A lack of response in patients with hyperthyroid disease to an initial dose of radioactive iodine (RAI) is not uncommon (1,2). The appropriate time for repeated treatment with RAI has not been evaluated before now. However, it has been accepted that a second dose of RAI should not be considered until 6 months after the initial dose was given (1,3). Although the effective half-life of iodine varies, it is approximately 6 days in healthy adults (4). Hyperthyroid patients have higher uptakes of RAI and faster turnover. Therefore, the 6-month waiting period to repeat RAI treatment seems generously long. The most important consideration is whether the patients can tolerate the morbid effects of hyperthyroid disease for another 6 months, particularly if they have not responded to medical therapy. Radioactive iodine is a safe and simple treatment for hyperthyroidism and has no identifiable radiation risks. Therefore, retreatment with RAI in a shorter time interval is not expected to cause any deleterious effects on patients (5–8). An acceptable reason for waiting as long as 6 months would be a possible delayed response of hyperthyroid patients to an initial RAI dose. In this retrospective study, we wanted to identify the frequency of late responses to RAI treatment in hyperthyroid patients and the appropriate time for retreatment with a second RAI dose.
We retrospectively reviewed the records of all hyperthyroid patients who were treated with RAI in our service during 1994 and 1995. There was one nuclear medicine physician in the service during these 2 years. The same physician treated all the patients in a consistent manner. Data concerning the demographics, clinical signs and symptoms of hyperthyroid disease, thyroid function tests (TFTs), gland size, RAI uptake values, thyroid scan diagnosis, and total RAI treatment dose were collected. Patients were considered hyperthyroid when clinical and chemical indications and elevated thyroid uptake were consistent with this diagnosis. Patients with Graves’ disease or toxic multinodular goiter were included in the study and treated in a similar manner. Patients with toxic autonomous nodules were excluded because they received higher doses of RAI. The RAI dose was calculated according to the formulaMATH
All patients received 120 μCi/g thyroid tissue, with the exception of four patients who received 150 μCi/g. Two of them had very large glands (90 to 100 g), so they were given higher doses. The reason for giving the other two patients a higher dose is not clear. The same physician estimated the thyroid gland size by palpation in all patients. The gland was estimated to be 30 to 40 g if palpable but not visible, 40 to 50 g when visible with the neck extended, and more than 50 g when visible without neck extension. All RAI uptakes values were measured within 1 month before treatment. The patients discontinued their antithyroid medications for at least 3 days before treatment. Most patients resumed taking their medication 48 hours after the treatment. Outcomes of patients were examined at 3 and 6 months after the treatment based on clinical assessment and TFTs. Outcomes of RAI treatments were separated into five categories:
I. Unimproved: No significant change in signs and symptoms and TFTs.
II. Residual symptoms: Partial improvement of signs and symptoms and TFTs.
III. Subclinical hyperthyroidism: No signs and symptoms but TFTs are abnormal (elevated T4, T3, depressed thyroid-stimulating hormone levels, or any of these).
IV. Normal: No signs and symptoms and normal TFTs.
V. Hypothyroid: Signs and symptoms and TFTs consistent with hypothyroid disease.
Patients were separated into two groups so we could identify any difference in outcomes between the patients who received one or two treatment doses. Group A included patients who required only one dose of RAI, and group B included patients who required a second dose.
The number of patients who required antithyroid medication to control their hyperthyroid disease after RAI treatment in the two groups was also investigated at 3- and 6-month intervals.
The clinical outcomes in the different categories (I to V) for both groups A and B were expressed as percentages of the total patient population in each group. Groups A and B were compared at 3 and 6 months using the chi-square analysis because the sample size was large. Probability values less than 0.05 were considered significant.
In 1994 and 1995, a total of 128 patients were treated with RAI for hyperthyroid disease. Twenty-eight patients who were lost to follow-up or their data were incomplete were excluded from the study. The remaining 100 patients were separated into group A, which included 80 patients, and group B, which included 20 patients. Group A had 77 patients with Graves’ disease and three patients with multinodular goiter, and group B had 19 patients with Graves’ disease and one patient with multinodular goiter. Table 1 shows the characteristics of the two groups.
Outcomes of Radioactive Iodine Treatment
The outcome of the patients after the initial dose of RAI in groups A and B were compared at 3 and 6 months.
Of the 80 patients in this group, 68 came to their 3-month follow-up visit (Table 2). Twenty-seven patients had become hypothyroid. All the other patients (41 patient) showed some degree of clinical improvement. At 6 months, 57 patients came back for their visit. These included 10 patients who did not come for their 3-month visit. The number of patients who became hypothyroid increased to 34 patients. The remaining patients also continued to improve at 6 months. None of the patients in this group was unimproved clinically at 3 or 6 months (Fig. 1).
In contrast, 8 of 20 patients in group B were unimproved clinically and chemically at 3 months (Table 2). These eight patients remained the same at 6 months. Three of six patients who had residual symptoms at 3 months deteriorated to join the unimproved category at 6 months. In addition, two of five patients who did not come to their 3-month visit came back at 6 months and reported that they were unimproved. This increased the number of patients in the unimproved category to 13 of 20 patients. The difference in the number of the unimproved patients at 3 and 6 months between the two groups was significant (P < 10-6). None of the patients in group B were normal or hypothyroid at 3 or 6 months (Fig. 2).
The trend in the use of antithyroid medications was also different between the two groups. Both groups had comparable use of antithyroid medications before the initial dose of RAI. There were 56 patients (70%) in group A and 13 patients (65%) in group B. After RAI treatment, the use of antithyroid medications decreased in group A patients from 26% to 10% and increased in group B from 55% to 70% at 3 and 6 months, respectively. The difference in the use of antithyroid medications after RAI treatment between the two groups was significant (P < 0.014 at 3 months and P < 1.6 × 10-7 at 6 months).
The results of our study clearly identify a significant difference in the response to the initial dose of RAI treatment in patients who require a single dose and those who require a second dose. Patients who did not respond to an initial treatment dose of RAI tend to continue with the same symptoms and signs or partially improve early after treatment and subsequently deteriorate again to their original hyperthyroid state by 6 months. The most important finding is that the eight patients in group B who were unimproved at 3 months remained the same at 6 months. This supports the need for earlier retreatment with a second dose of RAI in such patients. Our data suggest that the 3-month interval is an adequate period to identify nonresponders to an initial dose of RAI and to consider retreatment with a second dose. The rationale behind a 6-month waiting period before considering retreatment with RAI has not been adequately studied and there is insufficient data to support it.
None of the patients who responded to a single dose of RAI was unimproved at the 3- and 6-months intervals. This provides a safety measure against unnecessary retreatment with RAI in slow responders to an initial dose. Thus, if a patient shows any degree of improvement at 3 months, repeated evaluation at 6 months is warranted. Conversely, patients who are unimproved at 3 months can be retreated safely with RAI.
None of the patients who required a second dose of RAI were normal or hypothyroid at 3 or 6 months, even when 70% of the patients were taking antithyroid medications. Patients who became normal or hypothyroid as early as 3 months after RAI treatment are unlikely to represent treatment failures at 6 months. The distinction between treatment failure and recurrence of hyperthyroid disease may be based on the response of the patient in the few months after RAI treatment. Patients who do not improve or do so only partially and then rebound to their original hyperthyroid state in the first 6 months are considered treatment failures. Hyperthyroid patients who become subclinically hyperthyroid, euthyroid, or hypothyroid for longer periods ranging from 12 months to years and then return to their hyperthyroid state may be considered to have recurrent disease (9).
Although the ideal goal of RAI treatment is the euthyroid state (1,10), it has been recognized that hypothyroidism occurs in most patients (1,11). Nearly 60% of the patients are hypothyroid at the end of the first year, and the rate increases by approximately 3% with every additional year (3,12–14). Our results show that only 8% of the patients were euthyroid at the 3- and 6-month interval with a low dose of 120 μCi/g (15–17). More patients in group A were hypothyroid at 3 months (34%) and 6 months (42%). This supports hypothyroidism as a more realistic goal than euthyroidism (11,18–20). A lower dose per gram of the gland will increase the number of treatment failures, which was high in our study (15.6%) (1,13,21).
Although this was a retrospective study with possible inaccuracies in estimating gland size by palpation, the fact that the same physician performed the examinations and estimates supports consistency in gland size estimation in the two groups (14,22,23).
The effects of antithyroid medications on outcomes were not analyzed in detail because both groups were comparable in the use of antithyroid medication before the first dose of RAI (24–27).
Variability in the number of days the antithyroid medication was discontinued before RAI treatment and its effect on outcome is one of the shortcomings of a retrospective study (21). However, the focus of this study was to determine the appropriate timing for repeated treatment with RAI after initial treatment failure, regardless of the causes of the failure (28). We found that RAI failure is associated with a greater frequency of continued use of antithyroid medications past the 3-month visit.
Patients with hyperthyroid disease who are unimproved at 3 months after an initial dose of RAI treatment can be retreated with a second dose of RAI with no further delay.
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