Clinical Management of Patients with Hyperthyroidism

Symposium on Thyroid Disease

Clinical Patients with Clinical Management Management of of Patients with Hyperthyroidism Hyperthyroidism David S. Cooper, M.D.,* M.D., * and E. Chester Ridgway, M.D.t M.D. t

In previous articles, the pathogenesis and pathophysiology of the various forms of hyperthyroidism have been reviewed. This article will be devoted to a detailed discussion of the management of the hyperthyroid patient. The selection of appropriate therapy for the hyperthyroid patient is critically dependent on (1) determining that the patient has true hyperthyroidism and not one of the many forms of euthyroid hyperthyroxinemia88 and (2) establishing the etiology of the hyperthyroidism. Since hyperthyroidism is a syndrome with multiple etiologies, recognition of its various causes is crucial for proper patient management. Other factors also enter into the decision regarding therapy, including patient sex and age, the severity of the hyperthyroidism, the presence of other medical problems, patient preference, and the experience and background of the physician. Some aspects of treatment are controversial, and the opinions expressed below are, in many instances, only guidelines reflecting the management of hyperthyroid patients in the Massachusetts General Hospital Thyroid Clinic. DRUG THERAPY ANTITHYROID DRUGS

Mechanisms of Action Effects on Thyroid Hormone Biosynthesis. Propylthiouracil (PTU) and methimazole (Tapazole) are the only two antithyroid drugs approved for use in the United States. They are ale both thioureylenes, in. in which S 11

N-C-N

is incorporated into a 5- or 6-membered heterocyclic ring (Fig.

*Assistant

in Medicine, Massachusetts General Hospital; Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts Massachusetts General Hospital; Associate Professor of Medicine, Hart Associate Physician, Massachusetts· yard Medical School, Boston, Massachusetts

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56 1). Antithyroid compounds are actively concentrated by the thyroid gland. gland ..56 primarily to block the biosynthesis of thyroid hormone, having no They act prhnarily effect on the thyroid's ability to trap inorganic iodide or to release thyroid manner in which antithyroid drugs exert hormone into the circulation. The lnanner their effects on thyroid hormone biosynthesis is complex and is still not completely understood. The major actions are the inhibition of iodide binding to thyroglobulin to form mono- and diiodotyrosine (MIT and DIT), and the prevention of ofT4 T4 and T3 synthesis from MIT and DIT by inhibiting the subsequent coupling reaction. Extrathyroidal Effects. Although the most important therapeutic action of antithyroid drugs is the blockade of thyroid hormone biosynthesis, another important effect of one of the antithyroid drugs, PTU, is to inhibit clear that up to 80 per the peripheral conversion of T4 to T3. 1I It is now clear cent of the body's daily production of T3 is generated in the peripheral tis72 sues via monodeiodination of the outer ring of T4. T4.72 It is the opinion of many experts that T4 serves largely as a precursor for the more biologically active T3, and that most of the metabolic activity that is stimulated by thyroid hormone can be attributed to T3 alone. 51 As will be discussed, a number of pharmacologic agents can inhibit T4 to T3 conversion; among them is PTU, which causes an acute dose-related fall in serum T3 within hours of its administration. 18 IS Interestingly, methimazole does not inhibit T4 to T3 conversion, despite structural similarities with PTU. Effects on the Immune System. Graves' disease is the result of disordered immunity, with circulating antibodies that stimulate the thyrotropin 74 and an abnormally low suppressor cell population;3 these defects receptor74 are described more fully in preceding articles. Recent studies have suggested that the antithyroid drugs may have direct effects on the immune system to reverse the abnormalities, which, in theory, could lead to clinical

/NH-r=O /NH-~=O S=C ,

CH 11 NH-C - CH 2-CH 2-CH 3 223

"'NH-~ -

PROPYLTHIOUR AC IL PROPYLTHIOURACIL

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METHIMAZOLE METHIMA ZDLE Figure 1.

The structures of thiourea, propylthiouracil, and methimazole.

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improvement, apart from any direct effects on thyroid hormone biosynthesis or metabolism. In patients with Graves' disease, antithyroid drug therapy is associated with decreased circulating thyrOid-stimulating thyroid-stimulating anti60 and also with restoration of normal suppressor cell activity. 53 body titers 60 Since high levels of thyroid hormone can alter the immune system in animals, it is possible that some of the effects observed in hyperthyroid patients are simply due to normalization of thyroid function. 8o Further studies are needed in order for these questions to be resolved. However, the relationship between putative effects on autoimmunity and the induction of long-term remissions in Graves' disease has obvious therapeutic implications. Clinical Pharmacology As noted above antithyroid drugs are actively concentrated by the thy56 Although it is the intrathyroidal concentration, rather than the circuroid. 56 lating level of antithyroid drug, that determines its clinical activity, little is known about intrathyroidal antithyroid drug concentrations in humans. Jansson et al. have recently measured the methimazole content in the thyroid glands of patients undergoing surgery for Graves' disease. 47 These workers found that methimazole levels were simIlar in patients who were operated 3 to 6 hours after a dose compared with those operated 17 to 20 hours after a dose, implying a long intrathyroidal half-life. In other indirect studies, the inhibitory effects of PTU on iodide utilization were of considerably shorter duration than this. 5 As will be discussed, the longer duration of action of methimazole makes this drug particularly suited to once-a-day therapy. Antithyroid AntithyrOid drugs are almost completely absorbed from the gastrointestinal tract, 2 and peak serum levels occur about 1 hour after drug ingestion. The serum half-lives of PTU and methimazole are approximately 1 and 5 hours, respectively. The half-lives are not altered to any important l7, 19 The serum disappearance is prolonged in degree in hyperthyroidism. 17, patients with renal failure 2,. 16a or severe hepatic disease, 17, 29 but the therapeutic implications of these observations are unknown. PTU is heavily (60 to 80 per cent) bound to serum albumin,19 while methimazole is not prol7 This fact, plus the fact that PTU is ionized at neutral tein-bound at all. 17 pH, limits the passage of PTU across membranes. Therefore, compared with methimazole, which freely crosses the placental barrier57 and freely appears in breast milk,17 PTU only crosses plasma membranes one-tenth as 48 ,57 well. 48, 57 PTU is supplied as 50-mg tablets and methimazole comes in 5- and 10mg tablets. Since methimazole is at least 10 times more potent than PTU, starting doses are typically about 30 mg per day and 300 IIf llfgg per day for methimazole and PTU, respectively. Although both drugs llave have traditionally been given in divided doses every 8 hours, single daily doses of methimazole have recently become popular. 9, 33 Theoretically, this is a reasonable approach, given the long duration of action of methimazole. Although some experts have also advocated single-daily dose PTU therapy, this has not 36 In patients unable to been as successful as single-daily dose methimazole. 36 rectally.63 take oral medication, methimazole can be administered rectally. 63

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Side Effects Antithyroid drugs are somewhat notorious because of their side effects, but the spectrum and frequency of reactions are quite similar to those encountered with other commonly used therapeutic agents. Skin rash, arthralgias, and fever occur in up to 5 per cent of patients, and reactions may be more frequent with higher drug doses and in the pediatric age group. Rashes can often be managed with antihistamines, or the patient can be switched to the other antithyroid drug. Cross-sensitivity occurs in about 50 per cent of patients, however. Perhaps the most common side effect is a benign, transient leukopenia, occurring in approximately 10 per cent of patients; this is self-limited, is not associated with infection, and does not presage the development of agranulocytosis. Agranulocytosis is the most feared toxic reaction of antithyroid drugs. It occurs in approximately one out of every 200 patients (0.5 per cent), with a higher incidence in patients over age 40 and in those patients being treated with high doses of methimazole (>40 mg per day).18 Antithyroid 3 drug-related agranulocytosis almost invariably occurs within the first 3 months of therapy. Its onset is so sudden that routine monitoring of the patient's leukocyte count is of little value. Patients should be explicitly told to discontinue therapy if they develop a fever, pharyngitis, stomatitis, or other symptoms of bacterial infection, and to call their physician immediately for a white blood cell determination. Agranulocytosis is a self-limited condition, usually resolving in 5 to 15 days. A recent Japanese study has suggested that the recovery period is shortened with the use of glucocorticoid therapy. 38 Other serious but rare toxic reactions include hepatitis (usually with PTU), cholestatic jaundice (usually with methimazole), vasculitis, and a lupus-like syndrome. In general, if a patient has had a major side effect with one of the thioureylenes, the other one should not be given because of significant cross-sensitivity between the two drugs. POTASSIUM IODIDE

Iodide is the oldest form of drug therapy for hyperthyroidism due to Graves' disease. It acts to acutely block the release of thyroid hormone from the thyroid, and also inhibits thyroid hormone biosynthesis by interfering with intrathyroidal iodide utilization (the Wolff-Chaikoff effect)Y effect). 81 Unfortunately, the effects of iodides are usually transitory, owing to the thy24 roid gland's ability to overcome or "escape" from these inhibitory effects. 24 Thus, iodides are ordinarily not used as primary therapy for Graves' disease and should be avoided entirely in patients with toxic nodules or toxic nodular goiter because of the problem of iodine-induced hyperthyroidism. There are, however, several uses for iodides as adjunctive therapy. First, if after radioiodine therapy, the time until the patient becomes given shortly 3fter euthyroid is significantly shortened, because the irradiated thyroid has an increased sensitivity to iodides and fails to escape from the inhibitory 66 Indeed, transient hypothyroidism may develop if the dose of effects. 66 iodide is not titrated carefully. Similarly, in patients with recurrent hyper-

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thyroidism who have been previously treated with radioiodine or surgery, potassium iodide alone can often restore the euthyroid state. 10 Finally, potassium iodide is often used in combination with antithyroid agents or betaadrenergic blockers to prepare patients with Graves' disease for surgery. Potassium iodide is supplied either as a saturated solution (SSKI), containing 40 mg of iodide per drop, or as Lugol's solution, containing 8 mg of iodide per drop. A typical starting dose of SSKI is 3 to 10 drops daily (150 to 500 mg) in juice or water, which is approximately 1000 times the daily nutritional requirement for iodine. If iodide is to be used adjunctively with radioiodine, it should be started 1 week after the treatment, so as not to decrease the radiation dose to the thyroid by inhibiting iodide reuptake. After about 1 month, the dose should be titrated to the lowest amount necessary to control the patient's disease. Usually potassium iodide can be discontinued 3 to 6 months after radioiodine. Because radioiodine usually takes 3 to 12 months for its full effects to be realized, potassium iodide should be considered in those patients in whom more rapid control is desirable; in this situation, antithyroid drugs could also be used, but these agents have more frequent side effects. Potassium iodide, on the other hand, is very rarely associated with toxic reactions (fever, rash, sialadenitis) and can be used with somewhat less vigilance.

AGENTS THAT INHIBIT T4 CONVERSION TO T3

Since T3 is probably the major circulating active thyroid hormone, agents that inhibit T4 deiodination should be useful in treating hyperthyroidism. Propylthiouracil, but not methimazole, has the capacity to block T4 to T3 conversion, and, indeed, PTU may be particularly indicated in patients with very severe hyperthyroidism or thyroid storm, in whom a rapid reduction in serum T3 would be beneficial. A number of other agents l6 and the also block peripheral T4 deiodination, including glucocorticoids I6 ll (an. iodinated compounds amiodarone ll (an antianginal and antiarrhythmic agent) and the radiographic contrast agents iopanic acid (Telepaque)49 and sodium ipodate (Oragrafin).83 Given acutely, sodium ipodate can lower serum T3 concentrations even more rapidly than can PTU. Indeed, this agent has been used experimentally to treat hyperthyroidism,83 and it would be reasonable to use it in a severely hyperthyroid patient who was allergic to conventional antithyroid agents. In addition to its effect on T4 to T3 conversion, sodium ipodate is deiodinated in the circulation, and the resulting free iodide then has additional direct effects on the thyroid to inhibit secretion. Finally, the beta-adrenergic receptor blocking agents propranolol and ate nolo I or metoprolol) lower serum T3 by 15 to 20 per nadolol (but not atenolol cent by inhibiting T4 to T3 conversion. In vitro studies have shown that the effect of propranolol is not due to beta-receptor blockade but arises from its membrane-stabilizing effect.43 effect. 43 Beta-adrenergic receptor blockers are used extensively in the treatment of hyperthyroidism. The extent to which some of their beneficial effects are due to a lowering of serum 'T3 T3 concentrations is not known, but it is probably small. 70

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BETA-ADRENERGIC BLOCKING AGENTS

Many of the manifestations of hyperthyroidism are also seen in patients with pheochromocytoma, in whom circulating levels of catecholamines are high. However, circulating catecholamine levels are actually normal or low in hyperthyroidism,21 and attention, therefore, has focused on the beta-adrenergic receptor as the site at which thyroid hormone might exert its sympathomimetic effects. Recent studies have shown that myocardial and lymphocyte beta-adrenergic receptor number is increased in experimental hyperthyroidism,30 which could account for the striking similarities between hyperthyroidism and a state of enhanced adrenergic tone. However, the interrelationships are complex because of variable tissue responses to thyroid hormone, and the data are still limited. Agents that block beta-adrenergic receptors have been used to treat hyperthyroidism for many years, and there is a wide experience with these drugs. It is clear that beta blockers will rapidly ameliorate many of the disturbing features of the hyperthyroid state, including anxiety, palpitations, tremor, and heat intolerance,35 without affecting thyroid function (except for a minor decrease in serum T3 with certain agents). In addition, to varying degrees, other deleterious effects of hyperthyroidism may be improved, including negative nitrogen balance,28 increased cardiac output, 34 34 70 However, these parameters and elevated rates of oxygen consumption. 7o are never completely normalized with beta blockers,34 and hence, these agents are rarely indicated for primary therapy for Graves' disease or toxic nodules. As noted above, beta blockers are usually used adjunctively with either radioiodine or antithyroid drugs until the biochemical parameters 79 or in combination have normalized. Beta blockers have been used alone 79 25 with iodide to prepare hyperthyroid patients for surgery. As will also be discussed below, the only instances where beta blockers constitute a primary form of therapy for hyperthyroidism are in patients with thyroiditis or iodine-induced hyperthyroidism. Although propranolol has been the agent most widely used to treat the . symptoms of hyperthyroidism, newer beta blockers have several advantages over propranolol. Nadolol (Corgard) is a nonselective agent that can be taken once daily, and atenolol (Tenormin) and metoprolol (Lopressor) are selective beta1 antagonists that could be used cautiously in patients with a history of respiratory disease. Congestive heart failure is a contraindication to the use of these agents, except in the case of high output failure due hypo glycemia (diasolely to a rapid heart rate. Patients subject to attacks of hypoglycemia betic patients taking insulin or oral agents) should receive beta blockers cautiously, since the symptoms and signs of hypoglycemia are mediated by catecholamines.

RADIOACTIVE IODINE Background and Clinical Considerations

311) for the During the last four decades, the use of radioactive iodine ((1131 therapy of hyperthyroidism has become widely accepted and is currently

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the therapy of choice for adults with this disease. Radioiodine is usually administered orally as a colorless and tasteless liquid. After entering the bloodstream, it is concentrated in the thyroid with kinetics similar to that 1311 not trapped by the determined by the standard radioiodine uptake test. 131 1311 can thyroid is largely excreted in the urine and feces. Small amounts of 131 be found in the salivary glands as well as in the gastric mucosa. Once the radioactive iodine is trapped within the thyroid, it enters the intracellular iodine pool and is incorporated into thyroid hormones and thyroglobulin. It decays with a half-life of 8.05 days and delivers predominantly strong beta radiation. Over a period of weeks to months, follicular cells exposed to the radiation are destroyed, resulting in the amelioration of the hyperthyroid state. There is now considerable experience in radioiodine dosimetry for treatment of hyperthyroidism. The ultimate goal of therapy is to destroy overactive thyroid cells, a task that can usually be accomplished with a dose of 4000 to 8000 rads. In order to achieve this dosage level, four very impor1311 taken up tant factors need to be considered: (1) the maximal amount of 131 by the thyroid, (2) the size or amount of tissue to be irradiated, (3) the effective half-life of the isotope in the thyroid, and (4) the relative sensitivity of the thyroid to the radioactive iodine. Unfortunately, only the first of these is routinely measured in an accurate manner prior to therapy by the standard 24-hour radioiodine uptake test, leading to considerable variability in patient response to therapy. radio iodine therapy have been extensively reviewed. 77 The results of radioiodine Within a period of weeks to months, follicular cells are damaged or destroyed, thyroid gland size decreases, and the hyperthyroidism remits. The rapidity with which these events occur depends on the administered dose, as well as other poorly understood factors such as gland size and relative sensitivity of the thyroid to radioactive iodine. In general, 70 to 85 per cent of cases are cured by a single administration of radioactive iodine, an additional 10 to 20 per cent of cases require two doses, and less than 5 per cent require three or more doses. Within 6 to 8 weeks of the first dose, 50 to 75 per cent of patients will have a resolution of their symptoms and normalization of thyroid function studies. In addition to curing hyperthyroidism, the most important secondary consequence of radioactive iodine is the eventual development of primary hypothyroidism. This event will occur in most, and perhaps all, patients treated with radioactive iodine if follow-up is extended indefinitely. At least 50 per cent of patients are clinically hypothyroid 10 years after radioactive iodine administration, and as many as 80 per cent may be hypothyroid by 20 years. The rapidity and probability of developing hypothyroidism is pri1311 administered. Previous estimates of marily dependent on the dose of 131 the prevalence of hypothyroidism following radioactive iodine are probably low, since they were traditionally based on a clinical diagnosis of hypothyroidism. When modern thyroid function studies are used, including sensitive TSH assays, a failing thyroid with elevated TSH values is found much more frequently than would have been predicted by clinical assessment. For example, in 1974 (prior to the use of sensitive TSH assays) the Massachusetts General Hospital Clinic reported a 7 per cent incidence of hypot-LCi per gm) radioactive iodine therthyroidism 1 year after low-dose (80 ~Ci

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apy.14 In 1983, this same clinic reported that 56 per cent of patients treated with the same dose were hypothyroid after 1 year when the criterion for a diagnosis of primary hypothyroidism was an elevated serum TSH level. 66 Despite the fact that hypothyroid incidence figures are dramatically determined by radioactive iodine dose, it unfortunately appears that lowering the dose will not permanently protect patients from eventually developing hypothyroidism. In the various groups of patients studied, most have had an annual incidence rate for developing hypothyroidism of between 3 and 7 per cent. 31 31., 46 Lowering the dose of radioactive iodine reduces the number of patients with hypothyroidism after 1 year at the ex68 and does not alter the accrual rate pense of lowering the cure rate 68 31 thereafter. 31 Of considerable interest is the fact that surgical treatment of hyperthyroidism also has a 2 to 3 per cent annual incidence rate of hypothyroidism. This finding has led investigators to hypothesize that the genesis of hypothyrOidism hypothyroidism following therapy of hyperthyroidism is not merely due to radiation damage but may be multifactorial, perhaps being mediated in part by immunologic factors. 54 During the 2 to 6 months between 1311 treatment and achieving a euthyroid status, serum levels ofT4 and T3 gradually decline. In about one third of patients, serum T4 and T3 transiently increase in the first 10 days, presumably as a result of necrosis of thyroid cells and release of thyroid 77 Although this phenomenon is usually hormones into the circulation. 77 asymptomatic, it may result in persistent or worsening hyperthyroidism, so that during this important period of time, adjuvant measures are generally implemented. Beta-adrenergic blockade is the mainstay of such therapy and is generally used until the patient is euthyroid. The dose is titrated to abolish symptoms and reduce the resting pulse rate to 80 beats per minute. Other measures may include the use of antithyroid drugs or potassium iodide, starting approximately 1 week after radioactive iodine therapy and continuing for 2 to 6 months.

Complications of Radioactive Iodine

Short-Term. Acute side effects of radioactive iodine are unusual. About one third of patients will demonstrate increases in serum levels of 1311, thyroid hormones after 131 1, but only rarely has such a rise been associated with significant deterioration in the patient's condition. 59 Since most patients are concurrently treated with beta-adrenergic blocking agents, a rise in thyroid hormone levels is difficult to appreciate clinically. A small minority « 5 per cent) of patients will have tenderness in the area of the thyroid, presumably resulting from capsular swelling and cellular necrosis. If the tenderness is severe, glucocorticoid therapy is particularly effective in decreasing the pain. It has been said that the ophthalmopathy of Graves' disease may worsen in the weeks or months following radioactive iodine ther37 From 10 to apy, but data confirming this clinical impression are lacking. 37 15 per cent of patients develop transient hypothyroidism 1 to 4 months after 1311;71 the continued presence of a goiter is a clinical clue that the hypothyroidism may be transient. If hypothyroidism persists longer than 2 months, permanent hypothyroidism is likely. Long-Term. The chronic complications of radioactive iodine which were originally anticipated have not materialized. Worries ove. over possible ra-

J3Jel

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diation-induced carcinogenesis and teratogenesis have been partially alleviated by a number of long-term follow-up studies of patients treated with radioactive iodine. To date, there has not been any significant increase in the incidence of thyroid carcinoma,22, 44, 45 45 a finding that probably relates to the ablative nature of therapy that destroys the replicative potential of thyroid cells. Benign thyroid nodules may be more common in young people 22 Likewise, the incidence of leukemia however,22 after radioactive therapy, however. and other cancers has not been found to be significantly different from that 44 Although it has been over 40 years since radioacin control populations. 44 tive iodine was first introduced, it will still require larger groups of patients followed for still longer periods of time before an answer to these questions is known with certainty. certainty, The potential for genetic damage has been carefully reviewed, but the data are more theoretical. Although no discernible increase in genetic damage has been found in children born to parents who received radioiodine,6, 40, 69 the number of children studied has been too small and the time frame for such an analysis has been too short. Calculations have been made using assumptions of radiation dose to the gonad and the spontaneous mutation rate in the population to arrive at an estimate that radioactive iodine 64 "might" increase the birth defect rate from 0.8 per cent to 0.803 per cent. 64 Such a low rate for an increase in birth defects will require the study of many children from multiple generations before a rigorous evaluation can be made about the effects of radioiodine on the genetic pool. Contraindications to Radioactive Iodine Therapy Pregnancy is an absolute contraindication to radioactive iodine therapy. apy, Radioiodine easily crosses the placenta, and after the tenth to twelfth week of gestation, it is concentrated by the fetal thyroid, producing intrahypothyroidism, If the radioactive iodine is inadvertently adminisuterine hypothyroidism. tered in the first trimester, fetal hypothyroidism is not generally found, and fetal malformations are no greater than would be expected in a control pop73 ulation,73 Since maternal thyroid hormones do not pass the placental barulation. rier, such an exposed infant is at high risk for not only hypothyroidism but also mental retardation. A A pregnancy test should be done just prior to rehistory, ceiving radioiodine if pregnancy cannot be ruled out by history. SURGERY

Over the last century, surgery has played less and less of a role in the hyperthyroidism, In selected patients, however, surgery is management of hyperthyroidism. radioiodide, Thyroid sura reasonable alternative to antithyroid drugs or radioiodide. gery should only be performed by a surgeon with experience and interest in this area, since recent studies show that in competent hands, the mortality rate for a subtotal thyroidectomy approaches zero. 50, 52 52 Nevertheless, recurrent laryngeal nerve damage and permanent hypoparathyroidism do occur, albeit in very small numbers of patients «0.5 to 1 per cent).50 cent),50 Permanent hypothyroidism also occurs in a variable proportion of patients, depending on the size of the thyroid remnant, the presence of circulating antithyroid antibodies, and the duration of follow-up. Some surgeons report

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rates of postoperative hypothyroidism as low as 10 per cent,41 while others find that a high rate of postoperative hypothyroidism (approaching 60 per cent) is a necessary trade-off to avoid recurrent hyperthyroidism. 52 52 Transient hypothyroidism after surgery is also commonly seen in the first few months following surgery; if hypothyroidism persists longer than 4 to 6 months, however, permanent hypothyroidism is likely.79 Like the situation with radioiodine, the incidence of postoperative hypothyroidism follows a bimodal pattern, with a large number of patients becominf hypothyroid per.I.~nt mt per year) <12 months after surgery, and a small fraction (1 to 3 per latter group, subsequently developing late-onset hypothyroidism. In the iatter the hypothyroidism may simply be a reflection of the natural history of Graves' disease patients to ultimately become hypothyroid. 82 There are no absolute indications for surgery in the hyperthyroid patient, and the decision to operate often is based as much on personal and emotional factors as on medical factors. Children and adolescents, pregnant women who are poorly controlled with antithyroid agents, patients with very large goiters, and patients who do not wish to receive radioiodine radio iodine are the main surgical candidates. Once the decision has been made to operate, preparation of the patient is the most important function of the internist. The traditional method involves the administration administmtion of antithyroid drugs for 6 to 8 weeks until the patient is biochemically biochemicall) euthyroid, and then adding SSKI or Lugol's solution for 10 to 14 days (500 mg per day) to decrease the vascularity of the gland. Some authors have stated that the putative effects of iodide on gland vascularity are minimal, and that patients prepared with and without iodide have similar degrees of blood loss during surgery. 52, 52. 79 R~cently, the use of propranolol alone as pretreatment for surgical paR0cently, tients has been advocated. 52, 79 Propranolol is given in doses sufficient to lower the resting pulse to <80 beats per minute (usually about 160 mg per day) for several weeks prior to surgery. Although most rnost patients do well on this regimen, postoperative fever and tachycardia can be a problem in patients with severe hyperthyroidism, since the levels of T4 and T3 postoperatively are still elevated. 26 Propranolol must be continued for 7 to 10 ofT4 days postoperatively, since the half-life of T4 in the serum is 6.9 days. Perhaps a more reasonable approach is combined pretreatment with propranolol plus 10 days of potassium iodide,25 the latter bringing thyroid functime of surgery. Until tional parameters close to the normal range by the tirne wider experience has been gained with these newer regimens, however, the standard pretreatment with antithyroid drugs and iodide is preferred in our clinic. If surgery must be done under emergency conditions, treatment with intravenous propranolol plus iodide would be reasonable.

CLINICAL CONSIDERATIONS GRAVES'DISEASE

There is no "best" treatment for Graves' disease, and opinions regarding therapy vary widely, even among "experts."23 Perhaps the most critical

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factor entering into the therapeutic decision is the age of the patient. Therefore, the following discussion will be organized around this particular clinical feature. Children and Adolescents Although radioiodine has been used in children by several clinics with success, 6,6. 40, 40, 69 69 most physicians opt for antithyroid agents as the treatment of choice for young people; if drug therapy fails, surgery or radioiodine is then offered as an alternative. alternative, The reason for avoiding radioiodine radio iodine in this patient group is based on several factors, including the reported development of benign nodules in some young 131I-treated patients,22 the likelihood of lifelong thyroid hormone supplementation, and, perhaps most important, the lingering uncertainty over possible carcinogenesis and genetic damage from radioiodine. There is, at present, no clinical evidence to support such a notion, but the numbers of patients treated in childhood or adolescence are small, and the follow-up periods are relatively short. After Mter initiation of antithyroid drugs, the euthyroid state is usually achieved in 3 to 6 weeks with methimazole (30 mg per day) or PTU (300 mg per day). As noted earlier, single-daily dose methimazole is successful in most patients, and is particularly useful in children, in whom compliance is apt to be a problem. The time to achieve the euthyroid state depends on the severity of the underlying disease, the size of the thyroid (reflecting hormonal stores), and the drug dose. Once thyroid function has been normalized, the major question that arises is: how long should the drug be continued before attempting its withdrawal to see if the patient is in remission? The question of remission and its relation to antithyroid drug therapy is highly controversial. The debate has continued as the possibility has been recognized that antithyroid drugs may influence the immune system, and therefore the natural history of the disease. It was initially taught that antithyroid agents should be given for 1 to 2 years prior to discontinuation. 42 Recently, Greer and his associates have reported that the remission rate is similar whether drugs are simply given until the patient is biochemically euthyroid (3 months) or whether they are given for much longer time periods (that is, years).33 This has not been confirmed by all investigators, however,78 and it is our practice to administer antithyroid drugs for at least one year. This is an important question because prolonged drug exposure can be avoided in those patients destined to have an early remission. remission, 65 Higher doses of antithyroid drug may also increase the rate of remission,65 which would be in keeping with possible effects of these agents on the immune system. However, since higher drug dosages are also associated with an increased frequency of toxic reactions, conventional doses are still preferable. A number of diagnostic procedures have been advocated to predict whether a patient will go into remission once antithyroid drug therapy is discontinued. These include T3 suppression testing, TRH testing, and measurement of circulating thyroid-stimulating immunoglobulin titers. These tests are expensive and are often inaccurate; in practice, it is simpler to taper or withdraw the antithyroid drug and follow the patient. Remissions

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33 Reoccur more frequently in patients with small goiters and mild disease. 33 lapses usually occur within the first 3 months after drug discontinuation, 75 and close follow-up is necessary during this time. If relapse occurs, then antithyroid drugs can be reinstituted, or an alternative approach can be reco'nmended. reco nmended. In children and adolescents, we usually continue with the antithyroid drugs for another 1 to 2 years. If the patient appears to have had a remission, then life-long follow-up is mandatory, since most patients will have late relapses,75 while others will develop hypothyroidism many years later. 82

Young Adults (Age 18 to 30) Opinion is divided about the most appropriate way to manage patients with Graves' disease in this age group. In our own clinic, approximately 70 per cent receive radioiodine radio iodine and 30 per cent receive antithyroid drugs. In women who desire pregnancy in the near future, we prefer radioiodine, since this obViates obviates any concern about antithyroid drugs causing fetal goiter or hypothyroidism. As stated earlier, there is no evidence that radioiodine radio iodine causes genetic damage; the dose of radiation to the ovaries after a typical dose of radioiodine is 0.5 to 1 per mCi,64 similar to the radiation exposure after a gastrointestinal series. If the patient and physician opt for an initial trial of antithyroid drugs, these are given for 1 to 2 years. If, after drug radio iodine is usually given rather withdrawal, the patient has a relapse, radioiodine than embarking on a second course of antithyroid drugs. Adults over Age 30 In this age group, radioiodine is the treatment of choice. Occasionally potassium iodide or antithyroid drugs are given following the radioiodine dose to patients with more severe degrees of thyrotoxicosis. In patients with very severe hyperthyroidism, or in patients with underlying cardiac disease, it is wise to pretreat with antithyroid drugs to deplete the thyroid of stored hormone. As discussed above, this is done because some patients have a transient increase in thyroid hormone levels about 1 week after radio- . iodine, which could be a potential problem in an elderly patient with cardiac disease. Therefore, it is prudent to render such patients euthyroid with antithyroid agents prior to administering radioiodine. It should be recalled that the elderly are predisposed to developing agranulocytosis from antithyroid drugs, so that caution is necessary in this patient population. 18 PREGNANCY

One to two per 1000 pregnancies are complicated by hyperthyroidism due to Graves' disease. Obviously, radioiodine radio iodine is contraindicated in the pregnant patient, and antithyroid drugs have replaced surgery as the treat32,• 61, ment of choice in most centers. 32 61. 76 Although antithyroid drugs cross the placenta, PTU crosses to far less a degree than methimazole. 57 Therefore, PTU is the preferred antithyroid drug in pregnancy. Occasional reports of scalp defects (aplasia cutis)62 in babies born to mothers taking methimazole also makes PTU preferable.

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Once the euthyroid state has been achieved with PTU, the dose should be tapered to as low as possible (50 to 100 mg daily) as pregnancy progresses. Serum TSH should be monitored closely in antithyroid drugtreated pregnant patients, and serum T4 should be kept in the normal range for pregnancy, which, because of high levels of thyroid-binding globulin, is 12 to 17 ,.....g J.tg per dl, rather than 4 to 12 J.tg ,.....g per dl in the nonpregnant population. Graves' disease tends to improve spontaneously in the third trimester, and in a significant minority of patients, antithyroid drugs can be discontinued completely late in pregnancy. Close follow-up after delivery is mandatory, however, since the disease often recurs postpartum. In the past, patients who were taking antithyroid drugs were not permitted to breast-feed. Recent data, however, suggest that while methimazole does enter the breast milk in significant quantities,17 PTU does not. 48 We certainly do not encourage women taking PTU to breast-feed. However, if the petient prtient is strongly motivated, and if the baby's thyroid function is closely monitored, breast-feeding might be permitted. It should be noted parenthetically that radioactive iodine also gets into breast milk, so that breast-feeding is contraindicated for at least 1 month following radioiodine therapy. What are the hazards to the fetus from intrauterine exposure to antithyroid drugs? A goiter, indicating increased TSH stimulation of the thyroid, develops in about 10 per cent of infants,12 and even infants without goiter may have transiently increased TSH levels, suggestive of mild hypoIs However, long-term follow-up studies show than infants born thyroidism. 1s to mothers taking antithyroid drugs have no intellectual impairment compared with siblings or age-matclied controls. 13, 13. 58 The co-administration of thyroid hormone with antithyroid drugs has been advocated as a means of protecting the infant against the goitrogenic effects of the antithyroid agents. Unfortunately, thyroxine crosses the placenta very poorly, and it does not prevent neonatal goiter. Furthermore, its use could mask drug-induced maternal hypothyroidism and thereby lead the physician to give an unnecessarily high dosage of antithyroid drug. Therefore, the co-administration of thyroxine with antithyroid drugs is not recommended. 61, 61. 76 TOXIC ADENOMA AND TOXIC MULTINODULAR GOITER (PLUMMER'S DISEASE) TOXICADENOMAANDToXICMuLTINODULARGOITER(PLUMMER'sDISEASE)

Unlike the situation in Graves' disease, where spontaneous or drugrelated remissions frequently occur, remissions are not often seen in patients with a toxic nodule(s). Therefore, the preferred therapy is generally ablative, that is, surgery or radioiodine. Although the prevalence of toxic multinodular goiter is much greater in older age groups, toxic solitary nod39 Surgery may thereules are not uncommon in children and adolescents. 39 fore be selected as primary therapy in young patients. ·In In addition, adults with extremely large goiters may require very large doses of radioiodine (>50 mCi); even if they are cured of hypothyroidism, the size of the goiter may not change dramatically because of the presence of large areas of non-

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functioning tissue, calcifications, and fibrosis. In such patients, surgery may be a more reasonable choice of therapy. Proper preparation of the patient for surgery is essential, and guidelines are the same as those discussed earlier, except that iodide is omitted. The toxic solitary nodule and toxic multinodular goiter are particularly well suited to radioactive iodine therapy. In these clinical entities the autonomous nodule(s) produce excessive amounts of thyroid hormones which cause hyperthyroidism and suppress pituitary TSH secretion. As a result, nonautonomous areas in the thyroid are suppressed and fail to incorporate radioactive iodine. This allows the abnormal autonomous regions to be treated, while the remainder of the thyroid is protected from the ablative effects of the radioactive iodine. For this reason, hypothyroidism is an unusual consequence of radioactive iodine therapy of the toxic nodular goiter. It has been stated that solitary autonomous nodules are relatively resistant to radioactive iodine, thus necessitating very high doses. It has been our 1311 dose of 10 mCi has resulted in a greater than experience that a mean 131 90 per cent cure rate of the hyperthyroidism in patients with solitary toxic 131 67 Higher 131 1 doses are adenoma, and that hypothyroidism has not occurred. 67 usually required for toxic multinodular goiters because these glands are often quite large and most have radioactive iodine uptakes that are lower than those seen in Graves' disease or toxic solitary adenomas. Both of these factors increase the calculated radioactive iodine dose administered to the patient. Since toxic multinodular goiter usually occurs in the elderly, special vigilance is recommended in treating these patients with radioactive iodine. Many will have coincidental heart disease, and a release of thyroid hormones into the circulation could exacerbate the hyperthyroidism or their underlying disease. For this reason, we and many others prefer to pretreat older patients or patients with cardiac disease with antithyroid drugs to deplete intrathyroidal hormone stores and control the hyperthyroidism before giving definitive radioactive iodine therapy. The concomitant use of beta-adrenergic blocking agents is usually required. One controversial issue is whether prophylactic ablation of nontoxic autonomously functioning nodules is justifiable. The data of Hamburger suggest strongly that nodules 2:: ~ 3.0 cm in diameter have a 20 per cent 39 In our own chance of becoming toxic over a 1- to 6-year follow-up period. 39 clinic, patients with larger nodules who are not toxic are followed, except those who are above age 50 or who have underlying cardiac disease. In 1311 since the consethese latter groups, strong consideration is given to 131 quences of hyperthyroidism are more serious. SPECIAL THERAPEUTIC CONSIDERATIONS Subacute Thyroiditis and Painless Thyroiditis These self-limited conditions are discussed elsewhere in this volume. Symptomatic therapy (salicylates, glucocorticoids, beta-adrenergic blockers) is employed until the condition spontaneously resolves.

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Iodine-induced Hyperthyroidism Qodbasedow)27 is common in iodineIodine-induced hyperthyroidism (jodbasedow)27 deficient areas of the world but is rare in the United States. It typically occurs in patients with long-standing nontoxic goiters or autonomous nodules who are exposed to large amounts of iodide in the form of contrast agents. In Europe, the iodinated antiarrhythmic agent amiodarone has been associated with jodbasedow, but it has not been a major problem in this country. Iodine-induced hyperthyroidism is self-limited and is usually mild, but it can occasionally be quite severe. In mild cases, beta-adrenergic blocking agents suffice, but in more severely affected patients, antithyroid agents are employed. Often, the antithyroid drug dosage requirement is large and the response to therapy less satisfactory than is seen in Graves' disease. Obviously, radioiodine cannot be used because of the high circulating iodide concentrations. Thyroid Storm Thyroid storm is a life-threatening condition, characterized by extreme thyrotoxicosis, fever, delirium, and coma. 55 It typically follows surgery or infection in a patient not previously known to be hyperthyroid. Therapy consists of general supportive measures, combined with aggressive antithyroid drug therapy. PTU (300 mg ~very ~very 6 hours) is preferred because of its ,given orally or by nasogastric ability to block T4 to T3 conversion. It is .given tube; to be given intravenously, it must be especially formulated in alkaline solution. Following PTU administration, potassium iodide (10 drops orally every 8 hours) or sodium iodide (1 to 2 mg intravenously over 24 hours) should be given. Iodide should only be used after a dose of PTU has been given, in order to prevent iodide utilization by the thyroid. In addition to PTU and iodide, propranolol (80 mg orally every 6 hours or 2 to 4 mg intravenously every 4 hours) should be given to block the catecholamine-mediated effects. Finally, stress doses of systemic glucocorticoids (300 mg of hydrocortisone or its equivalent) are recommended because of the possibility of relative adrenal insufficiency. If conventional therapy fails, plasmapheresis has been used in several patients with good results. 44 ACKNOWLEDGMENTS

Dr. Cooper is a recipient of a New Investigator Research Award 1R23 AM28465-01. The authors thank Ms. Sharon Melanson for her expert secretarial assistance.

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4. Ashkar, F. S., Katims, R. B., Smoak, W. M., et al.: Thyroid storm treatment with blood exchange and plasmapheresis. J.A. M.A., 214:1275-1279, 1970. 5. Barnes, H. V., and Bledsoe, T.: A simple test for selecting the thioamide schedule in thyrotoxic()sis. J. Clin. Endocrinol. Metab., 35:250-255, 1972. 6. Becker, D. V.: The role of radioiodine treatment in childhood hyperthyroidism. J. Nucl. Med., 20:890-894, 1979. 7. Beierwaltes, W. H.: The treatment of hyperthyroidism with iodine-131, Semin. Nucl. Med., 8:95-103, 1978. 8. Borst, G. C., Eil, C., and Burman, K. D.: Euthyroid hyperthyroxinemia. Ann. Intern. Med., 98:366-378, 98:366--378, 1983. 9. Bouma, D. J., and Kammer, H.: Single daily dose methimazole treatment of hyperthyroidism. West. J. Med., 132:13-15, 132:1~15, 1980. 10. Braverman, L. E., Woeber, K. A., and Ingbar, S. H.: Induction of myxedema by iodide in patients euthyroid after radioiodine or surguical treatment of diffuse toxic goiter. N. :816--821, 1964. Engl. J. Med., 281 :816-821, 11. Burger, A., Dinichert, D., Nicod, P., et al.: Effect of amiodarone on serum triiodothyronine, 'reverse reverse triiodothyronine, thyroxine, and thyrotropin: A drug influencing peripheral metabolism of thyroid hormones. J. J. Clin. Invest., 58:255-259, 1976. J. Clin. Endocri12. Burrow, G. N.: Neonatal goiter after maternal propylthiouracil therapy. J. 25:40H08, 1965. nol. Metab., 25:403--408, 13. Burrow, G. N., Klatskin, E. H., and Genel, M.: Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J. J. BioI. Med., 51:151-156, 1978. 131 Maloof, F., et al.: Low-dosage 1311 therapy of thyrotox14. Cevallos, J. L., Hagen, G. A., Maloof, icosis (diffuse goiters). N. Engl. J. Med., 290:141-143, 1974. 15. Cheron, R. G., Kaplan, M. M., Larsen, P. R., et al.: Neonatal thyroid function after propylthiouracil therapy for maternal Graves' disease. N. Engl. J. Med., 304:525-528, 1981. 16. Chopra, 1. J., J., Williams, D. E., Origiazzi, J., et al.: Opposite effects of dexamethasone 3,3',5' -triiodothyronine (reverse T3) and 3,3' ,5on serum concentrations of 3,3' ,5'-triiodothyronine J. Clin. Endocrinol. Metab., 41 41:911-920, triiodothyronine (T3). J. :911-920, 1975. 16a.Cooper, 16a. Cooper, D. S.: Unpublished observations, 1984. 17. Cooper, D. S., Bode, H. H., Nath, B., et al.: Methimazole pharmacology in man: Studies using a newly developed radioimmunoassay for methimazole. J. Clin. Endocrinol. Metab., 58:47H79, 58:473-479, 1984. 18. Cooper, D. S., Goldminz, D., Levin, A. A., et al.: Agranulocytosis associated with anti98:26--29, 1983. thyroid drugs. Ann. Intern. Med., 98:26-29, 19. Cooper, D. S., Saxe, V. C., Maloof, Maloof, F., et al.: Studies of propylthiouracil using a newly developed radioimmunoassay. J. Clin. Endocrinol. Metab., 52:204-213, 1981. 20. Cooper, D. S., Saxe, V. C., Meskell, M., et al.: Acute effects of propylthiouracil (PTU) on thyroidal iodide organification and peripheral iodothyronine deiodination: correlation with serum PTU levels measured by radioimmunoassay. J. Clin. Endocrinol. Metab., 54:101-107, 1982. 21. Coulombe, P., Dussault, J. H., and Walker, P.: Plasma catecholamine concentrations in 25:97~979, 1976. hyperthyroidism and hypothyroidism. Metabolism, 25:973-979, 22. Dobyns, B. M., Sheline, G. E., Workman, J. J. B., et al.: Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: A report of the cooperative thyrotoxicosis therapy follow-up study, J. Clin. Endocrinol. Metab., 38:979--998, 1974. 23. Dunn, J. T.: Choice of therapy in young adults with hyperthyroidism of Graves' disease: A brief, case-directed poll of fifty-four thyroidologists. Ann. Intern. Med., 100:891893, 1984. J., Howard, W. J., et al.: Serum thyroxine and 24. Emerson, C. H., Anerson, A. J., triiodothyronine concentrations during iodide treatment of hyperthyroidism. J. Clin. 40:3~36, 1975. Endocrinol. Metab., 40:33-36, J. S. A., Irvine, ChB. W., et al.: Combination of potassium iodide 25. Feek, C. M., Sawers, J. and propranolol in preparation of patients with Graves' disease for thyroid surgery. N. J. Med., 302:883-885, 302:88~885, 1980. Engl. J. J., Forrest, A. L., et al.: Propranolol in the surgical treatment of hy26. Feely, J., Crooks, J., perthyroidism, including severely thyrotoxic J. Surg., 68:865-869, 68:865--869, 1981. thyrotoxiC patients. Br. J.

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27. Fradkin, J. J. E., and Wolff, J.: J.: Iodide-induced thyrotoxicosis. Medicine, 82:1-20, 1983. 28. Georges, L. P., Santangelo, R. P., Mackin, J. J. F., et al.: Metabolic effects of propranolol in thyrotoxicosis: Nitrogen, calcium, and hydroxyproline. Metabolism, 24:11-21, 1975. J. P., Orrego, H., et al.: Mechanism of alterations in propylthiouracil 29. Giles, H. G., Long, J. 31:559-563, disposition after long-term therapy. Clin. Pharmacol. Ther., 31 :55~563, 1982. 30. Ginsberg, A. M., Clutter, W. E., Shah, S. D., et al.: Triiodothyronine-induced thyrotoxJ. Clin. icosis increases mononuclear leukocyte l3-adrenergic J3-adrenergic receptor density in man. J. 67:1785--1791, 1981. Invest., 67:1785-1791, 1311 J. A., Gordon, E. S., and Sawin, C. T.: Hypothyroidism after low-dose 131 31. Glennon, J. treatment of hyperthyroidism. Ann. Intern. Med., 76:721-723, 1972. 32. Goluboff, L. G., Sisson, J. J. C., and Hamburger, J. J. I.: Hyperthyroidism associated with Ob stet. Gynecol., 44:107-116, 1974. pregnancy. Obstet. 33. Greer, M. A., Kammer, H., and Bouma, D. J.: J.: Short-term antithyroid drug therapy for J. Med., 297:173-176, 1977. the thyrotoxicosis of Graves' disease. N. Engl. J. 34. Grossman, W., Robin, N. I., Johnson, L. W., et al.: The enhanced myocardial contractil74:869ity of thyrotoxicosis: Role of the beta adrenergic receptor. Ann. Intern. Med., 74:86~ 874, 1971. 35. Grossman, W., Robin, N. I., Johnson, L. W., et al.: Effects of beta blockade on the peripheral manifestations of thyrotoxicosis. Ann. Intern. Med., 74:875-879, 74:875--879, 1971. 36. Gwinup, G.: Prospective randomized comparison of propylthiouracil. J.A.M.A., 239:2457-2459, 1978. 37. Gwinup, G., Elias, A. N., and Ascher, M. S.: Effect on exophthalmos of various methods J.A.M.A., 247:2135--2138, 1982. of treatment of Graves' disease. J. A. M. A., 247:2135-2138, 38. Hamada, N., Itoh, Hoh, K., Mototani, N., et al.: Effect of corticosteroids in 10 cases of methimazole-induced agranulocytosis. Endocrinol. Jpn., 28:823-827, 1981. 39. Hamburger, J. I.: Evolution of toxicity in solitary nontoxic autonomously functioning thy1089-1093, 1979. roid nodules. J. Clin. Endocrinol. Metab., 50: 50:108~1093, 40. Hayek, A., Chapman, E. M., and Crawford, J. D.: Long-term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N. Engl. J. Med., 283:94~953, 1970. 283:949-953, 41. Hedley, A. J., Bewsher, P. D., Jones, S. J., et al.: Late onset hypothyroidism after subtotal thyroidectomy for hyperthyroidism: Implications for long term follow-up. Br. J. Surg., 70:740--743, 70:740-743, 1983. et al.: Long-term outcome ofhyperthy42. Hershman, J. M., Givens, J. R., Cassidy, C. E., etal.: roidism treated with antithyroid drugs. J. Clin. Endocrinol. Metab., 26:803-807, 1966. 43. Heyma, P., Larkins, R. G., Higginbotham, L., et al.: D-propranolol and dl-propranolol I-thyroXine to 1-triiodothyronine. I-triiodothyronine. Br. Med. J., 3:24-25, both decrease conversion of I-thyroxine 1980. 44. Hoffman, D. A., McConahey, W. M., Diamond, E. L., et al.: Mortality in women hyperthyroidism. Am. J. Epidemiol., 115:243-254, 1982. treated for hyperthyroidislll. 45. Holm, L. E., Dahlqvist, I., Engs, M., et al.: Malignant thyroid tumors after iodine-131 303:18~219, therapy: A retrospective cohort study. N. Engl. J. Med., 303: 188-219, 1980. 46. Holm, L. E.: Changing annual incidence of hypothyroidism after iodine-131 therapy for J. Nucl. Med., 23:108-112, 23:1O~1l2, 1981. hyperthyroidism, 1951-1975. J. 47. Jansson, R., Dahlberg, P. A., Johansson, H., et al.: Intrathyroidal concentrations of J. Clin. Endocrinol. Metab., 57:12~ 57:129methimazole in patients with Graves' disease. J. 132, 1983. 48. Kampmann, J. P., Johansen, K., Hansen, J. M., et al.: Propylthiouracil in human milk: Revision of a dogma. Lancet, 2:736-738, 1980. 49. Kleinmann, R. E., Vagenakis, A. G., and Braverman, L. E.: The effect of iopanoic acid euthyrOid subjects. J. Clin. Endocrinol. on the regulation of thyrotropin secretion in euthyroid Metab., 51:399--403, 51 :399-403, 1980. 50. Klementschitsch, P., Shen, K., and Kaplan, E. L.: Reemergence of thyroidectomy as treatment for Graves' disease. Surg. Clin. North Am., 59:35-44, 59:35--44, 1979. 51. Larsen, P. R., Silva, J. E., and Kaplan, M. M.: Relationships between circulating and intracellular thyroid hormones: Physiological and clinical implications. Endocr. Rev., 2:87-102, 1981. 52. Lee, T. C., Coffey, R. J., Currier, B. M., et al.: Propranolol and thyroidectomy in the treatment of thyrotoxicosis. Ann. Surg., 195:766-773, 1982.

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53. Ludgate, M. E., McGregor, A. M., Weetman, A. P., et al.: Analysis ofT cell subsets in Graves' disease: Alterations associated with carbimazole. Br. Med. J., 288:526--530, 288:526-530, 1984. 131 1 54. Lundell, G., Holm, L. -E., Ljunggren, J. -G., et al.: Incidence of hypothyroid after 131 therapy for hyperthyroidism: Relation to pretherapy serum levels ofT3, T4 and thyroid antibodies. Acta Radiol., 20:225-230, 1981. 55. Mackin, J. F., Canary, J. J., and Pittman, C. S.: Thyroid storm and its management. N. Engl. J. Med., 291:1396-1398, 1974. 56. Marchant, B., Alexander, W. D., Lazarus, J. H., et al.: The accumulation of 35S-antithyroid drugs by the thyroid gland. J. Clin. Endocrinol., 34:847-851, 1972. 57. Marchant, B., Brownlie, B. E. W., McKay-Hart, D., et al.: The placental transfer of propylthiouracil, methimazole and carbimazole. J. Clin. Endocrinol. Metab., 45:11871193, 1977. 58. McCarroll, A. M., Hutchinson, M., McAuley, R., et al.: Long-term assessment of children exposed in utero to carbimazole. Arch. Dis. Child., 51 :532-536, 1976. 59. McDermott, M. T., Kidd, G. S., Dodson, Jr., L. E., et al.: Radioiodine-induced thyroid storm: Case report and literature review. Am. J. Med., 75:353-359, 75:35~359, 1983. 60. McGregor, A. M., Petersen, M. M., McLachlan, S. M., et al.: Carbimazole and the autoimmune response in Graves' disease. N. Engl. J. Med., 303:302-307, 1980. 61. Mestman, J. H., Manning, P. R., and Hodgman, J.: Hyperthyroidism and pregnancy. Arch. Intern. Med., 134:434-439, 1974. 62. Milham, Jr., S., and Elledge, W.: Maternal methimazole and congenital defects in children. Teratology, 5:125-126, 1972. 63. Nabil, N., Miner, D. J., and Amatruda, J. M.: Methimazole: An alternative route of administration. J. Clin. Endocrinol. Endocrino!. Metab., 54:180-181, 54:18(}-181, 1982. Gorman, C. C.A.: 64. Robertson, J. S., and Corman, A.: Gonadal radiation dose and its genetic significance Nue!. Med., 17:826-835,1976. 17:826-835, 1976. in radioiodine therapy of hyperthyroidism. J. Nucl. 65. Romaldini, J. H., Bromberg, N., and Werner, R. S., et al.: Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthy57:56~570, 1983. roidism. J. Clin. Endocrinol. Metab., 57:563-570, 66. Ross, D. S., Daniels, G. H., De Stefano, P., et al.: Use of adjunctive potassium iodide 31 (131 after radioactive iodine (1 1) treatment of Graves' hyperthyroidism. J. Clin. Endocrino!. Metab., 57:250-253, 57:25(}-253, 1983. nol. 67. Ross, D. S., Ridgway, E. C., and Daniels, G. H.: Successful therapy of solitary toxic 131 1 therapy with low prevalence of hypothyroidthyroid nodules: Relatively low dose 131 :488-490, 1984. ism. Ann. Intern. Med., 101 :488--490, 1311 therapy 68. Roudebush, C. P., Hoye, K. E., and DeGroot, J. J.: Compensated low-dose 131 of Graves' disease. Ann. Intern. Med., 87:441-443, 1977. 69. Safa, A. M., Schumacher, O. P., and Rodriguez-Antunez, A.: Long-term follow-up re- . 31 suIts in children and adolescents treated with radioactive iodine (1 (131 sults 1) for hyperthyroidism. N. Engl. J. Med., 292:167-171, 1975. 70. Saunders, J., Hall, S. E. H., Crowther, A., et al.: The effect of propranolol on thyroid hormones and oxygen consumption in thyrotoxicosis. Clin. Endocrinol., 9:67-72, 1978. 71. Sawers, J. S. A., Toft, A. D., Irvine, W. J., et al.: Transient hypothyroidism after iodine131 treatment of thyrotoxicosis. J. Clin. Endocrinol. Metab., 50:226-229, 1980. 72. Schimmel, M., and Utiger, R. D.: Thyroidal and peripheral production of thyroid hormones: Review of recent findings and their clinical implications. Ann. Intern. Med., 87:76(}-768, 1977. 87:760-768, 1311 therapy for hyperthyroidism in the 73. Stoffer, S. S., and Hamburger, J. I.: Inadvertent 131 first trimester of pregnancy. J. Nucl. Med., 17:146-149, 1976. auto immune thyroid 74. Strakosch, C. R., Wenzel, B. E., Row, V. V., et al.: Immunology of autoimmune Eng!. J. J. Med., 307:1499-1507, 1980. diseases. N. Engl. 75. Sugrue, D., McEvoy, M., Feely, J., et al.: Hyperthyroidism in the land of Graves: Results of treatment by surgery, radio-iodine and carbimazole in 837 cases. J. Med., 49:51-61, 1980. 76. Sugrue, D., and Drury, M. I.: Hyperthyroidism complicating pregnancy: Results of Ob stet. Cynecol., Gynecol., 87:970-975, 87:97(}-975, treatment by antithyroid drugs in 77 pregnancies. Br. J. Obstet. 1980. 77. Tamagna, E. I., Levine, G. A., and Hershman, J. M.: Thyroid-hormone concentrations after radioiodine therapy for hyperthyroidism. J. Nucl. Med., 20:387-391, 1979.

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