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Endocrine Care |
Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, Brazil
Address all correspondence and requests for reprints to: Ana Luiza Maia, M.D., Ph.D., Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil. E-mail: almaia{at}vortex.ufrgs.br
Abstract
The effect of antithyroid drugs on the efficacy of radioiodine (131I) treatment is still controversial. This study evaluated the effect of methimazole pretreatment on the efficacy of 131I therapy in Graves’ hyperthyroidism. Sixty-one untreated patients were randomly assigned to receive 131I alone (32 patients) or 131I plus pretreatment with methimazole (30 mg/d; 29 patients). 131I was administered 4 d after drug discontinuation. The calculated 131I dose was 200 µCi/g thyroid tissue as estimated by ultrasound, corrected by 24-h radioiodine uptake. Serum TSH, T4, and free T4 were measured 4 d before 131I therapy, on the day of treatment, and then monthly for 1 yr. Considering cure as euthyroidism or hypothyroidism, based on free T4 measurement, approximately 80% of patients from both groups were cured 3 months after beginning 131I treatment. After 1 yr the groups were similar in terms of persistent hyperthyroidism (15.6% vs. 13.8%), euthyroidism (28.1% vs. 31.0%), or hypothyroidism (56.3% vs. 55.2%). Relapsed patients presented larger thyroid volume (P = 0.002), higher 24-h radioiodine uptake (P = 0.022), and T3 levels (P = 0.002). Multiple logistic regression analysis identified T3 values as an independent predictor of therapy failure. In conclusion, pretreatment with methimazole had no effect on either the time required for cure or the 1-yr success rate of 131I therapy.
GRAVES’ DISEASE is one of the most prevalent autoimmune disorders in the United States and the most frequent cause of hyperthyroidism in adults aged 20–50 yr (1, 2). Antithyroid drugs have been one of the standard modalities of therapy for Graves’ hyperthyroidism, either as first choice therapy or as pretreatment before radioactive iodine in selected patients. The most important effect of antithyroid drugs on hyperthyroidism control is the inhibition of thyroid peroxidase, yet some studies also indicate a possible effect on modulation of the immunological process (3, 4, 5). Pretreatment with antithyroid drugs before radioactive therapy is usually recommended to deplete preformed stores of thyroid hormones and to decrease the risk for hyperthyroidism exacerbation (6), although recent studies have shown that thyroid hormone levels do not increase after radioiodine dosing (7, 8).
The influence of pretreatment with antithyroid drugs on the efficacy of radioactive iodine therapy (RAI) is controversial. Although some studies associate antithyroid drugs with higher rates of RAI treatment failure (9, 10, 11, 12, 13, 14), others do not report this association (15, 16, 17). In addition, it has been suggested that propylthiouracil, but not methimazole, may reduce the effectiveness of radioiodine therapy (18). In any case, the possible radioprotective properties of antithyroid drugs are the basis for an empirical increase in the dose of 131I. However, to date the association between antithyroid drugs and RAI has been analyzed by retrospective or nonrandomized studies whose conclusions may have been influenced by both selection bias and differences in the time interval between antithyroid drug discontinuation and radioactive therapy. Therefore, the purpose of the present randomized study was to evaluate the effect of pretreatment with methimazole on the efficacy of radioactive iodine therapy in Graves’ hyperthyroidism.
Subjects and Methods
Subjects
The study was carried out between February 1997 and March 2000. Consecutive patients with a recent diagnosis of Graves’ disease attending the Endocrine Division at Hospital de Clínicas de Porto Alegre were eligible. Graves’ hyperthyroidism was diagnosed on the basis of suppressed TSH levels by sensitive assay, elevated serum thyroid hormone levels, 24-h radioiodine uptake (RAIU), and detectable levels of anti-TSH receptor antibody. Exclusion criteria were previous treatment with radioiodine or thyroidectomy, signs of moderate or severe ophthalmopathy (proptosis >22 mm, ophthalmoplegia, chemosis, or lagophthalmos), severe heart disease (symptomatic coronary heart disease, class III heart failure, New York Heart Association criteria), debilitating conditions, and large and compressive goiters (>150 g). Patients previously treated with antithyroid drugs whose treatment had been interrupted at least 3 months before the study were included. Sixty-seven patients were enrolled. Five patients were lost to follow-up; one was excluded because of pregnancy. Thus, 61 patients participated in the study.
During the enrollment period the patients underwent a complete physical examination, including ocular examination and electrocardiogram. Data about duration of disease, previous antithyroid drug therapy, and history of smoking were recorded, and thyroid volume was assessed by ultrasound, always by the same observer. The study protocol was approved by the ethics committee at the hospital, and all patients gave written informed consent.
Treatment protocol and serial evaluation
Patients were randomly assigned to receive RAI alone (32 patients) or to receive pretreatment with antithyroid drugs in addition to RAI therapy (29 patients). In the first group patients received a single dose of radioiodine on the day of treatment (200 µCi/g thyroid tissue as estimated by ultrasound, divided by the fractional 24-h uptake value). A clinical and laboratory assessment was performed on the day of treatment and monthly for 1 yr after treatment.
In the second group patients were treated with methimazole (30 mg daily) until biochemical euthyroidism was achieved. Patients were considered to have reached euthyroidism when serum thyroid hormone levels were within the laboratory reference range. Patients received 131I 4 d after antithyroid drug discontinuation. The 131I dose was calculated in the same way as described for the first group, based on a second 24-h radioiodine uptake performed on the day of treatment. A clinical and laboratory assessment was carried out 4 d before radioiodine therapy, on the day of RAI treatment, and then monthly for 1 yr after RAI therapy.
The degree of thyrotoxicosis was always evaluated by the same
physician, who did not know whether the patient had received
methimazole, using Wayne’s questionnaire (euthyroidism, 
10;
suspicion of hyperthyroidism, 11–19; hyperthyroidism, 
20)
(19). Serum levels of T4, free
T4 (FT4), TSH, and TR
antibodies (TRAb) were measured in the morning on the days scheduled
for clinical and laboratory assessment, as described above. None of the
patients received antithyroid drug therapy after radioiodine therapy.
The ß-adrenergic blocking agent propranolol (80–120 mg/d) was given
to patients if tachycardia was greater than 120 beats/min.
Successful therapy was defined as euthyroidism or permanent hypothyroidism based on FT4 measurements obtained at each monthly visit. To avoid misclassification of the thyroid status, we used two consecutive serum FT4 measurements in normal or low range, or, in cases of borderline upper range values, three serum FT4 values. The time of cure (month) was considered when the first serum FT4 measurement reached and persisted in the normal or low range. Therapy failure was defined as the need to repeat 131I treatment or as persistent elevated thyroid hormone levels after 1 yr of 131I treatment.
Serum hormone measurements
Assays were performed on batched serum samples (duplicates) that
had been stored at -20 C pending study completion. Serum
T4 and T3 levels were
measured using RIA (Diagnostic Products, Los Angeles, CA;
Immunotech, Marseilles, France), and serum
FT4 was measured using Coat-a-Count
(Immunotech). Intraassay coefficients of variation were as
follows in euthyroid controls: T4, 3–8%;
T3, 7–10%; and FT4,
3–6%. For values in the hyperthyroid and hypothyroid ranges,
intraassay coefficients of variation were: hyperthyroid:
T4, 6–9%; T3, 6–12%;
and FT4, 4–8% and hypothyroid:
T4, 5–7%; T3, 6–10%;
and FT4, 4–6%. Interassay coefficients of
variation were as follows (euthyroid controls):
T4, 10%; T3, 12%; and
FT4, 7%. TSH was measured by a double antibody
sensitive assay (Immulite, Diagnostic Products). Plasma
levels of TSH antibodies were determined by RRA (CIS-Bio International, Cardiff, France). The reference ranges for each
of these assays is shown in Table 1
.
|
The baseline characteristics of the two groups of patients were
compared using 
2 test or Fisher’s exact test
for qualitative variables, or by t test or Mann-Whitney U
test for quantitative variables. The differences in the cumulative cure
rate between the groups were tested by Kaplan-Meier curves; comparisons
between nonremission curves were performed using the
Beslow-Gean-Wilcoxon test. Stepwise multiple logistic regression
analysis was used to identify independent predictors of treatment
failure. Only variables showing statistical significance
(P 0.05) in the univariate analysis were included in
the model as potential independent predictors of treatment failure. The
correlation between changes in thyroid volume, 24-h RAIU, calculated
radioiodine dose, and serum T3 levels was
assessed using Spearman’s rank correlation. The Statistical Package
for the Social Sciences 7.5 (SPSS, Inc., Chicago, IL) was
used for statistical analysis.
Results
Subjects
The characteristics of the 61 patients with Graves’
hyperthyroidism who were randomly assigned to receive RAI alone or RAI
plus antithyroid drug treatment are shown in Table 1
. There were no
significant differences between the two groups with respect to any of
the characteristics listed.
The median for the period of time required to achieve biochemical euthyroidism in the group of patients pretreated with antithyroid drugs was 12 wk (2–48 wk). The mean dose of RAI (10.6 ± 5.7 vs. 8.9 ± 4.6) and the number of patients using propranolol (3 vs. 2) and/or oral contraceptives (9 vs. 8) were similar in both groups. Methimazole was replaced with propylthiouracil (300 mg/d) in three patients who developed a cutaneous rash.
Patient follow-up
Kaplan-Meier estimates of cumulative cure rate yielded nearly
identical curves for the two treatment groups (Fig. 1). The successful cure rates 2 and 3
months after 131I therapy in patients from both
groups were approximately 57% and 77%, respectively. About 90% of
all patients cured with a single RAI dose responded in the first 3
months after 131I treatment. One patient in the
methimazole group required a second dose of 131I
before 1 yr due to persistently elevated serum levels of thyroid
hormone and development of atrial fibrillation.
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Prognostic factors for radioiodine therapy failure
In view of the lack of difference between the two treatment groups
concerning thyroid function outcome, all patients were grouped for
analysis of possible prognostic factors for therapy failure. Table 2 compares clinical and laboratory data
from patients who were successfully treated with data from subjects who
remained thyrotoxic after a single dose of RAI. Age (P
= 0.940), gender (P = 0.283), body mass index
(P = 0.166), duration of disease (P =
0.533), and TRAb titer (P = 0.748) were not associated
with therapy failure. Male patients at presentation had, however,
larger goiters (47.6 ± 23.2 vs. 33.7 ± 17.0;
P = 0.071) and higher concentrations of
T3 (578 ± 52.4 vs. 455 ±
202; P = 0.002) and FT4 than
females (7.7 ± 1.77 vs. 4.1 ± 1.4;
P = 0.0001). Although the percentage of smokers was
higher in the failure group, the difference was not significant
(P = 0.460). At baseline, patients in the treatment
failure group presented larger goiter (P = 0.002),
higher 24-h RAIU (P = 0.022), and higher basal serum
T3 levels (P = 0.002) than
patients who were cured after a single dose of radioiodine.
Nevertheless, multiple logistic regression analysis with radioactive
therapy failure as the dependent variable and thyroid volume, 24-h
RAIU, and serum T3 level as independent variables
identified only serum T3 levels as an independent
predictor of failure (estimated odds ratio, 1.0058; 95% confidence
interval, 1.0014–1.0102; P < 0.01), presumably
because of the high colinearity between the variables included in the
model. Therefore, we also analyzed the correlation between thyroid
volume, 24-h RAIU, and serum T3 levels in
successfully and unsuccessfully treated patients.
|
, A–C). Nevertheless, when
patients were analyzed in terms of therapy outcome, a significant
correlation was found only in the successfully treated group (results
not shown). Another interesting finding was that combinations of these
pretreatment variables could be strong predictors of therapy failure
(Fig. 2). We observed that only 4 of 61 patients (6.6%) presented 24-h
RAIU values of 90% or more and thyroid volume of 50 ml or more , and
all of them had to be treated again (100% treatment failure; Fig. 2A).
Six of 9 (67%) subjects who did not respond to a single dose of
radioiodine had 24-h RAIU values of 90% with basal serum
T3 levels exceeding 7.68 nmol/liter (500 ng/dl)
at presentation compared with only 6 of 52 (12%) successfully treated
patients (P < 0.02; Fig. 2B). Patients with serum
T3 levels exceeding 7.68 nmol/liter (500 ng/dl)
and goiter of 50 ml or more (7 of 61 patients) presented a higher
therapy failure rate than patients with smaller goiter and lower serum
T3 values (33% vs. 8% treatment
failure; P < 0.02; Fig. 2C). On the other hand, the
cure rate of 131I treatment was 96% in patients
who did not present any of these pretreatment characteristics (28
patients, 1 treatment failure).
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After 1 yr of follow-up, we did not observe any differences in the thyroid function outcome after RAI treatment between patients pretreated or not treated with methimazole. Furthermore, the period of time required to achieve cure was virtually identical in both groups. Persistent hyperthyroidism was associated with larger goiters, higher 24-h RAIU, and serum T3 levels at baseline. Subsequent analysis by multiple logistic regression analysis identified serumT3 values as an independent predictor of therapy failure.
The effect of antithyroid drugs on RAI therapy has long been the focus of discussion, and it is still a matter of debate (20). Some studies have reported that previous use of antithyroid drugs increases the rate of radioactive therapy failure due to a possible protective effect of antithyroid drugs against radioiodine (9, 10, 11, 12, 13, 14), whereas others did not observed similar effects of these compounds (15, 16, 17). As Einhorn and Säterborg (21) proposed that the radioresistance associated with thiourea resulted from the presence of a sulfhydryl group, it has been suggested that methimazole and carbimazole would not have this property, because they do not present sulfhydryl groups (22). In the present study the proportion of patients who were cured by RAI administration was not influenced by methimazole. However, one other explanation for our results would be that the 4 d of antithyroid drug interruption were enough to prevent the methimazole effect on effective 131I half-life and RAIU values (8, 23, 24, 25). Accordingly, it has been recently shown that RAI administration during the use of carbimazole results in a 5-fold increase in the possibility of treatment failure, although the radioprotective effect of these drugs was overcome by drug discontinuation a few days before radioiodine treatment (26). Another possibility would be that the relatively high 131I dose per gram of thyroid used in our protocol had overcame or obscured a methimazole effect on the response to lower 131I doses.
The cumulative cure rate observed in this study was virtually identical in both treatment groups, and this supports the absence of a methimazole effect on the efficacy of RAI therapy as well on the period of time required for disappearance of the hyperthyroid state. In fact, about 80% of patients from both groups were cured 3 months after radioiodine treatment. At least two inferences arise from this observation. First, Graves’ hyperthyroidism was cured faster in patients who received radioiodine alone if we consider the median period of 12 wk required to achieve biochemical euthyroidism with pretreatment with antithyroid drugs (8). Also, it seems that patients who did not respond 4 months after RAI administration have a very low probability of cure, and therefore a second dose of radioiodine should be considered.
Because RAI is increasingly being used both as first line treatment and in patients who relapse after medical therapy in Graves’ disease, some studies have attempted to identify factors that may predict the response to RAI therapy (27, 28, 29, 30, 31). Our data showed that goiter size, 24-h RAIU, and serum T3 levels at baseline were significantly associated with radioiodine therapy failure, although only serum T3 levels were an independent predictor factor after multiple logistic regression analysis. These results contrast with those of some studies (28, 31), but agree with the results of most others (27, 29, 30). Indeed, the strong influence of these three measurements, all part of the initial evaluation of Graves’ hyperthyroidism, to predict treatment outcome is an important finding of our study. The presence of large goiters (>50 ml) and 24-h RAIU values exceeding 90% were associated with therapy failure in all the cases observed, whereas the rate of therapy success in patients presenting 24-h RAIU values above 90% and very high serum T3 levels (>7.68 nmol/liter) was only 33%. These findings indicate that goiter size, 24-h RAIU, and serum T3 levels should be taken into account when making treatment decisions.
In agreement with most studies, age, sex, basal serum TRAb levels, and smoking habit did not differ significantly between patients who responded or did not respond to a single radioactive iodine dose (27, 28, 29, 30). A large retrospective study has recently identified male gender as an independent predictor of therapy failure (31) In our study all male patients were cured after receiving a single dose of radioiodine. Similarly to others (32), we observed that males presented with a more severe clinical and biochemical hyperthyroidism than women, but the proportional increase in calculated radioiodine dose was enough to overcome the severity of the disease.
Another interesting observation is related to the RAI dose given to patients who did not respond to treatment, as it has been suggested that an empirical increase in the delivered dose of radioiodine could bring the treatment failure rate down to an acceptable level (33). The dose received by patients who were not cured was about 30% higher than that received by cured patients, suggesting that dose correction based only on thyroid volume and 24-h RAIU is not enough to overcome the more severe disease in these cases (27). Indeed, we observed that, in contrast with successfully treated patients, patients who fail to respond to RAI treatment do not present a significant correlation between thyroid volume, 24-h RAIU, and serum T3 levels. However, it is important to call attention to the distinction between the administered 131I dose and the radiation delivered to thyroid. Although we used here dose as the millicuries of given 131I, in radiation biology dose refers to the radiation dose to tissue, and one of the variables that determines radiation dose is the effective half-life of the 131I in the thyroid gland, which was not determined in the present study. The presence of autonomous tissue with functional differences in uptake and iodine organification (28) may be an additional explanation for the fact that some cases of Graves’ disease are less sensitive to RAI therapy, similar to what is observed for multinodular goiters.
A possible limitation of this study is the number of patients in the
sample. We observed a difference of approximately 2% between the
groups. To determine the equivalence of both regimens in terms of
efficacy (
= 0,05 and ß = 0.20), 3841 patients would
have to be included in each group. In our view this possible difference
is not clinically significant enough to justify such a large study.
In conclusion, we demonstrated that methimazole pretreatment does not interfere with either the efficacy of RAI therapy or the period required to achieve control of hyperthyroidism in Graves’ disease. Furthermore, about 90% of successfully treated patients from both groups were cured within 3 months of RAI dosing, suggesting that Graves’ hyperthyroidism was cured faster in patients who did not receive pretreatment. As we have previously demonstrated that radioiodine therapy without pretreatment is safe, we believe that most patients with Graves’ hyperthyroidism could receive RAI therapy alone, avoiding the risk and costs associated with antithyroid drugs. Therapy failure was strongly associated with large goiters (>50 g), very high 24-h RAIU (>90%), and serum T3 levels above 500 ng/ml at baseline; patients with these characteristics should be closely followed, and if hyperthyroidism persists 4 months after radioiodine administration, a second radioiodine dose should be prescribed. Another approach could be to give such patients empirical higher doses of radioiodine at the time of first treatment.
Acknowledgments
We thank Dr. Álvaro Porto Alegre for performing the ultrasound examinations, and Dr. Ilza Vasquez de Moraes for carrying out the uptake studies and the administration of radioiodine. We are also indebted to Mrs. Ligia B. Crosseti and Francisco Lullier for technical assistance.
Footnotes
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Fundo de Incentivo a Pesquisa (Hospital de Clínicas de Porto Alegre), Brazil.
Abbreviations: FT4, Free T4; RAI, radioactive iodine therapy; RAIU, radioiodine uptake; TRAb, TR antibodies.
Received December 28, 2000.
Accepted April 18, 2001.
References
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), euthyroidism (
), and persistent
hyperthyroidism (
). To convert nanomoles per liter to nanograms per
dl, divide by 0.01536.