Treatment with Thionamides before Radioiodine Therapy for Hyperthyroidism:

Yes or No?
Luigi Bartalena, Fausto Bogazzi, Aldo Pinchera and Enio Martino

J. Clin. Endocrinol. Metab. 2005 90: 1256, doi: 10.1210/jc.2004-1999

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LETTERS TO THE EDITOR
Treatment with Thionamides before Radioiodine
Therapy for Hyperthyroidism: Yes or No?
To the editor:
We read with great interest the paper by Bonnema et al. published in
a recent issue of the Journal of Clinical Endocrinology and Metabolism (1).
This randomized clinical trial showed that the efficacy of radioiodine
(RAI) therapy for hyperthyroidism was reduced when RAI was admin-
istered after pretreatment with propylthiouracil (PTU) (1). Although the
results of Bonnema et al. are convincing, this effect might be specific for
PTU. In fact, two well-designed, prospective, randomized trials (2, 3)
failed to show any consequence of methimazole (MMI) pretreatment on
the efficacy of RAI therapy. This difference might be related to the longer
radioprotective effect of PTU. Because data of the literature and our own
experience indicated that MMI pretreatment does not affect successful
management of hyperthyroidism by RAI therapy, we treat all hyper-
thyroid patients with MMI for 23 months before RAI administration to
restore euthyroidism and to deplete intrathyroidal iodine stores (4). In
our opinion, this approach is particularly important in patients who are
old or have underlying nonthyroidal illness. In addition, prompt cor-
rection of hyperthyroidism is required in Graves patients with associ-
ated orbitopathy, because restoration of euthyroidism is associated with
a more favorable course of eye disease (5).
In the paper by Bonnema et al. (1), as well as in a previous report by
Burch et al. (6), RAI therapy was not followed by an increase in serum
thyroid hormone concentrations. However, because thyroid function
was evaluated 3 wk after RAI therapy (1), early and transient changes
in serum thyroid hormone levels might have been missed. In addition,
the results of Bonnema et al. clearly showed that, when RAI therapy was
given, serum thyroid hormone concentrations were markedly higher in
nonpretreated patients than in pretreated patients (1). Thus, although
the interval between randomization and RAI therapy was not specified,
nonpretreated patients were presumably exposed to a longer period of
uncontrolled hyperthyroidism than patients receiving thionamide pre-
treatment. As we mentioned earlier, we believe that this is not acceptable
in patients whose hyperthyroidism represents a threatening condition
and must be promptly and effectively controlled. Many thyroidologists
are concerned about the consequences of subclinical hyperthyroidism;
in our opinion, we should worry even more about the potential unto-
ward effects of overt hyperthyroidism. In this regard, we recently dem-
onstrated that lithium administration for a few days before RAI therapy
and for 2 wk thereafter can effectively prevent the increase in serum
thyroid hormone concentrations that follows RAI administration
and/or MMI withdrawal before RAI therapy (7). Lithium adjuvant
therapy was also associated with a prompter goiter shrinkage after RAI
therapy (7).
In conclusion: 1) the study by Bonnema et al. (1) demonstrated that
PTU pretreatment is associated with a lower efficacy of RAI therapy, but
MMI does not seem to share this effect; accordingly, we support the view
that MMI pretreatment should be given for a better control of hyper-
thyroidism before RAI therapy; 2) uncontrolled hyperthyroidism is an
unacceptable and potentially dangerous situation that requires a more
aggressive approach, particularly in at-risk patients; and 3) a short
course of lithium adjuvant therapy, shortly before and after RAI therapy,
is helpful to prevent the increase in serum thyroid hormone concen-
trations related to RAI therapy and/or thionamide withdrawal, to obtain
a prompter control of hyperthyroidism, and to achieve a more rapid
shrinkage of goiter.
Received October 11, 2004. Address correspondence to: Prof. Luigi Bar-
talena, Department of Clinical Medicine, University of Insubria, Division of
Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy.
E-mail: l.bartalena@libero.it or luigi.bartalena@uninsubria.it.
1256
The Journal of Clinical Endocrinology & Metabolism 90(2):1256 1257
Copyright 2005 by The Endocrine Society
Luigi Bartalena, Fausto Bogazzi, Aldo Pinchera, and Enio
Martino
University of Insubria (L.B.), Varese, Italy; and University of
Pisa (F.B., A.P., E.M.), Pisa, Italy
References
1. Bonnema SJ, Bennedbaek FN, Veje A, Marving J, Hegedus L 2004 Propyl-
thiouracil before 131I therapy of hyperthyroid diseases: effect on cure rate
evaluated by a randomized clinical trial. J Clin Endocrinol Metab 89:4439 4444
2. Andrade VA, Gross JL, Maia AL 2001 The effect of methimazole pretreatment
on the efficacy of radioactive iodine therapy in Graves hyperthyroidism:
one-year follow-up of a prospective, randomized study. J Clin Endocrinol
Metab 86:3488 3493
3. Braga M, Walpert N, Burch HB, Solomon BL, Cooper DS 2002 The effect of
methimazole on cure rates after radioiodine treatment for Graves hyperthy-
roidism: a randomized clinical trial. Thyroid 12:135139
4. Bogazzi F, Martino E, Bartalena L 2003 Antithyroid drug treatment prior to
radioiodine therapy for Graves disease: yes or no? J Endocrinol Invest 26:
174 176
5. Bartalena L, Tanda ML, Piantanida E, Lai A, Pinchera A 2004 Relationship
between management of hyperthyroidism and course of the ophthalmopathy.
J Endocrinol Invest 27:288 294
6. Burch HB, Solomon BL, Cooper DS, Ferguson P, Walpert N, Howard R 2001
The effect of antithyroid drug pretreatment on acute changes in thyroid hor-
mone levels after 131I ablation for Graves disease. J Clin Endocrinol Metab
86:3016 3021
7. Bogazzi F, Bartalena L, Campomori A, Brogioni S, Traino C, De Martino F, Rossi
G, Lippi F, Pinchera A, Martino E 2002 Treatment with lithium prevents serum
thyroid hormone increase after thionamide withdrawal and radioiodine therapy
in patients with Graves disease. J Clin Endocrinol Metab 87:4490 4495
doi: 10.1210/jc.2004-1999
Authors Response: Treatment with Thionamides
before Radioiodine Therapy for Hyperthyroidism:
Yes or No?
To the editor:
We thank Bartalena et al. (1) for their comment. The main purpose of
our study (2) was to clarify whether propylthiouracil impairs the efficacy
of radioiodine therapy in hyperthyroid diseases. It may be true that this
feature of propylthiouracil is unique among the antithyroid drugs avail-
able, perhaps due to the larger doses of propylthiouracil needed to
control the hyperthyroidism. We fully agree with Bartalena et al. that
untreated hyperthyroidism may have serious health consequences. The
risk of developing heart arrhythmias and osteoporosis are well known.
However, it is not elucidated by large controlled studies whether hy-
perthyroidism results in irreversible physical or mental impairment
despite attainment of euthyroidism. Nevertheless, we believe, probably
in agreement with most other physicians, that euthyroidism should be
obtained as soon as possible when overt hyperthyroidism is detected.
Treatment of hyperthyroidism can be achieved by antithyroid drugs,
radioiodine, or surgery. Obviously, total thyroidectomy with subse-
quent l-thyroxine substitution is a very quick way to restore euthy-
roidism, but this method is rarely the first choice (3). Therefore, the
choice initially stands between antithyroid drugs and radioiodine. A
head-to-head comparison between these two methods including an eval-
uation of patient satisfaction and the long-term performance has not
been conducted, but indeed this would be relevant. According to sur-
veys (3) performed in the early 1990s, physicians do not agree on the
primary therapy of choice. It is evident that both antithyroid drugs and
radioiodine are useful for controlling hyperthyroidism, but the time
Received November 8, 2004. Address correspondence to: Steen J. Bon-
nema, M.D., Ph.D., Department of Endocrinology and Metabolism,
Odense University Hospital, DK-5000 Odense C, Denmark. E-mail:
steen.bonnema@ouh.fyns-amt.dk.
 Letters to the Editor
interval until euthyroidism is obtained is most variable due to differ-
ences in the individual susceptibility to the treatment. The advantages
of using an antithyroid drug are clear: it is simple and cheap, easily
initiated, and the impact on the thyroid gland is reversible. On the other
hand, side effects may occur, and recurrence of hyperthyroidism is
encountered in a significant part of the patients after withdrawal of the
drug. In addition, if radioiodine subsequently is given, the cure rate may
be reduced by using an antithyroid drug pretreatment. Results in this
area have been conflicting, but based on recent randomized trials me-
thimazole (4, 5) seems neutral in this setting, whereas propylthiouracil
has a detrimental effect (2). Radioiodine results in definite cure of the
disease (often including permanent thyroid failure), but the success rate
is correlated to the thyroid dose, and a second radioiodine therapy may
be needed. It has not been settled by a randomized trial whether an
antithyroid drug or radioiodine is most effective in terms of the shortest
time interval to obtain euthyroidism. Other important issues in this
context are side effects and patient satisfaction. At present, the choice
between antithyroid drugs and radioiodine is based on individual fac-
tors, including patient preference and local traditions.
We agree with Bartalena et al. (1) that overtly hyperthyroid patients
should not go untreated. Therefore, as discussed in our paper (2), there
is no doubt that patients should be offered an antithyroid drug, if rapid
access to radioiodine is impossible. If radioiodine is given to untreated
hyperthyroid patients, the risk of a radioiodine-induced hyperthyroid
crisis is very low. In fact, the thyroid hormone levels steadily decline
after radioiodine therapy of hyperthyroid patients (2, 6, 7). In the studies
by Burch et al. (6) and Andrade et al. (7), the thyroid function was closely
monitored after radioiodine administration. Nevertheless, we agree that
the risk of a hyperthyroid exacerbation should be minimized, particu-
larly in elderly patients or in cases with known cardiovascular heart
diseases. Such patients should preferably be pretreated with antithyroid
drugs before radioiodine. The thyroid function after radioiodine may
also show a highly variable and unpredictable course, and the patients
should therefore be monitored relatively closely in this period. If the
antithyroid drug is discontinued before radioiodine administration, a
transient hyperthyroid relapse follows the treatment (2, 6). We recognize
that use of lithium in conjunction with radioiodine may be beneficial in
this setting (8), as outlined by Bartalena et al. (1). Although lithium seems
to increase the thyroid iodine retention, the final cure rate is not in-
creased by the adjuvant use of lithium 900 mg/d for 3 wk, as demon-
strated by a large randomized study (9). We do not use lithium, but we
recommend that the antithyroid drug, used initially to render the patient
euthyroid, is paused 4 d before and resumed 1 wk after radioiodine, with
final discontinuation of the drug if euthyroidism is verified 1 month
later. We have recently proved by a randomized trial (10) that such an
approach, using methimazole, results in a stable euthyroid state
J Clin Endocrinol Metab, February 2005, 90(2):1256 1257 1257
throughout this early period after radioiodine and without adversely
affecting the final outcome.
The ideal management of hyperthyroid disorders as well as the most
favorable radioiodine regimen still remains to be established. Indeed,
recognizing that lack of consensus prevails among centers handling
thyroid disorders, future well-designed studies should address these
issues.
Steen J. Bonnema and Laszlo Hegedus
Department of Endocrinology and Metabolism
Odense University Hospital
DK-5000 Odense C, Denmark
References
1. Bartalena L, Bogazzi F, Pinchera A, Martino E 2005 Treatment with thio-
namides before radioiodine therapy for hyperthyroidism: yes or no? J Clin
Endocrinol Metab 90:1256 (Letter)
2. Bonnema SJ, Bennedbk FN, Veje A, Marving J, Hegedus L 2004 Propyl-
thiouracil before 131I therapy of hyperthyroid diseases: effect on cure rate
evaluated by a randomized clinical trial. J Clin Endocrinol Metab 89:4439 4444
3. Solomon B, Glinoer D, Lagasse R, Wartofsky L 1990 Current trends in the
management of Graves disease. J Clin Endocrinol Metab 70:1518 1524
4. Andrade VA, Gross JL, Maia AL 2001 The effect of methimazole pretreatment
on the efficacy of radioactive iodine therapy in Graves hyperthyroidism:
one-year follow-up of a prospective, randomized study. J Clin Endocrinol
Metab 86:3488 3493
5. Braga M, Walpert N, Burch HB, Solomon BL, Cooper DS 2002 The effect of
methimazole on cure rates after radioiodine treatment for Graves hyperthy-
roidism: a randomized clinical trial. Thyroid 12:135139
6. Burch HB, Solomon BL, Cooper DS, Ferguson P, Walpert N, Howard R 2001
The effect of antithyroid drug pretreatment on acute changes in thyroid hor-
mone levels after 131I ablation for Graves disease. J Clin Endocrinol Metab
86:3016 3021
7. Andrade VA, Gross JL, Maia AL 1999 Effect of methimazole pretreatment on
serum thyroid hormone levels after radioactive treatment in Graves hyper-
thyroidism. J Clin Endocrinol Metab 84:4012 4016
8. Bogazzi F, Bartalena L, Brogioni S, Scarcello G, Burelli A, Campomori A,
Manetti L, Rossi G, Pinchera A, Martino E 1999 Comparison of radioiodine
with radioiodine plus lithium in the treatment of Graves hyperthyroidism.
J Clin Endocrinol Metab 84:499 503
9. Bal CS, Kumar A, Pandey RM 2002 A randomized controlled trial to evaluate
the adjuvant effect of lithium on radioiodine treatment of hyperthyroidism.
Thyroid 12:399 405
10. Bonnema SJ, Bennedbk FN, Gram J, Veje A, Marving J, Hegedus L 2003
Resumption of methimazole after 131I therapy of hyperthyroid diseases: effect
on thyroid function and volume evaluated by a randomized clinical trial. Eur
J Endocrinol 149:485 492
doi: 10.1210/jc.2004-2189