J C E M
O N L I N E
B r i e f
R e p o r t — E n d o c r i n e
C a r e
Outcome of Graves’ Orbitopathy after Total Thyroid
Ablation and Glucocorticoid Treatment: Follow-Up of
a Randomized Clinical Trial
Marenza Leo, Claudio Marcocci, Aldo Pinchera, Marco Nardi, Loredana Megna,
Roberto Rocchi, Francesco Latrofa, Maria Antonietta Altea, Barbara Mazzi,
Eleonora Sisti, Maria Antonietta Profilo, and Michele Marinò
Departments of Endocrinology (M.L., C.M., A.P., R.R., F.L., M.A.A., B.M., E.S., M.A.P., M.M.)
and Neuroscience (M.N., L.M.), University of Pisa, 56100 Pisa, Italy
Context: In a previous study, we found that total thyroid ablation (thyroidectomy plus 131I) is
associated with a better outcome of Graves’ orbitopathy (GO) compared with thyroidectomy
alone, as observed shortly (9 months) after glucocorticoid (GC) treatment.
Objective: The objective of the study was to evaluate the outcome of GO in the same patients of
the previous study over a longer period of time.
Design: This was a follow-up of a randomized study.
Setting: The study was conducted at a referral center.
Patients: Fifty-two of 60 original patients with mild to moderate GO participated in the study.
Interventions: Patients randomized into thyroidectomy (TX) or total thyroid ablation and treated
with GC were reevaluated in 2010, namely 88.0 ⫾ 17.7 months after GC, having undergone an
ophthalmological follow-up in the intermediate period.
Main Outcome Measures: The main outcome measures included the following: 1) GO outcome; 2)
time to GO best possible outcome and to GO improvement; and 3) additional treatments.
Results: GO outcome at the end of the follow-up was similar in the two groups. However, the time
required for the best possible outcome to be achieved was longer in the TX group (24 vs. 3 months,
P ⫽ 0.0436), as was the time required for GO to improve (60 vs. 3 months, P ⫽ 0.0344). Additional
treatments were given to a similar proportion of patients in each group (TX, 28%, total thyroid
ablation, 25.9%), but they affected GO beneficially more often in the TX group (28 vs. 3.7%,
P: 0.0412).
Conclusions: Compared with thyroidectomy alone, total thyroid ablation allows the achievement
of the best possible outcome and an improvement of GO within a shorter period of time. (J Clin
Endocrinol Metab 97: E44 –E48, 2012)
G
raves’ Orbitopathy (GO) is an autoimmune disorder
likely driven by autoantigens shared by thyroid and
orbital tissues (1– 6). Removal of thyroid antigens (total
thyroid ablation), by attenuating autoimmunity, may be
beneficial for GO (7). In patients with thyroid cancer and
antithyroid autoantibodies, ablation (achieved by a combination of near total thyroidectomy and 131I) is followed
by disappearance of autoantibodies (8). Furthermore, a
beneficial effect of ablation on GO was reported by retrospective studies (9, 10). Recently in a randomized study,
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2077 Received July 19, 2011. Accepted September 29, 2011.
First Published Online October 25, 2011
Abbreviations: ES, Eyelid surgery; GO, Graves’ Orbitopathy; GC, glucocorticoids; IQR, interquartile range; MS, muscle surgery; OD, orbital decompression; OR, orbital radiotherapy; TRAb, TSH receptor antibodies; TTA, total thyroid ablation; TX, near-total
thyroidectomy.
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we found that, compared with thyroidectomy alone, ablation is beneficial for GO in patients given glucocorticoids (GC), as observed at 9 months (11). Here we investigated the same patients over a longer period of time.
Statistics
Materials and Methods
Results
Patients, randomization, and treatments according
to the original study design
Baseline features and follow-up duration
As reported (11), features of the two groups at baseline
were similar, as were gender (TX: five men, 20 women;
TTA: nine men, 18 women) and age (TX: 45.7 ⫾ 8.8 yr;
TTA: 46.4 ⫾ 11.2 yr) at reevaluation. Follow-up duration
was 88.0 ⫾ 17.7 months, with no difference (P ⫽ 0.3391)
between TX (90.5 ⫾ 21.0, range 49 –129) and TTA
(85.8 ⫾ 13.9, range 55–115).
Sixty patients with Graves’ disease and mild to moderate GO
were randomized into near-total thyroidectomy (TX) or total
thyroid ablation (TTA) (near total thyroidectomy and 131I). Details on randomization, patient features, inclusion/exclusion criteria, and treatments were reported previously (11, 12). All patients were given iv GC as a deliberate part of the protocol.
However, in view of GO features, patients would have been
treated, even if not included in this study. The study was approved by the institutional review board. Informed consent was
obtained.
GO evaluation and timing
Patients were seen at baseline and 3 and 9 months after GC.
In 2010 they were asked to undergo a reevaluation. Fifty-two (25
TX, 27 TTA) patients accepted. Twenty-two TX and 25 TTA
patients had undergone an ophthalmological follow-up in our
department between 9 months and 2010 [number of visits: TX,
mean 4.7 ⫾ 2.3, range 1– 8, median five, interquartile range
(IQR) 2.7–7; TTA, mean 4.6 ⫾ 1.5, range 1–7, median five, IQR
4 –5.2; time intervals: TX, mean 1.8 ⫾ 0.8 yr, range 0.9 –3.4;
median 1.6 yr, IQR 1.2–2.3; TTA, mean 1.9 ⫾ 0.9 yr, range
0.9 – 4.3, median 1.5 yr, IQR 1.2–2.7]. This was not an ongoing
study, so there was not a standard schedule, and appointments
were made individually.
Ophthalmological measurements included the following: 1)
exophthalmometry; 2) eyelid width; 3) clinical activity score
(13); 4) diplopia; and 5) visual acuity. Patients who did not accept to be reevaluated had not undergone a follow-up in our
department and had been seen in other institutions. We could not
obtain their data because there were no records of eye features.
Serum assays
Free T4 (Lysophase; Sesto S. Giovanni, Italy), free T3 (Lysophase), and TSH (Delfia Wallac, Gaithersburg, MD) were measured approximately every 6 months. Hypothyroidism was
avoided by LT4 adjustments. Anti-TSH receptor antibodies
(TRAb; Brahms, Berlin, Germany) were measured at baseline
and at 9 months, at the intermediate visits, and in 2010.
End points
Primary end points were: 1) overall GO outcome, as reported
previously (11); 2) time to best GO outcome and/or to GO improvement; and 3) additional treatments. Secondary end points
were: 1) TRAb disappearance; and 2) quality of life. Time to best
possible GO outcome was the earliest time point at which we
observed the same outcome as in 2010. Time to GO improvement was the earliest time point at which improvement was
observed.
Normally distributed data: t test; nonnormally distributed
data: Mann Whitney U test; prevalences: ␹2 or Fisher exact test
when appropriate; and multiple testing: repeated measures
ANOVA.
Overall GO outcome and time to best possible GO
outcome and GO improvement
As reported (11), GO outcome was more favorable in
TTA at 9 months (P ⫽ 0.0019), but no difference (P ⫽
0.3081) was found at the end of follow-up (Fig. 1A), when
difference in improvement/worsening was not significant,
even when these categories were considered individually.
The time required to reach the best possible GO outcome
was longer in TX (median 24 months; IQR 3– 84) than in
TTA (median 3 months; IQR 3–9, P ⫽ 0.0436) (Fig. 1, B
and C). Likewise, the time for GO to improve was longer
in TX (median 60 months; IQR 3– 84) than in TTA (median 3 months; IQR 3–9, P ⫽ 0.0344) (Fig. 1, D and E).
The difference at 96 months (Fig. 1E) was not significant
(P ⫽ 0.398).
Additional treatments
Depending on the GO features, additional treatments
were offered after 9 months, namely additional GC, orbital radiotherapy (OR), orbital decompression (OD),
muscle surgery (MS), and/or eyelid surgery (ES). At 9
months 12 TTA and 22 TX patients had been ranked as
stable or worsened, of whom seven TTA and 13 TX had
features prompting additional treatments, which were accepted by five and seven of them, respectively. Two additional TTA patients who had ameliorated at 9 months were
given additional treatments for cosmetic purposes. Overall,
the number of patients given additional treatments was seven
in both groups, with no statistical difference. Treatments
given were the following: TX, two OR⫹GC, one OR alone,
one OD⫹MS, one OR⫹GC⫹OD⫹MS⫹ES, and three OD
alone; TTA, one OR⫹GC⫹OD⫹MS⫹ES, two OD⫹ES,
three OD alone, and one MS alone. Additional treatments
were not always sufficient to ameliorate GO according to our
criteria (11). Thus, amelioration was observed in eight of 14
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Leo et al.
Thyroid Ablation in Graves’ Orbitopathy
J Clin Endocrinol Metab, January 2012, 97(1):E44 –E48
tical difference (P ⫽ 0.8727). Likewise,
the time required for TRAb to become
undetectable was similar (TX: median
16.5 months, IQR 9 –96; TTA: median
9 months; IQR 9 –12.7; P ⫽ 0.0769).
TRAb levels decreased over time in
both groups (P ⬍ 0.0001), with no difference between groups (not shown).
Quality of life
Quality of life was assessed using the
European Group On Graves Ophthalmopathy questionnaire (14). Scores
were good in both groups (⬃80% of
positive answers), with no differences
between groups (not shown).
Discussion
Treatment of hyperthyroidism in patients with GO is controversial. A conservative strategy based on antithyroid
drugs is favored by some, whereas others, based on a proposed pathogenetic
link between thyroid and orbital tissues, advocate an ablative strategy
(1–7) because removal of thyroid antigens could be beneficial for GO. After
thyroidectomy alone or 131I alone, ablation is rarely complete. Therefore, toFIG. 1. A, Overall outcome of GO 9 months after the completion of glucocorticoid treatment
tal ablation, performed by thyroidecand then in 2010 (long term follow-up), after a mean period of 88.0 ⫾ 17.7 months (range
tomy plus 131I, has been proposed.
19 –129). B, Median ⫾ IQR (gray columns) and mean ⫾ SD (white columns) time required to
Retrospective studies suggest that abachieve the best possible outcome (the outcome observed at the end of the follow-up) of GO.
C, Percent of patients reaching the best possible GO outcome over time. Number of patients
lation may be beneficial for GO (9, 10),
available at each time point is indicated. D, Median ⫾ IQR (gray columns) and mean ⫾ SD
which was confirmed by our previous
(white columns) time required to reach an improvement of GO. E, Percent of patients with
randomized trial, in which we found a
GO improvement over time. Number of patients available at each time point is indicated.
beneficial effect of thyroidectomy ⫹ 131I
patients given additional treatments (57%). Considering the compared with thyroidectomy alone shortly after GC
total number of patients, additional treatments determined (11). Worth noting, ablation had been achieved much
an amelioration of GO compared with 9 months in 28% more often in TTA than in TX, as shown by serum thy(seven of 25) of TX but only in 3.7% of TTA patients (one roglobulin and radioiodine uptake (11).
of 27) (P ⫽ 0.0412). To determine whether additional treatIn this study, we investigated the same patients over a
ments affected our conclusions, we considered only patients
longer period of time. Patients underwent a new evaluawho had not received them. Also in this subgroup, GO
tion on average approximately 7 yr after GC, when GO
outcome at the end of follow-up did not differ (P ⫽
outcome was similar, regardless of thyroid treatment. De0.1802) between TX and TTA (Fig. 2A), whereas time
spite this, our study shows that ablation may still have
to GO improvement was shorter in TTA (P ⫽ 0.0299)
some advantages. Thus, the periods required to the best
(Fig. 2B).
GO outcome and to GO improvement were shorter in
TTA. Whereas TX patients needed approximately 2 yr to
TRAb disappearance
At the end of follow-up, TRAb were undetectable in 18 the best GO outcome and approximately 5 yr to GO imTX (72%) and 21 TTA patients (77.7%), with no statis- provement, TTA patients needed only 3 months for both.
J Clin Endocrinol Metab, January 2012, 97(1):E44 –E48
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is beneficial in patients not given GC.
Third, there was a 45-d difference between TX and TTA in terms of timing
of GC administration (11). Whether
this affected GO is unknown. Fourth,
this evaluation was not part of the original protocol, and the frequency of visits might have been affected by GO severity. However, the different timing of
FIG. 2. A, Overall outcome of GO in 2010 in patients who did not receive additional
GO response between the two groups
treatments. B, Median ⫾ IQR (gray columns) and mean ⫾ SD (white columns) time required to
reach an improvement of GO in patients who did not receive additional treatments.
seems to exclude this possibility. Fifth,
it is surprising that additional treatments were offered to similar proporThe overlap concerning time to best outcome (Fig. 1C)
tions of TTA and TX patients, although their greater imshould explain the relatively high, yet significant, P values.
pact in TX could speak in favor of TTA.
TRAb reflect GO severity and activity (15). Thus, a
In conclusion, thyroid ablation may be a possible stratshorter period would have been expected in TTA for
egy for GO. The apparent advantages are the better GO
TRAb to decrease or disappear. However, there was no
outcome in the short term and a shorter period for GO to
difference with TX. In addition, approximately 25% of
improve. Whether this is sufficient to offer ablation to
the patients still had detectable TRAb at the end of the
patients remains a matter of discussion. At present, this
follow-up, regardless of thyroid treatment, although the
procedure could be offered only to patients scheduled to
levels decreased over time. It may therefore be argued that
thyroidectomy, although we are not suggesting thyroidthe TTA advantages may not reflect a greater/faster atectomy as the first line thyroid treatment in GO, also in
tenuation of autoimmunity but rather other, unknown
view of its costs/risks. The additional costs of 131I should
phenomena. Whatever the case, our study still shows some
also be considered. Because of the reported, GC-preventapparent advantages of ablation on the GO outcome,
able, unfavorable effects of 131I on GO (1– 6), ablation
which may have clinical implications.
should not be considered in patients with contraindicaTo some extent, results in the long term reflected also
tions to GC.
additional treatments, which were given to a similar proportion of patients in each group and affected favorably
GO more often in TX. Nevertheless, additional treatments
Acknowledgments
did not influence our conclusions because GO outcome
and time to improvement were not affected when we con- Address all correspondence and requests for reprints to:
sidered only patients who had not received these treat- Michele Marinò, M.D., Department of Endocrinology, Uniments. Because these analyses were performed in a small versity of Pisa, Via Paradisa 2, 56100 Pisa, Italy. E-mail:
number of patients, they may require confirmation in [email protected].
This work was supported by Grants PRIN 2001068454 (to
larger series.
A.P.) and Grants PRIN 2004068078 and PRIN 20074X8RKK
In line with GO outcome, quality-of-life scores at the (to M.M.) from the Ministero dell’Istruzione, dell’Università e
end of follow-up were good in both groups with no sta- della Ricerca Scientifica, Rome, Italy.
Disclosure Summary: The authors have nothing to disclose.
tistical difference. Unfortunately, the questionnaire was
not administered at the intermediate visits because it
would have been interesting to know whether it had the
same behavior as GO. It may be argued that in TTA 131I References
might have caused some discomfort because of hypothy1. Bahn RS 2010 Graves’ ophthalmopathy. N Engl J Med 362:726 –
roidism due to LT4 withdrawal. This was not investigated,
738
but because GO is perceived as a much greater cause of
2. Wiersinga WM 2007 Management of Graves’ ophthalmopathy. Nat
Clin Pract Endocrinol Metab 3:396 – 404
discomfort than hypothyroidism, which was of very short
3. Bartalena L, Tanda ML 2009 Clinical practice. Graves’ ophthalduration, we believe this was unlikely.
mopathy. N Engl J Med 360:994 –1001
Some issues and possible weaknesses of this study
4. Bartalena L, Wiersinga WM, Pinchera A 2004 Graves’ ophthalmopathy: state of the art and perspectives. J Endocrinol Invest 27:295–
should be considered. First, we cannot answer the ques301
tion whether an ablative strategy is preferable to a con5. Bartalena L, Marcocci C, Tanda ML, Piantanida E, Lai A, Marinò
servative one. Second, patients were given GC, which cerM, Pinchera A 2005 An update on medical management of Graves’
tainly affected GO. Thus, it is not known whether ablation
ophthalmopathy. J Endocrinol Invest 28:469 – 478
E48
Leo et al.
Thyroid Ablation in Graves’ Orbitopathy
6. Marinò M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A
2004 Role of thyroglobulin in the pathogenesis of Graves’ ophthalmopathy: the hypothesis of Kriss revisited. J Endocrinol Invest 27:
230 –236
7. Catz B, Perzik SL 1969 Total thyroidectomy in the management of
thyrotoxic and euthyroid Graves’ disease. Am J Surg 118:434 – 439
8. Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone M, Masserini L, Grasso L, Pinchera A 2003 Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann
Int Med 139:346 –351
9. De Groot LJ, Benjasuratwong Y 1996 Evaluation of thyroid ablative
therapy for ophthalmopathy of Graves’ disease. Orbit 15:187–196
10. Moleti M, Mattina F, Salamone I, Violi MA, Nucera C, Baldari S,
Lo Schiavo MG, Regalbuto C, Trimarchi F, Vermiglio F 2003 Effects of thyroidectomy alone or followed by radioiodine ablation of
thyroid remnants on the outcome of Graves’ ophthalmopathy. Thyroid 13:653– 658
11. Menconi F, Marinò M, Pinchera A, Rocchi R, Mazzi B, Nardi M,
Bartalena L, Marcocci C 2007 Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves’
J Clin Endocrinol Metab, January 2012, 97(1):E44 –E48
12.
13.
14.
15.
orbitopathy treated with intravenous glucocorticoids. J Clin Endocrinol Metab 92:1653–1658
Marcocci C, Menconi F, Marino M, Rocchi R, Pinchera A 2007
Reply to Professor Wiersinga’s letter. J Clin Endocrinol Metab, electronic letters, July 13, 2007: http://jcem.endojournals.org/cgi/eletters/
92/5/1653#13513
Pinchera A, Wiersinga W., Glinoer D, Kendall-Taylor P, Koorneef
L, Marcocci C, Schleusener H, Romaldini J, Niepominiscze H, Nagataki S, Izumi M, Inoue M, Stockigt J, Wall J, Greenspan F, Solomon D, Garrity J, Gorman CA 1992 Classification of eye changes
of Graves’ disease. Thyroid 2:235–236
Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor
P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Currò
N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH,
Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz
S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM 2008
Consensus statement of the European group on Graves’ orbitopathy
(EUGOGO) on management of Graves’ orbitopathy. Thyroid 18:
333–346
Eckstein A, Esser J, Mann K, Schott M 2010 Clinical value of TSH
receptor antibodies measurement in patients with Graves’ orbitopathy. Pediatr Endocrinol Rev 7 (Suppl 2):198 –203
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