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

SELECTION OF 131-I Dosage

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 131-I 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].

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:

uCi given = (estimated thyroid weight in grams X uCi/g for appropriate weight from Table) / (fractional RAIU at 24 hours) (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.)

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).. 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 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, because it might offer certain advantages, 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 125-I. 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 5. Iodine-131 Therapy for Graves' Disease

Table 6. Dosage Schedule for 131I Therapy

Table 7. Conversion of International Units of Measurement

Course After Treatment

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 4-5th 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 T ₄level 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 fT ₄.

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 T ₄alone 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 T ₄level 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 131-I 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 T ₄level 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:

Table extra. Table - Extra

Studies of T4 degradation indicated a turnover half-time of four days. It was estimated that T ₄degradation 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.

Problems Associate With ¹³¹I Therapy

The immediate side effects of ¹³¹I therapy are typically minimal. As noted above, transient exacerbation of thyrotoxicosis can occur, and apparent thyroid storm has been induced within a day (or days) after 131-I therapy. A few patients develop mild pain and tenderness over the thyroid and, rarely, dysphagia. Some patients develop temporary thinning of the hair, but this condition occurs two to three months after therapy rather than at two to three weeks, as occurs after ordinary radiation epilation. Hair loss also occurs after surgical therapy, so that it is a metabolic rather than a radiation effect. If the loss of hair is due to the change in metabolic status, it generally recovers in a few weeks or months. However hair thinning, patchy alopecia, and total alopecia, are all associated with Graves' Disease, probably as other auto-immune processes. In this situation the prognosis for recovery is less certain, and occasionally some other therapy for the hair loss (such as steroids) is indicated. Permanent hypoparathyroidism has been reported very rarely as a complication of RAI therapy for heart disease and thyrotoxicosis[ 74- 76]. Patients treated for hyperthyroidism with 131-I received approximately 39 microGy/MBq administered (about 0.144rad/mCi) of combined beta and gamma radiation to the testes. This is reported to cause no significant changes in FSH, but testosterone declines transiently for several months, and there is no variation in sperm motility or % abnormal forms (76.1). Long term studies of patients after RAI treatment by Franklyn et al (76a) show a slight increase in mortality which appears to be related to cardiovascular disease, possibly related to periods of hypothyroidism.

Figure 4. Transient increase in TBII followed by a decrease in patients treated with 131I. Note that in this study a lower "TSI Index" means more TBII are present.

Worsening of ophthalmopathy---In contrast to the experience with antithyroid drugs or surgery, antithyroid antibodies including TSAb levels increase after RAI [ 77, 78]. (Fig. 11-4, above). Coincident with this condition, exophthalmos may be worsened [79].(Fig. 11-5, below). Although we believe that this change is an immunologic reaction to discharged thyroid antigens, this is conjecture, and the relationship of radiation therapy to exacerbation of exophthalmos remains uncertain. [79]Recent data indicates that there is a significant correlation[ 80, 80.1]. Nevertheless, we consider "bad eyes" to be a relative contraindication to RAI. Pretreatment with antithyroid drugs has been used empirically in an attempt to prevent this complication. Its benefit, if any, may be related to an immunosuppressive effect of PTU, described below. Treatment with methimazole before and for three months after I131 therapy has been shown to help prevent the treatment-induced rise in TSH-R antibodies which is otherwise seen. [81]

Administration of prednisone with ¹³¹I helps prevent exacerbation of exophthalmos, and this approach is now the standard approach in patients who have significant exophthalmos at the time of treatment [ 82, 82.1]. (Fig. 11-9, below) The recommended dose is 30 mg/day for one month, tapering then over 2-3 months. Of course prednisone or other measures can be instituted at the time of any worsening of ophthalmopathy. In this instance doses of 30-60 mg/day are employed, and usually are required over several months ( See Chapter 12). Thyroidectomy, with total removal of the gland, may be considered for patients with significant eye disease. Operative removal of the thyroid is followed by gradual diminution is TSH-R antibodies.(82.2 ), and as shown by Tallstedt is associated with a lower incidence of worsening eye problems than is initial RAI treatment. While treatment with prednisone helps prevent eye problems, it does not appear to reduce the effectiveness of RAI in controlling the hyperthyroidism(82.3).

Figure 5. More patients experienced worsening of exophthalmos following 131-I therapy than after surgery or ATD treatment.

Figure 9. Redrawn from Bartelena et al, New England J. of Medicine, 338:73-78,1998.Patients with Graves' Disease were followed on methimazole, or given 131-I, or 131-I with prednisone 0.4-0.5mg/kg starting 2 or 3 days after 131-I treartment, and continuing for one month, after which the dose was tapered. Patients are grouped according to those who worsened, were unchanged, or improved during each treatment during 12 months.

Failure of ¹³¹I to cure thyrotoxicosis in 2 or 3 treatments occurs occasionally, and rarely 4 or 5 therapies are given. The reason for this failure is usually not clear. The radiation effect may occur slowly. A large store of hormone in a large gland may be one cause of a slow response. Occasional glands having an extremely rapid turnover of ¹³¹I require such high doses of the isotope that surgery is preferable to continued ¹³¹I therapy and its attendant whole body radiation. If a patient fails to respond to one or two doses of ¹³¹I, it is important to consider that rapid turnover may reduce the effective dose. Turnover can easily be estimated by measuring RAIU at 4, 12, 24, and 48 hours, or longer. The usual combined physical and biological half-time of ¹³¹I retention is about 6 days. This may be reduced to 1 or 2 days in some cases, especially in patients who have had prior ¹³¹I therapy or subtotal thyroidectomy. If this rapid release of ¹³¹I is found, and ¹³¹I therapy is desired, the total dose given must be increased to compensate for rapid release. A rough guide to this increment is as follows:

Increased dose = usual dose X ( (usual half time of 6 days) / (observed half time of "X" days) )

Most successfully treated glands return to a normal or cosmetically satisfactory size. Some large glands remain large, and in that sense may constitute a treatment failure. In such a situation secondary thyroidectomy could be done, but it is rarely required in practice.

Patients who have been treated with RAI should continue under the care of a physician who is interested in their thyroid problem for the remainder of their lives. The first follow-up visit should be made six to eight weeks after therapy. By this time, it will often be found that the patient has already experienced considerable improvement and has begun to gain weight. The frequency of subsequent visits will depend on the progress of the patient. Symptoms of hypothyroidism, if they develop, are usually not encountered until after two to four months, but one of the unfortunate facts of RAI therapy is that hypothyroidism may occur almost any time after the initial response.

Hazards of 131-I Treatment

In the early days of RAI treatment for Graves' disease, only patients over 45 years of age were selected for treatment because of the fear of ill effects of radiation. This age limit was gradually lowered, and some clinics, after experience extending over nearly 40 years, have now abandoned most age limitation. The major fear has been concern for induction of neoplasia, as well as the possibility that ¹³¹I might induce undesirable mutations in the germ cells that would appear in later generations.

Table 8. Gonadal Radiation Dose (in Rads) From Diagnostic Procedures and 131I Therapy

Carcinogenesis

Radiation is known to induce tumor formation in many kinds of tissues and to potentiate the carcinogenic properties of many chemical substances. Radiation therapy to the thymus or nasopharyngeal structures plays an etiologic role in thyroid carcinoma both in children and in adults[ 83- 85]. ¹³¹I radiation to the animal thyroid can produce tumors, especially if followed by PTU therapy [86]. Cancer of the thyroid has appeared more frequently in survivors of the atomic explosions at Hiroshima and Nagasaki than in control populations [87]. Thyroid nodules, some malignant, have appeared in the natives of Rongelap Island as the result of fallout after a nuclear test explosion in which the radiation cloud unexpectedly passed over the island [88].

The experience at 26 medical centers with thyroid carcinoma after ¹³¹I therapy was collected in a comprehensive study of the problem. A total of 34,684 patients treated in various ways were included. Beginning more than one year after ¹³¹I therapy, 19 malignant neoplasms were found; this result did not differ significantly from the frequency after subtotal thyroidectomy. Thyroid adenomas occurred with increased frequency in the ¹³¹I-treated group, and the frequency was greatest when the patients were treated in the first two decades of life [39]. Holm et al [41] have thoroughly examined the history of a large cohort of ¹³¹I-treated patients in Sweden and similarly found no evidence for an increased incidence of thyroid carcinoma or other tumors. For reasons that are not clear, the injury caused by ¹³¹I therapy for Graves' disease seems to induce malignant changes infrequently.. This result may occur because the treatment has largely been given to adults with glands less sensitive to radiation, because damage from ¹³¹I therapy is so severe that the irradiated cells are unable to undergo malignant transformations or all cells are destroyed, or possibly because of the slow rate at which the dose is delivered [89] In up to one-half of patients followed for 5-10 years, there may be no viable thyroid cells remaining. We note that two studies reported above extend through an average follow-up period of 15 years. As described above [44.1], a recent report by Franklyn and coworkers indicated that there is an increased (3.25 fold) risk of mortality from cancer of the thyroid (and also bowel) after RAI, detected in along term follow up of a very large patient cohort. However it remains uncertain that this is related to hyperthyroidism per se, or radioiodine therapy.

While these data are reassuring in regard to 131-I use in adults, Chernoby made it clear that its use in children can not be considered safe. Children in the area surrounding Chernobyl have developed a hugely increased incidence of thyroid carcinoma predominately due to ingestion of iodine-131 [89.1]. The latency has been about 5 years, and younger children are most affected. Risk of carcinogenesis decreases with increasing age at exposure, and is much less common after age 12. However some data indicates that an increased incidence of thyroid carcinoma is seen even among adults exposed at Chernobyl.

Leukemia

The incidence of leukemia among patients treated with RAI for Graves' disease has not exceeded that calculated from a control group [90]. This problem was also studied by the consortium of 26 hospitals [91]. The incidence of leukemia in this group was slightly lower than in a control group treated surgically, but slightly higher in the latter group than in the general population.

Genetic Damage

In the group of RAI-treated patients, there has been no evidence of genetic damage, although, as will shortly be seen, this problem cannot be disregarded. In the United States, about 100 x 106 children will be born to the present population of over 200 x 106 persons. Approximately 4% of these children will have some recognizable defect at birth. Of these, about one-half will be genetically determined or ultimately mutational, and represent the the effects of the baseline mutation rate in the human species. These mutations are attributed in part to naturally occurring radiation.

All penetrating radiation, from whatever sources, produces mutations. The effects may vary with rate of application, age of the subject, and no doubt many other factors, and are partially cumulative. Nearly all of these mutations behave as recessive genetic factors; perhaps 1% are dominant. Almost all are minor changes, and those produced by experimental radiation are the same as those produced by natural radiation.

Whether or not mutations are bad is in essence a philosophic question. Most of us would agree that the cumulative effect of mutations over past eras brought the human race to its present stage of development. However, most mutations, at least those that are observable, are detrimental to individual human adaptation to the present environment. In terms of the human population as a whole, detrimental mutant genes must be eliminated by the death of the carrier. We can agree that an increase in mutation rate is not desirable. It is hardly worth considering the pros and cons of the already considerable spontaneous mutation rate.

In mice, the occurrence of visible genetic mutations in any population group is probably doubled by acute exposure of each member of the group over many generations to about 30 - 40 rads, and by chronic exposure to 100 - 200 rads [92]. This radiation dosage is referred to as the doubling dose. Ten percent of this increase might be expressed in the first-generation offspring of radiated parents, the remainder gradually appearing over succeeding generations. The change in mutation rate in Drosophila is in proportion to the dosage in the range above 5 rads. Data from studies of mice indicate that at low exposures (from 0.8 down to 0.0007 rads/min), the dose causing a doubling in the spontaneous rate of identifiable mutations is 110 rads [92]. Linearity, although surmised, has not been demonstrated at lower doses.

At present, residents of the United States receive about 300 mrad/year, or 9 rad before age 30, the median parental age. Roughly half of this dose is from natural sources and half from medical and, to a lesser extent, industrial exposure. The National Research Council has recommended a maximum exposure rate for the general population of less than 10 rad above background before age 30. (The present level may therefore approach this limit.)

The radiation received by the thyroid and gonads during ¹³¹I therapy of thyrotoxicosis can be estimated from the following formula:

Total beta radiation dose = 73.8 x concentration of ¹³¹I in the tissue (µCi/g) x average beta ray energy (0.19 meV) x effective isotope half-life

For illustration, we can assume a gland weight of 50 g, an uptake of 50% at 24 hours, a peak level of circulating protein-bound iodide (PB ¹³¹I) of 1% dose/liter, an administered dose of 5 mCi, a thyroidal iodide biologic half-life of 6 days, and a gamma dose of about 10% of that from beta rays. On this basis, the thyroid receives almost 4,100 rads, or roughly 1,600 rads/mCi retained. The gonadal dose, being about one-half the body dose, would approximate 2 rads, or roughly 0.4 rads/mCi administered.

If the radiation data derived from Drosophila and lower vertebrates are applied to human radiation exposure (a tenuous but not illogical assumption), the increased risk of visible mutational defects in the progeny can be calculated. On the basis of administration to the entire population of sufficient ¹³¹I to deliver to the gonads 2 rads or 2% of the doubling dose (assumed to be the same as in the mouse), the increase in the rate of mutational defects would ultimately be about 0.04%, although only one-tenth would be seen in the first generation. Obviously only a minute fraction of the population will ever receive therapeutic ¹³¹I. The incidence of thyrotoxicosis is perhaps 0.03% per year, or 1.4% for the normal life span. At least one-half of these persons will have their disease after the childbearing age has passed. Although most of them will be women, this fact does not affect the calculations after a lapse of a few generations. Assuming that the entire exposed population receives ¹³¹I therapy in an average amount of 5 mCi, the increase in congenital genetic damage would be on the order of 0.02 (present congenital defect rate) x 0.04 ( ¹³¹I radiation to the gonads as a fraction of the doubling dose) x 0.014 (the fraction of the population ever at risk) x 0.5 (the fraction of patients of childbearing age) = 0.0000056.

This crude estimate, developed from several sources, also implies that, if all patients with thyrotoxicosis were treated with ¹³¹I, the number of birth defects might ultimately increase from 4 to 4.0006%. This increase may seem startlingly small or large, depending on one's point of view, but it is a change that would be essentially impossible to confirm from clinical experience.

Unfortunately, it is more difficult to provide a reliable estimate of the increased risk of genetic damage in the offspring of any given treated patient. Calculations such as the above simply state the problem for the whole population. Since most of the mutations are recessive, they appear in the children only when paired with another recessive gene derived from the normal complement carried by all persons. Assuming that only one parent received radiation from ¹³¹I therapy amounting to 2% of the doubling dose, the risk of apparent birth defects in the patient's children might increase from the present 4.0% to 4.008%.

0.02 (present genetic defect rate) x 0.04 (fraction of the doubling dose) x 0.1 (fraction of defects appearing in the first generation) = 0.00008, or an increase from 4.0% to 4.008%.

Similar estimates can be derived by considering the number of visible mutations derived from experimental radiation in lower species.[ 92, 93]

6 x 10-8 (mutations produced per genetic locus per rad of exposure) x 104 (an estimate of the number of genetic loci in humans) x 2 (gonadal radiation in rads as estimated above) x 0.1 (fraction of mutations appearing in the first generation) = 0.00012 or 0.012%

On this basis, the increase in the birth defect rate would be from 4.0% to 4.012%. One important observation stemming from these calculations is that large numbers of children born to irradiated parents must be surveyed if evidence of genetic damage is ever to be found. Reports of "no problems" among 30 to 100 such children are essentially irrelevant when one is seeking an increase in the defect rate of about 4.0% to about 4.008%.

These statistics are presented in an attempt to give some quantitation to the genetic risk involved in ¹³¹I therapy, and should not be interpreted as in any sense exact or final. The point we wish to stress is that radiation delivered to future parents probably will result in an increased incidence of genetic damage, but an increase so slight that it is difficult to measure. Nonetheless, the use of ¹³¹I for large numbers of women who subsequently become pregnant will inevitably introduce change in the gene pool.

In considering the significance of these risks, one must remember that the radiation exposure to the gonads from the usual therapeutic dose of ¹³¹I may be only one or two times that produced during a procedure such as a barium enema [ 94, 95] and similar to the 10 rads received from a CAT scan. These examinations are ordered by most physicians without fear of radiation effect ( Table 11-8).

When assessing the risks of ¹³¹I therapy, one must, of course, consider the risks of any alternative choice of procedure. Surgery carries a small but finite mortality, as well as a risk of permanent hypoparathyroidism, hypothyroidism, and vocal cord paralysis. Some of these risks are especially high in children, the group in which radiation damage is most feared. Some physicians have held that ¹³¹I therapy should not be given to patients who intend subsequently to have children. In fact, there is at present little if any evidence to support this contention, as discussed above. Chapman [44] studied 110 women treated with ¹³¹I who subsequently became pregnant and were delivered of 150 children. There was no evidence of any increase in congenital defects or of accidents of pregnancy. Sarkar et al [96] also found no evidence of excess abnormalities among children who received ¹³¹I therapy for cancer. Other studies have confirmed the apparent lack of risk[ 42, 43]. It should be noted that no increase in congenital abnormalities has been detected among the offspring of persons who received much larger radiation doses during atomic bomb explosions [97].

Often the patient wishes to know about the possibility of carcinogenesis or genetic damage. These questions must be fully but delicately handled. It is not logical to treat a patient of childbearing age with ¹³¹I and have the patient subsequently live in great fear of bearing children. These problems and considerations must be faced each time a patient is considered for RAI therapy.

It has been reported that administration of Gingko biloba extracts (EGb 761) neutralized genotoxic damage as assessed by clastogenic factors (CFs) and micronuclei (MN) appearance induced by radioiodine treatment, without affecting the clinical outcome. Although (131)I therapy is generally safe, the data suggest that Gingko biloba extracts may prevent genetic effects of radioiodine therapy for hyperthyroid Graves' disease(97.1). This interesting report awaits confirmation