A. Graves Disease

Graves disease is the most common cause of thyrotoxicosis. It is an autoimmune disorder, characterized by an increase in synthesis and release of thyroid hormones. Autoantibodies, known as thyroid-stimulating immunoglobulins (TSI) or thyrotropin receptor antibodies (TRAb), bind to the TSH receptors in the thyroid cell membranes and stimulate the gland to overproduce thyroid hormones. The presence of these antibodies distinguishes Graves disease from autoimmune chronic lymphocytic (Hashimoto) thyroiditis. Both conditions usually have present serum antithyroid antibodies (TPO Ab or Tg Ab or both).

Graves disease is more common in women than in men (8:1). Its usual onset is between the ages of 20 and 40 years. It may be accompanied by infiltrative ophthalmopathy (Graves exophthalmos) and, less commonly, by infiltrative dermopathy (pretibial myxedemaeFigure 28-5). The thymus gland is typically enlarged and serum ANA levels are usually elevated. Many patients with Graves disease have a family history of either Graves disease or Hashimoto autoimmune thyroiditis. Histocompatibility studies have shown an association with group HLA-B8 and HLA-DR3.

eFigure 28-5. Pretibial Myxedema

Pretibial myxedema. (Reproduced with permission from Carl Grunfeld, MD)

Viral infections, including infections with SARS-CoV-2, have been reported to precipitate Graves disease. Vaccinations against SARS-CoV-2 also have triggered de novo Graves disease as well as relapses 4-30 days after infection or vaccination.

Patients with Graves disease have an increased risk of other systemic autoimmune disorders, including Sjogren syndrome, celiac disease, pernicious anemia, Addison disease, alopecia areata, vitiligo, type 1 diabetes mellitus, hypoparathyroidism, myasthenia gravis, and cardiomyopathy.

B. Toxic Multinodular Goiter and Thyroid Nodules

Autonomous hyperfunctioning thyroid nodules that produce hyperthyroidism are known as toxic multinodular goiter (Plummer disease). They are more prevalent among older adults and in iodine-deficient regions. A single hyperfunctioning nodule can also produce hyperthyroidism. Activating TSH receptor mutations are responsible for some toxic nodules. Toxic multinodular goiter and Graves disease may sometimes coexist in the same gland (Marine-Lenhart syndrome). Thyroid cancer is found in 5% of patients with toxic multinodular goiter.

C. Autoimmune (Postpartum or Silent) Thyroiditis and Subacute Thyroiditis

These conditions cause thyroid inflammation with release of stored hormone. They all produce a variable triphasic course: variable hyperthyroidism is followed by transient euthyroidism and progression to hypothyroidism (see Thyroiditis, above).

Silent thyroiditis is also known as subacute lymphocytic thyroiditis or "hashitoxicosis." It can occur spontaneously; women are affected four times more frequently than men. About 50% have antithyroid antibodies. Silent thyroiditis can also be caused by chemotherapeutic agents (such as tyrosine kinase inhibitors; denileukin diftitox; alemtuzumab; interferon-alpha; interleukin-2; and immune checkpoint inhibitors). Other drugs can cause silent thyroiditis, including lithium and amiodarone. In those with spontaneous silent thyroiditis, about 10-20% remain hypothyroid after 1 year. There is a recurrence rate of 5-10%; this rate is higher in Japan.

Postpartum thyroiditis refers to autoimmune thyroiditis that occurs in the first 12 months postpartum and occasionally after miscarriages. See Thyroiditis, above. About 22% of affected women experience hyperthyroidism followed by hypothyroidism, whereas 30% of such women have isolated thyrotoxicosis and 48% have isolated hypothyroidism. The thyrotoxic phase typically occurs 2-6 weeks postpartum and lasts 2-3 months. Over 80% have antithyroid antibodies. Most women progress to a hypothyroid phase that usually lasts a few months but that can be permanent.

Subacute thyroiditis is also known as "de Quervain" or "granulomatous" thyroiditis. It is typically caused by various viral infections. Women are affected four times more frequently than men. Patients typically experience a viral upper respiratory infection and develop an enlarged and extremely painful thyroid. About 50% of affected patients experience a symptomatic thyrotoxic phase that lasts 3-6 weeks. It is important to differentiate subacute thyroiditis from infectious (suppurative bacterial) thyroiditis. About 10% remain hypothyroid after 1 year. The recurrence rate is 1-4%.

D. Medication-Induced Hyperthyroidism

E. Pregnancy, Hcg-Secreting Trophoblastic Tumors, and Testicular Choriocarcinoma

Human chorionic gonadotropin (hCG) can bind to the thyroid's TSH receptors. Very high levels of serum hCG, particularly during the first 4 months of pregnancy may cause sufficient receptor activation to cause gestational thyrotoxicosis. About 20% of pregnant women have a low serum TSH during pregnancy, but only 1% of such women have clinical hyperthyroidism that requires treatment. Pregnant women are more likely to have hCG-induced thyrotoxicosis if they have high levels of serum asialo-hCG, a subfraction of hCG that has a greater affinity for TSH receptors. Such women are also more likely to suffer from hyperemesis gravidarum. This condition must be distinguished from true Graves disease in pregnancy, which usually predates conception and may be associated with high serum levels of TSI and antithyroid antibodies or with exophthalmos.

F. Rare Causes of Hyperthyroidism

Thyrotoxicosis factitia is due to intentional or accidental ingestion of excessive amounts of exogenous thyroid hormone. Struma ovarii is thyroid tissue contained in about 3% of ovarian dermoid tumors and teratomas. Such ectopic thyroid tissue can produce excess thyroid hormone from thyroid nodules or as a concomitant source of thyroid hormone excess with Graves disease. Pituitary TSH hypersecretion by a pituitary thyrotroph tumor or hyperplasia can rarely cause hyperthyroidism; serum TSH is elevated or inappropriately normal in the presence of true thyrotoxicosis. Pituitary hyperplasia may be detected on an MRI as a pituitary enlargement without a discrete adenoma being visible. This condition appears to be due to a diminished feedback effect of T₄ upon the pituitary. Some cases are familial. Metastatic functioning thyroid carcinoma can cause hyperthyroidism in patients with a heavy tumor burden. Recombinant human thyroid-stimulating hormone (rhTSH) can rarely induce hyperthyroidism when it is given prior to RAI therapy or scanning for metastatic differentiated thyroid cancer.

High levels of hCG can also cause thyrotoxicosis in some cases of pregnancies with gestational trophoblastic disease (molar pregnancy, choriocarcinoma). Some such pregnancies have produced thyrotoxic crisis. Men have developed hyperthyroidism from high levels of serum hCG secreted by a testicular choriocarcinoma.

A. Symptoms and Signs

Thyrotoxicosis can produce nervousness, restlessness, heat intolerance, increased sweating, palpitations, pruritus, fatigue, muscle weakness, muscle cramps, frequent bowel movements, weight change (usually loss), or menstrual irregularities. There may be fine resting finger tremors, moist warm skin, fever, hyperreflexia, fine hair, and onycholysis (eFigure 28-6). Angina or atrial fibrillation may also be present, sometimes in the absence of other thyrotoxic symptoms (apathetic hyperthyroidism). Women with postpartum thyroiditis are often asymptomatic or experience only minor symptoms, such as palpitations, heat intolerance, and irritability. Chronic thyrotoxicosis may cause osteoporosis. Even subclinical hyperthyroidism (suppressed serum TSH with normal FT₄) may increase the risk of nonvertebral fractures. Tetany is a rare presenting symptom.

eFigure 28-6. Onycholysis (Separation of the Nail from its Bed) in Graves Disease Usually Resolves Spontaneously as the Patient Improves

Onycholysis (separation of the nail from its bed) in Graves disease usually resolves spontaneously as the patient improves. (Reproduced, with permission, from Gardner DG, Shoback D [editors]. Basic & Clinical Endocrinology, 10th ed. New York, NY: McGraw-Hill; 2018.)

Patients with Graves disease usually have a diffusely enlarged thyroid that is frequently asymmetric and often accompanied by a bruit. However, there may be no palpable thyroid enlargement. The thyroid gland in painful subacute thyroiditis is usually moderately enlarged and tender. There is often dysphagia and pain that can radiate to the jaw or ear. With toxic multinodular goiter, there are usually palpable nodules. Patients with silent thyroiditis or postpartum thyroiditis have either no palpable goiter or a small, nontender goiter.

Cardiopulmonary manifestations of thyrotoxicosis commonly include a forceful heartbeat, premature atrial contractions, and sinus tachycardia. Patients often have exertional dyspnea. Atrial fibrillation or atrial tachycardia occurs in about 8% of patients with thyrotoxicosis, more commonly in men, older adults, and those with ischemic or valvular heart disease. The ventricular response from the atrial fibrillation may be difficult to control. Thyrotoxicosis can cause a thyrotoxic cardiomyopathy, and the onset of atrial fibrillation can precipitate HF. Echocardiogram reveals pulmonary artery hypertension in about 40% of hyperthyroid patients. Even "subclinical hyperthyroidism" increases the risk for atrial fibrillation and overall mortality. Hemodynamic abnormalities and pulmonary hypertension are reversible with restoration of euthyroidism.

Thyrotoxic crisis or "thyroid storm" is an extreme form of severe thyrotoxicosis and an immediate threat to life. The most common manifestations are cardiac (HF, severe sinus tachycardia [60%], ventricular fibrillation [13%], MI, and cardiogenic shock), agitation or delirium (63%), high fever, vomiting, diarrhea, dehydration, and hepatic impairment (52%). The presence of thyrotoxic crisis can be assessed by the Burch-Wartofsky score that is based on clinical manifestations: a score less than 25 excludes thyrotoxic crisis, while a score of 25-45 indicates incipient crisis, and a score greater than 45 indicates probable thyrotoxic crisis.

Eye manifestations that occur with hyperthyroidism are discussed in Thyroid Eye Disease, below.

Graves dermopathy (pretibial myxedema) occurs in about 3% of patients with Graves disease. It usually affects the pretibial region but can also affect the dorsal forearms and wrists and dorsum of the feet. It is more common in patients with high levels of serum TSI and severe Graves ophthalmopathy. Glycosaminoglycans accumulation and lymphoid infiltration occur in affected skin, which becomes erythematous with a thickened, rough texture (eFigure 28-5).

Thyroid acropachy is a rare skeletal manifestation of Graves disease. It presents with digital clubbing, swelling of fingers and toes, and radiographic findings of periostitis involving phalangeal and metacarpal bones. Extremity skin can become very thickened, resembling elephantiasis. Thyroid acropachy is ordinarily associated with ophthalmopathy and thyroid dermopathy. Most affected patients are smokers. The presence of thyroid acropachy is an indication of the severity of the autoimmunity; most patients have high serum titers of TSI.

Clinical hyperthyroidism during pregnancy has a prevalence of about 0.2%. It may commence before conception or emerge during pregnancy, particularly the first trimester. Pregnancy can have a beneficial effect on the thyrotoxicosis of Graves disease, with decreasing antibody titers and decreasing serum T₄ levels as the pregnancy advances; about 30% of affected women experience a remission by late in the second trimester. Undiagnosed or undertreated hyperthyroidism carries an increased risk of miscarriage, preeclampsia-eclampsia, preterm delivery, abruptio placenta, maternal HF, and thyrotoxic crisis (thyroid storm). Such thyrotoxic crisis can be precipitated by trauma, infection, surgery, or delivery and confers a fetal/maternal mortality rate of about 25%.

Thyroid-stimulating immunoglobulin (TSI, TSHrAb) crosses the placenta. If maternal serum TSI levels reach greater than 500% in the third trimester, the risk of transient neonatal Graves disease in the newborn is increased. Such thyrotoxic newborns have an increased risk of intrauterine growth retardation and prematurity.

Hypokalemic periodic paralysis occurs in about 15% of Asian or American Indian men with thyrotoxicosis and is 30 times more common in men than women. It is marked by sudden symmetric flaccid paralysis, along with hypokalemia and hypophosphatemia, that occurs during hyperthyroidism (often after intravenous dextrose, oral carbohydrates, or vigorous exercise) despite few, if any, of the classic signs of thyrotoxicosis. Attacks last 7-72 hours.

B. Laboratory Findings

Serum FT₄, T₃, FT₃, and T₄, thyroid resin uptake, and FT₄ index are all usually increased. Sometimes the FT₄ level may be normal but with an elevated serum T₃ (T₃ toxicosis). The severity of the elevation of serum FT₄ and FT₃ levels does not always correlate with the severity of thyrotoxic manifestations; patients with thyrotoxic crisis tend to have serum thyroid levels that are not significantly higher than those with less pronounced symptoms. Serum T₃ can be misleadingly elevated when blood is collected in tubes using a gel barrier, which causes certain immunoassays (eg, Immulite but not AxSYM analyzers) to report falsely elevated serum total T₃ levels in 24% of normal patients. Serum T₄ or T₃ can be elevated in other nonthyroidal conditions (Table 28-4. Factors that Can Cause Misleading Laboratory Tests for Hyperthyroidism).

Serum TSH is suppressed in hyperthyroidism (except in the very rare cases of pituitary inappropriate secretion of thyrotropin). Serum TSH may be misleadingly low in other nonthyroidal conditions (Table 28-4. Factors that Can Cause Misleading Laboratory Tests for Hyperthyroidism). The term "subclinical hyperthyroidism" is used to describe individuals with a low serum TSH but normal serum levels of FT₄ and T₃; in such patients, the overall prevalence of symptomatic hyperthyroidism is 0.7-1.8% in iodine-sufficient patients and 2-15% in patients with iodine deficiency. About two-thirds of patients with subclinical hyperthyroidism have serum TSH levels of 0.1-0.4 mIU/L (mild subclinical hyperthyroidism), while the remainder have serum TSH levels below 0.1 mIU/L (severe subclinical hyperthyroidism).

Hyperthyroidism can cause hypercalcemia, increased liver enzymes, increased alkaline phosphatase, anemia, and neutropenia. Hyperthyroidism also increases urinary magnesium excretion, which can lead to hypomagnesemia, functional hypoparathyroidism with hypocalcemia, and tetany (rarely). Hypokalemia and hypophosphatemia occur in thyrotoxic periodic paralysis.

Problems of diagnosis occur in patients with acute psychiatric disorders; about 30% of these patients have elevated serum T₄ levels without clinical thyrotoxicosis. The TSH is not usually suppressed, distinguishing psychiatric disorder from true hyperthyroidism. T₄ levels return to normal gradually.

In Graves disease, serum thyroid-stimulating immunoglobulin (TSI, TSHrAb) is usually detectable (65%). Very high serum TSI levels predispose to Graves ophthalmopathy. Serum TSH levels above 350 mIU/L can potentially cause false-positive TSI results. TPO Ab or Tg Ab are usually elevated but are nonspecific. Serum ANA are also usually elevated without any evidence of SLE or other rheumatologic disease.

With painful subacute thyroiditis, patients often have an increased WBC, ESR, and CRP. About 25% have antithyroid antibodies (usually in low titer) and serum TSI (TSHrAb) levels are normal. Patients with iodine-induced hyperthyroidism have undetectable serum TSI (or TSHrAb), no serum TPO Ab, and an elevated urinary iodine concentration. In thyrotoxicosis factitia, serum thyroglobulin levels are low, distinguishing it from other causes of hyperthyroidism.

With hyperthyroidism during pregnancy, women have an elevated serum total T₄ and FT₄ while the TSH is suppressed. An apparent lack of full TSH suppression in hyperthyroidism can be seen due to misidentification of hCG as TSH in certain assays. The serum FT₄ assay is difficult to interpret in pregnancy. Although the serum T₄ is elevated in most pregnant women, values over 20 mcg/dL (257 nmol/L) are encountered only in hyperthyroidism. The T₃ resin uptake, which is low in normal pregnancy because of high thyroxine-binding globulin (TBG) concentration, is normal or high in thyrotoxic persons.

Since high levels of T₄ and FT₄ are normally seen in patients taking amiodarone, a suppressed TSH must be present along with a greatly elevated T₄ (greater than 20 mcg/dL [257 nmol/L]) or T₃ (greater than 200 ng/dL [3.1 nmol/L]) in order to diagnose hyperthyroidism. In type 1 amiodarone-induced thyrotoxicosis, the presence of proptosis and serum TSI (TSHrAb) is diagnostic. In type 2 amiodarone-induced thyrotoxicosis, serum levels of interleukin-6 (IL-6) are usually quite elevated.

C. Radioisotope Uptake and Imaging

Note:All radioisotope testing is contraindicated during pregnancy or breastfeeding.

Radioiodine (¹²³ I) scanning can be helpful in some situations to determine the cause of hyperthyroidism but is unnecessary for diagnosis in patients with obvious Graves disease who have elevated serum TSI or associated Graves ophthalmopathy. A high thyroid RAI uptake is seen in Graves disease and toxic nodular goiter. The isotope is administered orally and thyroidal RAI uptake is determined at about 4-6 hours and again at 24 hours, when a scan is also performed. Normal RAI uptake is 3-16% at 4-6 hours and 8-35% at 24 hours; however, normal ranges vary by region. A low ¹²³ I RAI uptake is characteristic of iodine-induced hyperthyroidism and thyroiditis (subacute, silent, or postpartum), distinguishing them from Graves disease. Patients with type 1 amiodarone-induced thyrotoxicosis have RAI uptake that is usually detectable, while in type 2 amiodarone-induced thyrotoxicosis, thyroid RAI uptake is usually below 3%. Ideally, the RAI scan should include the pelvis to screen for concomitant struma ovarii (rare).

Misleadingly high thyroid RAI uptake has been reported in patients with the following conditions: kidney disease, iodine deficiency, hypochloremia, recovery phase from subacute or silent thyroiditis, lithium carbonate therapy, estrogen therapy, phenothiazine therapy, some congenital disorders of thyroid hormone synthesis, and following withdrawal of thiourea therapy (rebound phenomenon).

Technetium (Tc-99m) pertechnetate thyroid uptake is increased or normal with Graves disease, whereas those with thyrotoxicosis from thyroiditis (silent, subacute, postpartum) have reduced uptake. It is not helpful to distinguish type I from type II amiodarone-induced thyrotoxicosis, since uptake is typically reduced in both.

99mTc-sestamibi (MIBI) scanning usually shows increased uptake with type 1 amiodarone-induced thyrotoxicosis (AIT), decreased uptake in type 2 AIT, and intermediate uptake in mixed AIT.

D. Other Imaging

Thyroid ultrasound can be helpful in hyperthyroid patients with palpable thyroid nodules. Thyroid ultrasound shows a variably heterogeneous, hypoechoic gland in thyroiditis. Color flow Doppler sonography is helpful to distinguish type 1 amiodarone-induced thyrotoxicosis (enlarged gland with normal to increased blood flow velocity and vascularity) from type 2 amiodarone-induced thyrotoxicosis (distorted gland without increased vascularity).

MRI and CT scanning of the orbits are the imaging methods of choice to visualize Graves ophthalmopathy affecting the extraocular muscles. Imaging is required only in severe or unilateral cases or in euthyroid exophthalmos that must be distinguished from orbital pseudotumor, tumors, and other lesion. Chest, CT in Graves disease often detects an enlarged thymus gland.

A. Treatment of Graves Disease

Table 28-5. Medications for the Treatment of Hyperthyroidism outlines the treatment options for hyperthyroidism.

B. Treatment of Toxic Solitary Thyroid Nodules

Toxic solitary thyroid nodules are usually benign but may rarely be malignant. If a nonsurgical therapy is elected, the nodule should be evaluated with a fine-needle aspiration (FNA) biopsy. Medical therapy for hyperthyroidism caused by a single hyperfunctioning thyroid nodule may be treated symptomatically with propranolol ER and methimazole or PTU, as in Graves disease (Table 28-5. Medications for the Treatment of Hyperthyroidism). The dose of methimazole should be adjusted to keep the TSH slightly suppressed, so the risk of TSH-stimulated growth of the nodule is reduced. Surgical treatment is usually recommended for patients under age 40 years, for healthy older patients with toxic solitary thyroid nodules, and for nodules that are suspicious for malignancy. Patients are made euthyroid with a thiourea preoperatively and given several days of iodine, ipodate sodium, or iopanoic acid before surgery. Postoperative hypothyroidism usually resolves spontaneously, but permanent hypothyroidism occurs in about 14% of patients by 6 years after surgery. ¹³¹ I therapy may be offered to patients with a toxic solitary nodule who are over age 40 or in poor health (see Precautions for RAI use, above).

If the patient has been receiving methimazole preparatory to ¹³¹ I, the TSH should be kept slightly suppressed in order to reduce the uptake of ¹³¹ I by the normal thyroid. Nevertheless, permanent hypothyroidism occurs in about one-third of patients by 8 years after ¹³¹ I therapy. The nodule remains palpable in 50% and may grow in 10% of patients after ¹³¹ I.

C. Treatment of Toxic Nodular Goiter

Medical therapy for patients with toxic nodular goiter consists of propranolol ER (while hyperthyroid) and a thiourea, as in Graves disease (Table 28-5. Medications for the Treatment of Hyperthyroidism). Thioureas (methimazole or PTU) reverse hyperthyroidism but do not shrink the goiter. There is a 95% recurrence rate if the drug is stopped.

Surgical therapy is the definitive treatment for a large toxic nodular goiter, following therapy with a thiourea to render them euthyroid. Surgery is particularly indicated to relieve pressure symptoms or for cosmetic indications. Patients with toxic nodular goiter are not treated preoperatively with potassium iodide. Total or near-total thyroidectomy is recommended, since surgical pathology reveals unsuspected differentiated thyroid cancer in 18.3% of cases.

¹³¹ I therapy may be used to treat patients with toxic nodular goiter. See Precautions for RAI use, above. Any suspicious nodules should be evaluated beforehand for malignancy with FNA cytology. Patients are rendered euthyroid with methimazole, which is stopped 3-4 days before ¹³¹ I therapy. The approximate administered ¹³¹ I activity (dose) can be calculated for an average-size multinodular goiter, but smaller goiters require lower mcCi/g and larger goiters require higher mcCi/g dosing:

Administered Activity ¹³¹ I (*mcCi) = 150 (planned dose to thyroid in mcCi/g) × thyroid size (g) ÷ 24 h RAI uptake (decimal)

*Conversion Factor for Activity (Dose): MBq = mcCi × 0.037

The patient follows a low-iodine diet in order to enhance the thyroid gland's uptake of ¹³¹ I, which may be relatively low in this condition (compared to Graves disease). Relatively high doses of ¹³¹ I are usually required. Hypothyroidism can occur but less commonly than seen with RAI therapy for Graves disease. Recurrent thyrotoxicosis can occur, so patients must be monitored closely. Peculiarly, in about 1-5% of patients with diffusely nodular toxic goiter, the administration of ¹³¹ I therapy may induce Graves disease. Also, Graves ophthalmopathy has occurred rarely following 131I therapy for multinodular goiter.

D. Treatment of Hyperthyroidism from Thyroiditis

Patients with thyroiditis (subacute, postpartum, or silent) are treated with propranolol during the hyperthyroid phase, which usually subsides spontaneously within weeks to months. For symptomatic relief, begin propranolol ER until the heart rate is less than 90 beats per minute (Table 28-5. Medications for the Treatment of Hyperthyroidism). Ipodate sodium or iopanoic acid, 500 mg orally daily, promptly corrects elevated T₃ levels and is continued for 15-60 days until the serum FT₄ level normalizes. Thioureas are ineffective since thyroid hormone production is actually low in this condition. Patients are monitored carefully for the development of hypothyroidism and treated with levothyroxine as needed. With subacute thyroiditis, pain can usually be managed with NSAIDs and corticosteroids, but opioid analgesics are sometimes required.

E. Treatment of Hyperthyroidism During Pregnancy-Planning, Pregnancy, and Lactation

Due to the increased risk of congenital anomalies with every thiourea, all women who are planning to become pregnant are encouraged to consider definitive therapy with ¹³¹ I or surgery well before conception. Both men and women who are planning pregnancy should not have ¹³¹ I treatment within about 4 months of conception. See Precautions for RAI use, above. Dietary iodine must not be restricted for such women to protect the fetus from iodine deficiency.

First-trimester fetal exposure to thioureas (methimazole or PTU) increases the risk of birth defects by about 2%. The fetal anomalies associated with PTU are typically less severe than those associated with methimazole; therefore, PTU is the preferred thiourea for women actively seeking fertility and during the first trimester of pregnancy, despite the very low risk for hepatic necrosis. The most common fetal anomalies from PTU are preauricular and branchial sinus cysts and fistulas, renal cysts, hydronephrosis, intestinal bands with intestinal malrotation, and hypospadias; these anomalies are usually minor and surgically correctable. Women should be treated with PTU immediately prepregnancy and through the first trimester; during pregnancy, the dose of PTU is kept below 200 mg daily to avoid goitrous hypothyroidism in the infant. PTU can be switched to methimazole in the second trimester (see Thiourea drugs Psychiatric Disorders, above). Thiourea should be given in the smallest dose possible, permitting mild subclinical hyperthyroidism to occur, since it is usually well tolerated. About 30% of women with Graves disease experience a remission by the late second trimester.

Both PTU and methimazole cross the placenta and can induce hypothyroidism, with fetal TSH hypersecretion and goiter. Fetal ultrasound at 20-32 weeks' gestation can visualize any fetal goiter, allowing fetal thyroid dysfunction to be diagnosed and treated. Thyroid hormone administration to the mother does not prevent hypothyroidism in the fetus, since T₄ and T₃ do not freely cross the placenta. Fetal hypothyroidism is rare if the mother's hyperthyroidism is controlled with small daily doses of PTU (50-150 mg/day orally) or methimazole (5-15 mg/day orally). Serum total T₄ levels during pregnancy should be kept at about 1.5 × the prepregnancy level. Maternal serum TSI levels over 500% at term predict an increased risk of neonatal Graves disease in the infant.

Subtotal thyroidectomy is indicated for pregnant women with Graves disease or for fertile women of reproductive age who are sexually active and decline contraceptives, under the following circumstances: (1) severe adverse reaction to thioureas; (2) high dosage requirement for thioureas (methimazole greater than or equal to 30 mg/day or PTU greater than or equal to 450 mg/day); or (3) uncontrolled hyperthyroidism due to nonadherence to thiourea therapy. Surgery is best performed during the second trimester.

Both methimazole and PTU are secreted in breast milk but not in amounts that affect the infant's thyroid hormone levels. No adverse reactions to these drugs have been reported in breast-fed infants. See Table 28-5. Medications for the Treatment of Hyperthyroidism for recommended doses. It is recommended that the medication be taken just after breastfeeding.

F. Treatment of Amiodarone-Induced Thyrotoxicosis (Ait)

Patients with either type 1 or type 2 AIT require treatment with propranolol ER for symptomatic relief and methimazole (Table 28-5. Medications for the Treatment of Hyperthyroidism). After two doses of methimazole, iopanoic acid or sodium ipodate may be added to the regimen to further block conversion of T₄ to T₃ until the thyrotoxicosis is resolved. If iopanoic acid or sodium ipodate is not available, potassium perchlorate may be given in doses of less than or equal to 1000 mg daily (in divided doses) for a course not to exceed 30 days to avoid the complication of aplastic anemia. Amiodarone may be withdrawn but this does not have a significant therapeutic impact for several months because of its long half-life. For patients with type 1 AIT, therapy with ¹³¹ I may be successful, but only for those with sufficient RAI uptake. Patients with type 2 AIT are usually also treated with prednisone for about 2 weeks, which is slowly tapered and withdrawn after about 3 months. Subtotal thyroidectomy should be considered for patients with AIT that is resistant to treatment.

G. Treatment of Complications