Radioiodine in the treatment of hyperthyroidism

INTRODUCTION — Radioiodine is an effective treatment for Graves' hyperthyroidism. It had been the therapy of choice in the United States, selected by 60 percent of thyroid specialists who responded to a survey in 2011 [1]. Data subsequently have shown that long-term antithyroid drug use is safe [2], and an updated analysis using insurance claims data in the United States suggests that antithyroid drugs are used as initial therapy for 60 percent of patients, while only 33 percent of patients receive radioiodine [3].

Radioiodine is administered orally as sodium iodide (131-I) in solution or a capsule. The radioiodine is rapidly incorporated into the thyroid, and its beta emissions result in extensive local tissue damage. The net effect is ablation of thyroid function over a period of 6 to 18 weeks.

Radioiodine for the treatment of hyperthyroidism will be reviewed here. Other treatment options for Graves' hyperthyroidism and for toxic adenoma and toxic multinodular goiter (MNG) are reviewed separately. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter".)

INDICATIONS

Graves' disease — The therapeutic approach to Graves' hyperthyroidism consists of both rapid amelioration of symptoms with a beta blocker and measures aimed at decreasing thyroid hormone synthesis with either the administration of a thionamide, radioiodine ablation, or surgery [4]. Because all three treatment modalities are effective, the choice of therapy should involve active discussion between clinician and patient (table 1).

Radioiodine had been the most popular treatment for hyperthyroidism in the United States [1]; however, the use of thionamides has been increasing [3], and radioiodine use in the United States has decreased. Radioiodine is also less popular outside of the United States [1,5-7]. At Massachusetts General Hospital (Boston, USA) in 2019, the number of patients receiving radioiodine for hyperthyroidism was approximately 15 percent of that in 2006. The reasons for this decline include the risk of worsening thyroid eye disease despite the ameliorating effects of glucocorticoid treatment (see 'Glucocorticoids in patients with thyroid eye disease' below), controversial reports suggesting an increased risk of breast cancer (see 'Cancer' below), studies demonstrating the long-term safety of thionamides (see "Thionamides in the treatment of Graves' disease"), and the prominence on social media of patient dissatisfaction with permanent hypothyroidism [8]. The choice of therapy for Graves' disease is reviewed separately. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

Toxic adenoma or multinodular goiter — Depending upon patient preference, either radioiodine therapy or surgery had been considered the treatment of choice for these conditions. However, patients can now be managed, if preferred or necessary for other reasons, with long-term thionamide drugs. (See "Treatment of toxic adenoma and toxic multinodular goiter", section on 'Choice of therapy'.)

CONTRAINDICATIONS AND PRECAUTIONS

Pregnancy and breastfeeding — Pregnancy and breastfeeding are absolute contraindications to radioiodine therapy. Radioiodine should not be given for 6 to 12 weeks after cessation of breastfeeding to ensure that radioiodine will not be actively concentrated in breast tissue [9].

Fetal thyroid tissue is present by 10 to 12 weeks and would be destroyed by the radioiodine, potentially resulting in cretinism. A pregnancy test should be obtained in women of childbearing age before the administration of radioiodine.

Rarely, radioiodine is given inadvertently to a pregnant woman [10,11]. The infant may be normal, hyperthyroid (due to a radioiodine-induced increase in maternal thyrotropin receptor antibody [TRAb] levels, which in turn affect fetal thyroid function) [10], or hypothyroid [11], depending on when during the pregnancy the exposure occurred [12]. Each possibility should be considered and appropriate action taken immediately after delivery. In select centers with expertise, fetal thyroid function may be assessed in utero by percutaneous umbilical vein sampling after 20 weeks of gestation [13,14]. However, this procedure is associated with a risk of fetal loss. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid function in the fetus'.)

Thyroid eye disease — Radioiodine therapy, compared with thionamides or surgery, is associated with a twofold increase in the development or worsening of thyroid eye disease (Graves' orbitopathy). The changes are often mild and transient, at least in patients who have mild or no eye disease before therapy, but may be more significant in patients with more severe thyroid eye disease. (See 'Radioiodine and thyroid eye disease' below.)

●Moderate to severe thyroid eye disease – We consider moderate to severe or sight-threatening thyroid eye disease a contraindication to radioiodine therapy. Thionamides or surgery are the preferred options for such patients. While not recommended, patients who refuse surgery and who have had adverse reactions to thionamides may need to be offered radioiodine therapy with glucocorticoid coverage. (See 'Glucocorticoids in patients with thyroid eye disease' below and 'Radioiodine and thyroid eye disease' below.)

●Mild, active thyroid eye disease – Radioiodine should be used with caution in patients with active, mild thyroid eye disease and risk factors for deterioration, including smoking, a high baseline serum concentration of triiodothyronine (T3; eg, >325 ng/dL [5 nmol/L]) [15], or high TRAb levels [16]. While some experts do not treat such patients with radioiodine, in one randomized trial, no patient who received a course of oral prednisone following radioiodine developed new or progressive thyroid eye disease, while 15 percent of patients who did not receive steroids had new or progressive thyroid eye disease [17]. Thus, in patients with mild eye disease but risk factors for progression, concurrent administration of glucocorticoids should be administered (in the absence of major contraindications) to prevent deterioration of the eye disease (table 2). (See 'Glucocorticoids in patients with thyroid eye disease' below.)

Alternative treatment options for hyperthyroidism in patients with moderate to severe eye disease are reviewed separately. (See "Treatment of thyroid eye disease", section on 'Reversal of hyperthyroidism, if present'.)

APPROACH TO TREATMENT — The following approach to administering radioiodine is consistent with the American Thyroid Association (ATA) guidelines for the management of hyperthyroidism [9].

Verify negative pregnancy test — In women of childbearing age, a negative pregnancy test should be confirmed within 48 hours prior to treatment with radioiodine.

Pretreatment with methimazole

Rationale — The rationale for pretreatment with methimazole includes the following:

●There may be a transient exacerbation of hyperthyroidism after radioiodine, which is eliminated by pretreatment [18-20].

●Methimazole returns thyroid function to normal somewhat more rapidly than radioiodine, which can be important for patients who are not tolerating the symptoms of hyperthyroidism or who have comorbidities (eg, heart disease) that make them more vulnerable to the effects of hyperthyroidism.

In one study, for example, thyroid function was normal at a mean of 5.7 weeks after methimazole treatment, while in another study the mean level of thyroxine (T4) was still slightly above normal seven weeks after radioiodine [21,22]. This slightly shorter interval to achieve euthyroidism should not be considered a reason for pretreatment in all patients, since the side effects and potential toxicity from methimazole are significant.

●Hyperthyroidism is controlled by 12 weeks in 97 percent of patients taking methimazole, while 10 to 20 percent of patients receiving a single dose of radioiodine fail treatment altogether [23,24].

There is disagreement about the benefits of thionamide pretreatment in patients planning radioiodine therapy. In a meta-analysis of 14 randomized trials, adjunctive use of thionamides administered in the week before, during, or after radioiodine therapy increased the risk of treatment failure (relative risk [RR] 1.28, 95% CI 1.07-1.52) and reduced the risk of hypothyroidism (RR 0.68, 95% CI 0.53-0.87) [25]. However, patients who were pretreated with thionamides had a lower incidence of biochemical and clinical hyperthyroidism for several weeks after radioiodine therapy.

Candidates for pretreatment — Radioiodine can be administered as initial therapy for hyperthyroidism (without methimazole pretreatment) in most patients with hyperthyroidism, especially if they are receiving adequate therapy with a beta blocker. However, some patients, particularly older patients and others who are more susceptible to the effects of hyperthyroidism, can be first treated with methimazole until euthyroidism is achieved.

We prefer to pretreat with methimazole in the following patients:

●Older patients (>60 to 65 years) and others with comorbidities, such as coronary artery disease, atrial fibrillation, heart failure, or pulmonary hypertension.

●Patients with severe thyrotoxicosis (eg, free T4 two to three times the upper limit of normal) who are not tolerating the symptoms of hyperthyroidism, especially if on adequate doses of beta-blocking drugs. While pretreatment prolongs the period of intensive treatment, it shortens the period during which patients have many hyperthyroid symptoms.

Administration — In the absence of definitive data to support a specific treatment regimen, we prefer to pretreat with methimazole for four to six weeks before radioiodine. Radioiodine can then be administered once serum free T4 and total T3 or free T3 concentrations are in the normal range or after symptoms have subsided.

Our practice is to stop methimazole three days before and then restart methimazole three days after radioiodine is given to allow better control of thyroid function post-radioiodine administration. Methimazole is then tapered or stopped as thyroid function normalizes, usually between 4 and 18 weeks following therapy, as determined by thyroid function testing and the reduction in goiter size.

●Choice of thionamide – Methimazole is the thionamide of choice in all patients receiving treatment prior to radioiodine. (See "Thionamides in the treatment of Graves' disease", section on 'Choice of drug'.)

Controversy remains as to whether pretreatment with propylthiouracil (PTU) is more likely to result in treatment failure than pretreatment with methimazole. One meta-analysis did not find a difference between the two drugs [25]. However, in two nonrandomized trials that compared PTU and methimazole and were not included in the meta-analysis, cure rates after radioiodine in patients receiving PTU were half that of patients receiving methimazole [26,27].

●When to stop – Methimazole should be discontinued before radioiodine treatment in order to avoid impairing the efficacy of the radioiodine. In a randomized trial that compared stopping or continuing methimazole in 75 patients, the radioiodine treatment was successful in 61 percent of the patients in whom the drug was stopped eight days before radioiodine was administered, as compared with 44 percent in whom methimazole was not discontinued [28].

Most studies suggest that stopping two to three days before radioiodine is optimal. As examples:

•A comparison of the diagnostic and therapeutic radioiodine kinetics in 316 patients treated with radioiodine who did not receive pretreatment before therapy, or in whom it had been stopped for one to two days, found that alterations in uptake, uptake curves, and radioiodine half-life were restored to normal two days after discontinuation of the thiamazole (methimazole or carbimazole) and that the success rate of the treatment was 87 percent [29].

•In a study in which thionamides were stopped two versus seven days prior to radioiodine, post-radioiodine free T4 levels were higher in the seven-day group compared with the two-day group, while the 24-hour radioiodine uptakes and the outcome at six months and one and two years were identical [30].

•Another study found no increases in post-radioiodine thyroid hormone concentrations when carbimazole was held for only three days prior to radioiodine administration [31].

●When to restart – Our practice is to restart methimazole three days after radioiodine is given to allow better control of thyroid function post-radioiodine administration. Resumption of thionamide therapy three to seven days after radioiodine administration has been shown to result in less post-therapy rebound hyperthyroidism [32]. While a post-radioiodine increase in thyroid function will not necessarily occur, if the patient was pretreated with methimazole due to old age or cardiovascular morbidity, then we resume methimazole to avoid rebound hyperthyroidism and continue it until the radioiodine has resulted in hypothyroidism or euthyroidism.

Patients unable to take thionamides — In selected patients with Graves' disease in whom more rapid normalization of thyroid function is essential but who are allergic to thionamides, super saturated potassium iodide (SSKI) given daily, beginning one week after radioiodine, normalizes thyroid function several weeks earlier than in patients given radioiodine alone [22]. (See "Iodine in the treatment of hyperthyroidism".)

Low-iodine diet — While the radioiodine uptake can be increased by following a low-iodine diet, this is usually not recommended for patients with hyperthyroidism whose uptakes are frequently quite high on a normal-iodine diet. Avoiding iodine-containing supplements, including most multivitamins, for a week prior to treatment, however, may increase uptake and allow for lower administered doses of radioiodine.

Glucocorticoids in patients with thyroid eye disease — Radioiodine can cause the development or worsening of thyroid eye disease more often than thionamides or surgery. Glucocorticoids given concurrently with radioiodine may prevent worsening of eye disease (table 2) [33].

●Mild thyroid eye disease with risk factors – For patients with active, mild thyroid eye disease who have risk factors for progression (smoking or a high baseline serum concentration of T3 [eg, >325 ng/dL (5 nmol/L)] or high thyrotropin receptor antibodies [TRAb]) and who are being treated with radioiodine, we administer oral glucocorticoids (typically 30 mg prednisone daily starting one to three days after radioiodine and tapering and discontinuing within six to eight weeks). If radioiodine is administered to patients with risk factors for thyroid eye disease, careful monitoring for the development or progression of eye disease is necessary [15].

●Mild thyroid eye disease without risk factors – For patients with active, mild thyroid eye disease without risk factors for progression, the need for concurrent administration of glucocorticoids is uncertain. In the absence of major contraindications, we administer glucocorticoids to prevent exacerbation of thyroid eye disease.

Some experts do not treat patients with mild thyroid eye disease with radioiodine. However, in one trial, no patients with mild thyroid eye disease who received concurrent steroids had progression of disease, while 15 percent of patients who did not receive glucocorticoids had progression of disease [17]. In other studies of patients with initially mild thyroid eye disease, worsening after radioiodine therapy was prevented by the concurrent administration of oral glucocorticoids [33-36]. The dose and duration of treatment varied within the individual studies. In two trials, the initial dose of prednisone was 0.4 to 0.5 mg/kg body weight, initiated two to three days prior to radioiodine, continued for one month, and then tapered over two months [17,34]. In a third trial comparing oral prednisone (fixed starting dose of 35 mg prednisone tapered over 10 weeks) with intravenous methylprednisolone (500 mg/week for two weeks and 250 mg/week for two weeks), no patient receiving steroids had worsening eye disease after radioiodine [36]. In a retrospective cohort study, a lower starting dose of steroids (0.2 mg/kg body weight), with tapering over six weeks, was also shown to be effective in preventing exacerbations of eye disease in most patients [35]. (See 'Radioiodine and thyroid eye disease' below.)

●Moderate to severe thyroid eye disease – Radioiodine is contraindicated in patients with moderate to severe or sight-threatening thyroid eye disease. (See 'Thyroid eye disease' above.)

While not recommended, radioiodine with concomitant administration of glucocorticoids can still be considered in patients who refuse surgery and who have had adverse reactions to thionamides, or it can be considered after the patient has been stable for at least a year on thionamides. There are few data evaluating the impact of radioiodine with glucocorticoids on progression of moderate to severe thyroid eye disease [33].

●Smokers without active thyroid eye disease – Cigarette smokers who receive radioiodine have a high incidence of new or progressive thyroid eye disease [17,37]. In cigarette smokers without thyroid eye disease, there is no evidence for or against using prophylactic glucocorticoids to prevent the onset of eye disease [9]. If smokers with Graves' disease (and with no evidence of eye disease) are treated with radioiodine, some UpToDate contributors administer concurrent glucocorticoids, unless there is a contraindication to the use of glucocorticoids.

Of note, glucocorticoids reduce the effective thyroidal half-life of radioiodine by increasing renal plasma iodine clearance [38]. However, there are no reports that the addition of glucocorticoids reduces the overall effectiveness of radioiodine treatment of the hyperthyroid state.

Other — Other therapies to enhance the efficacy of radioiodine or to reduce the exacerbation of hyperthyroidism that may occur after radioiodine are not recommended. One therapy that has been evaluated as an adjuvant in radioiodine therapy is lithium.

Lithium may prolong the retention of radioiodine within the thyroid gland, which could increase the effectiveness of radioiodine therapy. In a retrospective cohort study, the cure rate was slightly higher in patients given lithium (900 mg/day) for 12 days starting 5 days before radioiodine (91 versus 85 percent) [39], but there was no difference in a randomized trial of radioiodine alone versus radioiodine plus lithium (900 mg/day) [40]. Lithium given coincident with radioiodine can prevent the transient increase in serum thyroid hormone concentrations following radioiodine [41]. Because of inconsistent data and the toxicity of lithium, we do not recommend its use in conjunction with radioiodine.

DOSING OF RADIOIODINE — Most experts advocate radioiodine doses that result in hypothyroidism. (See 'Low versus high' below.)

There is debate, however, over whether the dose of radioiodine should be fixed or individualized based upon the size of the thyroid gland and 24-hour radioiodine uptake and turnover [4,42]. We prefer to individualize the radioiodine dose based upon the size of the thyroid gland and the 24-hour radioiodine uptake. The dose is calculated based on the microcuries (microCi) or megabecquerels (MBq) per gram (g) of thyroid tissue to be delivered. (See 'Fixed versus calculated' below.)

Low versus high — The primary goal of radioiodine therapy in Graves' disease is to cure the hyperthyroidism by rendering the patient hypothyroid. In the past, it was controversial whether radioiodine should be given in a sufficient dose to induce hypothyroidism or a lower dose in an attempt to achieve a euthyroid state [42]. However, due to the high failure rate associated with lower doses designed to leave a patient euthyroid, most experts advocate radioiodine doses that result in hypothyroidism [9]. (See 'Monitoring' below.)

Hypothyroidism is less common initially after radioiodine treatment of toxic adenoma and toxic multinodular goiter (MNG). Areas of focal autonomy take up radioiodine well, while uptake is limited in adjacent and contralateral thyroid tissue that is suppressed by the hyperthyroid state. As a result, radioiodine tends to destroy only the autonomous areas, and most patients remain euthyroid after radioiodine administration [43]. Patients who develop hypothyroidism usually do so because uptake was not suppressed in the extranodular tissue [44] or because of coexistent chronic lymphocytic thyroiditis [15]. In up to 5 percent of patients with toxic MNG, radioiodine therapy may evoke the production of TSH receptor-stimulating antibodies, causing recurrent hyperthyroidism (due to Graves' disease) several months after treatment [45,46].

●Graves' disease – When radioiodine is used to treat patients with Graves' hyperthyroidism, we suggest high-dose therapy (150 to 200 microCi/g [5.9 to 7.4 MBq/g]). This will cure the hyperthyroidism and, in most patients, induce hypothyroidism in 12 to 18 weeks. Patients should then be started on full replacement doses of T4 if goiter is absent or slightly lower doses if goiter persists. A persistent goiter suggests incomplete destruction of the gland and the possibility of persistent autonomous thyroid tissue.

The American Thyroid Association (ATA) guidelines for the management of Graves' hyperthyroidism recommend a dose (typically 10 to 15 millicuries [mCi; 370 to 555 MBq]) sufficient to cause hypothyroidism, which can be accomplished equally well with either a fixed or individualized dose regimen [9].

For patients with Graves' disease, the dose of radioiodine is directly related to the cure rate and the incidence of hypothyroidism. As an example, in a trial of two fixed doses of radioiodine (5 versus 10 mCi equivalent to 185 versus 370 MBq) in 813 patients with hyperthyroidism, patients treated with the higher dose had a higher cure rate (85 versus 67 percent) and a higher incidence of hypothyroidism (61 versus 41 percent) [47]. A high dose of radioiodine (128 to 155 microCi/g of thyroid tissue [4.7 to 5.7 MBq/g]) cures the hyperthyroidism in 90 percent of patients but eventually causes hypothyroidism in at least 80 percent, whereas 14 percent have persistent hyperthyroidism requiring additional treatment [23].

Administering much higher doses (>200 microCi/g [7.4 MBq/g]) is not associated with higher rates of cure but may be used in patients who are being retreated after one or more treatment failures; in patients with very large goiters; or in patients who have been pretreated with thionamides, which causes mild radioresistance.

Although attempting to lower thyroid function to normal with a low dose of radioiodine may appear desirable, this approach has several disadvantages. In particular, low-dose radioiodine therapy is more likely to result in treatment failure, necessitating another dose in 6 to 24 months [48,49]. In addition, less than one-third of patients are euthyroid 10 years after therapy [50]. Many patients have chronic subclinical hyperthyroidism, with its associated risks of atrial fibrillation and reduced bone density. (See "Subclinical hyperthyroidism in nonpregnant adults".)

●Toxic adenoma or toxic multinodular goiter – The dose of radioiodine used to treat toxic adenoma or MNG is higher than that needed to treat Graves' disease (approximately 200 microCi/g [7.4 MBq/g]) [9]. (See "Treatment of toxic adenoma and toxic multinodular goiter", section on 'Radioiodine therapy'.)

Fixed versus calculated — We prefer to individualize the dose of radioiodine based upon the size of the thyroid gland and the 24-hour radioiodine uptake [51]. The goal of individualized dosing is to maximize cure and avoid unnecessarily high radiation exposures in patients with high radioiodine uptake. The use of a fixed dose of radioiodine is an alternative approach. Fixed dosing simplifies the approach to treatment and is less costly than an individually calculated dose. Fixed doses of 5, 10, or 15 mCi (185, 370, or 555 MBq) are commonly given to patients with Graves' hyperthyroidism.

One prospective, randomized trial compared a fixed dose with a calculated dose and reported an inverse relationship between therapeutic success and thyroid size in the patients treated with a fixed dose [52]. Success rates ranged from 100 percent for patients with thyroid volumes ≤15 mL to only 25 percent in patients with volume ≥75 mL. In another study, a semiquantitative fixed-dose regimen (5 mCi [185 MBq] for patients with small glands, 10 mCi [370 MBq] for those with medium glands, and 15 mCi [555 MBq] for those with large glands) was as effective as more elaborately calculated individual dosing [53]. These data favor an individualized approach to dosing because of the dependence of outcome on gland size.

However, other data favor a fixed approach. As an example, in a randomized trial comparing one of four dose methods (low fixed, high fixed, low calculated, high calculated) in 88 patients with Graves' disease, fixed doses of 6.4 mCi (235 MBq) or 9.4 mCi (350 MBq) were as effective as low- or high-calculated doses (80 or 120 microCi/g) [54]. After a mean follow-up of 63 months, the majority of patients (57 to 82 percent) were hypothyroid. Hyperthyroidism was present in 18 to 27 percent, and 0 to 19 percent were euthyroid. Clinical outcome was not related to the administered radioiodine dose (hyperthyroid, 334 MBq; euthyroid, 309 MBq; hypothyroid, 334 MBq).

Dose calculation — When calculating the dose of radioiodine to be administered to a patient, we prefer to correct the dose according to the 24-hour uptake. As an example, suppose that one wanted to deliver 160 microCi/g thyroid tissue to a patient whose thyroid gland size was approximately 30 g with a 24-hour uptake of 60 percent. In this patient, the administered dose would be:

This approach requires a trip to the hospital to measure 24-hour radioiodine uptake, but by measuring the uptake just before treatment, the etiology of the hyperthyroidism and the appropriateness of therapy are assured. It has the additional advantage of avoiding undertreatment that can occur when a fixed dose is given to patients with large goiters and low uptakes.

Chronic kidney disease — Although the dose of radioiodine is usually reduced in patients with thyroid cancer who have chronic kidney disease and are on dialysis, dose adjustments are not necessary in patients receiving radioiodine for hyperthyroidism [55]. The doses of radioiodine administered for the treatment of hyperthyroidism are much lower than those for thyroid cancer, and a larger fraction of the dose is taken up by the thyroid tissue, requiring less clearance by the kidney immediately after dosing. However, hemodialysis should be performed after the time of maximum uptake in the thyroid, which is approximately 10 hours [56]. A radiation safety team should be involved with the monitoring of the patient and the dialysis staff, facility, and equipment. Radiation precautions are required for at least one week after treatment.

POST-TREATMENT PRECAUTIONS — In 2011, the American Thyroid Association (ATA) published recommendations on radiation safety for patients, families, caregivers, and the public after radioiodine (131-I) therapy [57]. The recommendations are based upon clinical experience and available data. However, data on long-term outcomes are limited.

The doses of radioiodine administered for the treatment of hyperthyroidism are lower than those used to treat thyroid cancer. The majority of patients with hyperthyroidism can be treated with 131-I in the outpatient setting. As an example, patients receiving doses of up to 55 mCi (2035 MBq) for hyperthyroidism can typically be released without exceeding dose limits established by the Nuclear Regulatory Commission (NRC) [57,58]. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient release criteria'.)

Household contacts — Patients who receive radioiodine have the potential to expose their home and household contacts via saliva, urine, or radiation emitting from their body. They should be instructed to avoid the following during the restricted period:

●Sharing cups or utensils

●Sleeping in the same bed with another adult, pregnant woman, infant, or child

●Sexual contact

●Close contact with children and pregnant women

The period of post-treatment precaution varies with the dose administered and retained (table 3) [57,58]. In the United States, close daytime contact with adults should be avoided for approximately one, two, and five days, and sleeping with another adult should be avoided for approximately 3, 6, 8, and 11 days for doses of 10, 15, 20, and 30 mCi (370, 555, 740, 1110 MBq), respectively. The period of contact precautions for pregnant partners, infants, and children is longer (one to five days for daytime restrictions and 15 to 23 days for nighttime restrictions).

In Europe, where recommended dose to members of the public is less than 1 milliSieverts (mSv), these precautions are recommended for one, two, or three weeks, if treated with 5, 10, and 15 mCi (185, 370, 555 MBq), respectively [59]. In a survey of household members of patients who received treatment for hyperthyroidism, the dose received by the members was well below the limit of 5 mSv recommended by the NRC [60].

Future pregnancy — Pregnancy should be delayed four to six months after radioiodine therapy to ensure that hyperthyroidism is successfully cured and hypothyroidism corrected prior to conception. Some experts suggest delaying pregnancy for a year or more because TRAb levels increase after radioiodine and remain elevated for a year [61], which theoretically would increase the risk of fetal or neonatal hyperthyroidism. (See "Overview of thyroid disease and pregnancy", section on 'Fetal and neonatal Graves' disease'.)

However, unintended pregnancies after radioiodine treatment and during this interval should be allowed to proceed to term. Congenital anomalies do not appear to be more common in women treated with radioiodine [62]. The gonadal dose is approximately three rad, similar to that for hysterosalpingography or a barium enema [63]. The estimated risk of genetic damage is 0.005 percent, which is much lower than the spontaneous risk of 0.8 percent [64].

Conception should be delayed for three to four months in men to allow for adequate turnover of sperm production [9].

MONITORING — After radioiodine, all patients require monitoring for hypothyroidism or persistent hyperthyroidism. Most patients have normalization of thyroid function tests within 4 to 10 weeks [65]. Hypothyroidism may occur as early as four weeks. Hypothyroidism should be avoided as this is a risk factor for worsening thyroid eye disease. (See 'Radioiodine and thyroid eye disease' below.)

We measure serum free T4, total T3, and TSH at four to six weeks after radioiodine and then at four- to six-week intervals thereafter, depending upon the results of prior testing and change in thyroid size.

●If the patient becomes and remains euthyroid for six months, serum TSH should be measured at 6- to 12-month intervals for the patient's lifetime because of the ongoing occurrence of hypothyroidism after radioiodine therapy.

●If the patient becomes hypothyroid (as indicated by a low free T4), thyroid hormone should be initiated and the dose initially adjusted to maintain a normal free T4 level. Once euthyroidism is achieved on a stable dose of thyroid hormone replacement, TSH can be measured annually. (See "Treatment of primary hypothyroidism in adults", section on 'Dose and monitoring'.)

●If the patient has persistent hyperthyroidism, monitoring of thyroid tests should continue at four- to six-week intervals while additional therapy is planned. (See 'Persistent hyperthyroidism' below.)

The principal test used to follow the immediate effect of treatment of hyperthyroidism is the serum free T4 concentration. Measurement of serum TSH can be misleading in the early follow-up period because it can remain low for weeks or even months, even when the patient is biochemically euthyroid or even hypothyroid, with serum free T4 values well within or even below the normal range [66,67]. When both TSH and free T4 are low, measurement of serum T3 is necessary to distinguish between persistent hyperthyroidism (T3 elevated) and transient central hypothyroidism (T3 normal or low) associated with recovery of the hypothalamic-pituitary-thyroid axis after treatment of hyperthyroidism. Once steady-state conditions are assured, measurement of serum TSH is required to assess the efficacy of therapy. (See "Laboratory assessment of thyroid function", section on 'Monitoring treatment of hyperthyroidism'.)

The percentage of patients with Graves' disease who become hypothyroid within the first year after treatment varies directly with the dose of radioiodine. Hypothyroidism occurs in approximately 80 percent of patients receiving high-dose therapy (eg, 160 microCi/g) and 10 percent of patients receiving low-dose therapy (eg, 80 microCi/g) [23,49,50].

Hypothyroidism that develops within the first year may be transient. In a study of 260 patients who received radioiodine therapy for Graves' hyperthyroidism, for example, 67 developed hypothyroidism within the first year after treatment [68]. The hypothyroidism was transient in 58 percent. However, 70 percent of those with transient hypothyroidism became permanently hypothyroid in the subsequent 2 to 11 years.

Most patients who become euthyroid soon after radioiodine therapy develop hypothyroidism at a rate of 2 to 3 percent per year [49]. This occurs because of the late effects of radiation and of lymphocytic infiltration and destruction of thyroid tissue, a process similar to chronic lymphocytic (Hashimoto's) thyroiditis (see "Thionamides in the treatment of Graves' disease", section on 'Mechanism of remission'). Alternatively, patients who become euthyroid after therapy can develop recurrent hyperthyroidism. This occurs because of regrowth of thyroid remnants under continued stimulation of thyrotropin receptor antibodies (TRAbs).

In patients with a toxic adenoma or toxic multinodular goiter (MNG), hypothyroidism is less common initially after radioiodine treatment. However, there is an ongoing risk for developing hypothyroidism. In one long-term study, the prevalence of hypothyroidism after radioiodine for MNG was 64 percent after 24 years [69].

PERSISTENT HYPERTHYROIDISM — Approximately 10 to 20 percent of patients fail the first radioiodine treatment [23]. In a meta-analysis of 4822 patients with Graves' disease, treatment failure was correlated with male sex, administration of radioiodine more than six months after diagnosis, prior use of thionamides, 24-hour radioiodine uptake ≥60.26 percent, and thyroid volume ≥35.77 mL [70]. In patients with treatment-resistant Graves' disease (persistent hyperthyroidism six months following radioiodine), we typically administer a second dose of radioiodine. If the response to the first dose of radioiodine has been minimal and a large goiter persists, a second dose can be administered earlier, eg, four months after the initial dose.

Patients with rapid thyroidal iodine turnover whose two- to four-hour radioiodine uptake is higher than the 24-hour radioiodine uptake are more likely to have a poor response to radioiodine treatment. In one study, the initial cure rate (euthyroid or hypothyroid) was 28 percent in patients with high turnover (ratio of 2-hour to 24-hour radioiodine uptake ≥1), and 66 percent in patients with normal turnover (ratio <1). The patients with high turnover required 1.5 to 2 times the radioiodine dose to achieve a cure [71]. In addition, patients with large, isoechoic glands that have more colloid are more likely to be radioresistant than are hypoechoic glands, which have more densely packed cells. In one study, treatment failure occurred in 22 percent of patients with isoechoic and 7 percent with hypoechoic glands [72].

In one case report, pretreatment with lithium prolonged radioiodine retention and increased the efficacy of radioiodine therapy in a patient with radioiodine resistant Graves' disease [73]. Because of limited data and the potential toxicity of lithium, however, we do not recommend its routine use in patients with radioiodine-resistant Graves' disease.

ADVERSE EFFECTS — Radioiodine appears to be quite safe aside from causing hypothyroidism [74].

Radiation thyroiditis — There is a 1 percent (or lower) incidence of radiation thyroiditis after radioiodine therapy. Radiation thyroiditis can cause relatively severe thyroid pain that can last two to three weeks and may be associated with exacerbation of hyperthyroidism unless hormone stores were first depleted with thionamide therapy. (See 'Pretreatment with methimazole' above.)

Nonsteroidal antiinflammatory drugs (NSAIDs) are usually sufficient for analgesia, but prednisone may be required in severe cases.

Rebound hyperthyroidism — Weeks to months following radioiodine therapy, there may be a recurrent, albeit transient, hyperthyroidism, likely due to a radiation-related increase in thyrotropin receptor antibodies (TRAb) [20,75]. This should be distinguished from radiation-related thyroiditis, which typically develops within one to three weeks of radioiodine therapy. If rebound hyperthyroidism develops, methimazole should be restarted and continued until thyroid function normalizes. Ultimately, the radioiodine will cause hypothyroidism in most patients, and the methimazole can be tapered and stopped after one to two months.

Radioiodine and thyroid eye disease — Most [34,76,77], but not all [78-80], studies of patients with Graves' disease suggest that radioiodine therapy is associated with the appearance or exacerbation of thyroid eye disease (Graves' orbitopathy) more often than treatment with thionamides or surgery. The changes are often mild and transient, at least in patients who have mild or no eye disease before therapy. (See "Treatment of thyroid eye disease", section on 'Reversal of hyperthyroidism, if present'.)

The exacerbation of thyroid eye disease after radioiodine is thought to be due to an increase in levels of TRAbs following radioiodine treatment that persist for up to a year [61]. In contrast, TRAb levels tend to fall after surgery and during thionamide therapy.

There have been several randomized trials of different hyperthyroidism treatments in patients with Graves' disease [17,37,76]. As examples:

●In one trial, orbitopathy developed or worsened in 33 percent of the patients treated with radioiodine, as compared with 10 and 16 percent of those treated with methimazole and surgery, respectively [76]. This study was criticized, however, because all of the patients treated with radioiodine became hypothyroid, and treatment with thyroxine was delayed for several months. It is possible that high serum TSH concentrations were in part responsible for the development of orbitopathy [81].

●In another trial, the risk of worsening or new-onset orbitopathy was higher with radioiodine than thionamides (39 and 21 percent, respectively), in spite of early treatment of hypothyroidism in both groups [37]. The risk was primarily driven by an increase in new eye disease (38 versus 18 percent of those randomly assigned to methimazole), rather than worsening of existing eye disease.

●A third randomized trial compared treatment with radioiodine (120 to 150 microCi/g of thyroid tissue) alone, radioiodine followed by a three-month course of prednisone (0.4 to 0.5 mg/kg for one month, then tapered over two months), or methimazole for 18 months in 443 patients with Graves' hyperthyroidism and slight or no orbitopathy [17]. Of the 150 patients treated with radioiodine, 23 (15 percent) either developed or had worsening of orbitopathy two to six months after treatment (figure 1). The change was transient in 15 patients; it persisted in the other eight patients. In comparison, none of the 135 patients treated with radioiodine plus prednisone developed or had worsening of orbitopathy, and 50 of the 75 patients (67 percent) with orbitopathy in this arm of the study improved. In the 148 patients treated with methimazole, three (2 percent) with orbitopathy improved, four (3 percent) had worsening, and the other 141 had no change. These patients were closely followed for the development of hypothyroidism and treated immediately.

●In another study, administration of methimazole after radioiodine therapy did not prevent changes in orbitopathy [77].

Cancer — The Cooperative Thyrotoxicosis Therapy Follow-up Study Group followed 35,593 patients from 26 centers for cancer mortality after radioiodine therapy. An analysis of data through 1990 representing a mean follow-up of 21 years revealed no increase in overall cancer mortality [82,83].

Prolonged follow-up demonstrated a small increase in thyroid cancer risk that was most pronounced in those patients who received radioiodine for toxic nodular goiter (the number of thyroid cancer deaths was small [29 out of a total of 2950 cancer deaths] and the standardized cancer mortality ratio was 2.77, accounting for 18 excess deaths) [84]. Since the risk of thyroid cancer is known to be slightly increased among patients with nodular goiters, it is possible that at least some of the excess thyroid cancer risk is related to underlying thyroid disease. In a 24-year extension of the Cooperative Thyrotoxicosis Therapy Follow-up Study (18,805 patients), a 100 mGy organ exposure was associated with an increased risk of breast cancer (RR 1.12, 95% CI 1.003-1.32) and stomach cancer (RR 1.05, 95% CI 1.01-1.10) [85].

Another analysis of 7417 patients in the United Kingdom also found a significant increase in the incidence of thyroid cancer (nine cases versus three expected) and cancers of the small bowel [86]. There was a decrease in the overall cancer incidence (634 cases versus 761 expected). In a study of 2793 Finnish patients, there was an increase in the incidence rate ratio of cancer risk per 10,000 person-years (1.2 [1.1 to 1.5]) due to cancer of the breast, stomach, and kidney [87].

The above studies compared cancer risks in hyperthyroid patients treated with radioiodine to normal populations. In an Israeli study of hyperthyroid patients who received radioiodine (n = 2829) or antithyroid drugs (13,808), there was no difference in cancer incidence between the two groups (825 new cancers over a mean 7.3 years of follow-up) [88].

Overall mortality — Although radioiodine is safe and effective, some data indicate that it is associated with a slight but significant increase in later mortality, a risk that may be related to hyperthyroidism or longstanding subclinical hyperthyroidism, rather than radioiodine per se [89-92]:

●In a long-term study extending over 40 years that included 7209 patients and 105,028 person-years of follow-up, the standardized mortality ratio (SMR) for radioiodine-treated patients was 1.1 (95% CI 1.1-1.2) [89]. Most of the excess deaths occurred during the first year after treatment. The major association at this time was with the hyperthyroidism itself (SMR approximately 25). Other factors contributing to the excess deaths were total cardiovascular disease and femoral fractures. The data do not permit attribution of the excess deaths specifically to either the hyperthyroidism or the radioiodine.

●In a second population-based study by the same investigators, 2668 individuals over age 40 years treated with radioiodine for hyperthyroidism (between 1984 and 2002) were examined [91]. A slight excess in mortality was noted in the radioiodine patients compared to age- and period-specific mortality (SMR 1.14, 95% CI 1.04-1.24). However, the increased mortality risk was observed only in patients not requiring thyroid hormone therapy or prior to thyroid hormone replacement. No increased risk was seen during follow-up in patients taking thyroid hormone therapy. Patients with subclinical hypothyroidism (not receiving thyroid hormone) had excess mortality related to ischemic heart disease. These findings suggest that doses of radioiodine for the treatment of hyperthyroidism should be high enough to induce overt hypothyroidism. In addition, thyroid hormone therapy should be considered in patients with subclinical hypothyroidism after radioiodine treatment.

●In a third population-based study by the same investigators, 1036 individuals over age 40 had increased all-cause mortality during treatment with thionamides (SMR 1.30, 95% CI 1.05-1.61) and after radioiodine while still hyperthyroid (SMR 1.24, 95% CI 1.04-1.46) but not during T4 replacement of radioiodine-induced hypothyroidism [92].

●Another population-based study of 2793 patients reported an increase in mortality from cerebrovascular disease (relative risk [RR] 1.4), which was felt to be due to the hyperthyroidism per se rather than the radioiodine treatment [90].

In a population-based study of 3888 individuals successfully treated for hyperthyroidism, there was no increase in all-cause mortality [93]. The study did not specify the treatment modality.

Hospitalization rates for cardiovascular disease may also be higher after radioiodine therapy, as illustrated by a population-based study of 2611 treated patients and 2611 healthy controls. A higher rate of hospitalization for cardiovascular disease was observed in the radioiodine-treated patients (RR 1.12), including atrial fibrillation, cerebrovascular disease, hypertension, and heart failure, which remained elevated for up to 35 years after treatment [94].

Gonadal function — Radioiodine in the doses used to treat hyperthyroidism does not cause infertility or congenital anomalies in the offspring of treated patients [95] (see 'Future pregnancy' above). The total dose to the testes averages 39 microGy/MBq [96]. Radioiodine administration results in transient reductions in serum testosterone concentrations without change in serum follicle-stimulating hormone (FSH), improved sperm motility (low motility was seen in two-thirds of hyperthyroid patients before radioiodine), and no change in sperm concentration or morphology [96].

Pretibial myxedema — Radioiodine may also be associated with the onset or worsening of infiltrative dermopathy (pretibial myxedema) [97]. (See "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Low-iodine diet (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications – Radioiodine can be used for the treatment of hyperthyroidism due to Graves' disease, toxic adenoma, and toxic multinodular goiter (MNG). (See 'Indications' above and "Treatment of toxic adenoma and toxic multinodular goiter", section on 'Choice of therapy' and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

●Contraindications – Radioiodine should not be given to pregnant or lactating women. It is also contraindicated in patients with moderate to severe or sight-threatening thyroid eye disease (Graves' orbitopathy). (See 'Contraindications and precautions' above.)

●Pretreatment with methimazole – For patients with significant symptoms of hyperthyroidism and in older patients with underlying cardiac disease, we suggest starting a thionamide (methimazole) to achieve euthyroidism prior to radioiodine therapy (Grade 2B). We discontinue methimazole three days prior to radioiodine and restart three days after radioiodine therapy. For young and middle-aged patients who are less symptomatic, there is no need to pretreat with a thionamide, and radioiodine can be given soon after the diagnosis is made. (See 'Pretreatment with methimazole' above and "Thionamides in the treatment of Graves' disease".)

●Concurrent treatment with glucocorticoids for patients with thyroid eye disease – For patients with active mild thyroid eye disease who have risk factors for progression (smoking, a high baseline serum concentration of triiodothyronine [T3]; eg, >325 ng/dL [5 nmol/L], or high thyrotropin receptor antibodies [TRAbs]) and who are being treated with radioiodine, we recommend concurrent treatment with oral or intravenous glucocorticoids (table 2) (Grade 1B). For patients with active, mild thyroid eye disease without risk factors for progression, the need for concurrent administration of glucocorticoids is uncertain. In the absence of major contraindications, we generally administer glucocorticoids to prevent exacerbation of thyroid eye disease. (See 'Glucocorticoids in patients with thyroid eye disease' above.)

●Dosing – Radioiodine is administered orally as sodium iodide-131 (131-I) in solution or a capsule. For patients being treated with radioiodine, we suggest high- rather than low-dose radioiodine (Grade 2B). (See 'Dosing of radioiodine' above.)

We also suggest individualization of the dose based upon the size of the thyroid gland and the 24-hour radioiodine uptake (Grade 2C). We typically administer 160 microCi/g thyroid tissue (5.9 MBq/g) for Graves' hyperthyroidism and 200 microCi/g (7.4 MBq/g) for toxic adenoma/MNG. A fixed dose of 10 to 15 mCi (370 to 555 MBq) for Graves' hyperthyroidism and 15 to 20 mCi (500 to 740 MBq) for toxic adenoma/MNG is an alternative option, although higher fixed doses should be used for larger glands. (See 'Dose calculation' above.)

●Monitoring – After radioiodine, all patients require monitoring for hypothyroidism or persistent hyperthyroidism. We measure serum free T4, total T3, and TSH at four to six weeks after radioiodine and then at four- to six-week intervals thereafter, depending upon the results of prior testing and change in thyroid size. (See 'Monitoring' above.)

●Persistent hyperthyroidism – Approximately 10 to 20 percent of patients fail the first radioiodine treatment. In patients with treatment-resistant Graves' disease (persistent hyperthyroidism six months following radioiodine), we typically administer a second dose of radioiodine. If the response to the first dose of radioiodine has been minimal and a large goiter persists, a second dose can be administered earlier, eg, four months after the initial dose. (See 'Persistent hyperthyroidism' above.)