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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4439-4444
Copyright © 2004 by The Endocrine Society

Propylthiouracil before 131I Therapy of Hyperthyroid Diseases: Effect on Cure Rate Evaluated by a Randomized Clinical Trial

S. J. Bonnema, F. N. Bennedbæk, A. Veje, J. Marving and L. Hegedüs

Departments of Endocrinology and Metabolism (S.J.B., F.N.B., L.H.) and Nuclear Medicine (A.V., J.M.), Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Dr. Steen J. Bonnema, Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: steen.bonnema{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
A randomized clinical trial was performed to clarify whether pretreatment with propylthiouracil (PTU) before radioiodine (131I) therapy influences the final outcome of this therapy, as has been indicated by retrospective studies. Untreated consecutive hyperthyroid patients with Graves’ disease (n = 23) or a toxic nodular goiter (n = 57) were randomized to either PTU (+PTU; n = 39) or no pretreatment (–PTU; n = 41) before compensated 131I therapy. The median PTU dose was 100 mg, which was discontinued 4 d before treatment. The median 131I activity was 302 MBq (range, 87–600 MBq). After 131I therapy, the serum free T4 index increased in the +PTU group from 97.7 ± 47.5(±SD) nmol/liter at the time of therapy to 152.3 ± 77.6 nmol/liter at 3 wk (P < 0.001) and 140.4 ± 75.9 nmol/liter at 6 wk (P < 0.001). In the –PTU group, the serum free T4 index, which was initially 254.3 ± 145.7 nmol/liter, decreased significantly to 212.0 ± 113.0 nmol/liter at 3 wk (P < 0.05) and 165.8 ± 110.0 nmol/liter at 6 wk (P < 0.005). After 1 yr of follow-up, the treatment failure rate in patients with a toxic nodular goiter was four times higher in the +PTU group than in the –PTU group (nine of 20 vs. three of 25 patients; P = 0.06), whereas the difference among patients with Graves’ disease was less obvious (four of six vs. four of nine; P = 0.81). Patients in the +PTU group who were cured had higher serum TSH (s-TSH) levels at the time of 131I therapy than those who were not cured. By adjusting for a possible interfactorial relationship through a regression analysis, including the s-TSH level and type of disease, only PTU pretreatment had a significant adverse effect on the cure rate (P = 0.03). In conclusion, this randomized trial demonstrates that PTU pretreatment reduces the cure rate of 131I therapy in hyperthyroid diseases, although this adverse effect seems to be attenuated by the concomitant rise in s-TSH.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE USE OF radioactive iodine (131I) therapy as the definite cure of hyperthyroidism is widespread. According to a survey on the management of Graves’ disease (1), 30% of physicians prefer to render their patients euthyroid by antithyroid drugs (ATD) before 131I therapy. This strategy is presumably chosen to avoid a 131I-induced thyroid storm, which, however, is rarely encountered. If rapid access to 131I therapy is possible, the routine use of ATD pretreatment can be questioned. In addition, if relapse of hyperthyroidism occurs during long-term ATD treatment, this medication is usually continued until a few days before or during 131I therapy. However, several studies (2, 3, 4, 5, 6, 7, 8, 9, 10, 11) have consistently shown that patients who are treated with ATD before 131I therapy have an increased risk of treatment failure. Mostly, patients with Graves’ disease have been studied, whereas other studies also addressed toxic nodular goiter (2, 9, 10, 12, 13). Thus, it is generally accepted (14) that ATD have radioprotective properties, although this view is almost exclusively based on retrospective data (2, 3, 4, 5, 6, 7, 8, 9, 10, 11) and is still under debate (15). Indeed, this dogma was recently challenged by two randomized trials in Graves’ disease (16, 17), none of which showed such an adverse effect of methimazole pretreatment. It cannot be excluded that the earlier results may have been under the influence of selection bias, a source of error almost unavoidable in retrospective studies. One study (7), also retrospective, indicated that propylthiouracil (PTU), rather than methimazole, has a radioprotective effect. In view of the widespread use of PTU, we pursued, in a randomized set-up, whether PTU pretreatment in patients with either Graves’ disease or toxic nodular goiter impairs the effect of 131I therapy.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We enrolled consecutively patients with recurrent Graves’ disease or toxic nodular goiter, who were referred for 131I therapy at our institution. Criteria excluding patients from 131I therapy were age less than 18 yr, pregnancy or anticipation of pregnancy, lactation, suspicion of thyroid malignancy, large or partly intrathoracic goiter, and moderate/severe Graves’ ophthalmopathy. Reasons for not being eligible for the study were previous 131I therapy, ATD treatment within the last 3 months before admission, known allergic reaction to PTU, physical or psychiatric disabilities, or anticipation of practical difficulties in completion of follow-up.

Design

At inclusion, the patients, thus all being hyperthyroid, were randomized (computer-generated numbers in closed envelopes) to 131I therapy either with (+PTU) or without PTU pretreatment (–PTU). The PTU dose in the former group was adjusted guided by thyroid function tests, and 131I therapy was given when stable euthyroidism had been obtained (i.e. two consecutive sets of thyroid hormones within the normal range). PTU was discontinued 4 d before 131I therapy, with no subsequent resumption. In both groups, ß-blockade (propranolol) was instituted if severe hyperthyroid symptoms were present. In the post-131I period, thyroid function was monitored after 3, 6, and 12 wk and thereafter every 3 months for a follow-up period of 1 yr. If the patient had hyperthyroid symptoms in the early post-131I period, these were managed by ß-blockers. In case the hyperthyroidism persisted/recurred beyond 6 wk, PTU was instituted (–PTU group) or resumed (+PTU group), and this medication was subsequently tapered during the follow-up period. If this was not successful, a second 131I dose was eventually administered at the earliest, 9 months after the initial therapy. Hypothyroidism was treated with levothyroxine. If a low dose of levothyroxine was required, a trial of discontinuation was made within the follow-up period to ensure that the hypothyroidism was not transient. At the end of follow-up, the patients were classified as being hypothyroid, euthyroid, or hyperthyroid according to their thyroid function resulting from the initial 131I therapy (e.g. a patient developing myxedema after a second 131I administration due to failure of the initial 131I dose was classified as having recurrence). Euthyroidism was defined as serum free T4 (s-FT4) index and serum free T3 (s-FT3) index within the normal range; hypothyroidism was defined as serum TSH above the normal range, with or without s-FT4 index below the normal range; hyperthyroidism was defined as s-TSH below the normal range and s-FT4 index or s-FT3 index above the normal range. The study was approved by the ethics committee of the county of Funen, Denmark. All patients provided signed informed consent.

Methods and 131I therapy

Total serum T4 (normal range, 65–135 nmol/liter) and T3 (normal range, 1.00–2.10 nmol/liter) were measured by RIA [Diagnostic Products Corp., Los Angeles, CA) and Johnson & Johnson (Amersham, UK), respectively]. Serum TSH (normal range, 0.30–4.0 mU/liter) was determined by DELFIA (Wallac OY, Turku, Finland). FT4 and FT3 indexes were calculated multiplying the total T4 and T3 values, respectively, by T3 resin uptake (percentage). Serum antithyroid peroxidase antibodies (anti-TPOab) were determined at baseline and at the end of follow-up by the RIA DYNO test (Brahms Diagnostica, Berlin, Germany; normal range, <200 U/liter). Thyroid 99mTc scintigraphy was performed at baseline on a high resolution {gamma}-camera equipment. Thyroid ultrasound, including planimetric volume estimation, was performed at baseline and 1 yr after 131I by trained endocrinologists. This method for thyroid volume determination has intra- and interobserver coefficients of variation of 5% and 7%, respectively (18). A classification into Graves’ or nodular thyroid disease was based on the clinical presentation, the results of the imaging methods, and a determination of s-TSH receptor antibodies (Medi-Lab, Copenhagen, Denmark).

131I was given routinely as a single oral dose on an out-patient basis. The calculated 131I activity was 3.7 MBq/ml thyroid volume (estimated by planimetric ultrasonography) corrected for a 24-h thyroid 131I uptake of 100%. The maximum 131I activity was limited to 600 MBq according to the official health authority regulations. Glucocorticoids (25 mg/d prednisone for 28 d) were routinely used in patients with previously active or present mild Graves’ ophthalmopathy to prevent a reactivation/worsening of the orbital inflammation.

Statistical analysis

Anticipating a cure rate (euthyroidism or hypothyroidism within 1 yr) of 80% in the group without PTU pretreatment, a sample size of 29/group was calculated to provide 90% power to ensure detection of a difference in cure rate of at least 25% between the two arms. Baseline data are presented as the mean ± SD or as the median and range if not normally distributed. {chi}2-test, one- and two-way ANOVA, and Mann-Whitney test (if appropriate) were used to compare baseline characteristics and to analyze differences in outcome. A backward stepwise logistic regression analysis was employed for testing correlations. P < 0.05 (two-sided) was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics

During a period of 2 yr, 287 hyperthyroid patients were referred for 131I therapy (Fig. 1Go). In more than 90% of the 195 cases who were ineligible, this was due to ongoing ATD treatment initiated by the referring primary health care physician. Of the 81 patients who were initially included, 40 patients were randomized to the +PTU group, and 41 patients to the –PTU group. One patient in the +PTU group was secondarily excluded due to an allergic reaction to PTU. The remaining 80 patients completed 1 yr of follow-up (Fig. 1Go).



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  		FIG. 1. Trial profile.

 
Twenty-three individuals had Graves’ disease, and 57 had toxic nodular goiter (autonomously functioning toxic nodule in 20 and toxic multinodular goiter in 37 individuals). The baseline characteristics stratified for disease and randomization are shown in Table 1Go. Although no major differences were found between the groups with respect to the randomization, patients with toxic nodular goiter compared with those suffering from Graves’ disease had larger thyroid glands [median, 35 ml (range, 12–130 ml) vs. 21 ml (range, 9–58 ml); P = 0.03] and lower levels of thyroid hormones [FT3 index, 8.02 ± 5.70 vs. 4.23 ± 2.01 nmol/liter (P < 0.01); FT4 index, 340.9 ± 169.4 vs. 219.4 ± 105.4 nmol/liter (P < 0.01)]. In the +PTU group, the median time that elapsed before the patients became euthyroid was 10 wk (range, 5–30 wk), whereas the median PTU dose at the time of 131I therapy was 100 mg (range, 50–400 mg). Analyzing patients with Graves’ disease and toxic nodular goiter in concert, PTU treatment resulted in a decrease in the s-FT4 and s-FT3 indexes from initially 254.3 ± 130.5 and 5.16 ± 2.90 nmol/liter, respectively, to 97.7 ± 47.5 and 1.80 ± 0.63 nmol/liter, respectively (Fig. 2Go). At the time of 131I therapy, all patients in the +PTU group had thyroid hormone levels within the euthyroid range. The s-TSH was above the lower detection level of the assay (0.01 mU/liter) in 22 patients (56%), among whom 10 patients had levels within the normal range. The median level of s-TSH at the time of 131I therapy was significantly higher in the +PTU group than in the –PTU group (0.02 vs. <0.01 mU/liter; P = 0.004).


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  		TABLE 1. Group characteristics at inclusion before PTU treatment was commenced in the +PTU group

 


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  		FIG. 2. Changes in the s-FT4 index during the period before and early after 131I therapy. The hormone levels at randomization and during therapy are identical in the –PTU group, because 131I was given within 2 wk after the patient was allocated to this group. The gray area represents the normal range. Bars are the SEM. *, P < 0.01; **, P < 0.001 (comparing the +PTU and –PTU groups). P < 0.001 (analyzed by two-way ANOVA) for the overall between-group difference.

 
Determined on the day of the 131I therapy, the 24-h 131I thyroid uptake was 58.1 ± 11.9% in the +PTU group and 49.7 ± 15.4% in the –PTU group (P = 0.008). The 24-h thyroid 131I uptake did not deviate to any greater extent in patients with Graves’ disease (61.6 ± 13.6% in the +PTU group vs. 58.7 ± 14.3% in the –PTU group; P = 0.63), whereas a marked difference was found among those with a toxic nodular goiter (56.9 ± 11.3% in the +PTU group vs. 45.6 ± 14.2% in the –PTU group; P = 0.002). The median 131I activity administered was 302 MBq (range, 87–600 MBq; mean, 344 ± 174 MBq), but as a result of the higher thyroid 131I uptake, the +PTU group received less 131I activity than the –PTU group [median, 283 MBq (range: 87–600 MBq) vs. 332 MBq (range, 94–600 MBq); P = 0.47]. Due to a calculated 131I activity exceeding the maximum of 600 MBq, the administered activity was reduced and set at this limit in 13 patients (+PTU, six patients; –PTU, seven patients). Five patients in each group received glucocorticoids during 131I therapy as protection against 131I-induced ophthalmopathy.

Outcome

After 131I therapy, the s-FT4 index increased in the +PTU group to 152.3 ± 77.6 nmol/liter at 3 wk (P < 0.001) and 140.4 ± 75.9 nmol/liter at 6 wk (P < 0.001), as shown in Fig. 2Go. In the –PTU group, patients were hyperthyroid, by definition, at the time of 131I therapy. The s-FT4 index, which was initially 254.3 ± 145.7 nmol/liter, decreased significantly to 212.0 ± 113.0 nmol/liter at 3 wk (P < 0.05) and 165.8 ± 110.0 nmol/liter at 6 wk (P < 0.005) after therapy (Fig. 2Go). The intergroup difference was statistically significant at 3 wk (P < 0.01), but not at 6 wk (P = 0.23). Similar patterns were found for the s-FT3 index, although slightly blunted (data not shown). At 3 wk, 17 patients (44%) in the +PTU group had both normal s-FT4 index and normal s-FT3 index, whereas this applied to only 11 patients (27%) in the –PTU group. The corresponding numbers at 6 wk were 21 (54%) and 18 (44%) patients, respectively. In the posttherapy period, significantly more patients in the –PTU group needed ß-blockade, based on a clinical judgment, than in the –PTU group (16 vs. four patients; P = 0.008). The mean thyroid hormone levels in both groups were within the normal range at 12 wk after 131I therapy, but at this time patients in whom hyperthyroidism persisted started treatment with PTU. Fifteen patients in the +PTU group and 12 patients in the –PTU group required PTU in the posttherapy period due to recurrence/persistence of hyperthyroidism. Three and four of these individuals, respectively, remained euthyroid (and were classified as such) after withdrawal of the antithyroid drug within the study period, thus indicating a late-onset effect of 131I therapy.

After 1 yr of follow-up, 47 patients were classified as euthyroid, 13 developed permanent hypothyroidism, and the remaining 20 individuals had recurrence of the hyperthyroidism (Table 2Go). Although the incidences of hypothyroidism were nearly identical in the –PTU and +PTU groups, the risk of recurrence was approximately twice as high in the latter group (13 vs. seven patients; Table 2Go). Classifying the outcome into two categories, cured (euthyroidism or hypothyroidism) or not cured (recurrence), the treatment failure rate in patients with toxic nodular goiter was approximately 4 times as high in the +PTU group as in the –PTU group (P = 0.06; Table 2Go), whereas the difference among patients with Graves’ disease was less obvious (Table 2Go). Patients in the +PTU group who were cured had higher s-TSH levels at the time of 131I therapy than those who were not cured [median, 0.06 mU/liter (range, <0.01–2.36) vs. <0.01 (range, <0.01–0.91); P = 0.074]. Because PTU pretreatment and the level of s-TSH (being affected by PTU treatment per se) seemed to some extent to counterbalance each other with respect to the cure rate, these variables were analyzed in a logistic regression analysis. In addition, other independent factors with putative influence on the outcome were included, i.e. the initial thyroid volume, age, gender, serum anti-TPOab, and type of disease (Graves’ or toxic nodular goiter). Use of glucocorticoids during 131I therapy was omitted in the analysis because this variable was strongly linked to the presence of Graves’ disease and anti-TPOab. By adjusting for the interfactorial relationships, with cure rate as the dependent variable, only PTU pretreatment had a significant adverse effect (P = 0.03; Table 3Go).


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  		TABLE 2. Thyroid function 1 yr after 131I therapy according to the randomization

 

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  		TABLE 3. Key variables included in the regression analysis for prediction of the outcome of 131I therapy

 
For the euthyroid subgroup (n = 47), uninfluenced by either levothyroxine or a second 131I dose, the mean thyroid volume reduction was 37.9 ± 2.7% (±SEM) at the end of follow-up, without any significant difference between the –PTU and +PTU groups.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this study we have shown for the first time, in a randomized set-up, that PTU treatment before 131I therapy for hyperthyroid diseases approximately halves the cure rate at 1 yr. In contrast to the majority of previous studies, we ensured congruous 131I therapy in the two groups by correcting for not only the 24-h 131I thyroid uptake, but also thyroid size, reassured by a precise and accurate ultrasonographic technique (18). The detrimental effect of PTU per se may be even greater than the absolute number of cases indicates, because a statistically significant effect could be demonstrated only by taking the TSH level at the time of 131I therapy into account in a regression analysis. This measure was necessary because there was a clear interaction among cure rate, the serum TSH level, and PTU treatment. Although PTU treatment obviously leads to an increase in TSH, a lower TSH level was associated with a significantly higher risk of treatment failure. This latter relationship is well in accordance with earlier observations (19) and was apparent only in the +PTU group; untreated patients in nearly all cases had a fully suppressed serum TSH level. It remains to be clarified why serum TSH is correlated with cure rate. Hyperthyroid patients in whom a detectable serum TSH is accomplished within a short time after initiation of ATD treatment may have less severe disease than those in whom TSH remains suppressed for a long time despite normalization of the thyroid hormones.

Similar to other recent studies (9, 10, 13), performed to evaluate the efficacy of 131I therapy, we enrolled patients with both Graves’ disease and toxic nodular goiter. The patients comprised a selected cohort for mainly two reasons. First, those already taking ATD at admission were not eligible for inclusion. Secondly, only patients with recurrent Graves’ disease were treated with 131I, according to the routine at our institution. Recurrent Graves’ disease probably represents a more severe form of the disease than first incidence cases, a factor known to affect the outcome of 131I therapy (9). Although the cure rate may have been influenced by this fact, a selection bias between groups should be eliminated by the randomization. In view of the confounding role of TSH, it cannot be excluded that the impact of ATD pretreatment may be different in the two diseases, as was indicated by one study (10). In the present study the effect of PTU was most pronounced among patients with toxic nodular goiter, causing a reduction in cure rate by approximately a factor of 4. The study was not designed to compare the outcome in the two types of diseases, but, as shown by the regression analysis, this variable had absolutely no impact on the cure rate. Nevertheless, it needs to be confirmed whether the radioprotective effect of PTU per se is similar in Graves’ disease and toxic nodular goiter.

How PTU exerts its radioprotective effect is not clear. The cell damage induced by ionizing radiation is, at least in part, mediated through the production of reactive oxygen radicals. The lower metabolism resulting from ATD treatment may diminish the susceptibility to radiation. Two recent studies, both in rats, showed that PTU (20) as well as methimazole (21) in doses resulting in hypothyroidism ameliorate the oxidative tissue injury. Whether these observations have any clinical implication in the context of 131I therapy is unknown. It has previously been shown that ATD at physiological concentrations in cell cultures have scavenger-like properties by inhibiting hydrogen peroxide production (22). Because the doses of PTU used to achieve euthyroidism are much higher than those of methimazole, this may offer a possible explanation for the latter drug having a much weaker (or no) radioprotective effect. In fact, in contrast with the findings of our study, two recent randomized trials (16, 17) showed that methimazole treatment before 131I therapy does not interfere with the final cure rate. In a retrospective study (7), pretreatment with PTU before 131I therapy resulted in a reduction in cure rate, whereas methimazole had no influence on the outcome. However, taking the pitfalls of retrospective studies into account, a randomized clinical trial is required to compare methimazole and PTU head to head, although the number of patients in such a study probably needs to be large.

Should patients with newly diagnosed hyperthyroidism be treated with ATD to obtain euthyroidism before 131I therapy? This strategy is usually recommended to deplete thyroid hormone stores and avoid 131I-induced dumping of thyroid hormones into the circulation (23). On the average, we found no exacerbation of hyperthyroidism during 131I therapy in untreated patients. In line with other studies (24, 25), a steady decline in hormone levels was observed after 131I therapy, whereas patients rendered euthyroid before therapy experienced a temporary increase, but from a euthyroid level. Six weeks after 131I therapy, there was no significant difference between the s-T4 levels in the two groups. Because cases of thyroid storm are very uncommon (26), we believe that 131I therapy can be given to untreated hyperthyroid patients. The use of ß-blockers may be beneficial as adjuvant therapy (27). If, for some reason, there is an indication for ATD before 131I therapy, methimazole rather than PTU should be used to minimize the risk of treatment failure, as confirmed by our data. Alternatively, the 131I dose may be increased to overcome the PTU-dependent radioprotection. Although the susceptibility to 131I therapy shows a huge interindividual variation, a certain dose-response relationship exists (9, 28).

Whether PTU is radioprotective also when used in the post-131I period is uncertain. By resuming ATD after 131I therapy, euthyroidism can usually be maintained until the destructive effect of 131I ensues. Nevertheless, many physicians prefer not to resume ATD (1), probably due to reports (29, 30, 31, 32) suggesting that such a strategy reduces the cure rate. Parallel to the issue of ATD pretreatment, the evidence is based on retrospective studies, and the ideal set-up should be reconsidered. To underscore the importance of performing randomized trials, we showed recently (33) that resumption of methimazole 7 d after 131I therapy had no influence on the final outcome. Whether this also applies to PTU is unknown.


   Footnotes
 
Publication of this article was delayed at the request of the authors.

This work was supported by research grants from the Agnes and Knut Mørks Foundation, the A. P. Møller Relief Foundation, and the Novo Nordisk Foundation.

Abbreviations: ATD, Antithyroid drug; FT3, free T3; FT4, free T4; PTU, propylthiouracil; s-, serum; TPOab, thyroid peroxidase antibody.

Received February 10, 2004.

Accepted April 29, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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