Treatment - The Journal of Clinical Endocrinology & Metabolism

J Clin Endocrinol Metab, October 2009, 94(10):3700–3707 jcem.endojournals.org 3705
the follow-up period, but one patient was subject to orbital
decompression surgery (in group I). No significant
differences were found between the different centers for
worsening or development of TAO or the severity of hyperthyroidism
using the Cox test (results not shown).
During the first 12 months of follow-up, 87.7% of the
patients in group I and 86.0% in group M had no recorded
serum TSH above 4.5 mIU/liter. Worsening or development
of TAO was in a Mantel-Haenszel analysis not found
to be more frequent in the patients who at any occasion
had serum TSH above 4.5 mIU/liter (P � 0.49).
Discussion
Radioiodine treatment was shown to be associated with a
higher cumulative incidence of worsening or development
of TAO compared with medical therapy. In this study,
L-thyroxine therapy was introduced early in both treatment
groups to avoid hypothyroidism, which was in contrast
to the previous report by Tallstedt et al. (2). The time
for active follow-up by ophthalmologists was longer in the
present study compared with the two previous large prospective
randomized trials where radioiodine and medical
therapy were compared (2, 11). In the present study, the
proportion of worsening or development of TAO after
1-yr follow-up was 31% in the iodine-131 group and 16%
in the medical treatment group. The corresponding figures
were similar in Tallstedt et al. (2) (33 and 10%, respectively)
but lower in Bartalena et al. (11) (15 and 3%,
respectively).
In contrast to the results in Bartalena et al. (11), the
differences in the ophthalmological outcome between the
treatment groups in the present study were explained by de
novo development of TAO and not by worsening of preexisting
TAO. This may partly be explained by differences
in the study designs. In this study and that by Tallstedt et
al. (2), only newly diagnosed patients with Graves’ disease
were randomized, whereas in the study by Bartalena et al.
(11), 70% of all patients had a previous history of treatment
of Graves’ disease. Also, in the latter study a 3-month
course of antithyroid drugs was part of the protocol for
those treated with radioiodine. In the present study and in
that by Tallstedt et al. (2), TAO was present at randomization
in 13% of the patients, whereas this number was
50% in the study by Bartalena et al. (11). The discrepancy
in incidence data between this and previous studies may
also be explained by patient characteristics, sample size,
treatment practice, the assessment of TAO, and thresholds
for introducing steroid treatment.
It is well known that radioiodine treatment leads to a
prolonged release of TRAb and thyroid peroxidase antibody,
but the mechanism for this is not known. The rise in
serum antibodies against thyroid antigens after radioiodine
treatment mirrors an immune reaction in the thyroid
that may be the triggering event for the orbital inflammation,
assuming that the thyroid and orbital tissues share
resembling antigens (9, 12–17).
To the patients who were randomized to medical therapy,
L-thyroxine was given early by routine to achieve a
stable thyroid function and because previous studies have
shown that a more severe and unstable Graves’ disease is
a common denominator for the development of TAO (2,
9). Furthermore, the potential benefits on the immune system
by antithyroid drugs need to be pointed out (18–21).
If applicable for the present, such influences on the immune
system may have contributed to the lower frequency
of worsening or development of TAO that was observed
in the medically treated group.
Smoking is an established risk factor for TAO, and this
relationship was also confirmed in this study (22, 23).
Interestingly, in the group of smokers, worsening or development
of TAO was not significantly associated with
the choice of treatment for hyperthyroidism. This infers
that radioiodine may be an independent risk factor for
TAO and that this treatment-related risk factor is not as
strong in smokers as in nonsmokers. However, because
smokers who received radioiodine had the overall highest
risk of TAO, one might argue that radioiodine should be
avoided in smokers or be given together with immunesuppressive
prophylaxis.
Prophylactic steroid treatment has been shown to significantly
reduce the risk for TAO in radioiodine-treated
patients (11, 24). However, there have been discussions
about whether the eye changes observed after radioiodine
treatment warrant the use of prophylactic steroid treatment
as a rule (25–27). In this decision making, there is to
date no solid agreement about what risk factors should be
taken into account. Smoking habits and preexisting TAO
should probably be regarded, but presumably other possible
risk factors should also be considered, e.g. pretreatment
serum T 3 and antithyroid antibodies (28, 29). The
high proportion of de novo development of TAO in the
iodine-131 group implies that other factors besides clinically
apparent preexisting TAO should be considered in
the decision making regarding steroid prophylaxis in patients
who are treated for newly diagnosed Graves’
hyperthyroidism.
This present trial has both strengths and limitations.
The prospective randomized design, although open-label,
and the extensive follow-up time by both thyroidologists
and ophthalmologists strengthens the observations. Even
if the final study group did not meet the requisite of the
trial, the number of 313 patients makes this trial one of the
largest on the issue. Surgery was not included as a third