Hyperthyroidism is a common disorder, occurring in about 19 per 1000 women and 1.6 per 1000 men in North America (Burman, 1995). The annual incidence rate is 3 per 1000 women (Burman, 1995). In Europe, the annual incidence rate
is 25 per 100,000 people (Hay & Morris, 1996). Graves’ disease is the most common cause of hyperthyroidism. It most commonly occurs in young women in the reproductive years, but it can occur in children and in men and women of any age. In the older patient (>40 years), hyperthyroidism is usually caused by a toxic multinodular goiter. The prevalence of toxic multinodular goiter appears to vary depending on the rate of endemic goiter. In areas of iodine deficiency (eg, Malmo, Sweden), toxic multinodular goiter is more common, occurring in 9% to 21% of the patients with thyrotoxicosis. In areas of iodine excess (eg, Great Britain), the rate of toxic nodular goiter is 3% (Hay & Morris, 1996).

Excessive exogenous thyroid ingestion is a common cause of mild hyperthyroidism (Burman, 1995; Nuovo, 1995). This ingestion could be prescribed or surreptitious, and can be found in many persons taking doses of 0.2 mcg or greater of L-thyroxine, 0.075 mg/day or more of L-triiodothyronine, or more than 180 mg/day (3 grains) of thyroid extract.

Hyperthyroidism can also be caused by exposure to iodine in persons with a degree of thyroid autonomy (toxic nodules, multinodular goiter) (Burman, 1995; Hay & Morris, 1996). The hyperthyroidism can occur 3 to 8 weeks after an iodine load (eg, use of expectorant or intravenous contrast) and persists for several months. Likewise, use of amiodarone for cardiac arrhythmias can induce thyroiditis and cause hyperthyroidism, which is quite difficult to treat (Bartelena, 1996), because the iodine content of the drug is high (33%) and the half-life is prolonged (55 days). Radioactive iodine cannot be used in these cases, but antithyroid medication and steroids are helpful until the drug is eliminated and hyperthyroidism remits (Bartelena, 1996).

Rare cases of hyperthyroidism can be caused by excessive TSH secretion from a pituitary adenoma (Burman, 1995; Franklyn, 1994). These patients have goiter but no ophthalmopathy. Tumors of trophoblastic tissue (hydatidiform mole, choriocarcinoma) can also cause hyperthyroidism, because the human chorionic gonadotropin produced by such tumors has a weak thyroid-stimulating ability (Burman, 1995). Ectopic thyroid tissue within the ovary (struma ovarii, a dermoid tumor or teratoma of the ovary) can cause hyperthyroidism (Burman, 1995). Here, radioisotope scanning will show no uptake in the neck, but rather uptake in the pelvic area; this is diagnostic. In rare cases of thyroid cancer, patients will become hyperthyroid if they have a large amount of metastatic deposits of thyroid tissue (Burman, 1995).

Graves’ hyperthyroidism is an autoimmune disease caused by the production of antibodies that bind to the thyroid cell’s TSH receptor, altering its function. It is believed that an intrinsic thyroidal cell defect changes immune cell function, activating a normally suppressed population of B lymphocytes (Burman, 1995). The B lymphocytes produce the autoantibody thyrotropin-binding inhibitory immunoglobulin, which mimics the action of TSH (Burman, 1995). This causes excessive production of thyroid hormone and growth of the thyroid gland. Many believe that autoimmune thyroid disease, Graves’ and Hashimoto’s thyroiditis (discussed under hypothyroidism), although not immunogenetically identical, represent opposite ends of a single illness. Both diseases have strong genetic components, involve lymphocytic infiltration of the gland, and elaborate autoantibodies (Burman, 1995).

Graves’ hyperthyroidism appears to be an inherited disease because there is an increased frequency of certain genetic markers (histocompatibility complexes) in affected persons, especially HLA-B8 and DR3. In addition, there is a high concordance rate for the disease among monozygotic twins (Burman, 1995). Although autoantibodies cause the goiter and hyperthyroidism of Graves’ disease in a genetically predisposed person, not all people with these genetic markers develop autoimmune thyroid disease. The development of disease may be linked to an environmental stimulus that permits expression of the gene or allows the thyroidal defect. At present this stimulus is unidentified, but it may involve viral infections, sex hormone levels, or stress, factors that could change immune cell function.

Hyperthyroidism is also commonly the later stage of a multinodular goiter (Plummer’s disease) (Hay & Morris, 1996; Singer et al, 1995; Franklyn, 1994). In toxic multinodular goiter, the gland is more irregular and nodular than in Graves’ disease. Patients thus present with complaints of an enlarging neck mass or difficulty swallowing. Hyperthyroidism usually presents in an insidious manner and there is no infiltrative ophthalmopathy or dermopathy (Hay & Morris, 1996; Singer et al, 1995). In some cases, hyperthyroidism can follow exposure to drugs rich in iodine, such as intravenous contrast used in a computed tomography (CT) examination, the use of cough syrup with expectorants, or the use of amiodarone, an antiarrhythmic drug.

A few patients present with hyperthyroidism from a toxic (autonomous) nodule. This is found mostly in patients with a thyroid nodule that measures 3 cm or greater who are younger than 20 or older than 60 years (Hay & Morris, 1996).

Subacute thyroiditis (nonsuppurative thyroiditis, granulomatous thyroiditis, or De Quervain’s disease) is an inflammatory disease of the thyroid gland that can cause overt hyperthyroidism. It is the most common cause of pain and tenderness of the thyroid gland (Lazarus, 1996). Its onset can be abrupt or gradual, and the pain is over the thyroid gland, with radiation to the jaw, throat, and ears. Many patients give a history of a recent upper respiratory infection, and they may give a history of fever, sore throat, and myalgias. The pain and hyperthyroidism are transient, subsiding in weeks to 2 to 3 months. Transient hypothyroidism may follow this period of hyperthyroidism because of leakage of stored hormone from the gland and a disruption of the biosynthesis of hormone. Permanent hypothyroidism is unusual (Lazarus, 1996).

Thyroid inflammatory disease can present in a silent or painless mode (Lazarus, 1996). This usually occurs in the postpartum period, and it can be difficult to differentiate painless thyroiditis from early Graves’ disease. Nonetheless, postpartum thyroiditis is transient and does not lead to infiltrative ophthalmopathy. Women will report faster-than-expected weight loss after parturition, mood changes, anxiety, and palpitations that may all be erroneously attributed to the postpartum blues.

Most patients with hyperthyroidism have increased iodine uptake 24 hours after a tracer dose of radioactive iodine (¹³¹I). The exceptions, showing low uptake during clinical hyperthyroidism, are patients with thyroiditis or patients who have taken thyroid hormone or received iodine loads (intravenous contrast or amiodarone) before the test. Uptakes are done to confirm the presence of hyperthyroidism and are not necessary for the diagnosis of classic cases of Graves’ disease (Lazarus, 1996; Burman, 1995; Singer et al, 1995). Uptakes are also done to differentiate cases of thyroiditis from Graves’ if clinical cues are inadequate to distinguish these causes of hyperthyroidism.

Thyroid scans that allow images of the gland to be generated are done with labelled iodine (¹²³I) or pertechnetate (technetium, ⁹⁹Tc). Both radioisotopes emit gamma particles that are detected by a gamma camera. ⁹⁹Tc is less expensive and has a shorter half-life, allowing less radiation exposure. In Graves’ disease, the distribution of radionuclide within the thyroid is homogeneous, whereas toxic adenomas or toxic multinodular goiters are heterogeneous, showing some areas of increased uptake and other areas of decreased uptake (Burman, 1995; Hay & Morris, 1996). It is important that patients with areas of decreased uptake on thyroid scanning (cold nodules) are evaluated for thyroid cancer. Although most have multinodular goiters, some patients will harbor thyroid carcinoma in nonfunctioning tissue. Patients with hypothyroidism or thyroiditis demonstrate low or no uptake of radionuclide, and thyroid scans either cannot be generated or may look patchy (Lazarus, 1996).

Graves’ disease causes thickening of the eye muscles in more than 50% of patients; this can be detected by CT or magnetic resonance imaging (MRI) of the orbits. Orbital CT or MRI is particularly useful when the patient has euthyroid Graves’ (normal thyroid function) or unilateral eye involvement, where the etiology of the proptosis may not be easily recognized. Although CT scanning does expose the lens to radiation, it is the preferred imaging modality because of its lower cost and its ability to provide bony anatomic detail.

Antithyroid drugs that are available in the United States include propylthiouracil (PTU) and methimazole (Tapazole, MMI). Both work by inhibiting thyroid hormone synthesis, blocking iodine oxidation and iodotyrosine coupling. Both may inhibit antithyroid antibody production by inhibiting lymphocyte function. PTU also blocks, in a limited fashion, T₄ to T₃ conversion (Burman, 1995; Franklyn, 1994). Both drugs are absorbed
from the gut rapidly, but MMI is better concentrated in the gland and metabolized slowly (Singer et al, 1995). MMI is usually given as 10 to 40 mg/day in two or three doses; per day PTU is given in two or three doses a day at 300 to 1200 mg. The larger the goiter, the larger the dose given.

There is biochemical improvement in 2 to 6 weeks and clinical improvement in 4 to 6 weeks (Burman, 1995; Franklyn, 1994; Torring, 1996). Most patients reach euthyroidism in 8 to 10 weeks, and the dose can be reduced by 25% to 50% (Burman, 1995). Initial therapy is to inhibit thyroid synthesis altogether until thyroid stores are depleted. Once euthyroidism is reached, the goal is partial inhibition, being careful to prevent hypothyroidism, which could aggravate thyroid enlargement or orbitopathy. Failure to control hyperthyroidism is often caused by noncompliance with therapy or inadequate doses of drug; often T₄ levels fall, but T₃ levels are still elevated, leading to persistent hyperthyroidism.

Patients are seen every 4 to 6 weeks until euthyroid on the medication and then every 3 months thereafter (Burman, 1995; Franklyn, 1994). Antithyroid medication is given for up to 24 months or longer to ensure remission; shorter periods of treatment usually lead to a recurrence of the hyperthyroidism within months of drug withdrawal. Franklyn (1994) states that one study that looked at patients 1 year after stopping treatment for Graves’ disease found that 31% of patients who used antithyroid medication for 6 months were in remission, but 82% of patients on medication for 2 years were still euthyroid.

An alternative treatment protocol for Graves’ disease is to give high doses of antithyroid medication; when the patient responds, instead of decreasing the dose, thyroid supplement is added to prevent hypothyroidism. This dual therapy of “blockade and add back” allows higher doses of antithyroid drug to be given to suppress antithyroid antibody formation, supposedly increasing the rate of remission without causing hypothyroidism. The efficacy of this therapy has been shown in Japan and Europe. In a European study, medical therapy using antithyroid drug alone for 6 months and then with thyroxine for an additional 12 months was successful during a 4-year follow-up in 58% of young adults and 66% of adults over age 35 (Torring, 1996). This same therapy has not been as successful in North America, where the recurrence rate of hyperthyroidism (about 30%) was similar in patients given antithyroid medication and those given antithyroid medication followed by antithyroid medication plus thyroxine (McIver et al, 1996).

Inorganic iodine can decrease thyroid hormone levels by inhibiting the release of T₄ and T₃ by the thyroid gland (Burman, 1995; Franklyn, 1994). Iodide also blocks T₄ to T₃ conversion. This usually requires 5 to 10 mg of iodide daily. Escape from the antithyroid effects of iodide occurs within 7 to 14 days, but it is useful in patients with severe hyperthyroidism. Iodide is given several hours after starting antithyroid medication to avoid stimulating thyroid hormone synthesis. A saturation solution of potassium iodide (SSKI, 50 mg iodide/drop) or oral iodinated-contrast agents (Telepaque, 500 to 1000 mg b.i.d.) can be used (Burman, 1995).

Beta-adrenergic antagonists reverse many of the clinical symptoms and signs of hyperthyroidism. Propranolol is often used in a dosage of 40 to 160 mg/day to treat palpitations, tachycardia, nervousness, and hand tremors. Propranolol used alone does not reverse the catabolic effects of hyperthyroidism. It is the treatment of choice in thyroiditis and to control the symptoms of hyperthyroidism before ¹³¹I therapy becomes effective (Lazarus, 1996; Burman, 1995; Singer et al, 1995; Franklyn, 1994).

Radioactive iodine (¹³¹I) is an effective treatment for Graves’ disease because it reduces the volume of functioning thyroid tissue. The advantages of using radioactive ablation over antithyroid medication are its lack of side effects and its efficacy. Nonetheless, hyperthyroidism may not be reversed for many months. Thus, severely ill patients may need to be pretreated with antithyroid medication until they are more stable (Burman, 1995; Franklyn, 1994; Torring, 1996). Before therapy, iodine-containing drugs and contrast agents must be avoided. The usual dose of ¹³¹I is 8 to 12 mCi for Graves’ disease, delivering 10,000 to 20,000 rad to the thyroid (Burman, 1995). Higher doses of ¹³¹I (12 to 15 mCi) are given to patients who used antithyroid drugs before radioablation (Burch, 1994). Acute exacerbation of hyperthyroidism may occur within the first 2 weeks after treatment from radiation-induced thyroiditis (Franklyn, 1994). There may be some swelling of the goiter and neck pain, which responds to aspirin or steroids. Persistent hyperthyroidism may occur, especially if lower doses are used for treatment. Clinical and biochemical improvement occurs within 2 to 3 months; most patients are euthyroid or hypothyroid within 3 to 6 months. Hypothyroidism ensues in about 80% of treated persons within the following year, and 2% per year thereafter. Thyroidal underactivity is caused by radiation necrosis and the failure of the surviving cells to replicate.

Concerns that ¹³¹I can cause secondary thyroid cancers or other tumors has not been borne out in the literature (Burman, 1995; Franklyn, 1994). There may be a risk for gastric carcinoma in patients treated with ¹³¹I for Graves’ who have a family history of gastric cancer and pernicious anemia. Nonetheless, because of the concerns about potential gonadal radiation and leukemia, ¹³¹I is not the preferred treatment for children and adolescents or women in their reproductive years. Adult men may not face the same risk after exposure to ¹³¹I because the testicles are farther removed from the bladder than the ovaries and because the testicles manufacture new spermatocytes every 90 days.

Surgical treatment for hyperthyroidism is indicated for pregnant women who cannot tolerate antithyroid medication (Burman, 1995); patients with large goiters, especially those with compressive symptoms (Hay & Morris, 1996); patients intolerant of antithyroid medication who do not want radioactive iodine (Torring, 1996); and patients found to have coexistent suspicious nodules (Burman, 1995). Surgery can be preceded by short-term antithyroid medication, or in the nonpregnant patient iodide. Surgery is more expensive than treatment with radioiodine. Postoperative complications include vocal cord paralysis and transient or permanent hypocalcemia from hypoparathyroidism. Subtotal thyroidectomies, although safer in terms of less risk of vocal cord paralysis and hypoparathyroidism, may lead to recurrent hyperthyroidism because the thyroid remnant can be stimulated by remaining antithyroid antibodies. Many surgeons thus prefer to do near-total thyroidectomies (Burman, 1995) because it is difficult to reoperate in the neck. The recurrence rate for hyperthyroidism is about 3% to 8%; it tends to occur more than 5 years after surgery (Torring, 1996).

Surgical decompression is indicated if ophthalmopathy threatens vision.