Treatment - The Journal of Clinical Endocrinology & Metabolism

ORIGINAL ARTICLE
Endocrine Care
Thyroid-Associated Ophthalmopathy after Treatment
for Graves’ Hyperthyroidism with Antithyroid Drugs
or Iodine-131
Frank Träisk, Leif Tallstedt, Mirna Abraham-Nordling, Tommy Andersson,
Gertrud Berg, Jan Calissendorff, Bengt Hallengren, Pavo Hedner, Mikael Lantz,
Ernst Nyström, Vesna Ponjavic, Adam Taube, Ove Törring, Göran Wallin,
Peter Åsman, Göran Lundell, and the Thyroid Study Group of TT 96*
Context: Previous randomized trials have suggested an association between radioiodine treatment
for Graves’ hyperthyroidism and thyroid-associated ophthalmopathy (TAO).
Objectives: The aim of the study was to compare the occurrence of worsening or development of
TAO in patients who were treated with radioiodine or antithyroid drugs.
Design: We conducted a randomized trial (TT 96) with a follow-up of 4 yr.
Patients, Setting, and Intervention: Patients with a recent diagnosis of Graves’ hyperthyroidism
were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment
(150 patients). Early substitution with T 4 was given in both groups.
Main Outcome Measure: Worsening or development of TAO was significantly more common in
the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment
group (32 patients; 21.3%) (P � 0.001).
Results: The risk for de novo development of TAO was greater in patients treated with iodine-131 (53
patients)thanwithmedicaltreatment(23patients).However,worseningofTAOinthe41patientswho
had ophthalmopathy already before the start of treatment was not more common in the radioiodine
group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the
risk of worsening or development of TAO, and smokers treated with radioiodine had the
overall highest risk for TAO. However, in the group of smokers, worsening or development of
TAO was not significantly associated with the choice of treatment for hyperthyroidism.
Conclusions: Radioiodine treatment is a significant risk factor for development of TAO in Graves’
hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective
of treatment modality. (J Clin Endocrinol Metab 94: 3700–3707, 2009)
Treatment for hyperthyroidism may influence the development
and the course of thyroid-associated ophthalmopathy
(TAO). In a recent systematic review of randomized
controlled trials, radioiodine treatment was
shown to be associated with a definite risk of development
or progression of TAO compared with medical therapy
(1). Yet, conclusions are difficult to make because large
randomized trials are scarce and definitions of TAO are
generally heterogeneous.
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2009 by The Endocrine Society
doi: 10.1210/jc.2009-0747 Received April 14, 2009. Accepted July 20, 2009.
First Published Online September 1, 2009
*Author Affiliations are shown at the bottom of the next page
3700 jcem.endojournals.org J Clin Endocrinol Metab. October 2009, 94(10):3700–3707
Tallstedt et al. (2) reported in 1992 that radioiodine
treatment was associated with an increased risk for TAO
compared with both medical therapy and surgical thyroidectomy.
In that study, patients in the radioiodine
group received L-thyroxine only when biochemical hypothyroidism
occurred, which may have affected the outcome
(3–7). It was later demonstrated in a retrospective
analysis that early administration of L-thyroxine reduced
the occurrence of TAO (8). Although a later post hoc
Abbreviations: TAO, Thyroid-associated ophthalmopathy; TRAb, TSH receptor antibody.

J Clin Endocrinol Metab, October 2009, 94(10):3700–3707 jcem.endojournals.org 3701
analysis did not show an association between TAO and
posttherapy hypothyroidism (9), a new study in a similar
population with early administration of L-thyroxine
was strongly called for.
The principal aim of this study was to compare radioiodine
treatment and medical therapy for long-term worsening
or development of TAO. Smoking and hypothyroidism
as confounding risk factors were controlled for, and
L-thyroxine supplementation was given early, i.e. at 2 wk
after the initiation of treatment for hyperthyroidism in
both arms.
Patients and Methods
Study design
The study was designed as an open, randomized, prospective
multicenter trial. Patients were randomized to radioiodine
(group I) and medical treatment (group M) within each center
(stratified randomization). Randomization was made in blocks
over time and was performed by the Oncological Centre at the
Karolinska University Hospital in Stockholm.
The primary endpoint was the difference in the proportion of
patients with worsening or development of TAO during a 4-yr
follow-up in the two groups (intention-to-treat analysis). A comparison
(� � 0.05, two-tailed test) of the binomial proportions
between two groups of 300 patients each would give more than
90% probability (power) to detect a true difference of 10%.
Power estimates were based on the results from the previous trial
by Tallstedt et al. (2).
Enrollment in the study (TT 96) started in May 1996. By
the second half of 2002, it was obvious, however, that the
inclusion rate was too slow to obtain the full number of patients
within a reasonable period of time, and the study was
closed in 2003. This meant that with the above specifications
and the number of observations obtained so far (333 enrolled
patients), the study had a power of about 70% at least. With
the 4-yr clinical follow up, the study was terminated by the end
of 2007.
The study was approved by the ethics committee of the Karolinska
Institute (Ref.: KI 96-096).
Patients
Inclusion criteria were as follows: age, 35–69 yr; symptomatic
Graves’ hyperthyroidism; confirmation of the diagnosis by serum
TSH (�0.1 mIU/liter) and T 3 and/or free T 4 (elevated), thyroid
uptake of iodine-131, and radionuclide scans compatible with
Graves’ disease, i.e. an even distribution of radionuclide. Furthermore,
the activity of an orally administered dose of iodine-131
(as calculated for the patient to give an absorbed radiation dose
of 120 Gy) should not exceed 600 MBq, enabling the therapy to
be given on an outpatient basis (see formula in Iodine-131
section). Patients with a previous history of treatment with
antithyroid drugs, iodine-131, or thyroid surgery were excluded
as well as patients with severe TAO requiring treatment
with corticosteroids at the time of inclusion. This was
done because concomitant steroid treatment would limit the
possibility to evaluate the effect of the treatment for Graves’
disease on worsening or development of TAO. Additional
exclusion criteria were: incipient toxic crisis, coronary heart
disease, pregnancy, breast-feeding or pregnancy planned
within the following 2 yr.
The full number of patients that met the inclusion criteria is
not known, but the reported cases were 482. A total of 333
patients gave their informed consent to participate and were
enrolled in the study. For ethical reasons, clinical data were not
documented for the patients who did not wish to participate or
did not meet the inclusion criteria.
Of the 333 patients enrolled in the study, 313 were included
in the study group: 150 in the medical therapy group, and 163
in the radioiodine group (Table 1). The number of patients
belonging to each center was: Gothenburg, 58; Lund, 40; Malmoe,
73; and Stockholm, 142 patients, respectively. Twenty
patients were excluded: one patient had an incorrect diagnosis
(Hashimoto thyroiditis), 17 had no ophthalmological assessment
at randomization, and two had no follow-up visits.
These excluded patients had an average age of 50.1 yr, the
male/female ratio was 5/15, five of 18 were smokers, and two
were missing data.
The cumulative dropout (last observation carried forward)
from the ophthalmological follow-up in group I and group M,
respectively, was as follows: at 1 yr, 3 and 1%; at 2 yr, 6 and 3%;
and at 3 yr, 10 and 9%, respectively. At 4 yr (i.e. after protocol
for ophthalmological follow-up), 20% of the patients in both
groups were still followed by ophthalmologists.
Treatment for Graves’ hyperthyroidism
Medical
Methimazole was given 15 mg twice daily; at d 14, 50 �g of
L-thyroxine was added, and it was increased to 100 �g 2 wk later.
At 6 wk, the dose of L-thyroxine was adjusted to normalize the
levels of serum T 3 and free T 4 and to bring TSH to less than 0.4
mIU/liter. A slightly elevated serum free T 4 was accepted up to
20% above the upper normal limit.
Beta-blockers were used for symptomatic treatment. Patients
showing serious adverse reactions to methimazole received alternative
treatment. Methimazole was replaced by 150 mg propylthiouracil
three times daily in patients with minor adverse
reactions.
Antithyroid drug therapy was discontinued after 18 months
with an additional month of L-thyroxine substitution of 100 �g
daily, which thereafter was discontinued.
Departments of Endocrinology (E.N.), Oncology (G.B.), and Ophthalmology (T.A.), Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden; Departments of Endocrinology (P.H.)
and Ophthalmology (V.P.), Lund University Hospital, SE-221 85 Lund, Sweden; Departments of Endocrinology (B.H., M.L.) and Ophthalmology (P.Å.), Malmoe University Hospital, SE-205
02 Malmoe, Sweden; Department of Oncology, Radiumhemmet (G.L.), Department of Molecular Medicine and Surgery, Division of Surgery (G.W.), and Department of Endocrinology
(J.C.), Karolinska University Hospital, Karolinska Institute, SE-141 86 Stockholm, Sweden; Department of Clinical Neurosciences (L.T., F.T.), St. Erik Eye Hospital, Karolinska Institute, SE-112
82 Stockholm, Sweden; Department of Clinical Research and Education, Karolinska Institute and Department of Internal Medicine, Division of Endocrinology, (O.T.), Södersjukhuset, SE-118
83 77 Stockholm, Sweden; Department of Clinical Sciences, Division of Surgery (M.A.-N.), Danderyd Hospital, Karolinska Institute, SE-171 77 Stockholm, Sweden; and Department of
Information Science (A.T.), University of Uppsala, SE-751 20 Uppsala, Sweden

3702 Träisk et al. TAO after Antithyroid Drug or Iodine-131 Treatment J Clin Endocrinol Metab, October 2009, 94(10):3700–3707
TABLE 1. Characteristics of patients randomized to
treatment with iodine-131 or antithyroid drugs
Characteristics of
patients before start of
treatment Group I Group M
n 163 150
Age (yr) 51 (SD, 8) 50(SD, 8)
Age range (yr) 36–68 35–69
Female gender (patients) 141 (87%) 137 (91%)
Weight (kg) 65 (SD, 12)/160 a
67 (SD, 13)/145 a
Previous smoking (patients) 52 (32%) 39 (27%)/146 a
Current smoking (patients) 59 (36%) 62 (42%)/148 a
No. of cigarettes/day 13 (SD, 10) 12 (SD, 7)
No TRAb (patients) 10 (6%) 11 (7%)
Estimated pretreatment
duration of
hyperthyroidism
(months)
Radioiodine uptake at
24h(%)
64 (SD, 11)/162 a
Thyroid volume
62 (SD, 11)
�30 g (patients) 29 (18%) 35 (24%)
30–39 g (patients) 69 (42%) 53 (36%)
�40 g (patients) 65 (40%) 58 (39%)
TAO—present (patients) 22 (13%) 19 (13%)
Only eyelid
retraction—present
(patients)
31 (19%) 28 (19%)
TAO and retraction—absent
(patients)
110 (67%) 103 (69%)
Proptosis right eye (mm) 16 (SD, 2) 16(SD, 2)
Proptosis left eye (mm)
Patients with TAO before
start of treatment
16 (SD, 2) 16(SD, 2)
n 22 19
Proptosis right eye (mm) 18 (SD, 2) 18(SD, 2)
Proptosis left eye (mm) 17 (SD, 2) 17(SD, 3)
TAO activity index (see
Appendix I)
2.3 (SD, 1.7) 2.0 (SD, 0.0)
Impaired eye motility
(patients)
7 1
Eyelid retraction (patients) 14 8
Data includes age, sex, smoking habits, duration of hyperthyroidism
(the patient’s own assessment before randomization), TRAb,
radioiodine uptake at 24 h, thyroid volume, and TAO in the patients
who were randomized to iodine-131 or medical treatment for Graves’
hyperthyroidism. No patient in either group had optic neuropathy or
corneal ulcer. Differences between the two groups were
nonsignificant. Data on thyroid volume were missing in four patients in
the medical treatment group.
a
Number of available recordings, if data were missing.
5(SD, 4)/162 a
6(SD, 5)/148 a
Iodine-131
Beta-blockers were used as pretreatment to radioiodine. The
intention was to give one dose of radioactive iodine, aiming for
an estimated absorbed radiation dose in the thyroid gland of 120
Gy. The administered activity was calculated using the following
formula (10): Activity (MBq) � [23.4 � thyroid mass (grams) �
120 (Gy)]/[estimated uptake (0 h; %) � effective half-life (days)].
The thyroid mass was assessed by thyroid scintigraphy and by
palpation. Reference models of a thyroid gland were used to aid
the assessment (30, 40, 50, and 60 ml). The half-life of iodine-
131 and the estimated thyroid uptake at zero hours were calculated
from the initial 24-h thyroid iodine uptake and a new uptake
test 4 to 9 d later, i.e. the same day the radioiodine therapy
was given. L-Thyroxine substitution was administered with the
same type of regimen as used in Group M.
Follow-up by thyroidologist (endocrinologist or
oncologist)
Treatment for hyperthyroidism was monitored by clinical assessments
and laboratory evaluations of the serum T 3, free T 4,
and TSH levels as follows: at 6 and 10 wk and after 6, 9, 12, 15,
18, 24, 36, and 48 months in both groups, and in group I also at
4 months. Serum TSH receptor antibody (TRAb) and thyroid
peroxidase antibody (optional) were analyzed at randomization,
6, 12, 18, 24, 36, and 48 months in both groups. Smoking habits
and body weight were also registered.
At each visit, an ophthalmological assessment was done by
the physician. If at any time TAO developed or deteriorated, the
patients were referred to the ophthalmologist for additional eye
examinations.
Follow-up by ophthalmologist
Within the first 2 wk after enrollment, all patients were seen
by an ophthalmologist, and thereafter they were seen as part of
the study protocol at 3, 12, 24, and 36 months. After 36 months,
additional assessments were performed at the eye clinic upon
referral by the thyroidologists or if the patients were followed
because of established TAO. Also, during the 4-yr follow-up,
patients with active TAO had eye assessments by ophthalmologists
every 6 wk until the condition had markedly improved. At
each visit at the eye clinic, visual acuity, proptosis, eyelid retraction,
eyelid swelling, chemosis, conjunctival redness, impairment
of the eye movements, corneal ulceration, and optic nerve involvement
were documented (Appendix I, published as supplemental
data on The Endocrine Society’s Journals Online web site
at http://jcem.endojournals.org). Eyelid retraction alone was not
classified as TAO. Within each center, the majority of patients
were followed by the same ophthalmologist throughout the
study.
Change of TAO, with and without set criteria
At each visit, the ophthalmologists determined whether TAO
had worsened/developed, improved, or was unchanged. Here,
both the observed changes in activity and severity of TAO and
the reported eye symptoms were taken into account. However,
because the observed changes in TAO were sometimes minor and
transient, a post hoc validation was performed of the events
defined as worsening or development, improvement, and no
change of TAO. For this, modified criteria were chosen from a
trial where similar outcomes had previously been compared (11).
For the set criteria (worsening or development and improvement
of TAO), two of the following four decisive factors were required
(compared with baseline data): 1) change in exophthalmometry
readings of 2 mm or more; 2) improvement or deterioration of
the patient’s eye movements between the four scoring levels (Appendix
I: no impairment, clearly impaired, diplopia in the primary
position, fixation of the globe); 3) changes of visual acuity
caused by optic neuropathy; and 4) changes in two of the three
TAO activity measures (chemosis, eyelid edema, and conjunctival
redness). The patients who did not meet the criteria of improvement
or worsening or development of TAO were referred
to as having no change of TAO. The outcome for worsening or
development of TAO according to set criteria are reported separately
in Results.

J Clin Endocrinol Metab, October 2009, 94(10):3700–3707 jcem.endojournals.org 3703
Laboratory analysis
The laboratory analyses were performed at the different study
centers. The reference intervals as well as the analysis methodology
were consequently different. Also, the methods changed
during the time of the study. The lower reference limit for free T 4
at randomization was 8–11.7 pmol/liter, and the upper limit was
18–28 pmol/liter. Disregarding the fact that different methods
had been used, the levels of serum free T 4 at randomization were
not different in the two groups [in group I, 56.8 (SD 18.0) pmol/
liter; and in group M, 56.4 (SD 19.2) pmol/liter].
Statistical analysis
The primary endpoint hypothesis was tested by means of a � 2
test. The influence of possible prognostic factors on the time to
TAO was investigated with Cox regression analysis. The development
within the various subgroups was illustrated by means of
Kaplan Meier technique. P values were two-sided, and P � 0.05
was considered significant. The MEDLOG software system (release
2008-2; Information Analysis Corp., MEDLOG Systems,
Crystal Bay, NV) was used for storage of data and statistical
analysis.
Results
The two treatment groups were similar for the characteristics
listed in Table 1. Among the patients randomized for
iodine-131, two patients relapsed and had thyroid surgery
and further radioiodine treatment, respectively. Among
the patients randomized for and accounted for medical
treatment, 12 patients experienced adverse events that led
to change of therapy to radioiodine. Furthermore, 33
(22%) of the patients randomized for medical treatment
relapsed. Of those, five were treated with surgery, 25 with
radioiodine, and three with further medical therapy.
Among the patients in group M who received iodine-131
as treatment for relapse, only one subsequently developed
TAO (see Appendix II). Early administration of L-thyroxine
after radioiodine treatment was not associated with
arrhythmia or serious adverse effects.
In patients randomized to treatment with radioiodine,
a significantly higher cumulative incidence of worsening
or development of TAO (63 patients; 38.7%) was observed
compared with the group randomized to antithyroid
drugs (32 patients; 21.3%; � 2 , P � 0.001). The log
rank Mantel-Haenszel test for equality of the curves for
worsening or development of TAO confirmed this difference
(P � 0.001; see Fig. 2A).
In the patients with TAO already at the first visit (13.1%),
the overall course of the ophthalmopathy was not significantly
affected by the choice of treatment, but de novo development
of TAO was significantly more frequent in group
I (Fig. 1; P � 0.001). Of the 41 patients with preexisting
TAO, 10 patients in each group improved; one patient in
group I and two patients in group M had initial improvement
Number of patients
60
50
40
30
20
10
0
10
9
with a subsequent deterioration. Two patients in group I had
no change; nine and seven patients deteriorated in groups I
and M, respectively. If patients with only eyelid retraction
were included in the group with preexisting TAO, a Mantel-
Haenszel comparison between the treatment groups still
yielded a nonsignificant difference for worsening (P �
0.24) and an increased risk for de novo development of
TAO (P � 0.001).
Independent of the choice of treatment, smoking increased
the risk of worsening or development of TAO (P �
0.001; Fig. 2B). However, in smokers the choice of treatment
for Graves’ hyperthyroidism did not have a significant
impact on the outcome (P � 0.38; Fig. 2D), in contrast to
nonsmokers where iodine-131 treatment significantly increased
the risk of worsening or development of TAO (P �
0.001; Fig. 2C).
In a Cox regression analysis, both the choice of therapy
and smoking habits were shown to influence the risk of
worsening or development of TAO (Table 2). The effect of
therapy for hyperthyroidism on the time to worsening or
development of TAO was significantly different in the
group of smokers and nonsmokers (P � 0.01). In the Cox
regression statistics, this was analyzed by using the interaction
term iodine-131 therapy in smokers (Table 2). The
differences are demonstrated graphically in Fig. 2, C and D.
The associations between TAO and pretreatment laboratory
levels of thyroid hormone could merely be estimated,
because the methods and reference intervals differed
between the centers. However, taking these limitations into
consideration, the Cox regression analysis suggested that
higher free T 4 levels were associated with an increased risk
for TAO (Table 2).
In the post hoc analysis, using the set criteria for the
change in TAO, worsening or development of TAO was
also found to occur more often in group I (40 patients;
25%) than in group M (16 patients; 11%; P � 0.002). The
Mantel-Haenszel comparisons between different groups
as shown in Fig. 2, A–D, showed comparable results. The
53
23
worse pre-existing new development
Iodine-131
Medical
FIG. 1. Number of patients with worsening of preexisting TAO [10 of
22 patients (45%) in group I; and nine of 19 patients (47%) in group
M] and de novo development of TAO [53 of 141 patients (38%) in
group I; and 23 of 131 patients (18%) in group M] at any time during
follow-up.

3704 Träisk et al. TAO after Antithyroid Drug or Iodine-131 Treatment J Clin Endocrinol Metab, October 2009, 94(10):3700–3707
A B
Probability of W/D of TAO
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
^ ^
1
^ 2
Years after start of therapy
^ 3
corresponding significance level for the comparisons in
Fig. 2A was P � 0.002; Fig. 2B, P � 0.009; Fig. 2C, P �
0.001; and Fig. 2D, P � 0.44. The Cox regression results
for four risk factors when using the set criteria for TAO for
worsening or development of TAO are shown in Table 2.
Patients with TAO at randomization had the following
change during the time of follow-up according to the set
criteria: worsening of TAO in five and four patients, improvement
in seven and zero patients, and no change in 10
and 15 patients in group I and group M, respectively.
TABLE 2. Cox regression analysis for four possible risk
factors regarding worsening or development of TAO
with and without set criteria for worsening or
development of TAO
Covariate
Odds ratio
(95% CI) P value
Therapy (iodine-131 vs.
medical therapy)
4.05 (1.95 to 8.43) �0.001
Set criteria 7.72 (2.31 to 25.75) �0.001
Current smoking (yes vs. no) 5.20 (2.35 to 11.53) �0.001
Set criteria 9.80 (2.75 to 34.90) �0.001
Iodine-131 therapy in
smokers (smokers
treated with iodine-131
vs. all others)
0.29 (0.11 to 0.74) 0.010
Set criteria 0.14 (0.04 to 0.60) 0.007
Serum free T4 (pmol/liter) 1.01 (1.00 to 1.03) 0.012
Set criteria 1.03 (1.01 to 1.04) �0.001
CI, Confidence interval.
p

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

3706 Träisk et al. TAO after Antithyroid Drug or Iodine-131 Treatment J Clin Endocrinol Metab, October 2009, 94(10):3700–3707
treatment, which was reasonable because the ophthalmological
outcome after surgery and medical therapy did not
differ significantly in the earlier study by Tallstedt et al.
(2). The inclusion of patients aged 35–69 yr may limit
generalization of the results to other age groups. Changes
of TAO (improvement, worsening, de novo development)
were initially determined by clinical observations, as opposed
to preset criteria. Validation of the event of worsening
or development of TAO by the use of set criteria for
change in soft tissue signs, eye motility, vision, and exophthalmos
confirmed the results and hence gives strength
to our conclusions. Also, the data on TAO severity that by
nature is less likely to be biased and the use of corticosteroids,
which was more frequent in the iodine-131 group,
provides evidence that the observations were clinically
relevant.
The proportion of patients with relapse of Graves’ disease
after medical treatment was relatively low. This may
partly be explained by the exclusion of patients younger
than 35 yr and those with large goiters and TAO that
required corticosteroid treatment already at the start of
the trial. In the current study, relapse after medical treatment
that was treated with iodine-131 was not associated
with worsening or development of TAO.
In summary, this study confirms an association between
radioiodine treatment and TAO and between
smoking and TAO. A watchful follow-up for development
of TAO after iodine-131 treatment is important,
but clinically observed mild-moderate TAO at diagnosis
of Graves’ disease might not be critical for the choice
of treatment for hyperthyroidism. Smoking habits should
be considered in the decision making for treatment. Smokers
who were treated with radioiodine had the overall
highest risk for TAO, but the risk for TAO associated with
radioiodine treatment was not significant compared with
medical treatment in the group of patients who smoked.
More studies are called for to unveil additional risk factors
for TAO.
Acknowledgments
We thank Elisabeth Bjurstedt at the Department of Oncology,
Radiumhemmet, for secretarial help. We also thank the Karolinska
Institute, the staff of the Oncology Center and the Karolinska University
Hospital, and St. Erik Eye Research Foundation.
The Thyroid Study Group of the TT 96 trial is represented
by the authors listed above and the following collaborators:
G. Lindstedt from the Department of Clinical Chemistry,
Sahlgrenska University Hospital, Gothenburg; A. Michanek
from the Department of Oncology, Sahlgrenska University
Hospital, Gothenburg; K. Norrsell from the Department of
Ophthalmology, Sahlgrenska University Hospital, Gothenburg;
S. Valdemarsson from the Department of Endocrinology, Lund
University Hospital; M. Garkavij, J. Tennvall, and H. Widmark
from the Department of Oncology, Lund University Hospital; G.
Stigmar from the Department of Ophthalmology, Lund University
Hospital; Å. Arwidi and G. Bjelkengren from the Department
of Oncology, Malmoe University Hospital; B. Hemdahl
and H. Jönsson from the Department of Radiophysics, Malmoe
University Hospital; C. Becker from the Department of Clinical
Chemistry, Malmoe University Hospital; B. Freyschuss, J.
Hoffstedt, O. Tullgren, H. Wahrenberg, and A. Wennlund
from the Department of Endocrinology, Karolinska University
Hospital (Huddinge), Stockholm; S. Röjdmark, M. Sääf, and M.
Thorén from the Department of Endocrinology, Karolinska
University Hospital (Solna), Stockholm; B. Hamberger from
the Department of Surgery, Karolinska University Hospital,
Stockholm; and H. Blomgren, C. Hilding, and A.-L. Hjelm
Skog from the Department of Oncology, Karolinska University
Hospital, Stockholm.
Address all correspondence and requests for reprints to: Frank
Träisk, M.D., Ph.D., Department of Clinical Neurosciences, Karolinska
Institute, St. Erik Eye Hospital, Polhemsg. 50, SE-11282,
Stockholm, Sweden. E-mail: frank.traisk@sankterik.se.
This trial was planned in association with the Medical Council
for Research (Mediciska Forskningsrådet). Nycomed contributed
with funding for secretarial assistance.
Disclosure Summary: The authors have no conflicts of interest.
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