In many thyroid clinics, ¹³¹I therapy is now used for most patients with Graves' disease who are beyond the adolescent years. It is used in most patients who have had prior thyroid surgery, because the incidence of complications, such as hypoparathyroidism and recurrent nerve palsy, is especially high in this group if a second thyroidectomy is performed. Likewise, it is the therapy of choice for any patient who is a poor risk for surgery because of complicating disease.

The question of an age limit below which RAI should not be used frequently arises. With lengthening experience these limits have been lowered. Several studies with average follow-up periods of 12 - 15 years attest to the safety of ¹³¹I therapy in adults. ^39-41  In two excellent studies treated persons  showed no tendency to develop thyroid cancer, leukemia, or reproductive abnormalities, and their children  had no increase in congenital defects or evidence of thyroid damage. ^42-44  Franklyn and co workers recently reported on a population based study of 7417 patients treated with 131-I for thyrotoxicosis in England ^44.1 They found an overall decrease in incidence of cancer mortality, but a specific increase in mortality from cancer of the small bowel ((7 fold) and of the thyroid (3.25) fold.  The absolute risk remains very low, and it is not possible to determine whether the association is related to the basic disease, or to radioiodine treatment. Although there is much less data on long term results in children, there is a gradual tendency to use this treatment in teenagers over age 15-18, as discussed below. The epidemic of thyroid cancer apparently induced by radioactive iodine isotopes in infants and children living around Chernobyl suggests caution in use of 131-I in younger children.

Certain other findings may dictate the choice of therapy. Occasionally, the ¹³¹I uptake is significantly blocked by prior iodine administration. The effect of iodide dissipates in a few days after stopping exposure, but it may take 3-12 weeks for the effect of amiodarone or IV contrast dyes to be lost. One may either wait for a few days to weeks until another ¹³¹I tracer indicates that the uptake is in the toxic range or use an alternative therapeutic approach such as antithyroid drugs. 
    Sometimes a patient with thyrotoxicosis harbors a thyroid gland with a configuration suggesting the presence of a malignant neoplasm. These patients probably should have surgical exploration. While FNA may exclude malignancy, the safety of leaving a highly irradiated nodule in place for many years is not established. Currently few patients who will have RAI therapy are subjected to ultrasonagraphy or scintiscaning. However Stocker et al ^{found that 12% of Graves’ patients had cold defects on scan, and among these half were referred for surgery.  Six of 22, representing 2% of all Graves’ patients, 15% of patients with cold nodules, 25% of patients with palpable nodules, and 27% of those going to surgery have papillary cancer in the location corresponding to the cold defect.  Of these patients, one had metastasis to bone and two required multiple treatments with radioiodine.  They argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects(201a).  
    131}I therapy causes an increase in titers of TSH-RAbs, and anti-TG or TPO antibodies, which reflects an activation of autoimmunity. It probably is due to release of thyroid antigens by cell damage, or destruction of intrathyroidal T cells. Although completely satisfactory statistical proof is lacking, many thyroidologists are convinced that ¹³¹I therapy can lead to exacerbation of infiltrative ophthalmopathy, perhaps because of this immunologic response.  Tallstedt and associates have published data indicating   that 131-I therapy  causes exacerbation of ophthalmopathy in nearly 25% of patients, while surgery is followed by this response in about half as many. Thus, as described below, patients with significant ophthalmopathy may receive corticosteroids along with ¹³¹I, or may be selected for surgical management. Menconi et al recently compared the effects of total thyroidectomy (TT) to total thyroidectomy plus 131-I ablation (TTA)  in 60 patients with mild to moderate Graves’ ophthalmopathy, all of whom also received 12 infusions of  methyprednisolone over 10 weeks. The TTA group had significantly lower TG and RAIU when off medication, and at 9 months had significantly greater incidence of improvement, significantly fewer worsening cases, and better improvement in proptosis, symptom score, and decrease in diplopia. This study adds  evidence to the idea of avoiding RAI, and using surgery instead, in patients with significant eye problems [present at the time therapy is to be given(Menconi F, Marino M, Pinchera A, Rocchi R, Mazzi B, Nardi M, Bartalena L, Marcocci C. Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves' orbitopathy treated with intravenous glucocorticoids.J Clin Endocrinol Metab. 2007 May;92(5):1653-8). Because this is the first randomized prospective study on this issue, it is a very important observation.

The indications and contraindications for ¹³¹I therapy are given in Table 11-5.

The dosage initially was worked out by a trial-and-error method and by successive approximations. The introduction of ¹³¹I into therapy has been reviewed by E.M. Chapman ⁴⁵, who figured importantly in the development of this treatment. By about 1950, the standard dose had become 160 uCi ¹³¹ I per gram of estimated thyroid weight. Of course, estimating the weight of the thyroid gland by examination of the neck is an inexact procedure, but can now be made more accurate by use of ultrasound. Also, marked variation in radiation sensitivity no doubt exists and cannot be estimated at all. It was gratifying that in practice this dosage scheme worked well enough. Over the years some effort was made to refine the calculation. Account was taken of uptake, half-life of the radioisotope in the thyroid, concentration per gram, and so on, but it is evident that the result in a given instance depends on factors that cannot be estimated precisely. ^46,47 One factor must be the tendency of the thyroid to return to normal if a dose of radiation is given that is large enough to make the gland approach, for a time, a normal functional state; and in most  patients, "cure" is associated actually with partial or total thyroid ablation. Although we, and many endocrinologists, attempt to scale the dose to the particular patient, some therapists believe it is futile, advocate giving up this attempt, and provide a standard dose giving up to 10000 rads to the thyroid(47.1). Leslie et al reported a comparison of fixed  dose treatment and treatment adjusted for 24 hour RAIU, using low or high doses, and found no difference in outcome in either rate of control or induction of hypothyroidism on comparison of the methods.  They favor the use of a fixed dose treatment with a single high or low dose (47.2).

In the early 1960s, it was recognized that a complication of RAI therapy was a high incidence of hypothyroidism. This reached 20 - 40% in the first year after therapy and increased about 2.5% per year, so that by 10 years 50 - 80% of patients had low function. ⁴⁸ In 1964, in an effort to lower the dose of RAI and possibly reduce the incidence of late hypothyroidism, Hagen and colleagues reduced the quantity of ¹³¹I to 0.08 mCi per gram of estimated gland weight. ⁴⁸ No increase was reported in the number of patients requiring retreatment, and there was a substantial reduction in the incidence of hypothyroidism. Most of these patients were maintained on potassium iodide for several months after therapy, in order to ameliorate the thyrotoxicosis while the radioiodine had its effect. ^49,50 Patients previously treated with 131-I are sensitive to and generally easily controlled by KI. However KI often precipitates hypothyroidism in these patients, which may revert to hyperthyroidism when the KI is discontinued.

Many attempts have been made to improve the therapeutic program by giving the RAI in smaller doses. Reinwein et al. ⁵¹ studied 334 patients several years after they had been treated with serial doses of less than 50 uCi ¹³¹I per gram of estimated thyroid weight. One-third of these patients had increased levels of TSH, although they were clinically euthyroid. Only 3% were reported to be clinically hypothyroid.

Approaches to dosage adjustment usually include a factor for gland size, a standard dose in microCuries per gram, and a correction to account for ¹³¹I uptake. ⁵² The Thyroid Group at the University of Chicago used for many years a "Low Dose Protocol" designed to compensate for the apparent radiosensitivity of small glands and resistance of larger glands.⁵³ Using this approach, after one year, 10% of patients were hypothyroid, 60% are euthyroid, and 30% remained intrinsically toxic,⁵³ although euthyroid by virtue of antithyroid drug treatment. At ten year follow-up, 40% are euthyroid and 60% are hypothyroid. A problem with low-dose therapy is that about 25% of patients require a second treatment and 5% require a third. Although this approach reduces early hypothyroidism, it does so at a cost in time, money and patient convenience (Fig. 11-2). To answer these problems, we tended to re-treat, if need be, within six months, rather than waiting a full year, and employed propranolol and antithyroid drugs between ¹³¹I doses if needed. Unfortunately, our experience and that of others shows that even low-dose ¹³¹I therapy is followed by a progressive development of hypothyroidism in up to 40 - 50% of patients ten years after therapy.^54-57

Fig. 11-2. Comparison of outcome of treatment of thyrotoxicosis by 131I (left upper panel); 131I plus ATD + KI (right upper panel); surgery (left lower panel); and ATD (right lower panel); over ten years follow-up. Surgery produced the highest final percentage of euthyroidism without therapy, followed by ATD and 131I.

Impressed by the need to retreat nearly a third of patients, we have in recent years utilized a "Moderate Dose Protocol" Table 11-6). This is a fairly conventional program with a mean dose of about 9 mCi. The ¹³¹I dosage is related to gland weight and RAIU and is increased as gland weight increases. The calculation used is as follows:

Probably it is wise to do uptakes and treatment using either  capsules or   liquid isotope for both events. Rini et al have reported that RAIU done with isotope in a capsule appears to give significantly lower values (25 – 30% lower) than when the isotope is administered in liquid form, and this can significantly influence the determination of the dosage given for therapy(57.2). For the convenience of readers who may, like us, find difficult the conversion of older units in Curies, rads, and rems to newer units of measurement, we are providing Table 11-7. Berg et al report using a relatively similar protocol (absorbed doses of 100-120 Gy) and that 93% of their patients required replacement therapy after 1-5 years ^57.1. Some physicians advocate a planned complete destruction of the thyroid by ¹³¹I treatment, followed by replacement therapy.⁵⁸ For example, a dose is given that will result in about 7-20 mCi retained at 24 hrs. They argue that the near certainty of prompt control and the inevitability of hypothyroidism make this a realistic and preferable approach. However, over 50% of patients given low dose therapy remain euthyroid after ten years and can easily be surveyed at one- or two-year intervals. When giving large doses of 131-I it is prudent to calculate the rads delivered to the gland (as above), which can reach 40-50000. Such large doses of radiation can cause clinically significant radiation thyroiditis, and occasionally damage surrounding structures.  Franklyn and co-workers have recently analyzed their data on treatment of 813 hyperthyroid patients with radioactive iodide and corroborate many of the previously recognized factors involved in response.  Lower dose (in this case 5 mCi), male gender, goiters of medium or large size and severe hyperthyroidism were factors that were associated with failure to cure after one treatment.  They suggest using higher fixed initial doses of radioiodine for treating such patients (58.2), as do Leslie et al(58.3)

Pretreatment with antithyroid drug--Patients are often treated directly after diagnosis, without prior therapy with antithyroid drugs. This is safe and common in patients with mild hyperthyroidsm and especially those without eye problems. Often physicians give antithyroid drugs before ¹³¹I treatment in order to deplete the gland of stored hormone and to restore the FTI to normal before ¹³¹I therapy.   This offers several benefits.  The possibility of 131-I induced exacerbation of thyrotoxicosis is reduced, the patient recovers toward normal health, and there is time to reflect on the desired therapy and review any concerns about the use of radioisotope for therapy. If the patient has been on antithyroid drug, it is discontinued two days before RAIU and therapy.  Patients can be treated while on antithyroid drug, but this reduces the dose retained, reduces the post-therapy increment in hormone levels, but reduces the cure rate, so seems illogical(58.31) . When antithyroid drugs are discontinued the patients disease may exacerbate, and this must be carefully followed.  Beta blockers can be given in this interim, but there is no reason for a prolonged interval between stopping   antithyroid drug, and 131-I therapy, unless there is uncertainty about the need for the treatment. 
Although there is controversy on this point,  pretreatment with antithyroid drug does not appear in some studies to reduce the efficacy of ¹³¹I treatment.⁵⁹  The debate about the effect of antithyroid drug pretreatment on the efficacy of radioactive iodine therapy for Graves’ disease continues.  In a recent study in which patients were on or off antithyroid therapy, which was discontinued four days before treatment, there was no effect on the efficacy of treatment at a one year endpoint (59.2). In another study Bonnema et al found that PTU pretreatment , stopped 4 days prior to 131-I, reduced the efficacy of 131-I(59.4).

Pretreatment is usually optional but is logical in patients with large glands and severe hyperthyroidism.  Antithyroid drug therapy does reduce the pretreatment levels of hormone and reduces the rise in thyroid hormone level that may occur after radioactive iodide treatment.  This certainly could have a protective effect in individuals who have coincident serious illness such as coronary artery disease, or perhaps individuals who have very large thyroid glands (59.3).   It is indicated in two circumstances. In patients with severe heart disease, an ¹³¹I- induced exacerbation of thyrotoxicosis could be serious or fatal. We also have the impression, without proof, that pretreatment may reduce exacerbation of eye disease (see below), and it does reduce the post-RAI increase in antibody titers(59.1).   The treatment dose of 131-I is best given as soon as possible after the diagnostic RAIU in order to reduce the period in which thyrotoxicosis may exacerbate without treatment, and since any intake of iodine  (from diet or medicines or tests) would alter uptake of the treatment dose.

Post 131-I treatment--Many patients remain on beta-blockers but require no other treatment after 131-I therapy.  Antithyroid drugs can be reinstituted after 5 ( or preferably 7 ) days, with minimal effect on retention of the treatment dose of 131-I.  Alternatively, one may prescribe antithyroid drug (typically 10 mg methimazole q8h) beginning one day after administration of ¹³¹I and add KI (2 drops q8h) after the second dose of methimazole. KI is continued for two weeks, and antithyroid drug as needed. This promotes a rapid return to euthyroidism, but by preventing recirculation of ¹³¹I it can lower the effectiveness of the treatment. This method has been employed in a large number of patients at the University of Chicago, and is especially useful in patients requiring rapid control- for example, with CHF. A typical response is shown in Fig 11-3. It also has provided the largest proportion of patients remaining euthyroid at 10 years after therapy, in comparison to other treatment protocols. Glinoer and Verelst also report successful use of this strategy ^59.1. As noted, antithyroid drugs may be given starting 7-10 days after RAI without significantly lowering the radiation dose delivered to the gland.

Figure 11-3. 131-I-ATD-KI protocol.  Twenty-four hours after 131-I therapy, methimazole is instituted (5-10mg q8h), followed by KI ) two drops Lugol's solution or similar q8h) at the time of each subsequent dose of ATD.  KI is stopped at two weeks, and ATD continued or tapered as appropriate.

Use of 125-I-As an alternative to ¹³¹I, and because it might offer certain advantages, ¹²⁵I was tried in the treatment of thyrotoxicosis. ^{60 125}I is primarily a gamma ray emitter, but secondary low-energy electrons are produced that penetrate only a few microns, in contrast to the high-energy beta rays of ¹³¹I. Thus, it might theoretically be possible to treat the cytoplasm of the thyroid cell with relatively little damage to the nucleus. Appropriate calculations indicated that the radiation dose to the nucleus could be perhaps one-third that to the cytoplasm, whereas this difference would not exist for ¹³¹I. Extensive therapeutic trials have nonetheless failed to disclose any advantage thus far for ¹²⁵I. Larger doses -- 10-20 mCi -- are required, increasing whole body radiation considerably. ^61,62

Table 11-5. Iodine-131 Therapy for Graves' Disease

Table 11-6. Dosage Schedule for ¹³¹I Therapy

                                                         -DOSE PROTOCOL                                                    MODERATE-DOSE PROTOCOL

Table 11-7. Conversion of International Units of Measurement

Usually the T₄ level falls progressively, beginning in one to three weeks, if adequate treatment has been given. Labeled thyroid hormones, iodotyrosines, and iodoproteins appear in the circulation ⁶³ TG is released, starting immediately after therapy. Another iodoprotein, which seems to be an iodinated albumin, is also found in plasma. This compound is similar or identical to a quantitatively insignificant secretion product of the normal gland. It comprises up to 15% or more of the circulating serum ¹³¹I in thyrotoxic patients. ⁶⁴ It is heavily labeled after ¹³¹I therapy, and its proportional secretion is probably increased by the radiation. Iodotyrosine present in the serum may represent leakage from the thyroid gland, or may be derived from peripheral metabolism of TG or iodoalbumin released from the thyroid.

The return to the euthyroid state usually requires at least two months, and often the declining function of the gland proceeds gradually over six months to a year. For this reason, it is logical to avoid retreating a patient before six months have elapsed unless there is no evidence of control of the disease. While awaiting the response to ¹³¹I, the symptoms may be controlled by propranolol, antithyroid drugs, or iodide. Hypothyroidism develops transiently in 10 - 20% of patients, but thyroid function returns  to normal in most  of these patients in a period ranging from three to six months. These patients rarely become toxic again. Others develop permanent hypothyroidism and require replacement therapy. It is advantageous to give the thyroid adequate time to recover function spontaneously before starting permanent replacement therapy. This can be difficult for the patient unless at least partial replacement is given.Unfortunately, one of the side effects of treating hyperthyroidism is a common weight gain, averaging about 20 lbs through four years after treatment (64a).

Patients may develop transient increases in FTI and T3 at 2-4 months after treatment ^63.1, sometimes associated with enlargement of the thyroid. This may represent an inflammatory response to the irradiation, and the course may change rapidly with a dramatic drop to hypothyroidism in the 4-5^th month.

Hypothyroidism may ultimately be inescapable after any amount of radiation that is sufficient to reduce the function of the hyperplastic thyroid to normal.⁶⁵ Many apparently euthyroid patients (as many as half) have elevated serum levels of TSH long after ¹³¹I therapy, with "normal" plasma hormone levels. ⁶⁶ An elevated TSH level with a low normal T₄ level is an indicator of changes progressing toward hypothyroidism ⁶⁷. The hypothyroidism is doubtless also related to the continued autoimmune attack on thyroid cells. Hypofunction is a common end stage of Graves' disease independent of ¹³¹I use; it occurs spontaneously as first noted in 1895 ⁶⁸ and in patients treated only with antithyroid drugs. ⁶⁹ Just as after surgery, the development of hypothyroidism is correlated positively with the presence of antithyroid antibodies.

During the rapid development of postradiation hypothyroidism, the typical symptoms of depressed metabolism are evident, but two rather unusual features also occur. The patients may have marked aching and stiffness of joints and muscles. They may also develop severe centrally located and persistent headache. The headache responds rapidly to thyroid hormone therapy and suggests physiologic swelling of the pituitary. Hair loss can also be dramatic at this time.

In patients developing hypothyroidism rapidly, the plasma T₄ level and FTI accurately reflect the metabolic state. However, it should be noted that the TSH response may be suppressed for weeks or months by prior thyrotoxicosis; thus, the TSH level may not accurately reflect hypothyroidism in these persons and should not be used in preference to the FTI or fT4.

If permanent hypothyroidism develops, the patient is given replacement hormone therapy and is impressed with the necessity of taking the medication for the remainder of his or her life. It has been our policy not to prescribe thyroid hormone for those who develop only temporary hypothyroidism, although it is possible that patients in this group should receive replacement hormone, for their glands have been severely damaged and they may be likely to develop myxedema at a later date. Perhaps these thyroids, under prolonged TSH stimulation, may tend to develop adenomatous or malignant changes, but this has not been observed.    Many middle-aged women gain weight excessively after radioactive iodide treatment of hyperthyroidism.  Usually such patients are on what is presumed to be appropriate T4 replacement therapy.  Tigas et al note that such weight gain is less common after ablative therapy for thyroid cancer, in which case larger doses of thyroxine are generally prescribed.   Thus they question whether the excessive weight gain after radioactive iodide treatment of Graves’ disease is due to the fact that insufficient thyroid hormone is being provided, even though TSH is within the “normal” range.  They suggest that restoration of serum TSH to the reference range by T4 alone may not constitute adequate hormone replacement ^69a.

Permanent replacement therapy (regardless of the degree of thyroid destruction) for children who receive ¹³¹I may have a better theoretical basis. In these cases, it may be advisable to prevent TSH stimulation of the thyroid and so mitigate any (unproven) tendency toward carcinoma formation.

Exacerbation of thyrotoxicosis-During the period immediately after therapy, there may be a transient elevation of the T₄ or T₃ level, ⁷⁰ but usually the T₄ level falls progressively toward normal. Among our treated hyperthyroid patients with Graves' disease, we have observed only rare exacerbations of the disease. These patients have had cardiac problems such as worsening angina pectoris, congestive heart failure, or disturbances of rhythm such as atrial fibrillation or even ventricular tachycardia. Radiation-induced thyroid storm and even death have unfortunately been reported. ^71-73 These untoward events argue for pretreatment of selected patients who have other serious illness, especially cardiac disease, with antithyroid drugs prior to ¹³¹I therapy.

I.W., 48-Year-Old Woman: RAI-Therapy-Induced Exacerbation of Thyrotoxicosis

The patient developed nervousness and was told by her physician that she had a goiter, but no medication was prescribed. She subsequently experienced shaking hands, heat intolerance, palpitations, and crying. She was under a good deal of stress because of her husband's alcoholism and concern about a son who was in Vietnam, and a daughter-in- law with two young children who were living with her.

On examination, BP was 120/70, pulse rate 80, and respirations 16/min. The eyes were normal. The thyroid was about two to three times normal in size, diffusely enlarged, and rubbery. The heart was not enlarged on physical examination. The PMI was in the fifth left intercostal space at the midclavicular line. There was a grade 1 systolic murmur. There was no jugular venous distention. S-1 and S-2 were normal. The skin was warm and fine. She had 1 + pitting edema of the extremities. There was a fine tremor. The T₄ level was 14.2 µg/dl, and the FTI was 16.2. The anti-TG antibody titer was positive at 1/5120. The electrocardiogram showed LVH and a left bundle branch block. The RAIU was elevated at 47%. X-ray films showed a generalized enlargement of the heart. The ESR was 3 mm. Hemogram, urinalysis, electrolyte, and blood sugar test results were normal.

The patient was treated with 4.6 mCi of radioactive ¹³¹I. Twenty-eight days later, she experienced an episode of stabbing chest pain that woke her from sleep and caused breathlessness. She was brought to the emergency room, where an electrocardiogram revealed the changes previously described. At this time, she also described a similar episode occurring several weeks earlier, and stated that she had dyspnea after walking two or three blocks. There were no other symptoms of congestive heart failure. The BP was 120/80 and the pulse rate 120; results of the physical examination were otherwise unchanged.

While being admitted, the patient developed atrial fibrillation with a ventricular rate of 160/min. A gallop was present, and there were basilar rales. Diagnostic considerations included myocardial ischemia due to thyrotoxicosis, acute myocardial infarction, and pulmonary embolism. She was given 0.5 mg digoxin intravenously and propranolol to control her heart rate, receiving doses of up to 6 mg over 10 minutes intravenously to bring her rate to 120 BPM. She was stabilized on a dosage of propranolol of 30 mg every six hours, and was also given furosimide and potassium chloride. She was immediately started on PTU, 150 mg every six hours, and potassium iodide solution. She continued to experience episodes of stabbing chest pain and flushing. The heart rate declined with treatment to about 90, and BP was 120/80 to 140/80.

The initial T₄ level was 26.6 µg/dl, and the FT₄I was 47. Lung scan findings were unremarkable. The serum ASAT and LDH levels were normal. Serial electrocardiograms did not show evidence of myocardial infarction, and there was no evidence of pulmonary embolism. The CPK level was normal and the leukocyte count was never elevated.

During the subsequent days, while continuing to receive antithyroid drugs, potassium iodide, digoxin, propranolol, and diazepam, the patient had occasional chest pain, some shortness of breath, and sensations of flushing. She had no obvious symptoms of severe thyrotoxicosis.

The following values for T₄ and FTI were recorded:

Studies of T₄ degradation indicated a turnover half-time of four days. It was estimated that T₄ degradation exceeded 1 mg daily. On May 6, since potassium iodide seemed to be producing no effect, it was discontinued, and PTU was increased to 250 mg daily. The electrocardiogram eventually reverted to the pattern present before RAI therapy was instituted.

By July the patient's FTI had fallen to 1, the thyroid was normal in size, and she required replacement therapy. She continued to have occasional chest pain, but was otherwise without symptoms. Treatment during follow-up included digoxin and thyroxine.

It was believed that the patient's chest pain and atrial fibrillation represented effects of severe thyrotoxicosis induced by release of hormone from a gland damaged by radiation thyroiditis. The symptoms of thyrotoxicosis were not marked, perhaps because of the administration of propranolol and diazepam. PTU and potassium iodide treatment appeared to have little effect on the level of thyroid hormone, which reached remarkable levels. Potassium iodide was eventually discontinued, and subsequently the hormone levels returned to normal.