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Departments of Endocrinology (F.M., M.M., A.P., R.R., B.M., C.M.) and Neuroscience (M.N.), University of Pisa, 56124 Pisa, Italy; and Department of Clinical Medicine (L.B.), Section of Endocrinology, University of Insubria, 21100 Varese, Italy
Address all correspondence and requests for reprints to: Claudio Marcocci, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56100 Pisa, Italy. E-mail: c.marcocci{at}endoc.med.unipi.it.
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Abstract |
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Objective: Our objective was to evaluate the effects of TTA in patients with GO treated with iv glucocorticoids (GC).
Design/Setting: A prospective, single-blind, randomized study was conducted at a referral center.
Patients/Interventions: Sixty patients with mild to moderate GO were randomized into: 1) near-total thyroidectomy (TX); or 2) TX plus 131I (TTA) groups, and then treated with iv GC. Patients were evaluated 3 and 9 months after iv GC.
Main Outcome Measure: Overall improvement of GO at 9 months was the main outcome measure.
Results: The distribution of GO outcome at 9 months was significantly more favorable in TTA than in TX patients (P = 0.0014 by 
2 test). A cumulative significant (P = 0.0054) difference between the two groups at 3 and 9 months was found using a generalized linear model. Radioiodine uptake test and thyroglobulin assay in a patient sample showed complete ablation in the majority of TTA, but not of TX patients.
Conclusions: Compared with thyroidectomy alone, TTA is followed by a better outcome of GO in patients given iv GC. Whether TTA maintains this advantage in the long-term remains to be established.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the period 1998–2004, 123 consecutive patients with GD and mild-to-moderate and active GO were asked to participate in the study. Of these, 21 did not meet the inclusion criteria (see below) and 12 refused. Therefore, 90 patients were enrolled. Patients were randomized in blocks of 15 into: 1) TX (9 men, 21 women), or 2) TTA (10 men, 20 women). In the original design, a group receiving methimazole (MMI) for all the duration of the study had been included, and 30 patients had been randomized. However, later this group was excluded because patients differed from those of the other groups at baseline, and also because of the known immunosuppressive actions of MMI that might have affected GO.
Inclusion and exclusion criteria
Inclusion criteria were: 1) recent-onset hyperthyroidism (
6 months) treated only with antithyroid drugs (MMI in all cases); 2) thyroid volume 15 ml or greater, as assessed by ultrasound examination (this criterion was required by the Institutional Review Board to justify thyroidectomy); and 3) recent-onset GO (6 months), untreated, with the exception of local measures (artificial tears). GO inclusion criteria comprised at least two of the following: 1) clinical activity score (CAS) (15) of at least 3/7; 2) proptosis of 21 mm or greater in at least one eye; 3) intermittent or inconstant diplopia (16); and 4) eyelid width of 9 mm or greater in at least one eye.
Exclusion criteria were: 1) hyperthyroidism duration of 6 months or longer, or previously treated with radioiodine or thyroidectomy; 2) GO duration of 6 months or longer, or treated with GC, orbital radiotherapy, or orbital decompression; 3) major contraindications to GC; 4) severe GO, as defined by the presence of optic neuropathy or constant diplopia. An intent-to-treat approach was performed in patients who required other treatments for GO during the study.
Thyroid treatment and assessment of ablation
At baseline, patients were euthyroid on MMI for at least 10 wk. Euthyroidism was defined as serum free T4 and free T3 within the normal range and a serum TSH between 0.5 and 3.4 mU/liter. In the TX group, patients underwent TX and were then immediately given LT4 at replacement doses (1.6 µg/kg·d). Patients started GC treatment approximately 2 wk after TX. In the TTA group, patients underwent TX, followed 45 d later by ablation with 30 mCi of 131I. Between TX and ablation, patients were given T3 (40 µg/d) to maintain euthyroidism; T3 was withdrawn 2 wk before 131I. Median TSH values at ablation were 54.0 mU/liter [interquartile range (IQR), 28–71.6]. Immediately after 131I, patients were given LT4 (1.6 µg/kg·d) plus T3 (40 µg/d). T3 was withdrawn 2 wk later when patients started iv GC.
To assess the effectiveness of ablation, after the 9-month evaluation, the first consecutive 18 patients in each group discontinued LT4 and underwent a serum Tg measurement [only patients with undetectable serum anti-Tg autoantibodies (TgAb)] and a thyroid radioiodine uptake (RAIU) test after the administration of 2 mCi of 131I. Ablation was defined as a serum Tg concentration less than 0.5 ng/ml or a 3-h RAIU less than 1%.
GO treatment
All patients were given two iv infusions of methylprednisolone acetate on alternate days every other week, for a total of 12 infusions over a 10-wk period. The dose was 15 mg/kg for the first four infusions (maximum dose allowed, 1 g), and 7.5 mg/kg for the last eight infusions. The cumulative dose of GC ranged between 6 and 10 g. No major side effects were observed.
GO evaluation and timing
All patients underwent a GO assessment at baseline, every 6 wk during iv GC, and then 3 and 9 months after iv GC. GO evaluation included: 1) exophthalmometry, performed using an Inami exophthalmometer; 2) measurement of eyelid width; 3) evaluation of CAS; 4) assessment of ocular motility and diplopia; and 5) measurement of visual acuity. Patients were always seen by the same ophthalmologist (M.N.), who was blinded to thyroid treatment. All patients were seen together with other GO patients not participating in the study, so the ophthalmologist could not identify patients enrolled in this trial. Data were collected using a standardized clinical record form.
Serum assays and thyroid clinical evaluation
The following serum measurements were performed in all patients: free T4 and free T3 (Lysophase, Technogenetics, Milan, Italy); TSH (Delfia Wallac, Gaithersburg, MD), Tg (Diagnostic Products Corporation, Euro/DPC, Gwynedd, UK); TgAb and anti-TPO autoantibodies (TPOAb) (Sorin Biomedica, Saluggia, Italy); and anti-TSH-receptor antibodies (TRAb) (Brahms, Berlin, Germany). Assays were performed at baseline, immediately before iv GC, every 6 wk during iv GC, and every 3 months after iv GC, with the exception of Tg, TgAb, TPOAb, and TRAb, which were measured only at baseline and at 9 months. The dose of LT4 was adjusted based on serum assays, but adjustments were marginal because all patients were euthyroid during the follow-up. In patients who underwent assessment of ablation (see above), serum assays were also performed immediately before the tracer dose of 131I. At enrollment, thyroid ultrasound was performed in all patients, with measurement of the thyroid volume using the ellipsoid formula.
Primary outcome
The overall GO response at 9 months was the primary outcome of the study. GO was considered improved when at least two of the following criteria were fulfilled: 1) reduction in proptosis of at least 2 mm in at least one eye and with no increase of 2 mm or greater in the contralateral eye; 2) reduction of CAS by at least 2/7 points; 3) reduction in eyelid width of 2 mm or more in at least one eye, with no increase of 2 mm or more in the contralateral eye; and 4) disappearance or improvement of diplopia (change of degree from constant to inconstant, from inconstant to intermittent, or from intermittent to absent). GO was considered worsened when at least two of the following criteria were fulfilled: 1) increase in proptosis by 2 mm or more in at least one eye; 2) increase of CAS by at least 2/7 points; 3) increase in eyelid width of 2 mm or more in at least one eye; and 4) new appearance or progression of diplopia (change of degree from intermittent to inconstant and from inconstant to constant). In all other instances, GO was considered unchanged.
Secondary outcomes
Secondary outcomes included: 1) overall response of GO to GC at 3 months; and 2) response to GC of individual GO parameters, namely proptosis, CAS, eyelid width and diplopia, according to the above criteria.
Informed consent and approval
The study was approved by the local Institutional Review Board. Signed informed consent was obtained from all patients.
Data presentation and statistical analyses
Descriptive data are presented as median and IQR or percent prevalence. Data that were normally distributed (proptosis, CAS, and eyelid width), which was assessed using the Wilks Shapiro test, are also presented as mean ± SD. The following statistical tests were performed: 1) nonnormally distributed paired data, Wilcoxon signed rank; 2) comparisons of normally distributed unpaired data between groups, t test; 3) comparisons of nonnormally distributed unpaired data between groups, Mann-Whitney; and 4) comparisons of percent prevalences, 2 test or Fisher exact test when appropriate. The cumulative difference between the two groups at 3 and 9 months was analyzed using a generalized linear model (GLM, GeneMod) configured for repeated measures of categorical data. For all the above-mentioned tests, the P values were not adjusted for multiple testing.
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Results |
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Clinical, biochemical, and ophthalmological features of the two groups at baseline are illustrated in Table 1
. None of the parameters differed statistically between the two groups.
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Six patients (three in each group) left the study before the evaluation at 3 months, resulting in a drop-out rate of 10%. Four of these patients (two in the TX group and two in the TTA group) were lost to follow-up; two patients were excluded, one in the TX group because of the histological finding of a papillary thyroid cancer, which prompted 131I treatment, and one in the TTA group because of an unrelated, severe heart attack. In view of this, the analysis reported below refers to 27 patients in each group. Of these patients, two in the TX group were lost to follow-up between the 3- and 9-month evaluations and, therefore, results at 9 months in this group refer to only 25 patients.
Evaluation of ablation
To assess the extent of ablation, at the end of the study a sample of patients withdrew LT4 and underwent a serum Tg measurement (only if TgAb negative) and a RAIU test. At the time ablation was assessed, median TSH values were 67.9 mU/liter (IQR, 53.4–75) in the TX group and 66.3 mU/liter (IQR, 47.1–75) in the TTA group (P = 0.79 by Mann-Whitney). As shown in Fig. 1A, only two of eight (25%) patients in the TX group had Tg values below 0.5 µg/liter, whereas this was observed in 13 of 14 (93%) patients in the TTA group (P = 0.0049 by Fisher exact test), suggesting that nearly all patients in the latter group were ablated according to this criterion. Likewise, only four of 18 (22.2%) patients in the TX group had a 3-h RAIU value less than 1.0% compared with 14 of 18 (77.7%) in the TTA group (P = 0.002 by Fisher exact test) (Fig. 1B), again indicating that the majority of TTA patients were ablated. As an additional, indirect measure of thyroid ablation, we evaluated changes in serum thyroid autoantibody levels, because these are known to diminish or disappear after thyroid ablation (5). However, all antibodies decreased significantly in both groups, with the exception of TgAb in the TTA group, suggesting that, at least in the short-term, autoantibodies cannot be used as a parameter of ablation.
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As shown in Fig. 2A, the distribution of GO outcome at 9 months was significantly more favorable in the TTA group than in the TX group (P = 0.0014 by 2 test). No difference was observed at 3 months. The cumulative difference between the two groups at 3 and 9 months was found to be significant (P = 0.0054 by GLM).
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In an attempt to assess the effect of ablation regardless of thyroid treatment, we evaluated the outcome of GO at 9 months in the subgroup of patients in whom ablation had been tested by RAIU off LT4. As shown in Fig. 2B
, the distribution of GO outcome was significantly (P = 0.0214 by 2) more favorable in patients with RAIU less than 1% than in those with RAIU greater than 1%. The same calculations could not be performed according to Tg values in TgAb-negative patients because of the small number of TgAb-negative patients who underwent a Tg assay off LT4.
Outcome of individual GO parameters
As shown in Fig. 3A, the distribution of the outcome of proptosis was significantly more favorable in the TTA group than in the TX group at 9 months (P = 0.0271 by 2), but not at 3 months. In addition, a cumulative significant difference between the two groups was observed at 3 and 9 months (P = 0.0515 by GLM). The outcome of CAS was similar in the two groups (Fig. 3B), both by 2 and GLM. The distribution of the outcome of eyelid width was more favorable in the TTA group at both 3 (P = 0.0016 by 2) and 9 months (P = 0.0201 by 2), and a cumulative significant difference was also observed by GLM (P = 0.0008). The outcome of diplopia did not differ between the two groups, regardless of the statistical test used.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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It should be underscored that ablation was really achieved in the majority of patients treated with thyroidectomy and 131I, as shown by the undetectable serum Tg levels in TgAb-negative patients and by the absent RAIU off LT4, which was not the case in the majority of patients treated by thyroidectomy alone, although 20–25% of them were ablated. As a matter of fact, GO outcome at 9 months was better in patients ablated according to RAIU, regardless of thyroid treatment. Based on this observation, given the identical starting conditions and treatment for GO, the different outcomes in the TX and TTA groups were not casual and should be attributed to ablation.
Whether the conclusion that ablation is beneficial for GO applies in the long term remains to be established. However, based on the knowledge that the reduction up to disappearance of autoantibodies against thyroid antigens is pronounced especially 3 to 5 yr after ablation (10), it is reasonable to postulate that the effects of ablation may be even more pronounced after a longer follow-up period, which will be the subject of further studies.
There are three important issues and possible weaknesses of this study. First, we are unable to answer the question whether an ablative strategy is preferable to a conservative treatment (antithyroid drugs) of hyperthyroidism in patients with GO. In its original design, our study included a third arm, namely patients given MMI for all the duration of the trial. However, this group was excluded because it was found to be different from the other two groups at baseline and because the immunosuppressive actions of MMI might affect GO. A control group represented by patients not given any treatment for hyperthyroidism was admittedly unethical, and also not proper, because uncontrolled hyperthyroidism has a negative impact on GO (19). Thus, based on our findings, we can only conclude that in patients treated with iv GC, total ablation (TX plus 131I) is more beneficial for GO than TX alone, but no conclusions can be reached in comparison with antithyroid drugs. Second, although TTA was associated with a better outcome of GO after iv GC, regardless of thyroid treatment, the overall response to iv GC was relatively low compared with previous studies (1). This may reflect the fact that in this study only patients with mild to moderate, lowly active GO were included, in whom a relatively poorer degree of improvement is expected compared with patients with more severe and active forms of GO (1, 20). Third, all patients in the present study received iv GC, which certainly affected the outcome of GO regardless of thyroid treatment. Thus, it is not known whether TTA is beneficial for GO in patients not given GC.
In conclusion, our study shows that, in patients given iv GC, TTA is followed by a better outcome of GO in the short-term compared with thyroidectomy alone. However, we do not know whether ablation is to be preferred to a conservative approach (antithyroid drugs) or whether our conclusions apply also to the long term or to patients not given GC.
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Acknowledgments |
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Footnotes |
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The authors have nothing to disclose.
First Published Online February 13, 2007
Abbreviations: CAS, Clinical activity score; GC, glucocorticoid(s); GLM, generalized linear model; GO, Graves’ orbitopathy; IQR, interquartile range; MMI, methimazole; RAIU, thyroid radioiodine uptake; Tg, thyroglobulin; TgAb, anti-Tg autoantibodies; TPO, thyroperoxidase; TPOAb, anti-TPO autoantibodies; TRAb, anti-TSH-receptor antibodies; TTA, total thyroid ablation (TX and 131I); TX, near-total thyroidectomy.
Received August 16, 2006.
Accepted February 1, 2007.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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  L. Bartalena, L. Baldeschi, A. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M. Mourits, P. Perros, K. Boboridis, A. Boschi, et al. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO Eur. J. Endocrinol., March 1, 2008; 158(3): 273 - 285. [Full Text] [PDF]
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, P = 0.0016; 
