Diagnosing and Treating Hyperthyroidism

Emerg Med 38(3):24-38, 2006

Would you recognize the ophthalmopathic hallmarks of Graves’ disease? The characteristics of toxic multinodular goiters and adenomas? The “apathetic hyperthyroidism” of the elderly? How do you decide which laboratory tests are really needed to establish the diagnosis? The authors discuss these issues as well as key therapeutic and surgical considerations for the patient with signs of possible hyperthyroidism.

By Eliana Schenk, MD, Daniel S. Tung, MD, Geetha Soodini, MD, and Glenn R. Cunningham, MD

Hyperthyroidism has a prevalence of 1% in the general population, and it is more common in women by a ratio of 5:1. In older women, prevalence increases to 5%. Recognizing the signs and symptoms of hyperthyroidism and initiating prompt laboratory evaluation and treatment are crucial to preventing serious and potentially life-threatening complications.

A practical way to divide the causes of hyperthyroidism is to distinguish states of increased thyroid hormone synthesis from other pathologies (see box). This is important because definitive treatment ultimately depends on the cause of the hyperthyroidism.

Causes of Hyperthyroidism Increased thyroid hormone synthesis • Graves’ disease • toxic multinodular goiter • toxic adenoma • iodine excess • metastatic thyroid carcinoma • activating TSH receptor mutation • struma ovarii • TSH-secreting pituitary adenoma • chorionic gonadotropin-secreting tumors • hyperemesis gravidarum Other causes • subacute thyroiditis • silent thyroiditis • postpartum thyroiditis • thyroid destruction from amiodarone, radiation, infarction of an adenoma • ingestion of excess thyroid hormone or thyroid tissue TSH = thyroid-stimulating hormone

 

The purpose of this article is to provide emergency department and primary care physicians with a review of the clinical presentations of hyperthyroidism, as well as appropriate diagnostic testing and therapeutic strategies. We will focus specifically on the evaluation of the more common underlying etiologies of hyperthyroidism.

OVERPRODUCTION OF THYROID HORMONES

Hyperthyroidism affects most organs in the body. Symptoms and signs (see table) may be overt, most extremely so in the critical state called thyroid storm, or they may be more subtle, as in patients with other diseases or in the elderly.

The most common causes of hyperthyroidism due to overproduction of thyroid hormones are Graves’ disease, toxic multinodular goiter, and toxic adenoma.

Clinical ophthalmopathy occurs in about 50% of patients; however, almost 100% will have retro-orbital abnormalities if they are evaluated with an ultrasound or computed tomography (CT) scan. Although “lid lag” can occur with any cause of hyperthyroidism, the findings of exophthalmos, periorbital edema, and impaired extraocular motility are more specific for Graves’ disease. These changes develop within a year before or after the diagnosis of hyperthyroidism in 75% of patients who develop ophthalmopathy. Patients may complain of gritty or tearful eyes or diplopia in the early stages of the ophthalmopathy associated with Graves’ disease.

Thyroid dermopathy (pretibial myxedema) occurs in less than 5% of patients with Graves’ disease. It usually presents one to two years after the development of hyperthyroidism. Thyroid acropachy is a form of clubbing that is seen in less than 1% of patients with Graves’ disease. It is almost always associated with thyroid dermopathy.

Toxic multinodular goiter. More common in women and older patients, toxic multinodular goiters that are palpable vary in size and consistency. Cardiovascular symptoms, such as palpitations, tachycardia, shortness of breath, and angina, are common, and obstructive symptoms, such as dyspnea and stridor, may be found.

Toxic adenoma. Toxic adenomas usually present in younger patients in the fourth or fifth decade of life. Symptoms are frequently mild and more common when the nodule is greater than 2.5 cm in diameter. These nodules may be palpable on careful physical examination.

LIFE-THREATENING THYROID STORM

Thyroid storm is a rare but life-threatening syndrome that presents with severe hyperthyroidism and imminent end-organ damage. Frequently, there is an inciting event, such as infection or injury, that may cause an acute increase in thyroid hormone levels. The diagnosis is made clinically, based on the presence of fever (to 106ºF), tachycardia (heart rate above 140 bpm), and central nervous system changes (from agitation to coma), in conjunction with other features of hyperthyroidism. Graves’ disease is the most common underlying etiology.

ELDERLY PATIENTS

It should be noted that the presentation of hyperthyroidism in elderly patients can be atypical. They may present with fatigue, weakness, and weight loss, as well as cardiac abnormalities such as atrial fibrillation or congestive heart failure. Tachycardia (heart rate of 100 bpm or higher) is absent in about 40% of these patients. Absence of the classic hyperadrenergic symptoms, such as tachycardia, tremor, and lid or glove lag, has led to the term “apathetic hyperthyroidism” to describe the condition in the elderly. Older patients are also less likely to have a goiter, but toxic multinodular goiter is more common than in younger patients. Graves’ disease remains the most common underlying etiology of hyperthyroidism in the elderly.

Although a detailed history and careful physical examination can often lead the physician to a high suspicion of hyperthyroidism, there are other diseases that should be considered. These include anxiety or panic attack, manic episode, chronic infection, malabsorption, pheochromocytoma, and malignancy.

LABORATORY TESTING

Thyroid-stimulating hormone. The serum TSH level remains the best screening test of thyroid function because TSH is central to the negative feedback system. Small changes in serum T3 and T4 can cause significant alterations in TSH secretion, and third-generation TSH assays can differentiate between suppressed (<0.1 mU/L) and normal values. When TSH levels are suppressed, it is helpful to measure free T4 and T3 levels, which can confirm hyperthyroidism or aid in the detection of subclinical thyrotoxicosis (see algorithm below). Thyroid-stimulating hormone levels may also be suppressed in the setting of hypothalamic pituitary disease and in patients who were recently treated for hyperthyroidism.

Total serum T4 levels. Total serum T4 levels, measured by radioimmunoassay, have a high sensitivity in reflecting the functional state of most patients with thyroid disease. Levels are high in approximately 90% of patients, but they may be normal in those with low thyroid-binding globulin (TBG), those with T3 toxicosis, and those who are critically ill. Serum T4 levels may be high in euthyroid patients with increased TBG or altered thyroid-binding proteins.

Free T4 and T3 levels. Free and albumin-bound T4 and T3 are available for uptake into cells, where they bind to nuclear receptors. The TBG-bound hormone represents a circulating storage pool that is not immediately available for uptake into cells. Because genetic factors, drugs, and illness can alter the concentrations of binding proteins or interaction of the binding proteins with T4 and T3, the free and total hormone concentrations may not be concordant. Therefore, it is often necessary to estimate free hormone concentrations when altered TBG levels (as in estrogen treatment, pregnancy, or nephrotic syndrome, for example) are suspected or when there is a discrepancy in clinical and laboratory findings.

To avoid the effects of binding protein abnormalities, free T4 can be measured directly or estimated indirectly by the free thyroxine index (FTI). Free T4 levels are measured routinely, and in most cases it is not necessary to determine FTI or TBG levels. While equilibrium dialysis is the most accurate direct measurement of free T4, it is not a practical assay for most clinical laboratories. The calculated free T4 index is the product of the total T4 and the T3 resin uptake or the thyroid hormone-binding ratio. By providing the clinician with both measurements as well as the index, it is clear when the patient has a binding protein abnormality.

Alternatively, TBG can be measured directly to assess changes in this protein. Direct T3 and free FT3 measurements are available and are used for the diagnoses of T3 toxicosis.

Thyroid autoantibodies. Thyroglobulin antibodies and thyroid peroxidase antibodies are present in patients with both Graves’ disease and chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), but elevated TSH receptor-stimulating antibodies or thyroid-stimulating immunoglobulins are relatively more specific for Graves’ disease. This is most helpful in patients without obvious signs of Graves’ disease, in cases where it is not possible to assess iodine uptake by the thyroid, and in patients who are being treated with thionamides to assess their potential for remission. Otherwise, it is not cost-effective to order these tests routinely in hyperthyroid patients.

OVERT AND SUBCLINICAL HYPERTHYROIDISM

Hyperthyroidism can be either overt or subclinical. Overt hyperthyroidism is characterized by low serum TSH and high free T4 and T3 concentrations. Variations such as T3 toxicosis (low serum TSH, high free T3, and normal free T4) or T4 toxicosis (low serum TSH, high free T4, and normal T3) may be seen. Subclinical hyperthyroidism is characterized by low serum TSH and normal free T4 and T3 concentrations. Hyperthyroidism induced by TSH is a very rare cause of overt hyperthyroidism; it would be due to either a TSH-secreting pituitary adenoma or partial resistance to the feedback effect of T4 and T3. Patients with the latter usually are not hypermetabolic.

Rarely, patients with hyperthyroidism who are critically ill due to a nonthyroidal illness have normal serum free T4 and normal or even low T3 concentrations. Total serum T4 and even free T4 concentrations may be abnormal because of decreased protein-binding of T4, caused by either low serum concentrations of TBG or displacement of T4 from binding proteins by endogenous factors, drugs, or metabolites. Reverse (or inactive) T3 levels usually are elevated in these patients. This is due to the inhibition of 5’ monodeiodinase, which is the enzyme responsible for conversion of T4 to T3; in these cases, T4 is converted to reverse T3 by 5’ monodeiodinase.

RADIOACTIVE IODINE UPTAKE

The next step in the diagnostic process is to determine the cause of the hyperthyroidism. Usually, a radioactive iodine uptake and thyroid scan are performed for this purpose. This is done by measuring the radioactive iodine uptake at 4 and 24 hours after the radioactive iodine is given. ¹²³I is the preferred radionuclide because its short half-life causes little radiation exposure.

Hyperthyroidism with a high radioactive iodine uptake indicates de novo hormone synthesis. Graves’ disease, toxic adenoma, and toxic multinodular goiter all have high uptake. A thyroid scan will help distinguish between these possibilities. With Graves’ disease, the scan will show diffuse and even uptake; in toxic adenoma or toxic multinodular goiter, it will show one or more focal areas of uptake.

Thyroid inflammation can cause the release of preformed hormones from cell destruction, leading to transient hyperthyroidism. The radioactive ¹²³I uptake is low in these patients. While an ultrasound scan is useful for identifying a nodule and estimating thyroid gland size, this technique does not provide the functional information that the ¹²³I uptake and scan do.

TREATMENT STRATEGIES

Treatment will depend on the cause and the clinical setting of the hyperthyroidism. The more common causes of hyperthyroidism involve increased synthesis of thyroid hormone, with Graves’ disease being the most common; other causes include solitary toxic adenoma and toxic multinodular goiter. Each of these etiologies can be treated with an antithyroid drug, radioactive ¹³¹I, or surgery. In many cases, antithyroid drugs should be used to achieve euthyroidism prior to definitive therapy with ¹³¹I or surgery. In approximately one third of patients with Graves’ disease, an antithyroid drug alone for one year to 18 months may provide definitive therapy.

Drugs Used to Treat Hyperthyroidism Class Drug Conservative starting dose Maximum daily dose beta blockers propranolol 20 mg t.i.d. 640 mg metoprolol 25 mg b.i.d. 400 mg atenolol 25 mg/day 200 mg thionamides methimazole 5 mg b.i.d. 80 mg propylthiouracil 50-100 mg t.i.d. 1200 mg iodine SSKI 1-5 drops t.i.d. 10 drops t.i.d. Lugol's solution 3-5 drops t.i.d. 1 ml t.i.d. IV iodine 0.5-1 g q 8-12 h 1 g q 8 h bile acid resin cholestyramine 4 g b.i.d. 4 g t.i.d. glucocorticoids dexamethasone 2 mg IV q 6 h   hydrocortisone 100 mg IV q 8 h   lithium lithium 300 mg q 6 h 2400 mg SSKI = supersaturated solution of potassium iodide; IV = intravenous

Beta blockers. Beta blockers can be used for symptomatic control with any cause of hyperthyroidism (see table above). Propranolol and its beta-1-selective counterparts, metoprolol and atenolol, have all been shown to be effective in controlling the hyperadrenergic symptoms of hyperthyroidism. The inhibition of 5’ monodeiodinase, which in turn inhibits T4-to-T3 conversion, occurs after 7 to 10 days of beta blocker therapy. We routinely use propranolol, but beta-1-selective blockers are preferred in patients with asthma or chronic obstructive pulmonary disease and in patients who are less compliant in taking tablets multiple times a day.

It is important to note that beta blockers only control adrenergic symptoms. They do not alter the underlying pathogenesis of the hyperthyroid state.

Thionamides. The thionamides propylthiouracil (PTU) and methimazole are the primary antithyroid drugs used in the United States. (Carbimazole, an analogue of methimazole, is used in Europe.) Their primary effect is to block thyroid hormone synthesis by inhibiting thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin, an important step in the synthesis of thyroxine and triiodothyronine.

These drugs are most often used as primary treatment for individuals with Graves’ disease, in whom remission is more likely, and in patients with Graves’ opthalmopathy. Remission is more likely in patients with small goiters, high anti-thyroglobulin and anti-TPO antibody titers, and a milder degree of hyperthyroidism. They are also the preferred treatment in pregnant patients and in most children and adolescents. Ordinarily, these drugs are not used for definitive treatment of patients with toxic multinodular goiter or solitary autonomous nodules, because spontaneous remissions rarely occur in these cases.

Thionamides are also used to normalize thyroid function before the administration of radioiodine and to attenuate potential exacerbations following ablative radioiodine therapy. Pretreatment is recommended for the elderly and those with underlying cardiac disease, who may be more vulnerable to worsening thyrotoxicosis.

Methimazole has some advantages over PTU in most patients. It can be administered by once-daily dosing, and it has superior efficacy. Also, both retrospective and prospective studies have shown that methimazole does not alter the effectiveness of radioactive iodine therapy. Several retrospective studies indicate that PTU significantly reduces the efficacy of subsequent radioactive treatment, but there have been no prospective randomized controlled trials. Therefore, methimazole is preferable when radioiodine therapy is planned.

SIDE EFFECTS OF THERAPY

Both PTU and methimazole are associated with minor side effects, such as rash, urticaria, and gastrointestinal upset. These side effects are dose-related with methimazole, but such data are lacking for PTU.

Routine monitoring of the patient’s WBC count is not recommended, but patients should be instructed to discontinue the antithyroid drug and contact a physician immediately if they develop fever or a sore throat. The drug should be discontinued if the granulocyte count is less than 1000/mm3, and close monitoring is required if the count is between 1000 and 1500/mm3. Administration of granulocyte-colony stimulating factor G-CSF may shorten the time to recovery and length of hospitalization in patients with agranulocytosis due to antithyroid drugs.

Hepatotoxicity is a rare but major side effect of antithyroid drugs. Propylthiouracil-related hepatotoxicity is accompanied by laboratory evidence of hepatocellular injury, while the hepatic abnormalities seen with methimazole are cholestatic in nature. Liver function tests should be ordered prior to using either drug; mild abnormalities are fairly common in patients with Graves’ disease. Rare side effects like antineutrophil cytoplasmic antibody-positive vasculitis have been reported with PTU only.

The usual starting dose of methimazole is 15 to 30 mg as a single daily dose; for PTU, 100 mg three times a day. Follow-up testing of thyroid function every four to six weeks is recommended until the patient is euthyroid. The dose can be decreased while maintaining normal thyroid function. Serum TSH levels remain suppressed for weeks or months, despite normalization of thyroid hormone levels, so total or free T3 and T4 levels must be checked.

Propylthiouracil is preferred in the treatment of thyroid storm; it can be administered at a dose of 200 mg every four hours. The drug can be suspended in liquid for rectal administration and can be given intravenously by dissolving the tablets in normal saline made alkaline by sodium hydroxide.

OTHER MEDICATIONS

In cases of thyroid storm, severe hyperthyroidism, or preoperative preparation for emergent surgery, more rapid control of the hyperthyroid state can be achieved with beta blockers, thionamides, and additional medications, including iodine, cholestyramine, glucocorticoids, and lithium.

Iodine immediately inhibits both new hormone synthesis (by blocking organification, known as the Wolf-Chaikoff effect) and the release of thyroid hormone. It also decreases gland size and vascularity. This effect is transient, however, lasting approximately one to three weeks. One to five drops of a supersaturated solution of potassium iodine or Lugol’s solution can be given three to four times a day. Iodine usually is given 7 to 14 days prior to surgery. In thyroid storm, sodium iodine may be given intravenously at 0.5 to 1 gm every 8 to 12 hours. It is important to give the iodine at least one hour after administration of a thionamide to prevent possible worsening of hyperthyroidism.

The most common side effects are hypersensitivity reactions, such as rash or drug fever. Patients can also develop salivary gland swelling and oral symptoms, such as metallic taste, burning, or sore teeth and gums.

Other medications may be used in special circumstances. Cholestyramine can help to reduce T4 and T3 levels in severely hyperthyroid patients. Glucocorticoids block peripheral conversion of T4 to T3; they also have an immunomodulatory effect that may be beneficial in Graves’ disease. In thyroid storm, dexamethasone 2 mg every six hours or hydrocortisone 100 mg every eight hours should be adequate.

Rarely, for severely thyrotoxic patients unable to take thionamides and allergic to iodine, lithium carbonate may be used as an alternative agent. This drug inhibits the coupling of iodotyrosine residues to form T3 and T4, and it also inhibits release of thyroid hormone from the thyroid gland. Lithium carbonate 300 mg every six hours may be given in thyroid storm if the patient is allergic to iodine. Because of its narrow therapeutic window, its serum level should be monitored and maintained at or around 1 mEq/L.

TREATMENT WITH RADIOACTIVE IODINE

Radioactive iodine isotope ¹³¹I, given orally as a colorless and tasteless liquid, is taken up by various organs, but it is only organified in the thyroid gland. The absorption and organification of ¹³¹I leads to beta-radiation and destruction of thyroid follicles. Radioiodine is used in the treatment of Graves’ disease, solitary toxic nodule, and toxic multinodular goiter. Radioiodine is absolutely contraindicated during pregnancy and breastfeeding.

To minimize the risk of a transient exacerbation of hyperthyroidism or precipitation of thyrotoxic crisis following radioiodine administration, patients who are elderly, debilitated, severely hyperthyroid, or have cardiac disease may be given methimazole for six to eight weeks to achieve a euthyroid state prior to treatment. Methimazole should be discontinued for five days prior to radioiodine therapy. Methimazole may be restarted five days after radioiodine therapy if the patient is elderly, debilitated, or at risk for cardiac disease. Beta blockers may be given before, during, or after radioiodine therapy.

Radioiodine therapy may also cause development or worsening of Graves’ ophthalmopathy. One study showed an 8% risk of developing new ophthalmopathy and a 24% risk of worsening baseline ophthalmopathy after radioiodine therapy. To decrease this risk, prednisone may be initiated at the time of radioiodine treatment at a dose of 0.5 mg/kg for one month, then tapered over the next two months. Risk factors for development or worsening of ophthalmopathy include smoking, high pretreatment T3 levels, and high titers of thyroid-stimulating antibodies.

The dose of radioactive iodine varies with institutions. Efforts to calculate a more precise dose based on estimated gland size, uptake of ¹²³I, and the desired radiation per gram of tissue have not been very successful. Usually a dose of 5 to 15 millicuries is given for Graves’ disease. Higher doses are given for larger thyroid glands, lower 24-hour ¹²³I uptake, and toxic nodules. Many clinicians prefer a higher ablative dose to decrease the risk of relapse, pointing to the ease of treating the expected hypothyroid state. Other clinicians give a smaller dose in an attempt to achieve a euthyroid state.

After radioiodine treatment, thyroid function should be monitored at monthly intervals until euthyroidism is restored. Hyperthyroidism may persist for two to six months before radioiodine takes full effect, so a beta blocker should be given until euthyroidism is achieved. As noted previously, methimazole can be administered to older and cardiac-risk patients. Approximately 10% to 30% of patients may remain hyperthyroid at six months after treatment; retreatment may be offered at that time.

The risk of hypothyroidism is at least 20% in the first year after therapy, depending on the dose of radioiodine given. However, this risk persists at about 2% to 5% annually thereafter. The incidence of permanent hypothyroidism is lower after radioiodine treatment of toxic nodules, presumably because iodine uptake is suppressed in the remaining thyroid tissue. Transient hypothyroidism may occur within the first six months after radioiodine treatment, but hypothyroidism after six months is usually permanent.

Patients should avoid close and prolonged contact with children and pregnant women for several days after radioiodine therapy. Women treated with ¹³¹I should be advised to postpone attempts at conception for at least six months. Studies have shown that radioiodine therapy for hyperthyroidism in women of childbearing age does not decrease fertility or increase congenital malformations or the risk of cancer in the patient or fetus.

Mild pain may develop in some patients one to two weeks after radioiodine therapy from radiation thyroiditis. When this occurs, it can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs).

INDICATIONS FOR SURGERY

The appropriateness of subtotal thyroidectomy for hyperthyroidism will depend on the preferences and fears of the patient. Surgery may be chosen in cases of goiter causing obstructive symptoms or intolerance to thionamides; refusal to take antithyroid drugs or radioactive iodine; or recurrence after a trial of thionamide therapy for Graves’ disease, nodular goiter, or suspicion of malignancy. Because amiodarone-induced hyperthyroidism often responds poorly to antithyroid drugs and cannot be treated with radioactive iodine, it may best be treated with surgery. Finally, a few studies suggest that Graves’ disease patients with severe ophthalmopathy may benefit from near-total thyroidectomy, but the option of radioactive iodine with a three-month course of steroids, as previously discussed, is a viable option.

Patients should be made euthyroid with thionamide therapy prior to elective surgery. Once a euthyroid state is achieved, oral iodine is given 7 to 10 days preoperatively to reduce the vascularity of the gland. Subtotal thyroidectomy is more difficult in patients who have received prior radioiodine treatment. Total thyroidectomy may be considered in patients with severe opthalmopathy and high titers of thyroid-stimulating immunoglobulin. When performed by an experienced surgeon, subtotal thyroidectomy has a less than 1% risk of recurrent laryngeal nerve damage, a 1% to 2% risk of permanent hypoparathyroidism, and a 1% to 12% risk of persistent or recurrent hyperthyroidism, depending on the extent of the resection. Although approximately half of recurrences occur within five years, they can also develop decades after thyroidectomy. Hypothyroidism following subtotal thyroidectomy is common.

SPECIAL CONSIDERATIONS

Thyroiditis, exogenous hyperthyroidism, amiodarone-induced hyperthyroidism, and hyperthyroidism in pregnancy all warrant special consideration.

Thyroiditis. When thyroiditis causes hyperthyroidism by releasing pre-formed thyroid hormone from the thyroid gland, the hyperthyroid state will be transient, lasting a few weeks to months, and will typically be mild. Observation alone or monotherapy with a beta blocker for symptomatic relief is usually all that is needed.

The hallmark of subacute thyroiditis is pain. This condition occurs more often in the summer months and is frequently associated with an upper respiratory tract infection. Most often, treatment with an NSAID is adequate for pain control. For severe or refractory pain, high-dose prednisone (40 mg daily) should be initiated for immediate pain relief. Prednisone usually can be tapered over four to six weeks, then stopped. The hyperthyroid state is temporary, and beta blockers can be used for temporary symptomatic control.

Exogenous hyperthyroidism. Exogenous hyperthyroidism caused by ingestion of excess thyroid hormone also can lead to symptomatic hyperthyroidism. Here, the therapeutic options are limited, with beta blockers being the drug of choice. Thyroid hormone is cleared by the urinary and fecal routes. The latter route involves liver conjugation of T3 and T4 before excretion into bile and partial reabsorption in the intestine. This enterohepatic circulation is increased in hyperthyroidism from any cause. If a more rapid elimination of excess thyroid hormone is desired, cholestyramine (4 gm four times daily) may be given.

Amiodarone-induced hyperthyroidism. The usual dose of amiodarone contains approximately 7 to 20 mg of iodine, which is 50- to 100-fold higher than the recommended daily intake. After prolonged use, amiodarone has a half-life of 100 days. There is no relationship between the cumulative dose and the risk of hyperthyroidism. The prevalence in the United States of hyperthyroidism among amiodarone users is approximately 5%. The hyperadrenergic symptoms of hyperthyroidism may be blunted by amiodarone. Because amiodarone inhibits type 1 monodeiodinase, reverse T3 levels are elevated and T4 levels are more elevated than T3 levels.

Type 1 amiodarone-induced thyrotoxicosis (Type 1 AIT) is caused by increased synthesis of thyroid hormone. Patients with this condition usually have a latent abnormal thyroid gland prior to treatment, such as from Graves’ disease or nodular goiter.

Type II AIT is caused by a thyroiditis with release of preformed hormone from the direct toxic effect of the amiodarone. Serum IL-6 levels are markedly elevated in type II AIT but are normal or only mildly elevated in type I. Doppler scanning will show decreased flow in type II AIT but normal to increased flow in type I. However, it is often difficult to distinguish between these two causes of AIT.

Treatment of type 1 AIT requires high doses of a thionamide, but these patients may be refractory to medical therapy. If amiodarone can be stopped, delayed treatment with ¹³¹I is a good option. However, the cardiac disease may not allow discontinuation of the amiodarone or, if it is stopped, it may paradoxically worsen the symptoms of hyperthyroidism by removing the antiadrenergic effects of amiodarone. Thyroidectomy is a viable option in some of these patients.

For type II AIT, prednisone 40 to 60 mg daily tapered over a three-month course is the treatment of choice. When the cardiac condition permits, discontinuation of amiodarone may be helpful. Hyperthyroidism usually resolves in three to five months, and the patient is at risk for eventual hypothyroidism from destructive thyroiditis.

Hyperthyroidism in pregnancy. Untreated hyperthyroidism that complicates pregnancy can increase the risk of fetal loss. There is a possible association between methimazole and aplasia cutis in newborns, although the association is controversial. There also is some evidence that suggests less placental transfer of PTU, although conflicting evidence clouds this issue. However, most authorities prefer PTU in pregnant, hyperthyroid women. To reduce the risk of fetal hypothyroidism and goiter, the lowest possible dose should be given. The thyroid hormone level should be targeted at the upper limit of normal. Because pregnancy has an immunomodulatory effect on Graves’ disease, approximately 30% of patients can often be weaned off PTU by the third trimester and still remain euthyroid.

Propranolol and other beta blockers are safe, but radioactive iodine is absolutely contraindicated in pregnancy. If hyperthyroidism cannot be controlled by medication, thyroidectomy may be performed in the second trimester.

An infant born to a patient with Graves’ disease has a 1% to 5% risk for neonatal hyperthyroidism through placental transfer of maternal thyroid-stimulating antibodies. Maternal thyroid-stimulating immunoglobulin levels can be measured prior to delivery to assess the risk to the baby. The newborn also is at risk for neonatal hypothyroidism because both PTU and methimazole cross the placenta and can suppress the infant’s thyroid gland. Therefore, thyroid function must be tested at birth and treated accordingly.

The immunodulatory effect of pregnancy ends after delivery, so mothers with Graves’ disease are at risk of worsening hyperthyroidism after delivery. Propylthiouracil may be continued during breastfeeding. Because thionamides are present in breast milk, the baby’s thyroid function needs to be assessed periodically.

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