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Pretreatment with Propylthiouracil But Not Methimazole Reduces the Therapeutic Efficacy of Iodine-131 in Hyperthyroidism

Department of Medicine, Division of Endocrinology (R.E.I., L.V.), Department of Radiology (J.D.M.), Department of Preventive Medicine (A.J.B.), Department of Physiology and Biophysics (L.V., N.R.V.), University of Tennessee, Memphis, Tennessee 38163

Address all correspondence and requests for reprints to: L. Vanmiddlesworth, Ph.D., M.D., University of Tennessee, 894 Union Avenue, Memphis, Tennessee 38163. E-mail: lvanmid{at}physio1.utmem.edu

	Abstract

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Ninety-three hyperthyroid patients were treated with 1 dose of iodine-131 (¹³¹I) during the past 10 years. Thirty-three were pretreated with propylthiouracil (PTU), 22 with methimazole (MMI), and 38 received no antithyroid drugs (ATD). ATD were discontinued 5–55 days before ¹³¹I therapy in three fourths of the cases and more than 4 months before therapy in one fourth of the cases. The frequency of cures in the 3 groups, 6–8 months after radioiodine therapy, was retrospectively studied. The cure rate among those who discontinued PTU for 5–55 days before ¹³¹I was significantly reduced (24%), compared with those who discontinued MMI for the same duration (61%) or those who received no ATD (66%). When PTU was discontinued for more than 4 months, the cure rate was similar to those who received no ATD.

It is concluded that if ATD are used as initial therapy for hyperthyroidism, then PTU (but not MMI) may reduce the therapeutic efficacy of subsequent ¹³¹I. The reduction in cure rate was observed even when PTU was discontinued for as long as 55 days before ¹³¹I therapy.

To our knowledge, this is the first report to compare, in one study, the effects of pretreatment with PTU and MMI on ¹³¹I therapy.

	Introduction

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ANTITHYROID drugs (ATD) are widely used as initial therapy for hyperthyroidism (1), but the rate of permanent cure is disappointingly small (2). In the USA, most hyperthyroid patients ultimately undergo radioiodine therapy (3). Among ATD available in the USA, propylthiouracil (PTU) is the most popular (1, 3). Premedication with thiouracils has been shown to reduce the therapeutic effectiveness of radioiodine (4, 5), but similar reduction has not been observed when carbimazole or methimazole (MMI) (Tapazole, Lilly) was used (6, 7). In other studies, where the outcomes of patients pretreated with PTU and MMI were not separated, conflicting results were reported (8, 9, 10, 11, 12).

To reexamine this issue, the records of hyperthyroid patients who were never treated with ATD were separated from those pretreated with PTU or with MMI. The cure rates of the three groups were compared and found to be different.

	Subjects and Methods

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Patients were referred to and treated by the Endocrine Clinic of the Regional Medical Center of Memphis from 1987 through 1996. Our retrospective review of the medical records was approved by the Institutional Review Board. The diagnosis of hyperthyroidism was confirmed by clinical and laboratory evaluation in all patients. If there was no medical reason to favor one type of therapy, patients were offered a choice of radioiodine, ATD, or surgery. The choice of PTU or MMI was based primarily on the physician’s experience with the two drugs. If hyperthyroidism persisted or recurred, radioiodine therapy was recommended. In that case, ATD were discontinued and iodine-131 (¹³¹I) treatment was scheduled within 5–14 days. Approximately half of the patients returned within that period, whereas one fourth returned after 15–55 days; 12 patients did not return until after 4–36 months.

To be included in the study, all patients received radioiodine therapy for the first time and had adequate clinical and laboratory data, both before and 6–8 months after ¹³¹I therapy. Six patients were excluded, either because they received both PTU and MMI before ¹³¹I or received ATD in the first week after ¹³¹I.

The ¹³¹I was administered under surveillance of one physician (J. D. Massie). Each dose was preceded by a radionuclide scan and measurement of 24-h radioiodine uptake. The oral therapeutic dose was estimated to deliver approximately 120 µCi/g thyroid as: (estimated thyroid weight in grams x 120 µCi) ÷ (fractional 24-h uptake of radioiodine). The thyroid weight was estimated by palpation. No adjustment of the ¹³¹I dose was made in those who were pretreated with ATD, although some authors have recommended an arbitrary or 25% increment in ¹³¹I dose (4, 13) if ATD pretreatment had been used. After radioiodine, patients were usually maintained on propranolol until they became euthyroid or hypothyroid. If needed, PTU or MMI was also added, no sooner than 4 weeks after radioiodine.

For this study, cure of hyperthyroidism was defined by clinical and laboratory evidence of euthyroidism or hypothyroidism in the absence of ATD, 6–8 months after ¹³¹I therapy. Patients whose only abnormality was persistently undetectable TSH for more than 12 months, were considered to be therapeutic failures; there were five such cases, three of whom had no ATD; one had PTU, and one had MMI. It is recognized, however, that the incidence of hypothyroidism after ¹³¹I therapy increases with time (14).

Statistical analysis

The probabilities associated with PTU and MMI observed cure rates were calculated using the exact binomial distribution (15), with population proportion equal to the no-ATD observed cure rate. The variation of PTU and MMI cure rates from the no-ATD rate was tested by the exact binomial test (15), whereas the differences in mean age, ¹³¹I oral dose, and percent 24-h radioiodine uptake were tested by the Kruskal-Wallis procedure (15). All tests were conducted at the P = 0.05 level of significance.

	Results

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Table 1 summarizes the characteristics of the patients. The groups were comparable in mean age, gender, type of goiter, oral dose of ¹³¹I, and 24-h percent radioiodine uptake. Average doses of PTU and MMI were also therapeutically comparable. The cure rates for the cohorts of patients who discontinued ATD for 5–14, 15–30, and 31–55 days and 4–36 months, before ¹³¹I, were analyzed and compared with the no-ATD group. In addition, because of the small number of patients in the 15–30 day cohort (3 PTU and 1 MMI patient) and 31–55 day cohort (6 PTU and 4 MMI patients), the cumulative cohorts (5–30 and 5–55 days) were also analyzed (Fig. 1).

View larger version (63K): [in this window] [in a new window]   Figure 1. Rate of one-dose cure of hyperthyroidism after 131I therapy in patients with and without premedication with PTU or MMI. The number of patients in the 5–30- and 5–55 day cohorts is cumulative; therefore, patients in the 5–14 day cohort are included in both the 5–30 and 5–55 day cohorts, and those in the 5–30 day cohort are included in the 5–55 day cohort. NA, Not applicable; *, rates significantly lower than the no-ATD rate (P < 0.05).

In summary, the cure rate of hyperthyroidism from ¹³¹I therapy was significantly reduced after pretreatment with PTU, even when it was discontinued for 5–55 days before radioiodine. Similar premedication with MMI did not interfere with the response to ¹³¹I therapy.

	Discussion

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Crooks et al. (4) showed that premedication with methylthiouracil reduced the frequency of cure from subsequent ¹³¹I. This finding was recently confirmed by Tuttle et al. (5), using PTU.

Different results were reported by Goolden and Fraser (6) in 1969, using carbimazole, which is converted to MMI in vivo (16); they found equal cure rates from ¹³¹I, with and without carbimazole pretreatment. Connell et al. (17) found that pretreatment with carbimazole reduced the incidence of early hypothyroidism from ¹³¹I, although after 1 yr, the total number of cures (euthyroid plus hypothyroid) with and without carbimazole was similar. More recently, Marcocci et al. (7) tested MMI and found no interference with ¹³¹I therapy.

The findings of the present report are in agreement with the above investigations, although we have compared the two drugs in one study.

The reasons for the difference between the two ATD are not clear, and the subject needs more investigation. In 1965, Greig et al. (18) demonstrated that thiouracils were radioprotective, and the possible mechanisms were discussed. We are not aware of similar experiments with MMI.

PTU and its metabolites are concentrated and retained in human thyroids to a greater extent than MMI and its metabolites (19, 20, 21), although PTU has a shorter half-life in serum (22). Moreover, the therapeutic doses of PTU are 10 times greater than those of MMI (1). The effect of these metabolic differences between the two drugs, on the outcome of ¹³¹I therapy is unknown.

In recent years, there have been recommendations to increase the dose of ¹³¹I to treat hyperthyroidism (5, 23, 24), especially after pretreatment with ATD (4, 13). We suggest that if ATD premedication is indicated, then the use of MMI, instead of PTU, may prevent interference with ¹³¹I therapy and eliminate one reason to increase the dose of ¹³¹I. The prolonged interference from PTU (up to 55 days) was unexpected.

Received May 23, 1997.

Revised July 14, 1997.

Revised September 17, 1997.

Accepted October 10, 1997.

	References

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