Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone (Table 38–4).
The most common form of hyperthyroidism is Graves’ disease, or diffuse toxic goiter. The presenting signs and symptoms of Graves’ disease are set forth in Table 38–4.
Graves’ disease is considered to be an autoimmune disorder in which helper T lymphocytes stimulate B lymphocytes to synthe-size antibodies to thyroidal antigens. The antibody described pre-viously (TSH-R Ab [stim]) is directed against the TSH receptor site in the thyroid cell membrane and has the capacity to stimulate growth and biosynthetic activity of the thyroid cell. Spontaneous remission occurs but some patients require years of antithyroid therapy.
In most patients with hyperthyroidism, T3, T4, FT4, and FT3 are elevated and TSH is suppressed (Table 38–2). Radioiodine uptake is usually markedly elevated as well. Antithyroglobulin, thyroid peroxidase, and TSH-R Ab [stim] antibodies are usually present.
The three primary methods for controlling hyperthyroidism are antithyroid drug therapy, surgical thyroidectomy, and destruction of the gland with radioactive iodine.
Drug therapy is most useful in young patients with small glands and mild disease. Methimazole or propylthiouracil is administered until the disease undergoes spontaneous remission. This is the only therapy that leaves an intact thyroid gland, but it does require a long period of treatment and observation (12–18 months), and there is a 50–70% incidence of relapse.Methimazole is preferable to propylthiouracil (except in preg-nancy and thyroid storm) because it has a lower risk of serious liver injury and can be administered once daily, which may enhance adherence. Antithyroid drug therapy is usually begun with divided doses, shifting to maintenance therapy with single daily doses when the patient becomes clinically euthyroid. However, mild to moderately severe thyrotoxicosis can often be controlled with methimazole given in a single morning dose of 20–40 mg initially for 4–8 weeks to normalize hormone levels. Maintenance therapy requires 5–15 mg once daily. Alternatively, therapy is started with propylthiouracil, 100–150 mg every 6 or 8 hours until the patient is euthyroid, followed by gradual reduc-tion of the dose to the maintenance level of 50–150 mg once daily. In addition to inhibiting iodine organification, propylthiouracil also inhibits the conversion of T4 to T3, so it brings the level of activated thyroid hormone down more quickly than does methi-mazole. The best clinical guide to remission is reduction in the size of the goiter. Laboratory tests most useful in monitoring the course of therapy are serum FT3, FT4, and TSH levels.
Reactions to antithyroid drugs have been described above. A minor rash can often be controlled by antihistamine therapy. Because the more severe reaction of agranulocytosis is often her-alded by sore throat or high fever, patients receiving antithyroid drugs must be instructed to discontinue the drug and seek imme-diate medical attention if these symptoms develop. White cell and differential counts and a throat culture are indicated in such cases, followed by appropriate antibiotic therapy. Treatment should also be stopped if significant elevations in transaminases occur.
A near-total thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters. Patients are treated with antithyroid drugs until euthyroid (about 6 weeks). In addition, for 10–14 days prior to surgery, they receive saturated solution of potassium iodide, 5 drops twice daily, to diminish vascularity of the gland and simplify surgery. About 80–90% of patients will require thyroid supplementation following near-total thyroidectomy.
Radioiodine therapy utilizing 131I is the preferred treatment for most patients over 21 years of age. In patients without heart dis-ease, the therapeutic dose may be given immediately in a range of 80–120 μCi/g of estimated thyroid weight corrected for uptake. In patients with underlying heart disease or severe thyrotoxicosis and in elderly patients, it is desirable to treat with antithyroid drugs (preferably methimazole) until the patient is euthyroid. The medication is then stopped for 5–7 days before the appropriate dose of 131I is administered. Iodides should be avoided to ensure maximal 131I uptake. Six to 12 weeks following the administration of radioiodine, the gland will shrink in size and the patient will usually become euthyroid or hypothyroid. A second dose may be required in some patients. Hypothyroidism occurs in about 80% of patients following radioiodine therapy. Serum FT4 and TSH levels should be monitored regularly. When hypothyroidismdevelops, prompt replacement with oral levothyroxine, 50–150 mcg daily, should be instituted.
During the acute phase of thyrotoxicosis, β-adrenoceptor–blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20–40 mg orally every 6 hours, or meto-prolol, 25–50 mg orally every 6–8 hours, will control tachycardia, hypertension, and atrial fibrillation. Beta-adrenoceptor–blocking agents are gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90–120 mg three or four times daily, can be used to control tachycardia in patients in whom β blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4 levels. Bile acid sequestrants (eg, cholestyramine) can also rapidly lower T4 levels by increasing the fecal excretion of T4.
These forms of hyperthyroidism occur often in older women with nodular goiters. FT4 is moderately elevated or occasionally nor-mal, but FT3 or T3 is strikingly elevated. Single toxic adenomas can be managed with either surgical excision of the adenoma or with radioiodine therapy. Toxic multinodular goiter is usually associated with a large goiter and is best treated by preparation with methimazole (preferable) or propylthiouracil followed by subtotal thyroidectomy.
During the acute phase of a viral infection of the thyroid gland, there is destruction of thyroid parenchyma with transient release of stored thyroid hormones. A similar state may occur in patients with Hashimoto’s thyroiditis. These episodes of transient thyro-toxicosis have been termed spontaneously resolving hyperthyroidism. Supportive therapy is usually all that is necessary, such as β-adrenoceptor–blocking agents without intrinsic sympathomi-metic activity (eg, propranolol) for tachycardia and aspirin or nonsteroidal anti-inflammatory drugs to control local pain and fever. Corticosteroids may be necessary in severe cases to control the inflammation.
Thyroid storm, or thyrotoxic crisis, is sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life-threatening syndrome. Vigorous management is mandatory. Propranolol, 1–2 mg slowly intravenously or 40–80 mg orallyevery 6 hours, is helpful to control the severe cardiovascular manifestations. If propranolol is contraindicated by the presence of severe heart failure or asthma, hypertension and tachycardia may be controlled with diltiazem, 90–120 mg orally three or four times daily or 5–10 mg/h by intravenous infusion (asthmatic patients only). Release of thyroid hormones from the gland is retarded by the administration of saturated solution of potassium iodide, 10 drops orally daily. Hormone synthesis is blocked by the administration of propylthiouracil, 250 mg orally every 6 hours. If the patient is unable to take propylthiouracil by mouth, a rectal formulation∗ can be prepared and administered in a dosage of 400 mg every 6 hours as a retention enema. Methimazole may also be prepared for rectal administration in a dose of 60 mg daily. Hydrocortisone, 50 mg intravenously every 6 hours, will protect the patient against shock and will block the conversion of T4 to T3, rapidly bringing down the level of thyroactive material in the blood.
Supportive therapy is essential to control fever, heart failure, and any underlying disease process that may have precipitated the acute storm. In rare situations, where the above methods are not adequate to control the problem, plasmapheresis or peritoneal dialysis has been used to lower the levels of circulating thyroxine.
Although severe ophthalmopathy is rare, it is difficult to treat. Management requires effective treatment of the thyroid disease, usually by total surgical excision or 131I ablation of the gland plus oral prednisone therapy . In addition, local therapy may be necessary, eg, elevation of the head to diminish periorbital edema and artificial tears to relieve corneal drying due to exophthalmos. Smoking cessation should be advised to prevent progression of the ophthalmopathy. For the severe, acute inflam-matory reaction, a short course of prednisone, 60–100 mg orally daily for about a week and then 60–100 mg every other day, taper-ing the dose over a period of 6–12 weeks, may be effective. If steroid therapy fails or is contraindicated, irradiation of the poste-rior orbit, using well-collimated high-energy x-ray therapy, will frequently result in marked improvement of the acute process. Threatened loss of vision is an indication for surgical decompres-sion of the orbit. Eyelid or eye muscle surgery may be necessary to correct residual problems after the acute process has subsided.
Dermopathy or pretibial myxedema will often respond to topical corticosteroids applied to the involved area and covered with an occlusive dressing.
Ideally, women in the childbearing period with severe disease should have definitive therapy with131I or subtotal thyroidectomyprior to pregnancy in order to avoid an acute exacerbation of thedisease during pregnancy or following delivery. If thyrotoxicosis does develop during pregnancy, radioiodine is contraindicated because it crosses the placenta and may injure the fetal thyroid. Propylthiouracil (fewer teratogenic risks than methimazole) can be given in the first trimester, and then methimazole can be given for the remainder of the pregnancy in order to avoid potential liver damage. The dosage of propylthiouracil must be kept to the minimum necessary for control of the disease (ie, < 300 mg/d), because it may affect the function of the fetal thyroid gland. Alternatively, a subtotal thyroidectomy can be safely performed during the mid trimester. It is essential to give the patient a thy-roid supplement during the balance of the pregnancy.
Graves’ disease may occur in the newborn infant, either due to passage of maternal TSH-R Ab [stim] through the placenta, stimulating the thyroid gland of the neonate, or to genetic trans-mission of the trait to the fetus. Laboratory studies reveal an elevated free T4, a markedly elevated T3, and a low TSH—in contrast to the normal infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is usually found in the serum of both the child and the mother.
If caused by maternal TSH-R Ab [stim], the disease is usually self-limited and subsides over a period of 4–12 weeks, coinciding with the fall in the infant’s TSH-R Ab [stim] level. However, treatment is necessary because of the severe metabolic stress the infant experiences. Therapy includes propylthiouracil in a dose of 5–10 mg/kg/d in divided doses at 8-hour intervals; Lugol’s solu-tion (8 mg of iodide per drop), 1 drop every 8 hours; and propra-nolol, 2 mg/kg/d in divided doses. Careful supportive therapy is essential. If the infant is very ill, oral prednisone, 2 mg/kg/d in divided doses, will help block conversion of T4 to T3. These medications are gradually reduced as the clinical picture improves and can be discontinued by 6–12 weeks.
Subclinical hyperthyroidism is defined as a suppressed TSH level (below the normal range) in conjunction with normal thyroid hormone levels. Cardiac toxicity (eg, atrial fibrillation), espe-cially in older persons, is of greatest concern. The consensus of thyroid experts concluded that hyperthyroidism treatment is appropriate in those with TSH less than 0.1 mIU/L, while close monitoring of the TSH level is appropriate for those with less TSH suppression.
In addition to those patients who develop hypothyroidism caused by amiodarone, approximately 3% of patients receiving this drug will develop hyperthyroidism instead. Two types of amiodarone-induced thyrotoxicosis have been reported: iodine-induced (type I), which often occurs in persons with underlying thyroid disease (eg, multinodular goiter); and an inflammatory thyroiditis(type II) that occurs in patients without thyroid disease due to leak-age of thyroid hormone into the circulation. Treatment of type I requires therapy with thioamides, while type II responds best to glucocorticoids. Since it is not always possible to differentiate between the two types, thioamides and glucocorticoids are often administered together. If possible, amiodarone should be discontin-ued; however, rapid improvement does not occur due to its long half-life.