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

Pregnancy

Pregnancy is an absolute contraindication to ¹³¹I therapy. The fetus is exposed to considerable radiation from transplacental migration of ¹³¹I, as well as from the isotope in the maternal circulatory and excretory systems. In addition, the fetal thyroid collects ¹³¹I after the 12th week of gestation and may be destroyed. The increased sensitivity of fetal structures to radiation damage has already been described.

Physicians treating women of childbearing age with ¹³¹I should be certain that the patients are not pregnant when given the isotope. Therapy during or immediately after a normal menstrual period or performance of a pregnancy test are appropriate precautions if pregnancy is possible. Women should be advised to avoid pregnancy for at least six months, since it usually takes this long to be certain that retreatment will not be needed.

Treatment of Thyrotoxicosis with Drugs

Drug therapy for thyrotoxicosis was introduced by Plummer when he observed that the administration of iodide ameliorated the symptoms of this disease [98]. (Fig 11-6). Administration of iodide has since been used occasionally as the complete therapeutic program for thyrotoxicosis, and widely as an adjunct in preparing patients for subtotal thyroidectomy. In 1941 the pioneering observations of MacKenzie and MacKenzie [99] and Astwood [100] led to the development of the thiocarbamide drugs, which reliably block the formation of thyroid hormones. It soon became apparent that, in a certain proportion of patients with Graves' disease, use of these drugs could induce a prolonged or permanent remission of the disease even after the medication was discontinued. It is not yet understood why a temporary reduction in the formation of thyroid hormone should result in permanent amelioration of the disease.

Figure 6. KI in doses over 6 mg/day dramatically inhibits release of hormone from the Graves' thyroid, as shown after treatment in this study starting during day 4. Serum hormone levels (PBI) consequently fall.

The antithyroid drug that was initially introduced for treatment of Graves' disease was thiourea, but this drug proved to have a large number of undesirable toxic effects. Subsequently a number of derivatives and related compounds were introduced that have potent antithyroid activity without the same degree of toxicity. Among these substances are propyl- and methylthiouracil, methimazole, and carbimazole. In addition to this class of compounds, potassium perchlorate has been used in the treatment of thyrotoxicosis, but is infrequently employed for this purpose because of occasional bone marrow depression. This drug prevents the concentration of iodide by the thyroid. Beta adrenergic blockers such as propranolol have a place in the treatment of thyrotoxicosis. These drugs alleviate some of the signs and symptoms of the disease but have little or no direct effect on the metabolic abnormality itself. They do not uniformly induce a remission of the disease and can be regarded as adjuncts, not as a substitute for more definitive therapy.

Antithyroid drugs inhibit thyroid peroxidase, and PTU (not methimazole) has the further beneficial action of inhibiting T ₄to T ₃conversion in peripheral tissues. A most exciting new idea regarding their action stems from observations that antithyroid therapy is associated with a prompt reduction in circulating antithyroid antibody titers, [101]and anti-receptor antibodies. [77, 78, 102] Studies by MacGregor and colleagues [103]indicate that antibody reduction also occurs during antithyroid therapy in patients with thyroiditis maintained in a euthyroid state, thus indicating that the effect is not due only to lowering of the FTI in Graves' disease. These authors also found a direct inhibitory effect of PTU and carbimazole on antithyroid antibody synthesis in vitro and postulate that this is the mechanism for diminished antibody levels. [104]Other data argue against this hypothesis. [105, 105.1]

Antithyroid drug therapy is also associated with a prompt reduction in the abnormally high levels of activated T lymphocytes in the circulation [106]. Totterman and co-workers have shown this therapy causes a prompt and transient elevation of activated T suppressor lymphocytes in blood [107]. We and others [106, 108] have shown that during antithyroid drug treatment the reduced numbers of T suppressor cells present in most thyrotoxic patients return to normal. Antithyroid drugs do not directly inhibit T cell function [109]. All of these data argue that antithyroid drugs exert a powerful beneficial immunosuppressive effect on patients with Graves' disease. While much has been learned about this process, the exact mechanism remains uncertain. Evidence that antithyroid drugs exert their immunosuppressive effect by a direct inhibition of thyroid cell production of hormones has been reviewed by Volpe [109].

Long-Term Antithyroid Drug Therapy with Thiocarbamides

Many patients with Graves' disease under age 40 - 45 are given a trial of therapy with one of the thiocarbamide drugs. Younger patients, and those with recent onset of disease, small goiters [110], and mild disease, are especially favorable candidates, since they tend to enter remission most frequently. It is generally found that one-fourth to one-third of these patients who satisfactorily complete a one year course have a long term or permanent remission. The remainder need repeated courses of drug therapy, must be maintained on the drug for years or indefinitely [111, 112], or must be given some other treatment. It appears that the percentage of patients responding has progressively fallen over the past years from about 50% to at present 25 - 30%[113, 114]. This change was thought to reflect an alteration in iodide in our diet [115], which increased from about 150 µg/day in 1955 to 300 - 600 µg/day. However other factors including greater precision in diagnosis and more complete data probably play major roles in establishing the response rate recognized at present. Many physicians do not consider antithyroid drug therapy to be the most efficacious means of treating thyrotoxic patients because of the high recurrence rate.

Patients are initially given 100 - 150 mg PTU every 8 hours or 10 - 15 mg methimazole (Tapazole) every 12 hours. The initial dosage is varied depending on the severity of the disease, size of the gland, and medical urgency. Antithyroid drugs must usually be given frequently and taken with regularity since the half-time in blood is brief -- 1.65 hours or less for PTU [116]. Frequent dosage is especially needed when instituting therapy in a severely ill patient. Methimazole has the advantage of a longer therapeutic half-life, and appears to produce fewer reactions when given in low dosage. Propylthiouracil is preferred in patients with very severe hyperthyroidism and in pregnancy[117, 118]

In most thyrotoxic patients, the euthyroid state, as assessed by clinical parameters, and FTI, can be reached within 4 - 6 weeks. If the patient fails to respond, the dosage may be increased. Iodine-131 studies may be performed to determine whether a sufficiently large dose of medication is being employed [119], but these studies are rarely needed. In general, it is assumed that binding of the ¹³¹I should be nearly completely blocked, but the 24-hour ¹³¹I thyroid uptake in the patient under therapy may range from O% to 40%. This iodide is partly unbound and is usually released rapidly from the gland by administration of 1 g potassium thiocyanate or 400 mg potassium perchlorate. If perchlorate or thiocyanate does not discharge the iodide, it is obvious that binding of iodide is occurring despite the thiocarbamide therapy. The quantity of drug administered may then be increased. In experimental animals, the thiocarbamides block synthesis of iodothyronines more readily than they block formation of MIT and DIT. This observation suggests that a complete block in organification of iodide may not be necessary to produce euthyroidism. The patient's thyroid might accumulate and organify iodide and form iodotyrosines, but be unable to synthesize the iodothyronines. Clinical observations to prove this point are not available.

An RIA for PTU has been developed but has not proven useful in monitoring therapy [120]. Doses of 300 mg PTU produced serum levels of about 7.1 µg/ml, and serum levels of PTU correlated directly with decreases in serum T ₃levels.

It is theoretically possible to give therapeutic doses of methimazole by rectal administration in a saline enema or by suppository if the oral route is unavailable [121]. Propylthiouracil has also been administered in suppositories or in enemas and found to be effective in treating hyperthyroidism. In a recent study PTU tablets were mixed in mineral oil, and then with cocoa butter, and frozen, to produce 1 gm suppositories each containing 400mg PTU. Suppositories given 4 times daily maintained a therapeutic blood level(121a). Jongjaroenprasert et al compared the effectiveness of a 400 mg dose of PTU in 90 ml of water vs. 400 mg of PTU given in polyethylene glycol suppositories. Both methods were effective treatments, but the enema appeared to provide greater bioavailability (121.1).

Long Term Therapeutic Program After the initial period of high-dose therapy, the amount of drug administered daily is gradually reduced to a level that maintains the patient in a euthyroid condition, as assessed by clinical evaluation and serial observations of serum T4 , FTI, or T3 . These tests should appropriately reflect the metabolic status of the patient. Measurement of TSH level is useful when the FTI falls, to make sure that the patient has not been overtreated, but, as noted previously, TSH may remain suppressed for many weeks after thyrotoxicosis is alleviated. Serum T3 levels can also be monitored and are occasionally still elevated when the T ₄level is in the normal range. During the course of treatment, the thyroid gland usually remains the same in size or becomes smaller. If the gland enlarges, the patient has probably become hypothyroid with TSH elevation; this condition should be ascertained by careful clinical and laboratory evaluation. If the patient does become hypothyroid, the dose of antithyroid drug should be reduced. Decrease in size of the thyroid under therapy is a favorable prognostic sign, and more often than not means that the patient will remain euthyroid after the antithyroid drugs have been discontinued. The dose is gradually reduced as the patient reaches euthyroidism, and often one-half or one-third of the initial dose is sufficient to maintain control. The interval between doses -- typically 8-12 hours initially -- can be extended, and patients can often be maintained on twice- or once-a-day therapy with methimazole [122]. Alternatively, antithyroid drugs can be maintained at a higher dose, and thyroxine can be added to produce euthyroidism. Occasionally ingestion of large amounts of iodide interferes with antithyroid drug therapy.

The appropriate duration of antithyroid drug therapy is uncertain, but usually it is maintained for one year. Treatment for six months has been effective in some clinics but is not general practice [123]. Longer treatment -- such as one to three years -- does gradually increase the percentage of responders [124], but this increase must be balanced against the added inconvenience to the patient [125, 126]. Azizi and coworkers have reported treatment of a group of 26 patients for ten years, during which time no serious problems occurred, and the cost approximated that of RAI therapy(126.1). At least one study suggests that treatment with large doses of antithyroid drugs may increase the remission rate, perhaps because of an immunosuppressive action [125]. Body mass, muscle mass, and bone mineral content gradually recover, although bone mass remains below normal [125.1]. Risedronate treatment has been demonstrated to help restore bone mass in osteopenia/osteoporosis associated with Graves’ disease 125.2).

After the patient has taken the antithyroid drugs for a year, the medication is gradually withdrawn over one to two months, and the patient is observed at intervals thereafter. Most of those who will ultimately have an exacerbation of the disease do so within three to six months; others may not develop recurrent hyperthyroidism for several years [127]. Some patients may have a recurrence after discontinuing the drug that lasts for a short time, and then a remission without further therapy [128]. An earlier report that administration of iodide increases the relapse rate after drug therapy is withdrawn has not been confirmed [129]. Hashizume and co-workers recently reported that administration of T ₄to suppress TSH for a year after stopping antithyroid drugs produced a very high remission rate [130]. Similar results were found when T ₄treatment was given after a course of antithyroid drugs during pregnancy. [131]. These studies engendered much interest because of the uniquely high remission rate obtained by the continuation of thyroxine treatment to suppress TSH for a year or more after the usual course of antithyroid drug therapy. Possibly such treatment is beneficial since it inhibits the release of thyroid antigens. However subsequent studies have not found a beneficial effect of added T4 therapy [131.1,131.2]. It is not clear that the results are generally observed, or are, for some reason, peculiar to this study group.

The probability of prolonged remission correlates with reduction in gland size, disappearance of thyroid-stimulating antibodies from serum[132, 133], (Fig.11-8) return of T ₃suppressibility, decrease in serum TG, and a haplotype other than HLA-DR3 [130, 136]. However, none of these markers predict recovery or continued disease with an accuracy rate above 60-70% [136.1]. Long after apparent clinical remission, many patients show continued abnormal thyroid function, including partial failure of T ₃suppression, or absent or excessive TRH responses [127-140]. These findings probably indicate the tenuous balance controlling immune responses in these patients.

Figure 8. In this patient with Graves' Disease, the mixture of antibodies shifted during antithyroid therapy from  dominance by TSAb, to a dominant effect by TSBAb and TBII,  leading to spontaneous development of hypothyroidism. From Takasu et al, J. Endocrinol. Invest. 20:452-461, 1997.

The special problems associated with antithyroid drug therapy in pregnant women and in children are reviewed in Chapter 14.

Lactating women taking PTU have PTU levels of up to 7.7 µg/ml in blood, but in milk the level is much lower, about 0.7 µg/ml [141]. Only 1-2 mg PTU could be transferred to the baby daily through nursing; this amount is inconsequential except for the possibility of reactions to the drug. Azizi et al. studied intellectual development of children whose mothers took methimazole during lactation, and found that there was no evident effect on physical and intellectual development, at least in children whose mothers took up to 20 mg of MMI daily [141a].

It has long been known that some patients with Graves' disease eventually develop spontaneous hypothyroidism. [68]Reports have shown that most patients who become euthyroid after antithyroid drug therapy, if followed long enough, also develop evidence of diminished thyroid function [69]. In a prospective study, Lamberg et al [139]found that the annual incidence in these patients of subclinical hypothyroidism was 2.5%, and of overt hypothyroidism 0.6%.

Toxic Reactions To Antithyroid Drugs

The use of antithyroid drugs may be accompanied by toxic reactions, depending on the drug and dose, in 3 - 12% of patients[ 117, 118, 142- 146]. Most of these reactions probably represent drug allergies[ 147- 148]. Chevalley et al., in a study of 180 patients given methimazole[ 143], found an incidence of toxicity of 4.3%, broken down as follows: Total reactions 4.3%; Pruritus 2.2%; Granulocytopenia 1.6%; Urticaria 0.5% ;

The incidence of agranulocytosis in a large series of patients was 0.4%. [149]It occurs most frequently in older patients and those given large amounts of the drug (20-30 mg methimazole every eight hours) [117].Reactions tend to be most frequent in the first few months of therapy but can occur at any time, with small doses of drug, and in patients of all ages [117]. The most common reactions are fever and a morbilliform or erythematous rash with pruritus. Reactions similar to those of serum sickness, with migratory arthralgias, jaundice, lymphadenopathy, polyserositis, and episodes resembling systemic lupus erythematosus have also been observed [147]. Pyoderma gangrenosum can occur (147.1). Neutropenia and agranulocytosis are the most serious complications. These reactions appear to be due to sensitization to the drugs, as determined by lymphocyte reactivity in vitro to the drugs [148]. Occasionally agranulocytosis can develop even though the total WBC remains within normal ranges- a hazard to be remembered if differential counts are not done. Fortunately, even these problems almost always subside when the drug is withdrawn. Aplastic anemia with marrow hypoplasia has been reported (perhaps 10 cases), again with spontaneous recovery in 2-5 weeks in 70%, but fatal outcome in 3 patients [149]. Vasculitis is a fortunately rare complication during treatment with antithyroid drugs.

ANCA antibodies-Some patients develop antineutrophil cytoplasmic antibodies, either pericytoplasmic or cytoplasmic, with the vasculitis. Most cases appear to be associated with the use of propylthiouracil, and therapy includes cessation of the drug, sometimes treatment with steroids or cyclophosphamide for renal involvement, and rarely plasmapheresis. The commonest cutaneous lesion associated is leukocytoclastic vasculitis associated with purpuric lesions. Symptoms may include fever, myalgia, arthralgia, and lesions in the kidneys and lungs. Prognosis is usually good if the medication is discontinued, although death has occurred. ANCA positivity (pericytoplasmic, cytoplasmic, directed to myeloperoxidase, proteinase3, or human leukocyte elastase) can occur in patients on antithyroid drugs associated with vasculitis. It is also found without clinical evidence of vasculitis, and the significance of this finding is unclear [149.1]. Guma et al recently reported that, in a series of patients with Graves’ disease, 67% were found to be ANCA positive before medical treatment, and that 19% remained positive after one year of antithyroid treatment. This data suggests that ANCA antibodies reflect in some way the autoimmunity associated with Graves’ hyperthyroidism, rather than simply being a manifestation due to the treatment with antithyroid drugs (149.2). In addition to suppression of hematopoiesis and agranulocytosis, methimazole has been associated in one patient with massive plasmocytosis, in which 98% of the cells in the bone marrow were plasma cells. After discontinuation of the drug, and treatment with dexamethasone and G-CSF, the patient’s marrow recovered to normal (149.1).

Toxic hepatitis (primarily with propylthiouracil) and cholestatic jaundice (primarily with methimazole) are fortunately uncommon [150].Toxic hepatitis can be severe or fatal, but the incidence of serious liver complications is so low that routine monitoring of function tests has not been advised[ 151, 152]. Liver transplantation has been used with success in several patients [152.1].

Diffuse interstitial pneumonitis has also been produced by propylthiouracil [153].

Methimazole may be the drug least likely to cause a toxic reaction, but there is little difference between it and PTU. When the antithyroid drugs are prescribed, the patient should be apprised of the possibility of reactions, and should be told to report phenomena such as a sore throat, fever, or rash to the physician and to discontinue the drug until the cause of the symptoms has been evaluated. These symptoms may herald a serious reaction.

Methimazole is usually avoided in pregnant women, especially in early pregnancy. Karlsson et al reported in a Letter to the Editor in JCEM that esophageal atresia, omphalocele, or choanal atresia in Sweden occurred almost only in infants whose mothers took methimazole during early pregnancy, and suggest that this is a true, although fortunately very infrequent, complication of methimazole use. Their observations obviously suggest that methimazole should best not be given during early months of pregnancy (153.2).

Neutropenia-It is probably wise to see patients receiving the thiocarbamides at least monthly during the initiation of therapy and every two to three months during the entire program. Neutropenia can develop gradually but often comes on so suddenly that a routine white cell count offers only partial protection. A white cell count must be taken whenever there is any suggestion of a reaction, and especially if the patient reports malaise or a sore throat. A white cell count taken at each visit will detect the gradually developing neutropenia that may occur. While many physicians do not routinely monitor these levels, the value of monitoring is suggested by the study of Tajiri et al [144]. Fifty-five of 15398 patients treated with antithyroid drugs developed agranulocytosis, and 4/5 of these were detected by routine WBC at office visits. Low total leukocyte counts are common in Graves' disease because of relative neutropenia, and for this reason a baseline WBC and differential should be performed before starting anti-thyroid drugs. However, total polymorphonuclear counts below 2,000 cells/mm3 should be carefully monitored; below 1,200 cells/mm3 it is unsafe to continue using the drugs.

If a patient taking a thiocarbamide develops a mild rash, it is permissible to provide an antihistamine and continue using the drug to see whether the reaction subsides spontaneously, as it commonly does. If the reaction is more severe or if neutropenia occurs, another drug should be tried or the medication withdrawn altogether. Usually a switch is made to another thiocarbamide, because cross-reactions do not necessarily occur between members of this drug family. Alternatively, the program of therapy may be changed to the use of RAI, which may be given after the patient has stopped taking the antithyroid drug for 48 - 74 hours, or the patient may be prepared for surgery by the administration of iodides and propranolol.

In the event of severe neutropenia or agranulocytosis, the patient should be monitored closely, given antibiotics if infection develops, and possibly adrenal steroids. There is no consensus on the use of glucocorticoids, since they have not been shown to definitely shorten the period to recovery. Antithymocyte globulin and cyclosporin are also used [153.1]. Administration of recombinant human granulocyte colony stimulating factor (75 µg/day given IM) appears to hasten neutrophile recovery in most patients who start with neutrophile counts > 0.1 X 109/L [154]. Care must be taken to ensure against exposure to infectious agents, and some physicians prefer not to hospitalize their patients for this reason. If the patient is hospitalized, he or she should be placed in a special-care room with full bacteriologic precautions.

As noted above, thiocarbamides can also cause liver damage ranging from elevation of enzymes, through jaundice, to fatal hepatic necrosis. Any sign of liver damage must be carefully monitored, and progress of abnormalities in liver function tests demand cessation of the drug[ 147, 152].

B.Z., 18-Year-Old Man: Neutropenia From Propylthiouracil

B.Z. developed symptoms of hyperthyroidism at age 17. He also had a history of diabetes mellitus for six years, requiring insulin twice daily. The insulin requirement had recently increased. His personal physician noted symptoms of hyperthyroidism and thyroid enlargement, and referred him for evaluation. The BP was 140/75 and the pulse rate 110. There was no ophthalmopathy. The thyroid was symmetrically enlarged to about 40 g in weight; there was no nodularity or lymphadenopathy. The heart was hyperactive. There was mild infection of the conjunctiva. The FTI was elevated (13.7) and the TGHA test result was positive at 1/1280. The patient was given PTU, 150 mg every eight hours, and improved clinically, although after one month on therapy the FTI was still 13.5. The patient left for college and did not follow instructions to see a physician at the institution.

He continued to take PTU and returned 10 months later with symptoms of hypothyroidism, including fatigue, weight gain, and a puffy appearance. The skin was dry and cool. The thyroid now weighed 80 g. The T ₄level was 0.5 ug/dl, FTI 0.4, and TSH level 117 µU/ml. He had a hemoglobin level of 13 g% and a hematocrit of 37%. The white cell count was 2,000 mm3 with 10% polys, 79% lymphs, 10% monocytes, and 2% bands. The platelet count was 189,000/mm3. Medication was discontinued. He had no evidence of infection. There was no fever or chills and no throat irritation. One day later, the white cell count was 2,200/mm3 with 1% polys. Two days later, it was 2,800/mm3 with 19% polys, and after four days it reached 3,100/mm3 with 8% polys. The thyroid became smaller. After seven days the white cell count was 4,600/mm3 and the polys were 25%. The total neutrophil count was 1,150/mm3.

One month later, on physical examination there was a 35-g goiter and no evidence of hypothyroidism. The FTI was 10.5, and the T ₄level was 8.8 µg/dl. The white cell count was normal.

This young man had severe complications of PTU therapy during a prolonged period of unsupervised care. He developed hypothyroidism and thyroid enlargement, and at the same time a severe neutropenia. With withdrawal of antithyroid medication, the white cell count returned promptly to normal, as did the FTI. There has been no evidence of recurrent hyperthyroidism.

Potassium Perchlorate and Lithium

Potassium perchlorate was introduced into clinical use after it was demonstrated that several monovalent anions, including nitrates, have an antithyroid action. Perchlorate was the only member of the group that appeared to have sufficient potency to be useful. This drug, in doses of 200 - 400 mg every six hours, competitively blocks iodide transport by the thyroid. Accordingly, therapeutic doses of potassium iodide will overcome its effect. Institution and control of therapy with perchlorate are similar to those discussed for the thiocarbamides. Toxic reactions to this agent occur in about 4% of cases [155]and usually consist of gastric distress, skin rash, fever, lymphadenopathy, or neutropenia; they usually disappear when the drug is discontinued. The reaction rate is higher when doses of more than 1 g/day are given [155]. Nonfatal cases of neutropenia or agranulocytosis have been reported, and four cases of fatal aplastic anemia have been associated with the use of this drug [155]. Because of toxic reactions, perchlorate is not used at present for routine therapy. It has found a role in therapy of thyrotoxicosis induced by amiodarone [157]. Apparently blocking of iodide uptake is an effective antithyroid therapy in the presence of large body stores of iodide, while in this situation, methimazole and propylthiouracil are not effective alone.

Lithium ion inhibits release of T4 and T3 from the thyroid and has been used in the treatment of thyrotoxicosis, but is most effective when used with a thiocarbamide drug. It does not have a well-established place in the treatment of Graves' disease[ 157, 158]. It has possible value in augmenting the retention of ¹³¹I [159] and in preparing patients allergic to the usual antithyroid drugs or iodide for surgery, although propranolol is generally used for the latter problem.

Cholestyramine (4gm, q8h) for a month has been shown to hasten return of T4 to normal [159.1] by binding hormone in the gut. It can be used as an adjunct to help speed return of hormone levels to normal, and may be especially beneficial in thyroid storm.

Iodine

Plummer originally observed that the administration of iodide to thyrotoxic patients resulted in an amelioration of their symptoms. This reaction is associated with a decreased rate of release of thyroid hormone from the gland and with a gradual increase in the quantity of stored hormone. The effect of iodide on thyroid hormone release and concentration in blood is apparent in Figure 11-6. The mechanism of action may be by inhibition of generation of cAMP, and involves inhibition of proteolysis, but is not fully understood. Therapeutic quantities of iodide also have an effect on hormone synthesis through inhibition of organification of iodide. Iodide has similar but less intense effects on the normal thyroid gland, apparently because of the adaptive mechanisms described in Chapter 5.

Administration of large amounts of iodide to laboratory animals or humans blocks the synthesis of thyroid hormone and results in an accumulation of trapped inorganic iodide in the thyroid gland (the Wolff-Chaikoff effect, see Ch 2). The thyrotoxic gland is especially sensitive to this action of iodide. Raising the plasma iodide concentration to a level above 5 µg/dl results in a complete temporary inhibition of iodide organification by the thyrotoxic gland. In normal persons elevation of the inorganic 127I level results, up to a point, in a progressive increase of accumulation of iodide in the gland. When the plasma concentration is above 20 µg/dl, organification is also inhibited in the normal gland [160]. The sensitivity of the thyrotoxic gland, in comparison with that of the euthyroid gland, may be due to an increased ability to concentrate iodide in the thyroid, and its failure to "adapt" by decreasing the iodide concentrating mechanism.

When iodine is to be used therapeutically in Graves' disease, one usually prescribes a saturated solution of potassium iodide (which contains about 50 mg iodide per drop) or Lugol's solution (which contains about 8.3 mg iodide per drop). Thompson and co- workers [161] found that 6 mg of I- or KI produces a maximum response. This fact was reemphasized by Friend, who pointed out that the habit of prescribing the 5 drops of Lugol's or SSKI three times daily is unnecessary [162]. Two drops of Lugol's solution or 1 drop of a saturated solution of potassium iodide two times daily is more than sufficient.

The therapeutic response to iodide begins within two to seven days and is faster than can be obtained by any other methods of medical treatment. Only 3% of patients so treated fail to respond. Men, older persons, and those with nodular goiter are in the group less likely to have a response to iodide. Although almost all patients initially respond to iodide, about one-third respond partially and remain toxic, and another one-third initially respond but relapse after about six weeks [165]. The use of iodide as definitive therapy for thyrotoxicosis has been discarded in favor of the modalities previously described.

Iodides are sometimes given after ¹³¹I therapy to control hyperthyroidism, and are usually given as part of treatment before thyroidectomy.

Use of Drugs in Adjunctive Therapy for Graves' Disease

Propranolol, metopranol, atenolol

Beta-adrenergic blocking agents have won a prominent position in the treatment of thyrotoxicosis. Although they alleviate many of the signs and symptoms, they have little effect on the fundamental disease process[ 166, 167]. Palpitations, excessive sweating, and nervousness improve, and tremor and tachycardia are controlled. Many patients feel much improved, but others are depressed by the drug and prefer not to take it. Improvement in myocardial efficiency and reduction in the exaggerated myocardial oxygen consumption have been demonstrated [168]. Propranolol lowers oxygen consumption [169] and reverses the nitrogen wasting of thyrotoxicosis, although it does not inhibit excess urinary calcium and hydroxyproline loss [124]. Propranolol is useful in symptomatic treatment while physician and patient are awaiting the improvement from antithyroid drug or ¹³¹I therapy [171]. Some patients appear to enter remission after using this drug alone for six months or so of therapy[ 169, 172]. It has been useful in neonatal thyrotoxicosis [173] and in thyroid storm [174]. The drug must be used cautiously when there is evidence of severe thyrotoxicosis, or heart failure, but often control of tachycardia permits improved circulation. Beta blockade can induce cardiovascular collapse in patients with or without heart failure, and asystolic arrest (174a,b). Administration of beta blocker was shown by Ikram to reduce CO by 13% in patients with uncontrolled CHF, and apparently this reduction in CO can be near fatal in rare patients.
Some surgical groups routinely prepare patients for thyroidectomy with propranolol for 20 - 40 days and add potassium iodide during the last week [175]. The BMR and thyroid hormone level remain elevated at the time of operation, but the patient experiences no problems. We prefer conventional preoperative preparation with thiocarbamides, with or without iodide, and would use propranolol as an adjunct, or if the patient is allergic to the usual drugs.

Propranolol is usually given orally as 20 - 40 mg every four to six hours, but up to 200 mg every six hours may be needed. In emergency management of thyroid storm (see also Chapter 12) or tachycardia, it may be given intravenously (1 - 3 mg, rarely up to 6 mg) over 3 - 10 minutes and repeated every four to six hours under electrocardiographic control. Atropine (0.5 - 1.0 mg) is the appropriate antidote if severe brachycardia is produced.

Reserpine and Guanethidine

Drugs such as reserpine [177] and guanethidine [178] that deplete tissue catecholamines were used extensively in the past as adjuncts in the therapy for thyrotoxicosis, but fell into disuse as the value of beta -sympathetic blockade with propranolol became recognized.

Glucocorticoids, Ipodate, and Other Treatments

As described elsewhere, potassium iodide acts promptly to inhibit thyroid hormone secretion from the Graves' disease thyroid gland. PTU, propranolol, glucocorticoids [181], amiodarone, and sodium ipodate (Oragrafin Sodium) inhibit peripheral T ₄to T ₃conversion, and glucocorticoids may have a more prolonged suppressive effect on thyrotoxicosis [182]. Orally administered resins bind T ₄in the intestine and prevent recirculation [183]. All of these agents have been used for control of thyrotoxicosis [ 184, 185]. Combined dexamethasone, potassium iodide, and PTU can lower the serum T ₃level to normal in 24 hours, which is useful in severe thyrotoxicosis. Prednisone has been reported to induce remission of Graves' disease, but at the expense of causing Cushing's syndrome [187]. Ipodate (0.5 - 1 g orally per day) acts to inhibit hormone release because of its iodine content, in addition to its action to inhibit T4 to T3 conversion. This dose of ipodate given to patients with Graves' disease reduced the serum T ₃level by 58% and the T ₄level by 20% within 24 hours, and the effect persisted for three weeks[ 188, 189]. This dose of ipodate was more effective than 600 mg of PTU, which decreased the T ₃level by only 23% during the first 24 hours, whereas the T ₄level did not drop. Ipodate may prove to be a useful adjunct in the early therapy of hyperthyroidism, but will increase total body and thyroidal iodine. However, when the drug is stopped, the RAIU in Graves' patients usually returns to pre- treatment levels within a week [189]. Because it is the most effective agent available in preventing conversion of T4 to T3 , it has a useful role in managing thyroid storm ( Chapter 12).

Lithium Chloride-The use of lithium as an adjunct to therapy with radioiodine in treatment of hyperthyroidism was compared in a randomized prospective study. The lithium group received lithium carbonate 300 mg three times a day, for three weeks starting on the day of radioiodine administration. Patients had been made euthyroid with antithyroid drugs prior to RAI treatment. There was no effect on the percentage of patients cured. Ten percent of patients complained of side effects of the lithium (189.1).

Surgical Treatment

Subtotal thyroidectomy is an established and effective form of therapy for Graves' disease, providing the patient has been suitably prepared for surgery. In competent hands, the risk of hypoparathyroidism or recurrent nerve damage is under 1%, and the discomfort and transient disability attendant upon surgery may be a reasonable price to pay for the rapid relief from this unpleasant disease. In some clinics it is the therapy of choice for most young male adults, especially if a trial of antithyroid drugs has failed. Total thyroidectomy may be preferred in patients with serious eye disease or high TRAb levels, in order to keep down the incidence of recurrence [201]. With other effective methods available, it is necessary for the physician and the patient to decide on the form of therapy most suitable for the case at hand. Because of the potential but unproved risks of ¹³¹I therapy, it is not always possible to make an entirely rational choice; the fears and prejudices of the physician and the patient will often enter into the decision. Surgery is clearly indicated in certain patients. Among these are (1) patients who have not responded to prolonged antithyroid drug therapy, or who develop toxic reactions to the drug and for whatever reason are unsuitable for ¹³¹I therapy; (2) patients with huge glands, which frequently do not regress adequately after ¹³¹I therapy; and (3) patients with thyroid nodules that raise a suspicion of carcinoma. Stocker et al have reviewed the problem of nodules in Graves’ glands. They 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, had 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. These authors argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects(201a). Subtotal or near total thyroidectomy is often the treatment of choice for patients with amiodarone induced thyrotoxicosis, since response to ATDs is typically poor, and RAIU can not be given. Surgery may also have a place in therapy of older patients with thyroid storm and/or cardiorespiratory failure , who do not respond rapidly to intensive medical therapy(202a).

SURGERY IN PATIENTS WITH 0OPHTHALMOPATHY Contemporary data indicate that exophthalmos may be exacerbated by RAI therapy [80],although in some studies appearance of progressive ophthalmopathy was about the same after treatment with ¹³¹I as with surgery [79]. Thus, in the presence of serious eye signs, treatment with antithyroid drugs followed by surgery is an important alternative to consider, and total thyroidectomy is preferred [ 201, 204]. The preferential use of surgery rather than radioactive iodide in the management of patients with severe Graves’ ophthalmopathy, and the greater, more frequent exacerbation of eye disease after RAI therapy, has been supported in a number of studies including those by Torring et al [204a], Moleti et al [204b], and De Bellis et al [204c]. Marcocci et al, in contrast, report that near-total thyroidectomy had no efffect on the course of ophthalmopathy in a group of patients who had absent or non-severe preexisting ophthalmopathy. The relevance of this to patients with more severe ocular disease is uncertain, since it is logical to expect that in these patients there would be no effect of removing antigens, if they lacked any tendency to develop ophthalmopathy [204d]. Moleti et al recently reported on 55 patients with Graves’ disease and mild to moderate Graves’ ophthalmopathy, who underwent near-total thyroidectomy, and of whom 16 had standard ablative doses of radioactive iodide. They found that the course of ophthalmopathy, both short and long term after treatment, was significantly better in the group of patients who underwent thyroidectomy and ¹³¹I ablation, and suggest that this is a more effective means of inducing and maintaining ophthalmopathy inactive (204e). In a randomized, prospective study, total thyroidectomy, rather than partial thyroidectomy, was followed by a better outcome of GO in patients given iv glucocorticoids. Radioiodine uptake test and thyroglobulin assay showed complete ablation in the majority of total, but not of partial thyroidectopmy patients (204g).:

More enthusiastic surgeons have in the past recommended surgery for all children as the initial approach, claiming that there is less interference with normal growth and development than with prolonged antithyroid drug treatment [191]. Therapy for childhood thyrotoxicosis is discussed further below.

The rate of patient rehabilitation is probably quickest with surgery. Although the source of hormone is directly and immediately removed by surgery, the patient usually must undergo one to three months of preparation before operation. The total time from diagnosis through operative convalescence is thus three to four months. Antithyroid drugs, in contrast, provide at best only 30 - 40% permanent control after one year of therapy. Iodine-131 can assuredly induce prompt remission. Low dose protocols, as noted, are plagued by a need for medical management and retreatment over one to three years before all patients are euthyroid. Treatment with higher doses provides more certain remission at the expense of hypothyroidism.

There are several strong contraindications to surgery, including previous thyroid surgery, severe coincident heart or lung disease, the lack of a well-qualified surgeon, and pregnancy in the third trimester, since anesthesia and surgery may induce premature labor.

Preparation for Surgery

Antithyroid drugs of the thiocarbamide group are employed to induce a euthyroid state before subtotal thyroidectomy when surgery is the desired form of treatment. Two approaches are used. PTU or methimazole may be administered until the patient becomes euthyroid. After this state has been reached, and while the patient is maintained on full doses of thiocarbamides, Lugol's solution or a saturated solution of potassium iodide is administered for 7 - 10 days. This therapy induces an involution of the gland and decreases its vascularity, a factor surgeons find helpful in the subsequent thyroidectomy. In one study Lugol solution treatment resulted in a 9.3-fold decreased rate of intraoperative blood loss. Preoperative Lugol solution treatment decreased the rate of blood flow, thyroid vascularity measured by histomorphometry , and intraoperative blood loss during thyroidectomy(191.1).

The iodide should be given only while the patient is under the effect of full doses of the antithyroid drug; otherwise, the iodide may permit an exacerbation of the thyrotoxicosis. Alternatively patients may be prepared by combined treatment with antithyroid drugs and thyroxine. It is not obvious that one method is superior to the other. Severely ill patients can be prepared for surgery rapidly by combining several treatments-iopanoic acid 500mg bid, dexamethasone 1mg bid, antithyroid drugs, and beta-blockers(204f).

Pre-treatment should have the patient in optimal condition for surgical thyroidectomy. By this time the patient has gained weight, the nutritional status has been improved, and the cardiovascular manifestations of the disease are under control. At the time of surgery, the anesthesia is well tolerated without the risk of hypersensitivity to sympathoadrenal discharge characteristic of the thyrotoxic subject. The surgeon finds that the gland is relatively avascular. Convalescence is customarily smooth. The stormy febrile course characteristic of the poorly prepared patient in past years is rarely seen.

Reactions to the thiocarbamide drugs occasionally occur during preparation for surgery. If the problem is a minor rash or low-grade fever, the drug is continued, or a change is made to a different thiocarbamide. More severe reactions (severe fever or rash, leukopenia, jaundice, or serum sickness) necessitate a change to another form of therapy, but no entirely satisfactory alternative is available. One course is to administer iodide and propranolol and proceed to surgery. In some patients, it is best to proceed directly to ¹³¹I therapy if difficulties arise in the preparation with antithyroid drugs.

Propranolol has been used alone or in combination with potassium iodide [192] in preparation for surgery, and favorable results have generally been reported[193-195]. This procedure is doubtless safe in the hands of a medical team familiar and experienced with this protocol and willing to monitor the patient carefully to ensure adequate dosage. It is safe to use in young patients with mild disease, but we are reluctant to advise it as a standard protocol. We use propranolol as an adjunct, or combined with potassium iodide as the sole therapy only when complications with antithyroid drugs preclude their use and surgery is strongly preferred to treatment with ¹³¹I.

Amiodarone induced hyperthyroidism is typically difficult to manage, as described in Chapter 13. Administration of iopanoic acid, 1 gm daily for 13 days, has been shown to provide successful pre-operative therapy, reducing T ₃levels to normal (195a). Propranolol is the usual drug used for preparation of patients with amiodarone induced hyperthyroidism going to surgery.

Surgical Techniques and Complications

The standard operation is a one-stage subtotal thyroidectomy. General anesthesia is standard, but cervical plexus block and out-patient surgery is employed by some surgeons [192.1, 192.2]. Some clinicians argue for total-thyroidectomy in an effort to reduce recurrence rates, and point out that this operation seems to reduce anti-thyroid autoiommunity and reduces the chance of exacerbation of ophthalmopathy. The surgical technique is discussed in Chapter 21. Permanent cure of the hyperthyroidism is produced in 90 - 98% of patients treated this way. The amount of tissue left behind is about 4-10 grams, but this amount is variable. Taylor and Painter [196] found that the average volume of this remnant in 43 patients achieving a remission was about 8 ml, and Sugino et al recommended leaving 6 grams of tissue [196a]. The toxic state recurred in only two patients in their series, and in these twice the amount of tissue mentioned above was left. Ozaki also noted the importance of the amount of thyroid remaining as the principal predictor of eu- or hypo-thyroidism [196.1].There seems however to be no relation between the original size of the thyroid and the size of the remnant necessary to maintain normal metabolism. Motivated in part by economic considerations, there has been in recent years a reevaluation of thyroidectomy done under local anesthesia as a day-surgery proceedure. Pros and cons have recently been discussed [196.2]. In proper hands local anesthesia and prompt discharge seem acceptable, but most surgeons opt for the standard in hospital approach since it offers a more controlled operative setting and an element of safety the night after surgery.

Although surgery of the thyroid has reached a high degree of perfection, it is not without problems even in excellent hands. The complication rates at present are low [197]. Among 254 patients operated on at three Nashville hospitals in the decade before 1970, there was no mortality, only minor wound problems, a 1.9% incidence of permanent hypoparathyroidism, and a 4.2% recurrence rate [198]. Hypo-parathyroidism is the major undesirable chronic complication. Surgical therapy at the Mayo Clinic has in recent years [199] been associated with a 75% rate of hypothyroidism but only a 1% recurrence rate, as an effort was made to remove more tissue and prevent recurrences. There is typically an inverse relationship between these two results of surgery. In the recent experience of the University of Chicago Clinics, the euthyroid state has been achieved by surgery in 82%; 6% became hypothyroid, and the recurrence rate was 12% [200]. Palit et al. recently published a meta analysis of collected series of patients treated for Graves’ disease, either by total thyroidectomy or subtotal thyroidectomy. Overall, the surgery controlled hyperthyroidism in 92% of patients. There was no difference in complication rates between the two kinds of operations, with permanent laryngeal nerve injury occurring in .7 - .9% of patients, and permanent hypoparathyroidism in 1 – 1.6% of patients. Since many surgeons have become more familiar and capable with total thyroidectomy, and this avoids the possible recurrence of disease, although possibly slightly increasing the risk of nerve or parathyroid damage, total thyroidectomy has become a common or even preferred alternative to subtotal thyroidectomy for managing hyperthyroidism [200a]. Recurrence rates are higher in patients with progressive exophthalmos or positive assays for TRAb, suggesting that total thyroidectomy may be preferred in these cases. [201]Geographic differences in iodine ingestion have been related to the outcome. In Iceland, with a high iodine intake, postoperative hypothyroidism is less frequent, but recurrence is more common than in iodine-deficient Scotland [202].

Death rates are now approaching the vanishing point [203] Of the nonfatal complications, permanent hypoparathyroidism is the most serious, and requires lifelong medical supervision and treatment. Experienced surgeons have an incidence under 1% [205]. Unfortunately, the general experience is near 3%. More patients, perhaps 10%, develop transient post-operative hypocalcemia but soon recover apparently normal function. Perhaps these patients have borderline function that may fail in later years.

Unilateral vocal cord paralysis rarely causes more than some hoarseness and a weakened voice, but bilateral injury leads to permanent voice damage even after corrective surgery. Bilateral recurrent nerve injury may be associated with severe respiratory impairment when an acute inflammatory process supervenes and may be life-threatening. Fortunately, it is now extremely rare after subtotal thyroidectomy. Damage to the superior external laryngeal nerve during surgery (see Chapter 21) may alter the quality of the voice and the ability to shout without causing hoarseness. One may speculate whether declining skills in the techniques of subtotal thyroidectomy, attendant upon a dramatic fall in the use of this procedure, may lead to an increase in the hazards of the procedure.

Hypothyroidism, whether occurring after surgery or ¹³¹I therapy, can be readily controlled. Transient hypothyroidism is common, with recovery in one to six months. The presence of autoimmunity to thyroid antigens predisposes to the development of hypothyroidism after subtotal thyroidectomy for thyrotoxicosis. A positive test for antibodies to the microsomal/TPO antigen was found by Buchanan et al [206] to correlate with an increased incidence of postoperative hypothyroidism. The incidence of hypothyroidism is certainly of importance in weighing the virtues of ¹³¹I and surgical therapy. The ability of surgical therapy to produce a euthyroid state in many patients over long-term follow-up gives it one advantage over RAI therapy, but this must be weighed against the risk of hypoparathyroidism and recurrent nerve damage.

Course After Surgery

In the immediate postoperative period, patients should be followed closely. They should ideally have a special duty nurse or family member providing watch during the first 24 hours, and a tracheotomy set and calcium chloride or gluconate for infusion should be at the bedside. During this period, undetected hemorrhage can lead to asphyxiation. Current use of drains with constant suction helps protect against this problem. Transient hypocalcemia is common, resulting from trauma to the parathyroid glands and their blood supply and also possibly to rapid uptake of calcium by the bones, which have been depleted of calcium by the thyrotoxicosis [207]. Oral or intra- venous calcium supplementation suffices in most instances to control the symptoms. The calcium may be given slowly intravenously as calcium gluconate or calcium chloride in a dose ranging from 0.5 to 1.0 g every 4-8 hours, as indicated by clinical observation and determination of Ca2+.

Some surgeons give their patients replacement thyroid hormone for an indefinite period after the operation in an attempt to avoid transient hypothyroidism and to remove any stimulus to regeneration of the gland. It is not obvious that this is either necessary or efficacious. In 50-70% of patients, the residual gland is able to form enough hormone to prevent even transient clinical hypothyroidism. Serum hormone levels should be determined every two to four months until it is clear that the patient does not need replacement.

Probably the thyroid remnant is not normal. It has a rapid ¹³¹I turnover rate and a small pool of stored organic iodine. Suppressibility by T ₃administration returns within a few months of operation in some patients. TSAb tend to disappear from the blood in the ensuing 3 - 12 months [208-210]. After subtotal thyroidectomy, thyrotoxicosis recurs in 5 - 10% of patients, often many years after the original episode. The long term outcome of thyroid surgery for hyperthyroidism was reviewed by the Department of Surgery at Karolinska Institute and Hospital at Stockholm, Sweden. Of 380 patients observed and treated by surgery for thyrotoxicosis, primarily by subtotal thyroidectomy, 1% developed permanent hypoparathyroidism. Recurrent disease occurred in 2%. The operators intended to leave less than two grams of thyroid tissue, which presumably accounts for the low recurrence rate (210.1).

Long Term Follow-Up

Finally, adequate follow-up must be carried out after any kind of treatment of Graves' disease. Recurrence is always possible, either early or late, and there is always the threat that the ophthalmopathic problems may worsen when all else in the progress of the patient seems favorable. A surprisingly large proportion of patients who have had subtotal thyroidectomy for Graves' disease and who are clinically euthyroid can be shown to have an abnormal TRH response (excessive or depressed), and up to a third have elevated serum TSH levels [210, 211]. Some of them are undoubtedly mildly hypothyroid, whereas others are close to euthyroid but require the stimulation of TSH to maintain this state. These patients should have replacement T ₄therapy if the elevated TSH persists. Over subsequent years the residual thyroid fails in more patients, due either to reduced blood supply, fibrosis from trauma, or continuing autoimmune thyroiditis. After 10 years, and depending on the extent of the original surgery, 20 - 40% are hypothyroid. This continuing thyroid failure is also seen after antithyroid drug therapy with ¹³¹I and represents the natural evolution of Graves' disease.

Special Considerations in the Treatment of Thyrotoxicosis in Children

Thyrotoxicosis may occur in any age group but is unusual in the first five years of life. The same remarkable preponderance of the disease in females over males is observed in children as in the adult population, and the signs and symptoms of the disease are similar in most respects. Behavioral symptoms frequently predominate in children and produce difficulty in school or problems in relationships within the family. Thyrotoxic children are tall for their age, probably as an effect of the disease. These children are restored to a normal height/age ratio after successful therapy for the thyrotoxicosis. Permanent brain damage and craniosynostosis are reported as complications of early childhood thyrotoxicosis ( 211.1). Bone age is also often advanced [212].

No more is known about the cause of the disease in children than in adults. Diagnosis rests upon eliciting a typical history and signs and upon the standard laboratory test results. Normal values for children are not the same as for adults during the first weeks of life, and these differences, as noted in Chapter 6, should be taken into account.

Therapy of Childhood Graves’ Disease

In some clinics, RAI is used in the treatment of thyrotoxicosis in children. In one report, 73 children and adolescents were so treated. Hypothyroidism developed in 43. Subsequent growth and development were normal. [213]In another group of 23 treated with ¹³¹I, there were 4 recurrences, at least 5 became hypothyroid, and one was found to have a papillary thyroid cancer 20 months after the second dose [214]. Safa et al. [40] reviewed 87 children treated over 24 years and found no adverse effects except the well-known occurrence of hypothyroidism. Hamburger has examined therapy in 262 children ages 3 - 18 and concludes ¹³¹I therapy to be the best initial treatment [42]. Read et al (214.1) reviewed there experience with 131-I over a 36 year period, including six children under age 6, and 11 between 6 and 11 years. No adverse effects on the patients or their offsprings were found, and they advocate 131-I as a safe and effective treatment. Nevertheless, most physicians remain concerned about the risks of carcinogenesis, and the experience of Chernobyl has accentuated this concern. This problem was more fully discussed earlier in this chapter. Others believe that the risks of surgery and problems with antithyroid drug administration outweigh the potential risk of ¹³¹I therapy. This problem was recently critically reviewed by Rivkees et al [214.1]. They point out the significant risks of reaction to antithyroid drugs, and of surgery. Surgery may have a mortality rate in hospital in children of about one per thousand operations, although this may have decreased in recent years. Among problems with radioactive iodide therapy, they note the minimal whole body radiation, possibly worsening of eye disease, and the apparent lack of significant thyroid cancer risk so far reported among children treated with I-131 for Graves’ disease. They assumed that risk would be lower in children after age five, and especially after age ten, and if all thyroid cells were destroyed. They advise using higher doses of radioiodine to minimize residual thyroid tissue, and avoiding treatment of children under age five, but they believe that RAI is a convenient, effective, and useful therapy in children with Graves’ disease. Concern about the potential long term induction of cancer by RAI given to children is discussed above. Many physicians remain reluctant to use 131-I in children under age 16-18.

Although ¹³¹I therapy may gain acceptance, the most common choice for therapy is between antithyroid drugs and subtotal thyroidectomy [213.1]. Proponents of antithyroid drug therapy believe that there is a greater tendency for remission of thyrotoxicosis in children compared to adults and that antithyroid drug therapy avoids the psychic and physical problems caused by surgery in this age group. With drugs the need for surgery (or ¹³¹I) can be delayed almost indefinitely until conditions become favorable.

As arguments against surgery, one must consider the morbidity and possible, although rare, mortality. Surgery means a permanent scar, and the recurrence rate is much higher (up to 15%) than that observed in adults. If the recurrence rate is kept acceptably low by performing near-total thyroidectomies, there is always an attendant rise in the incidence of permanent hypothyroidism, and greater potential for damage to the recurrent laryngeal nerves and parathyroid glands. Damage to the parathyroids necessitates a complicated medical program that may be permanent, and is one of the major reasons for opposing routine surgical therapy in this disease. However Rudberg et al [216] reported that, in a series of 24 children treated surgically, only one had permanent hypoparathyroidism, and two recurred within 12 years. Soreide et al [203] operated on 82 children and had no post-op nerve palsy, no tetany, nor mortality, and point out that surgery can provide a prompt, safe, and effective treatment. Childhood Graves’ disease was managed by near-total thyroidectomy in 78 patients of average age 13.8 years as reported by Sherman et al. Transient hypoparathyroidism and RCN damage were seen. Only three patients required subsequent 131-I treatment. Eighty-five % of those with ophthalmopathy were improved after surgery. The authors conclude that the treatment is safe and effective when performed by experienced surgeons (203.1).Others have pointed out the high relapse rate with all forms of therapy in the pediatric age group [214].

The main argument favoring surgery is that it may correct the thyrotoxicosis with surety and speed, and result in less disruption of normal life and development than is associated with long-term administration of antithyroid drugs and the attendant constant medical supervision. Often children are unable to maintain the careful dosage schedule needed for control of the disease.

Finally, antithyroid drug therapy is the usual preferable initial therapy in children. Favorable indications for its use are mild thyrotoxicosis, a small goiter, recent onset of disease, and especially the presence of some obvious emotional problem that seems to be related to precipitation of the disease. Antithyroid drug administration necessitates much supervision by the physician and the parents, the permanent remission rate will be 50% or less [215], and there is always the possibility of a reaction to the medication.

There is no consensus on secondary treatment. Some physicians favor surgery if the patient and parents seem incapable of following a regimen requiring frequent administration of medicine for a prolonged period or drug reactions occur. A factor that must be remembered in selecting the appropriate course of therapy is the experience of the available surgeon. Lack of experience contributes to a high rate of recurrence, permanent hypothyroidism, or permanent hypoparathyroidism. Other physicians believe the possible but unproven risks of ¹³¹I are more than outweighed by the known risks of operation, and ¹³¹I treatment is increasingly accepted for patients over age 15.

If antithyroid drugs are chosen as primary therapy, the patient is initially given a course of treatment for one or two years, according to the dosage schedule shown in Table 11-9. The dosage of PTU needed is usually 120 - 175 mg/m2 body surface area daily divided into three equal doses every eight hours. Methimazole can be used in place of PTU; approximately one-tenth as much, in milligrams, is required. During therapy the dosage can usually be gradually reduced. Many patients will be satisfactorily controlled by once-a-day treatment. Although the plasma half-life of methimazole in children is only 3-6 hours, the drug is concentrated in the thyroid and maintains higher levels there for up to 24 hours after a dose [215.1].

The program is similar to that employed in adult thyrotoxicosis. It is sensible to see the child once each month, and at that time to make sure that the program is being followed and progress made. Any evidence of depression of the bone marrow should prompt a change to an alternative drug or a different form of treatment, as discussed below.

At the end of one or two years the medication is withdrawn. If thyrotoxicosis recurs, a second course of treatment lasting for one year or more may be given. A decrease in the size of the goiter during therapy is good evidence that a remission has been achieved. Progressive enlargement of the gland during therapy implies that hypothyroidism has been produced. This enlargement can be controlled by reduction in the dose of antithyroid drug or by administration of replacement thyroid hormone. There is no adequate rule for deciding when medical therapy has failed. After courses of antithyroid drug therapy totaling two to four years and attainment of age 15, if the patient still has not entered a permanent remission it is probably best to proceed with surgical or ¹³¹I treatment. Barrio et al (215.1) reported on truly long term antithyroid drug therapy, which achieved 40% remissions in pediatric patients, with average time to remission of 5.4 years. Non-remitters were cured by RAI or surgery.

Occasionally a drug reaction develops while the condition is being controlled with an antithyroid drug. A change to another thiocarbamide may be satisfactory, but patients should be followed carefully. If a reaction is seen again, or if severe neutropenia occurs, it is usually best to stop antithyroid drug therapy and (1) give potassium iodide and an agent such as propranolol and to proceed with surgery, or (2) to give ¹³¹I. RAI therapy will be necessary if surgery is contraindicated by uncontrollable thyrotoxicosis,for whatever reason, or with prior thyroidectomy. If surgery is elected, the patient should be prepared with an antithyroid drug such as PTU in a dosage and duration sufficient to produce a euthyroid state, and then should be given iodide for seven days before surgery. Lugol's solution, or a saturated solution of potassium iodide, 1 or 2 drops twice daily, is sufficient to induce involution of the gland.

Thyrotoxicosis in children has been recently reviewed(215.2)

Table 9. 

Surface area	Weight (lbs)	Approximate daily dose of PTU
Metrically minded physicians can divide weight by 2 to approximate kilograms. Surface area in square meters.
0.1	5	15
0.2	10	30
0.5	30	75
0.75	60	110
1.0	90	150
1.25	110	190
1.5	140	225
2.0	200	300

Intrauterine and Neonatal Thyrotoxicosis

Thyrotoxicosis in utero is a rare but recognized syndrome occurring in pregnant women with very high TSH-R stimulating Ab in serum, due to transplacental passage of antibodies, or can develop in the neonate. It is possible to screen for this risk by assaying TSAb in serum of pregnant women with known current or prior Graves' Disease. Intra-uterine thyrotoxicosis causes fetal tachycardia, failure to grow, acceleration of bone age, premature closure of sutures, and occasionally fetal death. Multiple sequential pregnancies with this problem have been recorded. Clinical diagnosis is obviously inexact. Antithyroid drugs can be given, but control of the dosage is uncertain [217]. Propylthiouracil is considered to be the safest drug to use, because of fetal anomalies attributed to methimazole exposure in early pregnancy( 217.1). Luton et al (217.1) recently provided their extensive experience in managing these difficult cases. Measurement of TSAb is important. Patients with negative TSAb assay, and not on ATD, rarely have any fetal problem. Mothers with positive TSAb or on ATD must be monitored by following maternal hormone and TSH levels, fetal growth , heart rate, and by ultrasound for evidence of goiter or other signs of fetal hyper- or hypothyroidism. If maternal hormone levels are low and TSH elevated, with fetal goiter and evidence of hypothyroidism, ATD therapy is reduced and intra-amniotic T ₄may be given. If maternal T ₄levels high and TSH low, with fetal goiter and signs of fetal hyperthyroidism, increased doses of ATD are suggested. If the probable metabolic status of the fetus is not clear, fetal blood sampling is feasible although carrying significant risk to the fetus. Plasmapheresis to reduce maternal TRAb has been recommended, but few facts are available. Thyrotoxicosis in pregnancy is discussed in Ch.14.

Thyrotoxicosis is rare in the newborn infant and is usually associated with past or present maternal hyperthyroidism. [218]Neonatal hypermetabolism usually arises from transplacental passage of TSAb. Frequently the infant is not recognized as thyrotoxic at birth, but develops symptoms of restlessness, tachycardia, poor feeding, occasionally excessive hunger, excessive weight loss, and possibly fever and diarrhea a few days after birth. The fetus converts T4 to T3 poorly in utero, but switches to normal T4 to T3 deiodination at birth. This phenomenon may normally provide a measure of protection in utero that is lost at birth, allowing the development of thyrotoxicosis in a few days. The syndrome may persist for two to five weeks, until the effects of the maternal antibodies have disappeared. The patient may be treated with propranolol, antithyroid drugs given according to the schedule above, and iodide. The antithyroid drug can be given parenterally if necessary in saline solution after sterilization by filtration through a Millipore filter. Newborn infants with thyrotoxicosis are frequently extremely ill, and ancillary therapy, including sedation, cooling, fluids in large amounts, electrolyte replacement, and oxygen, are probably as important in management as specific therapy for the thyrotoxicosis. Propranolol is used to control the tachycardia (218.1). Because of the increased metabolism of such infants, attention to fluid balance and adequacy of nutrition are important.

The patient usually survives the thyrotoxicosis, and the disease is typically self-limiting, with the euthyroid state being established in one or two months. Antithyroid medication can be gradually withdrawn at this time.

Graves' disease can also occur in the newborn because the same disturbance that is causing the disorder in the mother is also occurring independently in the child. Hollingsworth et al [219] have described their experience in such patients. The mothers did not necessarily have active disease during pregnancy. Graves' disease persisted in these patients from birth far beyond the time during which TSAb of maternal origin could persist. Advanced bone age was one feature of the disorder. Behavioral disturbances were later found in some of these children at a time when they were euthyroid.

General Therapeutic Relationship of the Patient and Physician

The foregoing discussion explains several methods for specifically decreasing thyroid hormone formation. They are, in a sense, both unphysiologic and traumatic to the patient. As a good physician realizes in any problem, but especially in Graves' disease, attention to the whole patient is mandatory.

During the initial and subsequent interviews, the physician caring for a patient with Graves' disease must determine the nature of the psychic and physical stresses. Frequently major emotional problems come to light after the patient recognizes the sincere interest of the physician. Typically the problem involves interpersonal relationships and often is one of matrimonial friction. The upset may be deep-seated and may involve very difficult adjustments by the patient, but characteristically it is related to identifiable factors in the environment. To put it another way, the problem is not an endogenous emotional reaction but a difficult adjustment to real external problems. On the other hand, one must be aware that the emotional lability of the thyrotoxic patient may be a trial for those with whom he or she must live, as well as for the patient. Thus thyrotoxicosis itself may create interpersonal problems. From whatever cause they arise, these problems are dealt with insofar as possible by the wise physician.

We have been unimpressed by the benefits of formal psychiatric care for the average thyrotoxic patient, but are certain that sympathetic discussion by the physician, possibly together with assistance in environmental manipulation, is an important part of the general attack on Graves' disease. In other cases, personal problems may play a less important etiologic role but may still strongly affect therapy by interfering with rest or by causing economic hardship.

In addition to providing assistance in solving personal problems, two other general therapeutic measures are important. The first is rest. The patient with Graves' disease should have time away from normal duties to help in reestablishing his or her psychic and physiologic equilibria. Patients can and do recover with appropriate therapy while continuing to work, but more rapid and certain progress is made if a period away from the usual occupation can be provided. Often a mild sedative or tranquilizer is helpful.

Another important general measure is attention to nutrition. Patients with Graves' disease are nutritionally depleted in proportion to the duration and severity of their illness. Until metabolism is restored to normal, and for some time afterward, the caloric and protein requirements of the patient may be well above normal. Specific vitamin deficiences may exist, and multivitamin supplementation is indicated. The intake of calcium should be above normal.

SUMMARY

This chapter has dealt with the diagnosis and treatment of Graves' disease. Diagnosis of the classic form is easy and depends on the recognition of the cardinal features of the disease and confirmation by such tests as TSH and FTI.

The differential diagnosis includes other types of thyrotoxicosis, such as that occurring in a nodular gland, accompanying certain tumors of the thyroid, or thyrotoxicosis factitia, and nontoxic goiter in a patient with symptoms that imitate those of thyrotoxicosis. Types of hypermetabolism not of thyroid origin must also enter the differential diagnosis. Examples are certain cases of pheochromocytoma, polycythemia, lymphoma, and the leukemias. Pulmonary disease, infection, parkinsonism, pregnancy, or nephritis may stimulate certain features of thyrotoxicosis.

Treatment of Graves' disease cannot yet be aimed at the cause because it is still unknown. One seeks to control thyrotoxicosis when that seems to be the major indication, or the ophthalmopathy when that aspect of the disease appears to be more urgent.

The available forms of treatment, including surgery, drugs, and ¹³¹I therapy, are reviewed. There is a difference of opinion as to which of these modalities is best, but to a large degree guidelines governing choice of therapy can be drawn.

Antithyroid drugs are widely used for treatment on a long- term basis. About one-third of the patients undergoing long-term antithyroid therapy achieve permanent euthyroidism. Drugs are the preferred initial therapy in children and young adults.

Subtotal thyroidectomy is a satisfactory form of therapy, if an excellent surgeon is available, but is used infrequently by many thyroidologists. The combined use of antithyroid drugs and iodine makes it possible to prepare patients adequately before surgery, and operative mortality is approaching the vanishing point. Many young adults, especially males, are treated by surgery if antithyroid drug treatment fails.

Currently, most endocrinologists consider RAI to be the best treatment, and consider the associated hypothyroidism to be a minor problem. Evidence to date after well over four decades of experience indicates that the risk of late carcinogenesis must be near zero. The authors advise this therapy in most patients over age 40, and believe that it is not contraindicated above the age of about 15. Dosage is calculated on the basis of ¹³¹I uptake and gland size. Most patients are cured by one treatment. The principal side effect is the occurrence of hypothyroidism. This complication occurs with a fairly constant frequency for many years after therapy and may be an inevitable complication in many patients if cure of the disease is to be achieved. Many therapists accept this as an anticipated outcome of treatment.

Thyrotoxicosis in children is best handled initially by antithyroid drug therapy. If this therapy does not result in a cure, surgery may be performed. Treatment with ¹³¹I is accepted as an alternative form of treatment by some physicians.

Neonatal thyrotoxicosis is a rarity. Antithyroid drugs, propranolol and iodide may be required for several weeks until maternally-derived antibodies have been metabolized.

The physician applying any of these forms of therapy to the control of thyrotoxicosis should also pay heed to the patient's emotional needs, as well as to his or her requirements for rest, nutrition, and specific antithyroid medication.