatment with broad-spectrum antibiotics are required. Cross-reactivity between methimazole and propylthiouracil for agranulocytosis can occur. As a result, patients must pursue an alternative therapy for the treatment of hyperthyroidism.
Vasculitis can occur as drug-induced lupus or with the development of antineutrophil cytoplasmic antibodies (ANCA). Though rare, it occurs more frequently in Asian patients treated with propylthiouracil. Patient presentation includes acute renal dysfunction, arthritis, skin ulceration, and upper and lower respiratory symptoms. Antithyroid medication must be discontinued. Severe cases require additional treatment with glucocorticoids or cyclophosphamide.
Hepatotoxicity may occur with methimazole and propylthiouracil but in differing forms.5,10 Methimazole can induce a cholestasis that is slowly reversed with discontinuation of the drug. Propylthiouracil can induce liver failure that is fatal in a small portion of patients, typically developing in the first 3 months of therapy if it occurs. The FDA added a black box warning for propylthiouracil in April 2010, warning of the risk of severe liver injury and acute liver failure. As a result, methimazole should be recommended as the first-line antithyroid medication. Routine monitoring of liver function tests is not recommended but the development of hepatotoxicity symptoms including fatigue, jaundice, dark urine, and easy bruising should prompt patients to seek medical attention. Discontinuation of propylthiouracil is required. The development of any life-threatening side effects including agranulocytosis, vasculitis, or hepatotoxicity precludes future use of antithyroid medications.
Beta-Adrenergic Blocking Drugs
Beta-adrenergic blocking agents are used as adjunctive therapy to ameliorate the symptoms of hyperthyroidism, including anxiety, palpitations, and tremor, until thyroid hormone levels normalize.5,6 Propranolol and nadolol minimally inhibit the conversion of T4 to T3. Choice of beta-adrenergic blocking agent can depend on concomitant disease states and frequency of dosing.
Hyperthyroidism can develop during pregnancy.5,6,10 Due to the risk of miscarriage, preeclampsia, and preterm delivery, treatment must be started. The use of radioactive iodine is contraindicated, and surgery should be avoided; therefore, antithyroid drugs should be used.5 Both methimazole and propylthiouracil can be used, although both are categorized as class D agents by the FDA due to the risk of fetal hypothyroidism.10 Propylthiouracil is preferred over methimazole, as methimazole has been associated with congenital abnormalities like aplasia cutis and gastrointestinal defects.5,6 Thyroid levels should be maintained at the upper limit of normal with the lowest dose possible to reduce the risk of neonatal hypothyroidism. In some patients, symptoms improve during the third trimester such that antithyroid medications can be discontinued, but hyperthyroidism may worsen during the postpartum period. Both antithyroid drugs are secreted in breast milk in low concentrations, but may be safe in nursing mothers.
Thyroid storm is a life-threatening event that results from the exaggerated effects of elevated thyroid hormones.11,12 The condition occurs rarely but has a 20% to 30% mortality rate. Contributing factors include infection, trauma, diabetic ketoacidosis, certain medications, and inappropriate administration of antithyroid hormones or levothyroxine. Patients present with exaggerated symptoms of hyperthyroidism, and usually have fever, tachycardia, confusion or coma, and gastrointestinal disturbances. Laboratory evaluation reveals undetectable TSH concentrations with elevations in free T4 and T3 that appear similar to uncomplicated hyperthyroidism. Hyperglycemia and elevated liver enzymes may also be present. Treatment recommendations include high-dose beta-adrenergic blocking agents administered concomitantly with propylthiouracil, glucocorticoids, stable iodide, and supportive care. Propylthiouracil is recommended preferentially over methimazole due to its ability to block the peripheral conversion of T4 to T3. The precipitating event should also be managed appropriately.