TREATMENT OF HYPERTHYROIDISM WITH RADIOACTIVE IODINE

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TREATMENT OF HYPERTHYROIDISM WITH RADIOACTIVE IODINE Michael M. Kaplan, MD, Donald A. Meier, MD, and Howard J. Dworkin, MD

Radioactive iodine (RAI) therapy for hyperthyroidism was first used in 1941 by physicians at Massachusetts General Hospital in Boston.7,58 The first nuclide used was I3OI, which has a half-life of 12.4 hours. In 1946, I 3 l I became readily available from the Oak Ridge National Laboratory in Tennessee as a spin-off of atomic energy research conducted during World War 11. The relatively low cost convenient half-life of 8 days and the effectiveness of treatment of hyperthyroidism with l3II rapidly led to its widespread adoption. It has become one of the standard therapies for hyperthyroidism and is now used throughout the world. Attempts have been made to use another isotope, 1251, for the treatment of hyperthyroidism in the hope of avoiding subsequent long-term hypothyroidism; however, it has no advantage over I3lI. The properties of 1231that make it excellent for thyroid imaging-a short half-life, an appropriate gamma radiation emission energy, and a low radiation dose delivered to the thyroid gland-also make it ineffective for the ablation of thyroid tissue. Thus, only I3'I is currently used for ablative thyroid therapy, both for hyperthyroidism and thyroid cancer. SELECTION OF PATIENTS FOR THERAPY Physiologic Considerations: Uptake of Radioactive Iodine

A prerequisite for RAI therapy is adequate thyroidal uptake of the isotope. Diseases appropriate for RAI treatment are Graves' disease, toxic autonomous nodules, and toxic multinodular goiters. Thyroid ablation is not indicated for

From the Department of Nuclear Medicine (MMK, DAM, HJD) and the Division of Endocrinology (MMK), Department of Internal Medicine (MMK, HJD), William Beaumont Hospital, Royal Oak, Michigan

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 27 * NUMBER 1 * MARCH 1998

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central [thyrotropin (TSH)-dependent] hyperthyroidism and for patients with other causes of hyperthyroidism who have low RAI uptakes. Conventionally, a 24-hour thyroid RAI uptake is measured using either l 3 I I or IZ3I. However, shorter measurement times can be used, and the 24-hour thyroid RAI uptake can be predicted with reasonable accuracy from a 5- to 6hour value.% A short uptake time allows the uptake test and I3lI therapy to be performed in a single day, a great convenience to the patient who must travel a long distance to the clinic or who would otherwise have to miss an extra day of work. Any patient who is a candidate for RAI therapy, even one with obvious Graves' disease, should undergo an RAI uptake test within a few days of (and preferably immediately before) receiving a therapeutic I3'I dose, because some patients are found to have blocked uptake. This is presumably caused by exposure to large amounts of stable iodine, the source of which cannot always be identified. When a very low uptake is encountered, it sometimes rises back to normal or high levels after a few weeks. However, some types of iodine exposure, such as from amiodarone treatment or retained contrast material after lymphangiography or myelography, may block thyroidal RAI uptake for months or years. The uptake is sometimes in the normal range but suboptimal for effective 13*1 treatment, especially in patients with a toxic autonomous nodule or a toxic multinodular goiter. The uptake can often be significantly increased by having the patient follow a low-iodine diet for 1 or by treating the patient with a loop such as furosemide, 20 mg daily for 5 days, before the uptake study. Clinical Considerations

In the patient with one of the hyperthyroid conditions treatable with RAI, an antithyroid drug (ATD), or surgery, the choice among these treatment modalities involves clinical factors, physician preference, and patient choice. Pregnancy and breast-feeding are absolute contraindications to RAI treatment. Women who are trying to conceive should be willing to use contraception for a few months after receiving RAI. However, women who are planning to conceive more than a few months in the future are good candidates for l3]I therapy, because, during future pregnancies, such women will need either levothyroxine (L-T~)treatment, which has no adverse effects in pregnancy, or no thyroid medication. If ATD treatment is chosen, and continues to be needed during pregnancy, the dose must be monitored frequently because there are potential suppressive effects on fetal thyroid function. There is no indication that treating a hyperthyroid woman with RAI adversely affects the outcome of subsequent pregnancies. Many clinicians are hesitant to treat young patients with RAI because of concern regarding the possibility of late adverse effects of the radiation exposure. However, in many centers, teenagers and young adults in their reproductive years are treated with I3'I for hyperthyroidism, and the results in several series of young patients (summarized by Zimmerman and Lteif elsewhere in this volume) are entirely satisfactory. The clinical guidelines for hyperthyroidism published by the American Thyroid AssociationMand the American Association of Clinical endocrinologist^^^ do not include young age as a contraindication to l3lI therapy. One special situation is the young hyperthyroid patient with a single toxic adenoma, because 1311treatment will deliver a radiation dose to the extranodular thyroid tissue in a range associated with an increased risk of subsequent thyroid

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nodules.z7The authors are aware of two reported thyroid cancers in this situation and discuss this possibility with young patients with toxic autonomous nodules (and their parents) in planning treatment; often, surgical treatment is recommended. Another unusual situation is the patient with hyperthyroid Graves’ disease who also has a hypofunctioning thyroid nodule. All such nodules are evaluated by needle biopsy. Surgical management is recommended if the cytology is suspicious or positive for malignancy. 13’1 treatment is planned postoperatively if cancer is found and iodine-concentrating tissue remains, because the thyroidstimulating antibody will probably persist and can not be suppressed by L-T, treatment. With this strategy, any remaining tumor will not be exposed to an initial low dose of I3lI that might decrease the response to a subsequent postoperative ablative dose. Some older patients present with very large toxic multinodular goiters with a low enough RAI uptake that M I therapy will predictably be ineffective. Occasionally, it is possible to reduce the patient’s internal pool of stable iodine by administering a loop diuretic or low-iodine diet and to raise the RAI uptake enough to consider 1311 treatment. Dosimetry considerations for such patients are discussed later in this article. However, the RAI uptake can not always be improved sufficiently, necessitating another type of treatment. Another clinical factor that must be considered is whether the patient may be at an increased risk for complicated thyrotoxicosis, either in the form of thyroid storm or lesser complications that can still cause substantial morbidity and that sometimes require hospitalization. For such patients, the safest strategy may be definitive therapy with a relatively high dose of 1311after brief pretreatment with an ATD with or without a beta-blocker when necessary (and possible), followed by ATD therapy starting about 2 to 3 days after the I3lI. Sherman and c o - ~ o r k e r shave ~ ~ identified risk factors for complicated thyrotoxicosis. Among them are pre-existing heart disease or neuropsychiatric disease; no medical insurance or Medicaid insurance; fair, poor, or no compliance with prescribed antithyroid medication; and a serum T, concentration more than twice the upper limit of normal. Physician Preference Physicians’ attitudes toward the available treatments for hyperthyroidism vary systematically in different parts of the 49, 66, 71 During the 1980s, there seems to have been a liberalization of the attitude of members of the American Thyroid Association concerning RAI treatment of hyperthyroid young adults.19,66 The majority of members who responded to a 1988 to 1989 survey preferred RAI (with or without ATD pretreatment) as the primary therapy for hyperthyroidism in eight of nine clinical scenarios, the exception being a 19year-old patient.66Even in the latter case, 33% of the respondents selected RAI as the preferred primary treatment. Thyroid specialists in some other parts of the world restrict their use of RAI therapy to a much greater degree than is the current practice in North America.z6,49, 71 Patient Choice

The other important determinant in the decision to use RAI versus surgical or ATD treatment in hyperthyroidism is the patient’s (or parent or guardian’s) preference. Patients should be informed about the potential risks associated with

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all of the treatment modalities, the risks of untreated hyperthyroidism, and the possibility of a remission if they have Graves’ disease. They should be told that all three treatments are medically acceptable unless a contraindication exists to one or more. For some patients, the concept of deliberately eliminating a bodily organ is distasteful; for others, the probable need for lifelong thyroid hormone treatment is troublesome; and, for yet others, the available studies do not convince them that RAI treatment is safe. Such patients (or parents) will generally choose ATD treatment in the hope that it will be associated with a remission of the Graves’ disease. The rare patient will be unwilling to accept either RAI or the risks of side effects of ATD treatment and will choose surgery. The authors believe that it is appropriate for patients to be given their choice of therapy, and that the pros and cons of all three treatments should be presented to the patient and documented. Comparison of Treatment Modalities for Hyperthyroidism

Table 1 presents the authors’ assessment of the advantages and disadvantages of RAI, ATD, and surgical therapy for hyperthyroidism. Table 1. COMPARISON OF TREATMENT MODALITIES FOR THE

CORRECTION OF HYPERTHYROIDISM Treatment 1311

Advantages

Disadvantages

Definitive, safe, simple; predictable outcome

Lifelong L-T~ treatment usually needed; unsuitable in pregnant patients and nursing mothers Side effects; low long-term remission rate; more frequent visits needed

Antithyroid drugs

May avoid need for lifelong medication

Surgery

Definitive, rapid; eliminates large nodular goiters

Expensive; requires general anesthesia and hospitalization; risk of recurrent nerve or parathyroid damage; outcome dependent on surgeon’s expertise; lifelong L - T treatment ~ usually needed

Particularly Suitable for

Most patients

Pretreatment before RAI; pregnant patients; patients afraid of radiation exposure; young patients with mild disease and small goiter Young patients with toxic autonomous nodules; pregnant patients not controlled by, or allergic to, ATD; large multinodular goiters with low RAI uptake; patients with coexistent suspicious nodules; patients who refuse other treatments

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PRETREATMENT WITH ANTITHYROID DRUGS BEFORE RADIOIODINE THERAPY Opinions vary as to which patients need pretreatment before 1311 administration. RAI therapy sometimes produces a radiation thyroiditis and follicular disruption, with release of stored thyroid hormone into the circulation?', 70 Thyroiditis peaks between 10 and 14 days after dosing,1° resulting in an occasional patient who experiences worsening of hyperthyroid symptoms. There have been rare cases of thyroid storm occurring after RAI thera~y.4~ Accordingly, elderly patients and patients with pre-existing heart disease, fever, severe systemic illness, or debility should generally be pretreated with a thiourea ATD, either methimazole or propylthiouracil, to deplete thyroid hormone stores and 13, 22 to avoid exacerbation of thyrotoxic~sis.~, The decision to pretreat other hyperthyroid patients before radioiodine therapy is controversial. Becker and Hurley5 advise pretreating older patients and those with complicating illnesses. Mechanick and D a v i e ~believe ~ ~ that all patients should be rendered euthyroid prior to RAI therapy. W a r t ~ f s k ytends ~~ to treat all patients initially with ATD, and FranklynZ3treats most patients with either ATD or a beta-blocker before RAI therapy. In the authors' experience, RAI therapy causes no problems for most patients, and only elderly patients with cardiac or other severe nonthyroid diseases and those with very severe thyrotoxic symptoms need ATD pretreatment. Patients in whom thyrotoxic symptoms are bothersome can be treated with beta-blockers until radioiodine has a clinical effect. Depending on gland size and the dose of radioiodine, this often occurs within 3 to 4 weeks. Long-acting propranolol, 80 to 160 mg/day, or atenolol, 50 to 150 mg/day, can be employed, but larger doses may be necessary in more severely symptomatic patients. In patients rendered euthyroid with ATD before radioiodine therapy beta-adrenergic blockers are usually not necessary, especially if the ATD is resumed after I3'I is administered. Because both propylthiouracil and methimazole act by inhibiting thyroperoxidase-mediated iodination, they must be discontinued for at least 3 days, including the time for a 24-hour RAI uptake, before I 3 l I administration. ATDs can be resumed 2 to 3 days later, if needed. Most investigators have reported that pretreatment with an ATD results in relative radioresistance, necessitating a larger dose of l3II than would otherwise be s e l e ~ t e d . ~ This , ' ~ , may ~ ~ relate to a very short biologic half-life of 13'T because of thyroidal iodine depletion from the ATD, with a small iodine pool and rapid t u r n ~ v e r .Cooper14 ~ recommends that the RAI dose be increased by 25% in patients given an ATD before RAI therapy, and the authors concur with this suggestion. DOSE SELECTION Despite more than 50 years' experience with RAI therapy, no unanimity exists regarding dose selection, although certain guidelines have become generally accepted. It is useful to consider the criteria for dose selection separately for Graves' hyperthyroidism and toxic nodular goiter. However, regardless of the manner in which the 13'1 dose is chosen, or which cause of hyperthyroidism is being treated, hypothyroidism can occur weeks, months, or years after RAI treatment. Each patient (or his or her parents or guardians) should clearly understand this before therapy, along with the logical implications that lifelong L-T, treatment may be necessary, and that lifelong follow-up evaluation will be

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needed to monitor thyroid function or L-T, dose. This disadvantage of RAI treatment must be considered in the context of observations that the health and quality of life of patients taking L-T, for iatrogenic or spontaneous hypothyroidism are no different from those of the general Five approaches to dose selection in patients with Graves’ disease have been employed: (1) small doses repeated as necessary, (2) a large ablative dose, (3) a ”sliding scale” based on thyroid size, (4) a standard formula for administered dose based on estimated thyroid size, and (5) precise dosimetry for the administered In addition, Becker and Hurley5have championed a method based on radiation dose delivered to the thyroid in grays or rads. The high incidence of ultimate hypothyroidism after RAI therapy for Graves’ disease has been the stimulus for an ongoing search for improved methods of dose selection. Eventual hypothyroidism was recognized in the early 1960s when Chapman’s group showed a 20% to 40% incidence of hypothyroidism 1 year after RAI therapy and a subsequent incidence of approximately 2.5% per year resulting in hypothyroidism in 50% to 80% of patients after 10 yearsz9In the 1971 Thyrotoxicosis Follow-up Study of 11,000 patients with Graves’ disease treated with a single dose of I3*I and followed up for a mean period of 7.5 years, a 35% incidence of hypothyroidism was found. After the first 2 years, the rate of hypothyroidism was 3% per year.6The diagnosis of hypothyroidism was established by clinical findings and protein-bound iodine determinations; certainly, a much higher incidence of hypothyroidism would have been found by sensitive TSH testing. Members of the University of Chicago Thyroid Group were early proponents of a low-dose 1311 protocol designed to take into account the higher doses needed by larger thyroid glands.17A sliding scale based on gland size resulted in retained doses at 24 hours ranging from 1.48 MBq (40 pCi) per gram for glands weighing 10 to 20 g to 3.7 MBq (100 pCi) per gram for glands weighing more than 100 g. After 1 year, 10%of patients were hypothyroid, 60% euthyroid, and 30% still hyperthyroid. Thus, approximately 30%of patients required second or third doses. After 10 years, 60% were hypothyroid and 40% e~thyr0id.l~ These workers have subsequently employed a moderate-dose protocol which doubles the 1311 dose retained. Impressed by the high incidence of eventual hypothyroidism, some therapists have proposed a high initial l3II dose, anticipating hypothyroidism in a 78 matter of months and planning prompt initiation of replacement lev~thyroxine?~, This approach can simplify follow-up for some patients but will also result in an unnecessarily high radiation burden for others. The most common method of dose determination employs a formula based on estimated thyroid size and 24-hour RAI uptake but does not take into account the biologic half-life of the radioiodine, which can vary widely. The administered dose in MBq or mCi is given according to the formula: MBq

kBq (desired)/g =

X

gland weight (g)

70uptake a t 24 hours

X

10

or mCi

=

pC1 (desired)/g

X

gland weight (8)

% uptake at 24 hours x 10

Recommendations for the desired dose per gram of tissue vary widely, as shown in Table 2. Cooper14suggests 2960 to 4440 kBq/g (80 to 120 pCi/g), which generally results in doses of 185 to 555 MBq/g (5 to 15 mCi/g) and a radiation dose of 50 to 100 Gy (5000 to 10,000 rad). Becker and Hurley5 suggest doses of 2030 to 2960 kBq/g (55 to 80 pCi/g) for the usual patient, resulting in radiation doses of 50 to 70 Gy (5000 to 7000 rads). To minimize the duration of symptoms, they propose larger doses per gram of tissue of 5920 to 7400 kBq (160 to 200 pCi) in severely hyperthyroid patients or in patients with underlying cardiac d i ~ e a s eSuch . ~ patients should generally be pretreated with ATD.

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Table 2. RECOMMENDED Y DOSAGE SCHEDULES FOR HYPERTHYROIDISM Desired l3lI Dose/g* Source

kBq

pCi

Cooper14 Becker and Hurley5 Usual patient Severely hyperthyroid or cardiac patient Authors Thyroid size 50 g or less 50 to 80 g More than 80 g

2960-4440

80-1 20

2040-2960 5920-7400

55-80 160-200

3700-4440 5550-6 480 7400

100-1 20 150-1 75 200

’The values in this table are for use in conjunction with the formula listed in the text

The authors attempt a one-dose cure with 13*1 to minimize the duration of the hypothyroidism and the frustration, morbidity, and expense associated with repeat doses. This is accomplished by using desired dose per gram values in the previous formula that are based on thyroid size as shown in Table 2. Using these guidelines, approximately 95% of patients are cured of hyperthyroidism with one RAI dose, and less than 1%require more than two doses. Most become hypothyroid within 3 months. Virtually all patients who received three doses had very large goiters and were treated as outpatients with less than 1.1 GBq (30 mCi). In the United States, recent changes in Nuclear Regulatory Commission (NRC) rules now allow outpatient I3II doses greater than 1.1 GBq (30 mCi). Practitioners in countries with more restrictive policies will have difficulty following the authors’ recommendations. Investigators at various centers are attempting more precise dosimetry in comparison with the current methods of estimating thyroid size by palpation and estimating the biologic half-life of the RAI by a single 24-hour uptake. Thyroid volume can be accurately measured by Bockisch and coworkers9 developed an elegant technique for precise dosimetry and showed that late RAI uptake measurements at 96 or 192 hours accurately predicted cumulative activity. Several groups have used repeated RAI uptakes to determine more precisely the effective 1311 half-life.” Others have suggested that thyroidstimulating antibody activity may help in dose selection?* Only long-term follow-up studies will determine whether the incidence of eventual hypothyroidism will be lowered by these techniques. Clinical experience suggests differences in radiation sensitivity in the thyroid of patients with Graves’ disease, even after volume and I3lI half-life are taken into account. Larger RAI doses are indicated in the elderly and when an initial dose has failed to render the patient euthyroid. Patients pretreated with ATD need approximately a 25% increase in administered dose, and patients with large goiters need large doses. Variables such as the degree of cell differentiation and the phase of the cell cycle affect radiation sensitivity in some cell types, but studies of such factors in thyroid cell systems are lacking. The combined effects of ATD pretreatment and large goiter size on RAI responsiveness are illustrated by the case records of a 43-year-old woman with a large (80 g) toxic diffuse goiter who presented with severe hyperthyroidism including severe vomiting. The patient was pretreated with propylthiouracil which was subsequently interrupted for 3 days. The 24-hour RAI uptake was

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45%, and the patient was treated with 1.07 GBq (28.9 mCi) of 1311[5.99 MBq/g (162 pCi/g)]. Three months later, the patient was still hyperthyroid with an estimated gland size of 60 g. The 24-hour RAI uptake was now 62%, and she was given another 1.1 GBq (29.9 mCi) of I3lI (11.43 MBq or 309 pCi/g). Three months after this second dose, the thyroid size was 20 g, the free T4 was borderline high, and the TSH was still low. Six months later, the patient was clinically and biochemically euthyroid. Undermining all of the techniques for dose selection is the natural history of autoimmune thyroid disease, wherein hyperthyroidism from Graves’ disease can culminate in hypothyroidism without any ablative therapy because of coexistent Hashimoto’s t h y r ~ i d i t i s .Cooper ~~ points out in his article on p. 225 of this issue that in 5% to 20% of patients treated only with ATD, spontaneous hypothyroidism develops. For patients with toxic multinodular goiters and solitary toxic autonomous thyroid adenomas, different principles apply. Because I3’I is concentrated in the autonomously functioning nodules, the suppressed extranodular tissue receives far less radiation. When the TSH normalizes after RAI therapy, the previously suppressed extranodular tissue regains normal function. These toxic nodular 14, 31, 47, 39 The authors rarely give a dose less goiters require larger doses of than 740 MBq (20 mCi), and significantly larger doses are often necessary depending on gland size and RAI uptake, which tends to be much lower than in Graves’ hyperthyroidism. Doses ranging from 1.1 to 2.77 GBq (30 to 75 mCi) are not uncommonly required. Concern has been expressed about possible airway compromise from swelling owing to acute radiation thyroiditis when very large goiters are treated. Hamburger and Hamburger3’ treated 35 patients with toxic multinodular goiters estimated at 100 g or more with doses ranging from 0.925 to 7.4 GBq (25 to 200 mCi), attempting to deliver 7.4 MBq/g (200 pCi/g), and encountered no 40 reported that large doses of RAI complications. Huysmans and were effective and safe in 19 elderly patients with multinodular goiters larger than 100 g which were already causing tracheal compression. Twelve patients had dyspnea and stridor. Fifteen were euthyroid, and four hyperthyroid. RAI was given intravenously at a dose of 3.7 MBq (100 pCi) per gram (2.6 ? 1.0 GBq or 70 ? 28 mCi). Measurements obtained on MR imaging showed a mean thyroid volume reduction of approximately 40% after 1 year and of 50% to 60% after 3 to 5 years. The smallest cross-sectional area of the tracheal lumen increased 36%? 38% at 1 year. No complications were encountered. In the total series of approximately 80 patients with large compressive nodular goiters treated for volume reduction, no clinically relevant exacerbations of compressive symptoms have been seen. It can be concluded that large doses of RAI are generally safe and often effective in the management of large toxic multinodular goiter. Because this type of goiter usually occurs in an elderly patient, pretreatment with ATDs should be employed until the patient is completely euthyroid. The outcome in a patient treated by the authors is a dramatic example of the safety and efficacy of large-dose RAI therapy. An 80-year-old man presented with hyperthyroidism, including a 30-pound weight loss, atrial fibrillation with a ventricular rate of 108 beats per minute, and the largest goiter two of the authors (DAM, MMK) have ever seen, about 250 to 300 g (Fig. 1). The patient reported that the goiter had been present for 60 years. After propylthiouracil treatment for 9 months, necessitated by several nonthyroidal medical problems, the patient was treated with 7.51 GBq (203 mCi). No symptoms of radiation thyroiditis or tracheal compromise occurred. Propylthiouracil was tapered over 3 more months. Seven months after RAI therapy, free T, and TSH levels were

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Figure 1. A, Patient with massive toxic rnultinodular goiter before i311 treatment. 8,The same patient 1 year after treatment with 203 rnCi of j3'I, showing a marked decrease in the size of the left thyroid lobe. The persistent nodule in the right lobe has low, irregular tracer uptake on imaging studies, suggesting extensive degeneration.

normal; and 1 year after therapy, the estimated gland size was 80 to 100 g (Fig. 1). Treatment with RAI for a large toxic multinodular goiter with a relatively low RAI uptake will not always control the patient's hyperthyroidism and may take a long time to exert its full effect. If the patient with this type of goiter does not have an unusual risk for surgical or anesthetic complications, thyroid surgery may be the preferred treatment. RADIATION SAFETY CONSIDERATIONS AFTER TREATMENT WITH RADIOIODINE

In the United States, persons handling radioiodine must be licensed by the NRC. For many years, NRC rules have mandated that patients treated with

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more than 30 mCi (1.1GBq) of 13’1 be hospitalized in a shielded room to minimize radiation exposure to others. Although no new scientific data have been reported, a more recent analysis by the NRC has determined that it is safe to release patients from hospital confinement after the administration of radioactive materials when the whole-body burden of 1311is greater than 30 mCi.73,74 Perhaps this appreciation of safety for those persons near a radioactive patient derives, in part, from the lack of untoward events in the patients themselves, whose radiation exposure is much greater than that of persons around them. The NRC regulatory reanalysis was initiated in response to petitions by licensees for rule changes. ”Based on this analysis, the decision was made that adoption of the 5 millisievert (0.5 rem) limit is consistent with” the previous published NRC regulatory code and the recommendations of the International Commission on Radiological Protection. “A benefit is in reduced hospital stays that provide emotional benefits to patients and their families and result in lower health care costs.’’n Because the previous 30-mCi rule for 1311 hospitalization in the United States is no longer in effect, the NRC licensee may authorize the release of any patient who has been given a radiopharmaceutical containing 13’1if, ”the total effective dose equivalent to any other individual from exposure to the released individual (the patient) is not likely to exceed 5 millisieverts (0.5 rem). It is required that the patient must be provided with written instructions on actions recommended to maintain doses to others as low as reasonably achievable if the total effective dose equivalent to others is likely to exceed 1 millisievert (0.1 rem).”74Patients receiving less than 7.0 mCi (259 MBq) of I3’I need no instructions. A licensee must maintain records for 3 years in most instances.74The NRC Regulatory Guide contains formulas and tables to assist in the application of the details.74 A questionnaire to be filled out by the patient prior to l 3 I I therapy is suggested as a reasonable way to determine habits and home living conditions. This becomes a decision-making tool for the physician, as well as a record of compliance with the regulations. The NRC Regulatory Guide should be reviewed in detail by all NRC licensees.74 The guidelines for precautions that patients are asked to follow for the first few days after 1311 therapy deal with activities of daily life-physical contact with others, especially pregnant women and small children; whether, and for how long, to sleep in a separate bed; bathroom practices; the handling of household items often used by more than one person, such as eating utensils, bed linens, towels, and washcloths; and maintaining a high fluid intake to increase urinary iodine e ~ c r e t i o n Each . ~ ~ NRC licensed institution may develop its own post-RAI therapy patient instructions. The authors currently use the following precautions, which fulfill the new regulations as judged by the health physicists at their hospital. 1. Avoid close contact with children and pregnant women for at least the first 2 days. An occasional hug is not harmful, but prolonged contact is discouraged. 2. Maintain a prudent distance from others for at least the first 2 days (e.g., two arm lengths or approximately 6 feet). 3. Sleep alone in a separate room for at least the first night. 4. Do not travel by airplane or mass transportation for at least the first day. 5 . Do not travel on a prolonged automobile trip (more than 2 hours at a time) with others for at least the first 2 days. 6. Have the sole use of a bathroom for at least the first 2 days. If this is not possible, clean the bathroom when finished. Any observed body fluids should be wiped up with a tissue and flushed down the toilet.

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Rinse the sink after use. Continue to maintain good bathroom hygiene for 3 days. 7. Flush the toilet three times after each use for at least the first 2 days. 8. Use separate, disposable eating utensils during the first 3 days, or wash eating utensils and dishes in a dishwasher before others use them during this time. 9. Avoid mouth-to-mouth contact. Keep items that contact the mouth (e.g., toothbrush, glass) from use by other individuals for 3 days. 10. Clothing worn directly in contact with the skin during the first 3 days after the therapy dose should be laundered separately before reuse. 11. For answers to any questions about the precautions, medical complications, or other concerns, contact the Nuclear Medicine Department at (department phone number). NRC regulations do not explicitly forbid breast-feeding but clearly imply that it should be stopped or interrupted for many weeks. In agreement with the Society of Nuclear Medicine65and the European Thyroid Association,2a the authors inform nursing women who are to be treated with I3’I that they must finish the weaning process before RAI therapy. PATIENT FOLLOW-UP AFTER RADIOIODINE THERAPY FOR HYPERTHYROlDlSM

The optimal schedule for follow-up visits in the first 3 months after RAI therapy depends on the patient’s overall condition and the I3’I dosing philosophy. When the relatively high, size-based doses in Table 2 are used, the authors see patients for re-evaluation 6 and 12 weeks afterward if they are not taking ATD and 4, 8, and 12 weeks after therapy if patients are taking ATD or are otherwise fragile. Patients are asked whether they have noticed any change in thyrotoxic symptoms, in the amount of swelling in the neck, in vision, eye comfort, and eye appearance, and whether symptoms have appeared suggesting hypothyroidism. The symptoms most suggestive of hypothyroidism in this setting are muscle cramps, heavy menstrual bleeding, constantly feeling cold, and constipation; however, these symptoms, even in combination, are not completely reliable. The most pertinent aspects of the physical examination are assessments of whether the patient’s weight, thyroid size, or eye findings have changed, and whether tremor, tachycardia, or abnormally brisk reflexes that were present prior to therapy are improving. A distinct decrease in thyroid size at the 6-week checkup is a fairly reliable sign that RAI treatment will be successful, even if blood levels of thyroid hormone are still high. For patients taking ATDs after RAI therapy, the decision to reduce the dose or stop the medication is individualized at the 4-, 8-, and 12-week follow-up visits, according to the clinical and laboratory findings. In patients not taking an ATD, if serum levels of thyroid hormone 6 weeks post-RAI therapy are low or in the lower half of the normal range, L-T~ therapy is started even if the TSH level is still suppressed. In many patients, the TSH level may not rise above treatment, despite low free T4 and T, normal until about 12 weeks after levels and hypothyroid symptoms that begin several weeks earlier.75Although in some of these patients L - T ~ must be discontinued, the great majority continue to need it and would otherwise become hypothyroid within the next several weeks. Patients with ophthalmopathy might be at greater risk for adverse eye changes if they become significantly hypothyroid. If serum levels of thyroid

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hormone are in the upper half of the normal range or are still elevated, the authors do not start L-T., treatment, and the patient is instructed to return in another 6 weeks. The symptoms suggestive of hypothyroidism are reviewed, and the patient is told to inform us if these symptoms develop before a scheduled revisit so that he or she can be seen promptly. Some patients who remain hyperthyroid 6 weeks after RAI treatment are distinctly hypothyroid 3 to 5 weeks later. Patients who are euthyroid 12 weeks after RAI treatment are instructed to return 2 to 3 months later, depending on thyroid size, symptoms, and whether the results of blood tests are high-normal, mid-normal, or low-normal. If the patient is still euthyroid 5 to 6 months after RAI treatment, he or she is asked to return about 1 year post-RAI therapy, with a reminder to call for instructions if symptoms develop that are suggestive of hypothyroidism. Patients who remain hyperthyroid at the 12-week evaluation can be considered for retreatment with l3II. If they have few or tolerable symptoms, observation for another 1 to 3 months is appropriate, because there can be some additional improvement in thyroid function. However, if the serum levels of thyroid hormone are substantially elevated, symptoms remain troublesome, and the thyroid gland is still significantly enlarged, a second treatment 3 months after the initial treatment is often appropriate. If borderline or mild hyperthyroidism remains 3 to 6 months after the initial I3'I treatment, the patient may be treated with inorganic stable iodine, such as Lugol's solution (strong iodine solution USP, containing about 8 mg of iodine per drop), 3 drops by mouth in a glass of water once daily, or with saturated solution of potassium iodide (SSKI) (potassium iodide oral solution USP containing about 50 mg of iodine per drop), one drop by mouth in a glass of water once daily. Patients who have been treated with RAI are much less likely to escape from the antithyroid effects of stable iodine in comparison with patients who have not received RAI. After stable iodine treatment for 6 to 12 months, the medication is discontinued, and many of these patients remain euthyroid. Treatment for 6 to 12 months with a low-dose ATD can also be considered in this setting, although the chances of allergic reactions are probably less with stable iodine. Inorganic stable iodide is not useful immediately after RAI treatment, because escape from the acute antithyroid effect is common.59 Occasionally, patients who become euthyroid or hypothyroid promptly will subsequently recover some thyroid function.', 57 Those who have been started on L - T ~treatment may be able to stop it. Other patients may have recurrent hyperthyroidism. The frequency of this rebound of thyroid function depends in part, on the method of I3'I dose selection; higher doses make recovery of function less likely. The authors believe that the size of the thyroid gland 3 to 6 months after RAI treatment may be a predictive variable; the larger the thyroid remnant, the more likely function will recover.

SIDE EFFECTS OF RADIOIODINE THERAPY Carcinogenesis

The greatest concern regarding the use of RAI treatment for hyperthyroidism has been the possibility of carcinogenesis. After more than 50 years of using RAI for the diagnosis and treatment of hyperthyroid patients and despite many published series of cases and literature reviews, no clear consistent cause-

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and-effect relationship has been proved between medical radioiodine use and subsequent 2 f l , 30, 36, 54 Extensive studies have shown no indication of an increase in subsequent leukemia or thyroid cancer risk in hyperthyroid patients treated with 1311. Because of observations in individual series of possible increased incidences of stomach or breast cancer, further studies are always recommended in discussions of this topic. However, studies reporting possible increased risks of one or another cancer have been beset by a lack of clear doseeffect relationships, by inconsistencies concerning which cancer might occur more often, by a lack of rigorously chosen control comparisons in nonrandomized or retrospective reviews, and by the use of l3II only in older patients in some study populations. Local Side Effects in the Thyroid Gland and Nearby Structures

Short-term side effects following the administration of 1311 for the treatment of hyperthyroidism, other than subsequent hypothyroidism, have been extremely rare.37Radiation thyroiditis of clinical significance is almost never seen, and the occasional patient with minor thyroid discomfort is easily managed with reassurance and analgesics. With adequate pretherapy care, thyroid storm is not seen. A few cases have been reported of autoimmune Graves’ disease following 1311 therapy for toxic nodular goiters and after spontaneous infarction of toxic autonomous thyroid Huysmans and c o - ~ o r k e r observed s~~ thyrotoxicosis 3 to 10 months after I3lI therapy in three of their patients treated for large nontoxic nodular goiters. Nygaard and c o - w ~ r k e r sreported ~~ the development of thyrotoxicosis 3 or more months after l3II treatment in 5% of 191 patients with nontoxic goiters. Such cases result from the MI-induced release of thyroid autoantigens, which stimulate production of TSH-receptor antibodies50that, in turn, activate the TSH receptors in the residual thyroid tissue. Patients with preexisting antithyroid antibodies seem to have an increased risk for this phenomen~n.~O There are no allergic reactions to RAI treatment, because the chemical form of the administered iodine is inorganic iodide, and the mass of iodine in a therapeutic 1311 dose of 370 MBq (10 mCi) is 0.81 pg.53This contrasts with the recommended daily allowance of 150 pg of iodine established by the Food and Nutrition Board of the US National Research Council2zand with typical dietary iodine intake levels in the United States of several hundred micrograms daily. Therefore, patients who have had reactions to organo-iodine radiocontrast agents or other organo-iodine drugs such as amiodarone and patients with seafood allergies (who are actually allergic to a protein in the seafood and not to iodine) can still be treated with RAI without the risk of an allergic reaction. There is no convincing evidence that 1311 treatment damages the parathyroid glands or other structures in the neck. Reported cases of patients with such problemsz8are so rare that the coincident extrathyroidal abnormalities are most reasonably considered chance occurrences. Fertility and Pregnancy

Effects of l3II on pregnancy remain a concern. Patients are usually advised not to become pregnant for at least 4 to 6 months post therapy, although there

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are no human data to support this advice based on gonadal radiation exposure considerations. However, infertility and first-trimester pregnancy loss can be produced by persistent hyperthyroidism or inadequately treated post-RAI therapy hypothyroidism; and, typically, 3 to 6 months are required for patients to be rendered euthyroid and stabilized with or without L-T~ after RAI treatment. Fertility is unaffected by prior I3lI therapy.56All female patients in the childbearing years should have a beta-HCG pregnancy test just prior to I 3 l I thera~y.6~ If there is any question of pregnancy, it is prudent to delay 1311therapy until the start of the next menstrual cycle and to obtain a repeat negative HCG test. The fetal thyroid begins to concentrate iodine at 10 to 12 weeks’ gestation,21,35 and 1311 given after that time may produce fetal hypothyr~idism~~ but does not always do so. The available small-scale post-RAI therapy studies have failed to find an increase in genetic or congenital If RAI therapy is administered inadvertently during pregnancy because of a false-negative pregnancy test or a procedural lapse, the following advice is appropriate. 1. The majority of children born after in utero

13*1

exposure are clinically

2. There is a chance of transient or permanent hypothyroidism. However, even if the RAI exposure occurs after the fetal thyroid begins to concentrate iodine (about 10 to 12 weeks’ gestation),the infant’s thyroid function is normal most of the time.67The infant will be checked at birth through the use of cord serum tests. Intrauterine testing by cord blood sampling (cordocentesis) could be considered. If hypothyroidism occurs, prompt institution of L-T~treatment results in normal growth and development in the great majority of cases, but close medical monitoring of the child will be needed in infancy, and lifelong L-T~ treatment may be necessary. 3. The risk to the child of other radiation-related adverse effects is small. A slightly increased risk of maIignancy or abnormal development is conceivable but has not been demonstrated. 4. If the patient would consider therapeutic abortion, this option is available to her. However, because the risks to the child are sufficiently low, the authors do not consider a medical recommendation for termination of the pregnancy to be required. 5. It is not known whether there is an increased risk of spontaneous pregnancy loss. If so, the increased risk is probably small.60,67 6. Referral to a clinical geneticist or health physicist is available if such counseling would be helpful in deciding whether to continue the pregnancy. Radioiodine Treatment and Graves’ Ophthalmopathy

A long-standing concern is whether RAI therapy might worsen or induce Graves’ ophthalmopathy. Tallstedt and LundelP recently reviewed nine articles dealing with this topic and discussed the multiple and varied shortcomings of each. Two additional studies had discordant results. Kung and colleague^^^ randomized 120 patients with newly diagnosed hyperthyroidism to l3II or methimazole therapy for 12 months. The risk for development or exacerbation of Graves’ ophthalmopathy was higher in those with no ophthalmopathy initially in comparison with those with pre-existing Graves’ ~phthalmopathy.~~ Conversely, Pinchera and colleagues,*6in a prospective and controlled study of 26

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consecutive patients, found that those with pre-existing Graves’ ophthalmopathy were more likely to have an exacerbation of the eye abnormalities after RAI in comparison with ATD, but that patients with no pre-existing Graves’ ophthalmopathy did not have new ophthalmopathy after RAI. This group and other workers3*52 have found that exacerbation of Graves’ ophthalmopathy after RAI can be prevented by the concomitant administration of glucocorticoids. Despite the persistent suspicion that Graves’ ophthalmopathy is more likely to worsen after RAI in comparison with ATD or surgical treatment of hyperthyroid Graves’ disease, the studies to date all have significant flaws. Gorman and co-workersI6 have reviewed the substantial evidence that RAI therapy does not aggravate Graves‘ ophthalmopathy. It is generally accepted that hypothyroidism after RAI therapy should be avoided; early replacement of thyroxine after lnlI seems to A randomized reduce the incidence of worsening Graves’ ~phthalmopathy.~~ prospective study underway in Sweden is comparing RAI therapy with ATD with regard to the development of ophthalmopathy.6R Recent studies show that the radiation thyroiditis following RAI therapy releases stored antigen with a resultant increase in thyroid autoantibodies.”, 15, 43 It is suggested that ophthalmopathy may be related to a cross-reactive antigen between thyroid cells and orbital fibroblasts leading to infiltration of the orbit by activated T cells.2 Release of this shared antigen may then aggravate preexisting Graves’ ophthalmopathy. This has led to re-evaluation of the 30-yearold concept that ablative doses of I3II may be helpful in patients with progressive ophthalmopathy4 by eradicating the thyroid and its possible cross-reactiving antigen. DeGroot and colleagues’6found that almost all patients with worsening ophthalmopathy after 13’1had residual nonsuppressible thyroid tissue even if they were hypothyroid and required replacement L-T,,.These investigators have now treated about 40 patients with severe eye disease after RAI therapy with one or more ablative doses of 740 to 1100 MBq (20 to 30 mCi) of l3lI and have noted a slow improvement in the ophthalmopathy, which was worsening or stable in all patients before the ablative therapy.15The potential role of ablative therapy needs to be evaluated by prospective studies. Although the benefit of ablative doses of I3’I has yet to be proven, the authors recommend that the initial dose be high enough to ensure a one-dose cure to avoid the release of additional amounts of thyroid antigens that might occur with subsequent treatments. Also unclear at this time is whether the immunosuppressive effects of ATD have a beneficial effect on ophthalmopathy. I3lI therapy can be employed in the patient with pre-existing Graves’ ophthalmopathy, but it is essential to counsel the patient that the eye findings may worsen after the hyperthyroidism is corrected, regardless of the treatment that is used. Patients with moderate-to-severe eye disease should undergo an ophthalmologic evaluation by an ophthalmologist experienced with Graves’ ophthalmopathy. It also seems prudent to avoid post-RAI therapy hypothyroidism by the judicious use of early L-T~ replacement and to consider concomitant prednisone treatment in patients with severe, or even moderate, ophthalmopathy. The initial dose of prednisone is generally 60 to 80 mg daily, and a gradual taper of the dose is started after 2 to 4 weeks. The duration of prednisone treatment is 3 to 12 months, depending on the clinical response and side effects. All of the usual glucocorticoid side effects may occur, including weight gain, peptic ulcer disease, mental changes, and glucose intolerance. Both the potential benefits of corticosteroid treatment and the possible side effects should be presented to the patient.

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SUMMARY Treatment of hyperthyroidism with RAI has been performed for more than a half century with efficacy and safety. For its optimal use, the physician must employ appropriate patient selection criteria and clinical judgment concerning pretreatment patient preparation. The dose of the I3lI needed remains an area of uncertainty and debate; thus far, it has not been possible to resolve the tradeoff between efficient definitive cure of hyperthyroidism and the high incidence of post-therapy hypothyroidism. Early side effects are uncommon and readily manageable. Other than the need for long-term monitoring and, in most cases, lifelong L-T~ treatment, late adverse consequences of this treatment remain only conjectural. The available follow-up studies support the current majority opinion of North American thyroid specialists that RAI treatment is an excellent choice for most hyperthyroid patients. ACKNOWLEDGMENT The authors thank Cheryl Culver-Schultz, Radiation Safety Officer of William Beaumont Hospital, Royal Oak, MI, for development of our radiation safety guidelines for patients.

References 1. Aizawa Y, Yoshida K, Kaise N, et al: Frequency and significance of transient hyperthyroidism after radioiodine ablation for Graves’ hyperthyroidism. Clin Endocrinol (Oxf) 46:l-5, 1997 2. Bahn RS, Heufelder AE: Pathogenesis of Graves’ ophthalmopathy. N Engl J Med 329:1468-1475, 1993 3. Bartalena L, Marcocci C, Bogazzi F, et al: Use of corticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med 321:1349-1352, 1989 4. Bauer FK, Catz B: Radioactive iodine therapy for progressive malignant exophthalmos. Acta Endocrinol 51:15-22, 1966 5. Becker DV, Hurley J R Radioiodine treatment of hyperthyroidism. In Sandler MP, Coleman RE, Wackers FJT, et a1 (eds): Diagnostic Nuclear Medicine. New York, Williams & Wilkins, 1996, pp 943-958 6. Becker DV, McConahey WM, Dobyns BM, et al: The results of radioiodine treatment of hyperthyroidism. A preliminary report of the Thyrotoxicosis Therapy Follow-up Study. In Fellinger K, Hofer R (eds): Further Advances in Thyroid Research, vol 1. Vienna, Verlage der Wiener Medizinischen Akademie, 1971, pp 603-609 7. Becker DV, Sawin CT: Radioiodine and thyroid disease: The beginning. Semin Nucl Med 26:155-164, 1996 8. Berg GEB, Michanek AMK, Holmberg ECV, et a1 Iodine-131 treatment of hyperthyroidism: Significance of effective half-life measurements. J Nucl Med 36:228-232, 1996 9. Bockisch A, Jamitzky T, Derwanz R, et al: Optimized dose planning of radioiodine therapy of benign thyroidal diseases. J Nucl Med 34:1632-1638, 1993 10. Burch HB, Solomon BL, Wartofsky L, et al: Discontinuing antithyroid drug therapy before ablation with radioiodine in Graves’ disease. Ann Intern Med 121:553-559, 1994 11. Burch HB, Wartofsky L Graves’ ophthalmopathy: Current concepts regarding pathogenesis and management. Endocr Rev 14:747-793, 1993 12. Clerc J, Izembart M, Dagousset F, et al: Influence of dose selection on absorbed dose profiles in radioiodine treatment of diffuse toxic goiters in patients receiving or not receiving carbimazole. J Nucl Med 34:387-393, 1993 13. Cooper DS: Antithyroid drugs and radioiodine therapy: A grain of (iodized) salt. Ann Intern Med 121:612-614, 1994

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therapy for Graves‘ disease: Prognostic factors and the role of methimazole. J Clin Endocrinol Metab 79:542-546, 1994 42. Lakshmanan M, Schaffer A, Robbins, et al: A simplified low iodine diet in 1-131 scanning and therapy of thyroid cancer. Clin Nucl Med 13:866-868, 1988 43. Marcocci C, Bartelena L, Bogazzi F, et al: Relationship between Graves’ ophthalmopathy and type of treatment of Graves’ hyperthyroidism. Thyroid 2171-178, 1992 44. Maxon HR, Thomas SR, Boehringer A, et al: Low iodine diet ablation of thyroid remnants. Clin Nucl Med 8:123-126, 1983 45. McDermott MT, Kidd GS, Dodson LE Jr, et al: Radioiodine induced thyroid storm: Case report and literature review. Am J Med 75:353-359, 1983 46. Mechanick JI, Davies TF: Medical management of hyperthyroidism: Theoretical and practical aspects. In Falk SA (ed): Thyroid Disease, ed 2. Philadelpha, LippincottRaven, 1997, pp 253-296 47. Meier DA, Dworkin HJ: The autonomously functioning thyroid nodule. J Nucl Med 32:30-32, 1991 48. Murakami Y, Takamatsu J, Sakane S, et al: Changes in thyroid volume in response to radioactive iodine for Graves’ hyperthyroidism correlated with activity of thyroidstimulating antibody and treatment outcome. J Clin Endocrinol Metab 81:3257-3260, 1996 49. Nagayama Y, Izumi M, Nagataki S: Management of hyperthyroidism due to Graves’ disease in Japan in 1988. Endocrinol Japan 36:299-314, 1989 50. Nygaard B, Knudsen JH, Hegedus L, et al: Thyrotropin receptor antibodies and Graves’ disease, a side-effect of I3’I treatment in patients with nontoxic goiter. J Clin Endocrinol Metab 822926-2930, 1997 51. Peterson K, Bengtsson C, Lapidus L, et al: Morbidity, mortality and quality of life for patients treated with levothyroxine. Arch Intern Med 1502077-2081, 1990 52. Prummel MF, Mourits MP, Berghout A, et a1 Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med 321:1353-1359, 1989 53. Quimby EH, Feitelberg S, Gross W Radioactive Nuclides in Medicine and Biology. New York, Lea and Feibiger, 1970, p 28 54. Saenger EL, Thoma GE, Tompkins EA: Incidence of leukemia following treatment of hyperthyroidism: Preliminary report of the Cooperative Thyrotoxicosis Therapy Follow-up Study. JAMA 205855-862,1968 55. Safa AM, Skillem PG: Treatment of hyperthyroidism with a large initial dose of sodium iodide 1-131. Arch Intern Med 135:673-675, 1975 56. Sarkar S, Beierwaltes W, Gill S, et al: Subsequent fertility and birth histories of children and adolescents treated with 1311 for thyroid cancer. J Nucl Med 1746M64, 1976 57. Sawers JSA, Toft AD, Irvine WJ, et al: Transient hypothyroidism after iodine-131 treatment of thyrotoxicosis. J Clin Endocrinol Metab 50:226-229, 1980 58. Sawin CT, Becker DV: Radioiodine and the treatment of hyperthyroidism: The early history. Thyroid 7163-176, 1997 59. Schimmel M, Utiger R D Acute effect of inorganic iodide after l3II therapy for hyperthyroidism. Clin Endocrinol ( 0 x 0 6:329-332, 1977 60. Schlumberger M, DeVathaire F, Ceccarelli C, et al: Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 37606412, 1996 61. Shafer RB, Nuttall FQ: Acute changes in thyroid function in patients treated with radioactive iodine. Lancet 263.5637, 1975 62. Shapiro B: Optimization of radiodine therapy of thyrotoxicosis: What have we learned after 50 years? J Nucl Med 34:1638-1641, 1993 63. Sherman SI, Simonson L, Ladenson PW: Clinical and socioeconomic predispositions to complicated thyrotoxicosis: A predictable and preventable syndrome? Am J Med 101:192-198, 1996 64. Singer PA, Cooper DS, Levy EG, et al: Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 273808-812, 1995

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65. Society of Nuclear Medicine: Guidelines for Patients Receiving Radioiodine Treatment. New York, Society of Nuclear Medicine, 1991, pp 1-7 66. Solomon 8, Glinoer D, Lagasse R, et a1 Current trends in the management of Graves’ disease. J Clin Endocrinol Metab 70:1518-1524, 1990 67. Stoffer SS, Hamburger JI: Inadvertent 13’1 therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 17146-149, 1976 68. Tallstedt L, Lundell G: Radioiodine treatment, ablation, and ophthalmopathy: A balanced perspective. Thyroid 7241-245, 1997 69. Tallstedt L, Lundell G, Blomgren H, et al: Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 130:494-497,1994 70. Tamagna EI, Levine GA, Hershman JM: Thyroid-hormone concentrations after radioactive iodine therapy for hyperthyroidism. J Nucl Med 20:387-391, 1979 71. Tominaga T, Yokoyama N, Nagataki S, et al: International differences and approaches to 1-131 therapy for Graves’ disease: Case selection and restrictions recommended to patients in Japan, Korea and China. Thyroid 7:217-220, 1997 72. Tuttle RM, Patience T, Budd S Treatment with propylthiouracil before radioactive iodine therapy is associated with a higher treatment failure rate than therapy with radioactive iodine alone in Graves’ disease. Thyroid 5:243-247, 1995 73. US Nuclear Regulatory Commission, Division of Regulatory Applications: Regulatory analysis on criteria for the release of patients administered radioactive material. Washington, DC, US Nuclear Regulatory Commission, NUREG-1492, 1997 74. US Nuclear Regulatory Commission, Office of Nuclear Regulatory Research: Release of patients administered radioactive materials. Washington, DC, US Nuclear Regulatory Commission Regulatory Guide 8.39, 1997 75. Uy HL, Reasner CA, Samuels MH. Pattern of recovery of the hypothalamic-pituitarythyroid axis following radioactive iodine therapy in patients with Graves’ disease. Am J Med 99:173-179, 1995 76. Volp6 R: Autoimmune thyroiditis. In Burrow GN, Oppenheimer JH, Volp6 R: Thyroid Function and Disease. Philadelphia, WB Saunders, 1989, pp 191-207 77. Wartofsky L Radioiodine therapy for Graves’ disease: Case selection and restrictions recommended to patients in North America. Thyroid 7213-216, 1997 78. Wise PH, Ahmad A, Burnet RB, et al: Intentional radioiodine ablation of Graves’ disease. Lancet 2:1231-1232, 1975

Address reprint requests to Michael M. Kaplan, MD Associated Endocrinologists 6900 Orchard Lake Road Suite 203 West Bloomfield, MI 48322