[D] If 131I therapy is chosen, how should it be accomplished?

[D1] Preparation of patients with GD for 131I therapy

    Patients with GD who are at increased risk for complications due to worsening of hyperthyroidism (i.e., those who are extremely symptomatic or have free T4 estimates 2–3 times the upper limit of normal) should be treated with beta-adrenergic blockade prior to radioactive iodine therapy. 1/+00 
    Pretreatment with methimazole prior to radioactive iodine therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism (i.e., those who are extremely symptomatic or have free T4 estimate 2–3 times the upper limit of normal). 2/+00
    Task force opinion was not unanimous; one person held the opinion that pretreatment with methimazole is not necessary in this setting.

    Medical therapy of any comorbid conditions should be optimized prior to administering radioactive iodine. 1/+00

131I has been used to treat hyperthyroidism for six decades. This therapy is well tolerated and complications are rare, except for those related to ophthalmopathy (see section [T].) Thyroid storm occurs only rarely following the administration of radioactive iodine (50,51). In one study of patients with thyrotoxic cardiac disease treated with radioactive iodine as the sole modality, no clinical worsening in any of the cardinal symptoms of thyrotoxicosis was seen (52). The frequency of short-term worsening of hyperthyroidism following pretreatment with ATD therapy is not known. However, the use of methimazole (MMI) or carbimazole, the latter of which is not marketed in the United States, before and after 131I treatment may be considered in patients with severe thyrotoxicosis (i.e., those who are extremely symptomatic or have free T4 estimates 2–3 times the upper limit of normal), the elderly, and those with substantial comorbidity that puts them at greater risk for complications of worsening hyperthyroidism (53,54). The latter includes patients with cardiovascular complications such as atrial fibrillation, heart failure, or pulmonary hypertension and those with renal failure, infection, trauma, poorly controlled diabetes mellitus, and cerebrovascular or pulmonary disease (50). These comorbid conditions should be addressed with standard medical care and the patient rendered medically stable before the administration of radioactive iodine. In addition, beta-adrenergic blocking drugs should be used judiciously in these patients in preparation for radioiodine therapy (20,55).

One committee member felt that MMI use is not necessary in preparation, as there is insufficient evidence for radioactive iodine worsening either the clinical or biochemical aspects of hyperthyroidism, and it only delays treatment with radioactive iodine. In addition, there is evidence that MMI pretreatment may reduce the efficacy of subsequent radioactive iodine therapy (6,52,56).

Technical remarks: If given as pretreatment, MMI should be discontinued 3–5 days before the administration of radioactive iodine, restarted 3–7 days later, and generally tapered over 4–6 weeks as thyroid function normalizes. Over several decades, there have been reports that pretreatment with lithium reduces the activity of 131I necessary for cure of Graves’ hyperthyroidism and may prevent the thyroid hormone increase seen upon ATD withdrawal (57–59). However, this is not used widely, and there is insufficient evidence to recommend the practice.

[D2] Administration of 131I in the treatment of GD

    Sufficient radiation should be administered in a single dose (typically 10–15 mCi) to render the patient with GD hypothyroid. 1/++0 
    A pregnancy test should be obtained within 48 hours prior to treatment in any female with childbearing potential who is to be treated with radioactive iodine. The treating physician should obtain this test and verify a negative result prior to administering radioactive iodine. 1/+00
The goal of 131I is to control hyperthyroidism by rendering the patient hypothyroid; this treatment is very effective, provided sufficient radiation is deposited in the thyroid. This can be accomplished equally well by either administering a fixed activity or by calculating the activity based on the size of the thyroid and its ability to trap iodine (44). The first method is simple, and there is evidence that 10 mCi (370 MBq) results in hypothyroidism in 69% (representing cure) at 1 year (60) and 15 mCi (450 MBq) results in hypothyroidism in 75% at 6 months (61). The second method requires three unknowns to be determined: the uptake of radioactive iodine, the size of the thyroid, and the quantity of radiation (µCi or Bq) to be deposited per gram (or cc) of thyroid (e.g., activity (µCi) = gland weight (g)×150 µCi/g×[1/24 hour uptake on% of dose]). The activity in µCi is converted to mCi by dividing the result by 1000. The most frequently used uptake is calculated at 24 hours, and the size of the thyroid is determined by palpation or ultrasound. One study found that this estimate by experienced physicians is accurate compared with anatomic imaging (62); however, other investigators have not confirmed this observation (63). There is wide variation in the recommended quantity of 131I that should be deposited (i.e., between 50 and 200 µCi/g). Historically, activities at the low end of the spectrum have led to a higher proportion of treatment failures (41).

Alternately, a more detailed calculation can be made to deposit a specific number of radiation absorbed dose (rad) or Gy to the thyroid. Using this approach, it is also necessary to know the effective half-life of the 131I (44). This requires additional time and computation and, because the outcome is not better, this method is seldom used in the United States. Evidence shows that to achieve a hypothyroid state, >150 µCi/g needs to be delivered (61,64,65). Patients who are on dialysis or who have jejunostomy or gastric feeding tubes require special care when being administered therapeutic doses of radioiodine (66).

Propylthiouracil (PTU) treatment before 131I increases the radioresistance of the thyroid (51,67). Whether MMI may have the same effect is unclear (51). Use of higher activities of 131I may offset the reduced effectiveness of 131I therapy following antithyroid medication (53,54). A special diet is not required before radioactive iodine therapy, but excessive amounts of iodine, including iodine-containing multivitamins, should be avoided for at least 7 days. A low-iodine diet may be useful for those with relatively low RAIU to increase the proportion of radioactive iodine trapped.

 A long-term increase in cardiovascular and cerebrovascular deaths has been reported after 131I therapy, likely due to the hyperthyroidism rather than the treatment (56). While this study also found a small increase in cancer mortality, long-term studies of larger numbers of patients have not shown a statistically significant increase in cancer deaths following this treatment (68–74). In some men, there is a modest fall in the testosterone to luteinizing hormone (LH) ratio after 131I therapy that is subclinical and reversible (75). Conception should be delayed for 4–6 months in women to assure stable euthyroidism (on thyroid hormone replacement following successful thyroid ablation) and 3–4 months in men to allow for turnover of sperm production. However, once the patient (both genders) is euthyroid, there is no evidence of reduced fertility and offspring of treated patients show no congenital anomalies compared to the population at large.

Technical remarks: Rendering the patient hypothyroid can be accomplished equally well by administering either a sufficient fixed activity or calculating an activity based on the size of the thyroid and its ability to trap iodine. Fetuses exposed to 131I after the 10th to 11th week of gestation may be born athyreotic (76,77) and are also at a theoretical increased risk for reduced intelligence and/or cancer. In breast-feeding women, radioactive iodine therapy should not be administered for at least 6 weeks after lactation stops to ensure that the radioactivity will no longer be actively concentrated in the breast tissues.

    The physician administering the radioactive iodine should provide written advice concerning radiation safety precautions following treatment. If the precautions cannot be followed, alternative therapy should be selected. 1/+00
All national and regional radiation protection rules regarding radioactive iodine treatment should be followed (78). In the United States, the treating physician must ensure and document that no adult member of the public is exposed to 0.5 mSv (500 milli-roentgen equivalent in man [mrem]) when the patient is discharged with a retained activity of 33 mCi (1.22 GBq) or greater, or emits ≥ 7 mrem/h (70 µSv/h) at 1 m.

Technical remarks: Continuity of follow-up should be provided and can be facilitated by written communication between the referring physician and the treating physician, including a request for therapy from the former and a statement from the latter that the treatment has been administered.

[D3] Patient follow-up after 131I therapy for GD

    Follow-up within the first 1–2 months after radioactive iodine therapy for GD should include an assessment of free T4 and total T3. If the patient remains thyrotoxic, biochemical monitoring should be continued at 4–6 week intervals. 1/+00

Most patients respond to radioactive iodine therapy with a normalization of thyroid function tests and clinical symptoms within 4–8 weeks. Hypothyroidism may occur from 4 weeks on, but more commonly between 2 and 6 months, and the timing of thyroid hormone replacement therapy should be determined by results of thyroid function tests, clinical symptoms, and physical examination. Transient hypothyroidism following radioactive iodine therapy can rarely occur, with subsequent complete recovery of thyroid function or recurrent hyperthyroidism (79). When thyroid hormone replacement is initiated, the dose should be adjusted based on an assessment of free T4. The required dose may be less than the typical full replacement, and careful titration is necessary owing to nonsuppressible residual thyroid function. Overt hypothyroidism should be avoided, especially in patients with active GO (see section T2). Once euthyroidism is achieved, lifelong annual thyroid function testing is recommended.

Technical remarks: Since TSH levels may remain suppressed for a month or longer after hyperthyroidism resolves, the levels should be interpreted cautiously and only in concert with free T4 and T3 estimates.

[D4] Treatment of persistent Graves’ hyperthyroidism following radioactive iodine therapy

    When hyperthyroidism due to GD persists after 6 months following 131I therapy, or if there is minimal response 3 months after therapy, retreatment with 131I is suggested. 2/+00

Technical remarks: Response to radioactive iodine can be assessed by monitoring the size of the gland, thyroid function, and clinical signs and symptoms. The goal of retreatment is to control hyperthyroidism with certainty by rendering the patient hypothyroid. Patients who have persistent, suppressed TSH with normal total T3 and free T4 estimates may not require immediate retreatment but should be monitored closely for either relapse or development of hypothyroidism. In the small percentage of patients with hyperthyroidism refractory to several applications of 131I, surgery could be considered (80).