Radioiodine in the treatment of Graves' hyperthyroidism

INTRODUCTION — 

Radioiodine is one of three effective treatment modalities for Graves' hyperthyroidism. It is administered orally as sodium iodide (131-I) in a capsule or rarely in solution. The radioiodine is rapidly incorporated into the thyroid, and its beta emissions result in extensive thyroid tissue damage. The net effect is diminution or ablation of thyroid function in most patients over a period of 2 to 12 months, with many patients becoming hypothyroid or euthyroid within two to three months.

Radioiodine for the treatment of Graves' hyperthyroidism will be reviewed here. Other treatment options for Graves' hyperthyroidism and the treatment of 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".)

CLINICAL USE

Patient selection — The treatment of Graves' hyperthyroidism consists of rapid amelioration of hyperadrenergic symptoms with a beta blocker and measures aimed at decreasing thyroid hormone synthesis with either the administration of a thionamide (methimazole or carbimazole in most cases), radioiodine ablation, or surgery [1]. Because all three treatment modalities are effective, the choice of therapy should involve active discussion between clinician and patient (table 1). (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Treatment options'.)

Radioiodine is a good option for the treatment of hyperthyroidism due to Graves' disease for patients who:

●Prefer definitive therapy and do not have thyroid eye disease, especially if they are at increased risk for surgical complications

●Patients who cannot take a thionamide because of adverse reactions or poor adherence

Selection of therapy is reviewed in more detail separately. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

Declining use of radioiodine — The use of radioiodine for the treatment of Graves' hyperthyroidism has been decreasing globally [2,3]. The reasons for this decline include:

●The prominence on social media of patient dissatisfaction with permanent hypothyroidism [4], and a desire to avoid lifelong thyroid hormone replacement therapy [3].

●Risk of worsening thyroid eye disease despite the ameliorating effects of glucocorticoid treatment. (See 'Patients with thyroid eye disease' below.)

●Controversial reports suggesting an increased risk of breast cancer and other solid tumors with radioiodine treatment. (See 'Cancer' below.)

●Studies demonstrating the long-term safety of thionamides. (See "Thionamides in the treatment of Graves' disease".)

Contraindications and precautions

Pregnancy and breastfeeding — Pregnancy and breastfeeding are absolute contraindications to radioiodine therapy.

●Pregnancy – Fetal thyroid tissue is present by 10 to 12 weeks and would be destroyed by the radioiodine, potentially resulting in cretinism. Before the administration of radioiodine, a pregnancy test should be obtained in all females between menarche (or age 12) and menopause with an intact uterus. (See 'Verify negative pregnancy test' below.)

Rarely, radioiodine is given inadvertently to a pregnant woman [5,6]. 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) [5], or hypothyroid [6], depending on when during the pregnancy the exposure occurred [7]. 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 [8,9]. 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'.)

●Breastfeeding – Radioiodine should not be given for 6 to 12 weeks after cessation of breastfeeding and milk production to ensure that radioiodine will not be actively concentrated in breast tissue [10]. If there is urgency to treat a woman who is or had been breastfeeding, lactation can be suppressed with the dopamine agonist cabergoline [11]; however, routine use of cabergoline has been associated with dizziness, orthostatic hypotension, and rare neurologic side effects [12]. (See "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Lactation suppression'.)

Thyroid eye disease (Graves' orbitopathy) — In patients with Graves' disease, radioiodine therapy (compared with thionamides or surgery) is associated with an 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 they may be more significant in patients with more severe thyroid eye disease (table 2). (See 'Appearance or exacerbation of thyroid eye disease' below and "Clinical features and diagnosis of thyroid eye disease", section on 'Assessment of disease severity and activity'.)

●Moderate-to-severe thyroid eye disease – We consider moderate-to-severe or sight-threatening thyroid eye disease a contraindication to radioiodine therapy (table 2). 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 'Patients with thyroid eye disease' below and "Treatment of thyroid eye disease", section on 'Reversal of hyperthyroidism, if present'.)

●Mild, active thyroid eye disease – Radioiodine should be used with caution in patients with mild, active (table 2 and table 3) thyroid eye disease, particularly patients with risk factors for deterioration, such as [13,14]:

•Cigarette smoking – High baseline serum concentration of triiodothyronine (T3; eg, >325 ng/dL [5 nmol/L])

•High TRAb levels

For patients with mild, active thyroid eye disease who prefer treatment with radioiodine, glucocorticoids given concurrently with radioiodine may prevent worsening of eye disease (table 4). (See 'Patients with thyroid eye disease' below.)

PRETREATMENT MANAGEMENT

Severe thyrotoxicosis or older patients — Because thyroid function may transiently worsen in the weeks following radioiodine administration, we suggest pretreatment with methimazole to achieve euthyroidism prior to radioiodine therapy 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 thyroxine [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 with methimazole prolongs the period of intensive treatment, it shortens the period during which patients have many hyperthyroid symptoms.

In most other patients, radioiodine can be administered as initial therapy for hyperthyroidism (without methimazole pretreatment), especially if they are receiving adequate therapy with a beta blocker.

Pretreatment with antithyroid drugs shortens the time to euthyroidism (eg, 5.7 versus 7 weeks) and prevents post radioiodine ablation exacerbations of hyperthyroidism [15-18]. These benefits are likely clinically important only for people at high risk of severe thyrotoxicosis or risk of sequelae of continued hyperthyroidism. Pretreatment with antithyroid drugs may slightly increase the risk of treatment failure. As an example, in a meta-analysis of 14 randomized trials, patients who took thionamides in the week before, during, or after radioiodine therapy had a lower incidence of biochemical and clinical hyperthyroidism for several weeks after radioiodine therapy compared with those who did not take thionamides [18]. However, they had an increased risk of treatment failure (33 versus 23 percent, relative risk [RR] 1.28, 95% CI 1.07-1.52) but a reduced risk of hypothyroidism.

Methimazole pretreatment

●Preferred thionamide – Methimazole is the thionamide of choice in all patients receiving treatment prior to radioiodine. For patients intolerant of methimazole due to allergic reactions, hives, or gastrointestinal upset, propylthiouracil (PTU) is an alternative, but it may be associated with the same side effects as methimazole in approximately one-half of the patients. (See "Thionamides in the treatment of Graves' disease", section on 'Initiation of therapy' and "Thionamides: Side effects and toxicities", section on 'Common, minor adverse effects'.)

Controversy remains as to whether pretreatment with 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 [18]. 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 [19,20]. Cure rates after methimazole pretreatment and after radioiodine without pretreatment were similar.

●Timing of administration

•In the absence of definitive data to support a specific duration, we pretreat with methimazole until serum free T4 and total T3 or free T3 concentrations are in the normal range. This usually takes four to six weeks.

•Our practice is to stop methimazole three days before radioiodine treatment to avoid impairing radioiodine efficacy.

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 [21]. Most studies suggest that stopping two to three days before radioiodine is optimal [22-24].

•We restart methimazole three days after radioiodine is given to allow better control of thyroid function post-radioiodine administration. A post-radioiodine increase in thyroid function will not always occur. However, if the patient was pretreated with methimazole due to old age or cardiovascular morbidity, then we resume methimazole to avoid rebound hyperthyroidism. Resumption of thionamide therapy three to seven days after radioiodine administration has been shown to result in less post-therapy rebound hyperthyroidism [25].

•We then continue methimazole until the radioiodine has resulted in hypothyroidism or euthyroidism. It 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. (See 'Monitoring' below.)

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 [26]. (See "Thionamides: Side effects and toxicities" and "Iodine in the treatment of hyperthyroidism".)

Patients with thyroid eye disease

Mild thyroid eye disease — For patients with mild thyroid eye disease (table 2) who prefer treatment with radioiodine, glucocorticoids given concurrently with radioiodine may prevent worsening of eye disease (table 4) [27]. (See 'Contraindications and precautions' above and 'Adverse effects' below.)

We assess the clinical activity score (CAS) to inform the decision about glucocorticoid use (table 3). In patients with active thyroid eye disease, the timing of radioiodine ablation and the decision to pretreat with glucocorticoids should be determined in collaboration with the ophthalmologist.

Although glucocorticoids reduce the effective thyroidal half-life of radioiodine by increasing renal plasma iodine clearance [28], there are no reports that the addition of glucocorticoids reduces the overall effectiveness of radioiodine treatment of the hyperthyroid state.

●CAS ≥3 – For patients with active (table 3), mild thyroid eye disease, particularly those with 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 [TRAbs]) 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 [13]. (See 'Monitoring' below.)

●CAS <3 – For patients with inactive, mild thyroid eye disease who are being treated with radioiodine, radioiodine may be administered without glucocorticoids, although many experts also offer glucocorticoids to patients with inactive, mild thyroid eye disease.

Some experts simply avoid radioiodine in patients with mild thyroid eye disease. 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 (figure 1) [29]. In this trial, 443 patients with Graves' hyperthyroidism and slight or no thyroid eye disease were randomly assigned to treatment with radioiodine (120 to 150 microcuries (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 [29]. Of the 150 patients treated with radioiodine alone, 23 (15 percent) either developed or had worsening of thyroid eye disease two to six months after treatment. 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 thyroid eye disease, and 50 of the 75 patients (67 percent) with thyroid eye disease in this arm of the study improved. In the 148 patients treated with methimazole, three (2 percent) with thyroid eye disease 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 other trials in patients with initially mild thyroid eye disease, worsening after radioiodine therapy was prevented by the concurrent administration of oral glucocorticoids [27,30,31]. The dose and duration of treatment varied within the individual studies. Doses reported to prevent exacerbation of thyroid eye disease include:

●Prednisone (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 [29,30].

●Prednisone (fixed starting dose of 35 mg prednisone tapered over 10 weeks) or intravenous methylprednisolone (500 mg/week for two weeks and 250 mg/week for two weeks) [31]. Glucocorticoids were administered 48 hours after radioiodine.

●Prednisone (0.2 mg/kg body weight) initiated one day after radioiodine, with tapering over six weeks [32].

Moderate-to-severe — Radioiodine is contraindicated in patients with moderate-to-severe or sight-threatening thyroid eye disease. (See 'Thyroid eye disease (Graves' orbitopathy)' 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 [27].

Smokers without active thyroid eye disease — Cigarette smokers who receive radioiodine have a high incidence of new or progressive thyroid eye disease [29,33]. In cigarette smokers without thyroid eye disease, there is no evidence for or against using prophylactic glucocorticoids to prevent the onset of eye disease [10]. If smokers with Graves' disease (and with no evidence of eye disease) are treated with radioiodine, the author of this topic, but not all UpToDate contributors, would administer concurrent glucocorticoids, unless there is a contraindication to the use of glucocorticoids. (See "Treatment of thyroid eye disease", section on 'Smoking cessation'.)

Iodine intake — While the radioiodine uptake can be increased by following a low-iodine diet, this is usually not recommended for patients with Graves' hyperthyroidism whose uptakes are frequently quite high on a normal-iodine diet. Supplements with high doses of iodine should generally be avoided. Avoidance of high-dose supplements may increase the radioiodine uptake and allow for lower administered doses of radioiodine.

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

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) [34], but there was no difference in a randomized trial of radioiodine alone versus radioiodine plus lithium (900 mg/day) [35]. Lithium given coincident with radioiodine can prevent the transient increase in serum thyroid hormone concentrations following radioiodine [36]. Because of inconsistent data and the potential toxicity of lithium, we do not recommend its use in conjunction with radioiodine.

RADIOIODINE ADMINISTRATION — 

The following approach to administering radioiodine is consistent with the American Thyroid Association (ATA) guidelines for the management of hyperthyroidism [10].

Treatment setting (outpatient) — Radiation safety guidelines vary among countries. In the United States, the majority of patients with hyperthyroidism can be treated with sodium iodide (131-I) in the outpatient setting since the doses of radioiodine administered for the treatment of hyperthyroidism are lower than those used to treat thyroid cancer [37,38]. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient release criteria'.)

Verify negative pregnancy test — In females between menarche (or age 12) and menopause, with an intact uterus, a negative pregnancy test should be confirmed within 48 hours prior to treatment with radioiodine.

Radioiodine dosing

Individualized versus fixed approach — We prefer to individualize the dose of radioiodine based upon the size of the thyroid gland and the 24-hour radioiodine uptake [39]. The goal of individualized dosing is to maximize cure and avoid unnecessarily high radiation exposures in patients with high radioiodine uptake [40]. The use of a fixed dose of radioiodine is an alternative approach. Fixed dosing simplifies the approach to treatment, reduces the patient's missed work days, and is less costly than an individually calculated dose.

The ATA guidelines for the management of Graves' hyperthyroidism recommend a dose (typically 10 to 15 millicuries [mCi; 370 to 555 megabecquerels (MBq)]) sufficient to cause hypothyroidism, which can be accomplished equally well with either a fixed or individualized dose regimen [10]. Although some data favor an individualized over a fixed approach to dosing because of the dependence of outcome on gland size [41], other data suggest similar outcomes with the less costly 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) [42]. 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).

Selection of dose — Whether utilizing an individualized or a fixed dosing approach, the primary goal of radioiodine therapy in Graves' disease is to cure the hyperthyroidism by rendering the patient hypothyroid (see 'Monitoring' below). 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 [43,44]. In addition, less than one-third of patients are euthyroid 10 years after therapy [45]. Many patients have chronic subclinical hyperthyroidism, with its associated risks of atrial fibrillation and reduced bone density. (See "Subclinical hyperthyroidism in nonpregnant adults".)

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) [46].

A high calculated 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 [47]. 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.

●Individualized dose calculation – An individualized dose is calculated based on the microCi or MBq per gram of thyroid tissue to be delivered. We typically administer 160 microCi/g thyroid tissue (5.9 MBq/g) for Graves' hyperthyroidism. We adjust 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 appropriateness of therapy is 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.

●Fixed dose selection – Fixed doses of 5, 10, or 15 mCi (185, 370, or 555 MBq) are commonly given to patients with Graves' hyperthyroidism. In general, 15 mCi is used for patients with larger thyroid glands, with lower doses reserved for smaller thyroid glands. In one study, which included patients with Graves' disease or toxic adenoma/toxic multinodular goiter (MNG), 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 [48].

No dose adjustment for 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 [49]. 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 [50]. 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 [38]. Data on long-term outcomes are limited. The recommendations, based upon clinical experience and available data, are reviewed briefly below. Additional information, including safety for household contacts, personal hygiene, and airline travel, is reviewed in more detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Radiation safety'.)

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 5) [37,38]. 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, and 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, and 555 MBq), respectively [51]. 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 Nuclear Regulatory Commission (NRC) [52]. The radiation exposure after a single chest radiograph is 0.1 mSv and is 0.4 mSv after a mammogram.

Future fertility

●Women – 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 thyrotropin receptor antibody (TRAb) levels increase after radioiodine and remain elevated for up to a year [53], 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. Infertility and congenital anomalies do not appear to be more common in women treated with radioiodine [54]. The gonadal dose is approximately three rad, similar to that for hysterosalpingography or a barium enema [55]. The estimated risk of genetic damage is 0.005 percent, which is much lower than the spontaneous risk of 0.8 percent [56].

●Men – Conception should be delayed for three to four months in men to allow for adequate turnover of sperm production [10].

MONITORING

Clinical evaluation — After radioiodine administration, in-person evaluation for assessment of thyrotoxic or hypothyroid symptoms, progression or new onset of thyroid eye disease, and for any change in goiter size should be performed initially every four to six weeks, coincident with measurement of thyroid function tests. Once stability has been achieved, less frequent evaluation is required. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Evaluation'.)

Thyroid function tests — After radioiodine, all patients require monitoring for hypothyroidism, or transient or persistent hyperthyroidism. Most patients have normalization of thyroid function tests within 4 to 10 weeks [57]. Hypothyroidism may occur as early as four weeks and should be treated with levothyroxine. Untreated hypothyroidism should be avoided as this is a risk factor for worsening thyroid eye disease. (See 'Appearance or exacerbation of thyroid eye disease' below.)

A persistent goiter suggests incomplete destruction of the gland and the possibility of persistent autonomous thyroid tissue.

●Frequency of testing post ablation – We measure serum free T4, total T3, and thyroid-stimulating hormone (TSH) at four to six weeks after radioiodine and then at four- to six-week intervals thereafter, depending upon the results of prior testing, patient-reported symptoms, and change in thyroid size.

The principal tests used to follow the immediate effect of treatment of hyperthyroidism are the serum free T4 and T3. 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 [58,59]. When both TSH and free T4 are low, measurement of serum T3 is necessary to distinguish between persistent hyperthyroidism (T3 thyrotoxicosis) 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 radioiodine therapy. (See "Laboratory assessment of thyroid function", section on 'Monitoring treatment of hyperthyroidism'.)

●Patients who develop hypothyroidism – If the patient becomes hypothyroid (as indicated by a low free T4 and low or normal total T3), levothyroxine 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'.)

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) [44,45,47].

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 [60]. 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. Levothyroxine should not be withheld in patients with low free T4 because of the possibility of transient hypothyroidism.

●Patients with euthyroidism – 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.

Most patients who become euthyroid soon after radioiodine therapy develop hypothyroidism at a rate of 2 to 3 percent per year [44]. 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).

●Patients with persistent hyperthyroidism – If the patient has persistent hyperthyroidism, monitoring of thyroid tests should continue at four- to six-week intervals while additional therapy is planned. Some patients may need to resume or initiate antithyroid drugs to control thyrotoxic symptoms. (See 'Methimazole pretreatment' above and "Thionamides in the treatment of Graves' disease".)

In patients with 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.

Approximately 10 to 20 percent of patients have persistent hyperthyroidism after the first radioiodine treatment [47]. 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 [61].

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- 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 [62]. 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 [63].

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 [64]. 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. (See 'Lithium (not recommended)' above.)

ADVERSE EFFECTS — 

Radioiodine appears to be quite safe aside from causing hypothyroidism [65].

Radiation thyroiditis — There is a 1 percent (or lower) incidence of radiation thyroiditis after radioiodine therapy. It usually occurs within 5 to 10 days after treatment. 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 'Methimazole pretreatment' 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 (TRAbs) [17,66]. This should be distinguished from radiation-related thyroiditis based on the timing of the symptoms and the absence of thyroid pain and tenderness. Radiation thyroiditis typically develops shortly after treatment (eg, within 5 to 10 days 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.

Appearance or exacerbation of thyroid eye disease — Most [30,33,67,68], but not all [69-71], 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. In randomized trials, the rate of new onset or progression of thyroid eye disease was approximately 30 to 40 percent with radioiodine compared with 10 to 20 percent with thionamides [33,67]. The changes are often mild and transient, at least in patients who have mild or no eye disease before therapy. (See 'Thyroid eye disease (Graves' orbitopathy)' above.)

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 more than a year [53]. In contrast, TRAb levels tend to fall after surgery and during thionamide therapy. The development of hypothyroidism with an elevated TSH is also associated with an increased risk of development or progression of thyroid eye disease [67,68,72]. Glucocorticoids administered concurrently has been shown to prevent progression of existing thyroid eye disease [27,30]. (See 'Patients with thyroid eye disease' above.)

Cancer — Some [73-76], but not all [75,77-79], reports suggest an increased risk of certain cancers (eg, thyroid, breast, small bowel) after radioiodine treatment. Whether there is an increased risk of breast cancer remains controversial. The increased risk of thyroid cancer is in patients with toxic multinodular goiter (MNG), who generally receive a higher dose of radioiodine, and are known to have a slightly increased risk of thyroid cancer at baseline.

Reports from the Cooperative Thyrotoxicosis Therapy Follow-Up Study include the following:

●An analysis of cancer mortality data through 1990 (35,593 patients from 26 centers) representing a mean follow-up of 21 years revealed no increase in overall cancer mortality [77,78].

●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) [73].

●Using modeling to assess organ radiation exposures, 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 (relative risk [RR] 1.12, 95% CI 1.003-1.32) and stomach cancer (RR 1.05, 95% CI 1.01-1.10) [74].

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 [75]. However, there was a decrease in the overall cancer incidence (634 cases versus 761 expected). In a study of 2793 Finnish patients, cancer incidence was higher in patients treated with radioiodine than in a population-based control group (118.9 versus 94.9 per 10,000 person-years, rate ratio 1.25 [95% CI 1.08-1.46]) due to cancer of the breast, stomach, and kidney [76].

The above studies (except the study that modeled radiation exposures), 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 (n = 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) [79].

Overall mortality — Although radioiodine is safe and effective, some [80-83], but not all [84], 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 [81-83]. As examples:

●In a population-based study, 2668 individuals over age 40 years treated with radioiodine for hyperthyroidism (between 1984 and 2002) were examined [82]. A slight excess in mortality was noted in the radioiodine patients compared with age- and period-specific mortality ratio (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 another 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 [83].

Major adverse cardiovascular events — Hospitalization rates for cardiovascular disease may be higher after radioiodine therapy. As an example, in a population-based study of 2611 treated patients and 2611 healthy controls, the rate of hospitalization for cardiovascular disease was 637.1 per 10,000 person-years in the radioiodine-treated patients versus 476.4 per 10,000 person-years in the control group (rate ratio 1.12 [95% CI 1.03-1.21]). Hospitalizations were higher for atrial fibrillation, cerebrovascular disease, hypertension, and heart failure, and they remained elevated for up to 35 years after treatment [85].

However, in a nationwide study from Taiwan with 114,052 individuals with new-onset hyperthyroidism, 1238 received radioiodine and 107,052 were followed on antithyroid drugs. Patients treated with radioiodine had a lower risk of major adverse cardiovascular events (a composite outcome of acute myocardial infarction, stroke, heart failure, and cardiovascular mortality). The hazard ratio (HR) for major adverse cardiovascular events was 0.45 (95% CI 0.22-0.93) for radioiodine compared with those taking antithyroid drugs [86].

Gonadal function — Radioiodine in the doses used to treat hyperthyroidism does not cause infertility or congenital anomalies in the offspring of treated patients [87] (see 'Future fertility' above). The total dose to the testes averages 39 microGy/MBq [88]. 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 [88].

Pretibial myxedema — Radioiodine therapy may also be associated with the onset or worsening of infiltrative dermopathy (pretibial myxedema) [89]. (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

●Clinical use

•Patient selection – Radioiodine can be used for the treatment of hyperthyroidism due to Graves' disease in patients who prefer definitive therapy and do not have thyroid eye disease, especially if they are at increased risk for surgical complications, and for patients who cannot take a thionamide because of adverse reactions or poor adherence. (See 'Patient selection' above.)

•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 management

•Older patients or patients with severe thyrotoxicosis – For older patients (eg, >60 years) with underlying cardiac disease and for patients with severe thyrotoxicosis (eg, free T4 two to three times the upper limit of normal) who are not tolerating the symptoms of hyperthyroidism while taking adequate doses of beta-blocking drugs, we suggest pretreatment with a thionamide (methimazole) (Grade 2C). Methimazole pretreatment shortens the time to euthyroidism and prevents post-radioiodine exacerbations of hyperthyroidism, which may benefit people with severely symptomatic thyrotoxicosis and those who have high risk for sequelae of continued hyperthyroidism. (See 'Severe thyrotoxicosis or older patients' above and "Thionamides in the treatment of Graves' disease".)

For most other 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.

•Patients with mild thyroid eye disease – For patients with mild, active (clinical activity score [CAS] ≥3) thyroid eye disease (table 3) who are being treated with radioiodine, we recommend treatment with oral or intravenous glucocorticoids (table 4) (Grade 1B). Glucocorticoids are typically started one to three days after radioiodine and continued for six to eight weeks. Glucocorticoids given with radioiodine may prevent worsening of eye disease but may be associated with known adverse effects (eg, diabetes, osteoporosis, risk of infection). (See 'Patients with thyroid eye disease' above.)

For patients with mild, inactive (CAS <3) thyroid eye disease, radioiodine may be administered without glucocorticoids, although many experts offer glucocorticoids to patients with mild, inactive thyroid eye disease. (See 'Patients with thyroid eye disease' above.)

●Radioiodine administration – Radioiodine is administered orally as sodium iodide-131 (131-I) in a capsule or rarely in a solution. We individualize the dose based upon the size of the thyroid gland and the 24-hour radioiodine uptake. We typically administer 160 microCi/g thyroid tissue (5.9 MBq/g). The use of a fixed dose of radioiodine (eg, 10 to 15 mCi [370 to 555 MBq]) is an alternative approach.

The goal of individualized dosing is to maximize cure and avoid unnecessarily high radiation exposures in patients with high radioiodine uptake. Fixed dosing simplifies the approach to treatment, reduces the patient's missed work days, and is less costly than an individually calculated dose. Whether utilizing an individualized or a fixed dosing approach, the primary goal of radioiodine therapy in Graves' disease is to cure the hyperthyroidism by rendering the patient hypothyroid. (See 'Radioiodine dosing' above.)

●Post-treatment precautions – 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 close contact and sharing of cups or utensils during the restricted period. The restricted period is determined by the dose administered and retained (table 5). (See 'Post-treatment precautions' above.)

●Monitoring – After radioiodine, all patients require monitoring for hypothyroidism or persistent hyperthyroidism. We measure serum free thyroxine (T4), total triiodothyronine (T3), and thyroid-stimulating hormone (TSH) 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. The principal tests used to follow the immediate effect of treatment of hyperthyroidism are the serum free T4 and T3. Patients should also be evaluated for thyrotoxic or hypothyroid symptoms, progression or new onset of thyroid eye disease, and for any change in goiter size. (See 'Monitoring' above.)

●Adverse effects – Adverse effects of radioiodine include hypothyroidism, onset or progression of thyroid eye disease, radiation thyroiditis, and rebound hyperthyroidism. There may be an increased risk of breast cancer and other solid tumors with higher doses. Overall mortality does not appear to be increased in patients whose hyperthyroidism is effectively treated. (See 'Adverse effects' above.)