The frequency of hyperthyroidism is 1.2% of general population worldwide, including 0.5% of overt hyperthyroidism and 0.7% of subclinical hyperthyroidism.1 Approximately 60% to 80% of cases with thyrotoxicosis are Graves’ disease (GD), and its prevalence may be variable in different populations.1 The treatment of patients with GD reduces mortality and morbidity of the patients.2
Radioactive iodine therapy (RIT) is a safe and effective way in treatment of GD and is often considered as the first line of treatment in the United States.3 However, there is no consensus on the optimal dose of radioiodine, and different dose strategies have been used successfully for treatment of GD.3,4
Graves’ ophthalmopathy (GO) is an autoimmune disorder that is considered the most important and prevalent form of extrathyroidal manifestation of GD5 and is clinically evident in 20% to 25% of patients with GD.6
The new development or flare up of GO is reported in 15% to 33% of patients after RIT.7,8 The mechanism of GO is an autoimmune reaction to protein receptors of TSH, which expresses both in thyroid gland tissue and orbit, and cytokines play an important role in GO.9 Actually, the infiltration of extraorbital muscles takes place by activated T-cells. The release of cytokines such as IL1, TNF, and INFγ would cause the activation of fibroblasts and increase of glycosaminoglycans synthesis, which sustain water and cause muscle inflation. In the progressive disorder, it causes irreversible muscle fibrosis. The increase in fatty tissue is another reason of enlargement of orbital volume.9 The worsening of GO may be related to the destruction of thyroid cells and the elevation of thyroid autoantibodies after radioiodine therapy.10,11 Although RIT may be associated with worsening of GO, the concomitant use of glucocorticoids was successful in preventing ophthalmic flare up without influencing thyroid outcome.7 However, there is no prospective study of the effect of radioiodine dose on ophthalmic complications.
The aim of this study was to investigate the effect of different dose strategies on ophthalmic complications and to compare fixed and calculated dose (CD) strategies in terms of effectiveness of therapy.
METHODS AND PATIENTS
We studied 92 patients with GD who referred for radioiodine therapy to our department and had no or inactive ophthalmopathy (clinical activity score [CAS] < 3). The study was explained to all patients, and those who agreed to participate signed an informed written consent. The study was a part of clinical trial and approved by local ethic committee (#922896). All the patients were interviewed to get demographic information followed by thyroid and ophthalmologic examination. Ophthalmologic examination included Snellen chart examination and measurement of proptosis using a Hertel exophthalmometer (Keeler, United Kingdom). Furthermore, CAS was determined for all patients using CAS questionnaire.1 All of the ophthalmic measurements were done by a trained physician.
If the patient was receiving antithyroid drugs, the patient was asked to discontinue it for at least 3 days before treatment.12 Radioactive iodine uptake (RAIU) was measured 2 and 24 hours after administration of 370 KBq (10 μCi) of 131I using a thyroid uptake system (Picker, United States). Thyroid ultrasonography was performed using a 12-MHz linear probe (Mediso, V10, South Korea) for thyroid volume determination. Thyroid volume in milliliter was considered equal to thyroid weight in milligram.
All the patients were entered into 1 of 3 groups using simple randomization and treated with radioiodine. In the group 1, all patients received a fixed low dose (FLD) of 259 MBq (7 mCi) of 131I. In group 2, a fixed high dose (FHD) of 555 MBq (15 mCi) of 131I was administered to all patients, and in group 3, a CD of 131I was administered according to the Marinelli-Quimby formula to deliver 5.55 MBq (150 μCi) of 131I/g of thyroid weight (Fig. 1).
Follow-up of patients included clinical examination, measurement of thyroid function tests, and thyroid ultrasonography, 6 and 12 months after treatment. Also, ophthalmologic examination was repeated 6 months after treatment. The response to radioiodine therapy was defined as hypothyroidism (elevated TSH and reduced T4 or TSH ≥ 10 mIU/L), subclinical hypothyroidism (elevated TSH < 10 mIU/L with normal T4 an T3), or euthyroidism (normal TSH, T3, and T4).13 The patients with hyperthyroidism (TSH < 0.5 mIU/L and elevated T4 or T3) or subclinical hyperthyroidism (TSH < 0.5 mIU/L with normal T3 and T4) were considered nonresponders.1 Thyroid hormone (levothyroxine) was administered to all patients with hypothyroidism during follow-up to keep TSH level at approximately 1 mIU/L. No patient received corticosteroid.
All statistical analysis was done using SPSS software, V16.0 (SPSS Inc, Chicago, IL). Descriptive analysis and frequency tables were used for general description of data. The comparison of quantitative variables in 3 groups was done using analysis of variance with Bonferroni test as a post hoc analysis for mutual comparison between 2 groups. The χ2 test was used for comparison of frequency in 3 groups. P < 0.05 was considered significant in all comparisons.
We studied 92 patients (34 male and 58 female) with a mean age of 38.2 ± 12.0 years (age range, 18–67 years). Twelve patients (13%) were smoker. The mean RAIU was 35.9% ± 21.2% and 62% ± 16% at 2 and 24 hours, respectively. Overall, 29, 32, and 31 patients were studied in FLD, FHD, and CD groups, respectively. Although all the patients in FLD and FHD groups received fixed doses of 259 MBq (7 mCi) and 555 MBq (15 mCi), respectively, patients in CD group received a wide range of activity from 74 MBq (2 mCi) to 580.9 MBq (15.7 mCi) with a mean dose of 240.5 ± 133.2 MBq (6.5 ± 3.6 mCi). Table 1 shows comparison of different variables in 3 groups and indicates that 3 groups were not significantly different regarding age, sex ratio, RAIU, or being smoker.
Pretreatment ophthalmic examination in 3 groups showed no significant difference in visual acuity and proptosis; however, CAS was higher in CD group. Table 2 shows comparison of pretreatment ophthalmic examination in 3 groups.
All the patients completed ophthalmic examination 6 months later; however, 6 patients (6.5%) did not perform thyroid laboratory tests at follow-up examination. Of 86 patients tested for thyroid function tests, hyperthyroidism is relieved (responders) in 59 patients (68.6%) 6 months after treatment. Table 3 shows response rate in different groups, 6 and 12 months after radioiodine therapy. Using analysis of variance, the response rate was not significantly different between 3 groups 6 months after treatment (P = 0.2). Furthermore, comparing every 2 groups mutually, we could not find any significant statistical difference in response rate 6 months after radioiodine treatment. On the other hand, looking at the response rate, 12 months after RIT, we noted that response rate tends to be higher in FHD and CD groups compared with FLD group (P = 0.05). We noted that although the mean radioiodine dose was slightly lower in the CD (240.5 MBq) group compared with FLD (259 MBq), the response rate 12 months after therapy was higher in the CD group, suggesting more effective treatment with CD strategy (P = 0.05). Although P values just touched the significance level, the effect size could not be overlooked. Interestingly, the response rate was not significantly different in FHD and CD groups (P = 0.69), whereas the mean dose in FHD patients (555 MBq) was more than 2 times higher than mean dose in CD (240.5 MBq) group, confirming more effective RIT in CD group.
Table 4 shows the ophthalmologic variables in 3 groups before and 6 months after RIT. Overall, visual acuity was unaffected while proptosis and CAS were increased significantly after RIT. Furthermore, 6 months after RIT, 77.2% (71/92) had no change in CAS, whereas 18.5% (17/92) had an increase in CAS and 4.3% (4/92) experienced a reduction in CAS. Ophthalmologic variables according to the radioiodine dose and therapy categorization are shown in Table 5. The amount of change in proptosis and CAS (the difference between pretherapy and posttherapy) was calculated and considered as delta proptosis and delta CAS, respectively. The highest change in proptosis was seen in FHD group. Using post hoc analysis, we compared groups mutually and found that proptosis was increased more significantly in the FHD group (0.84 ± 0.88 for right eye and 0.75 ± 1.07 for left eye) compared with other groups (P < 0.05), whereas the FLD group (0.38 ± 0.68 for right eye and 0.38 ± 0.56 for left eye) and CD group (0.32 ± 0.6 for right eye and 0.29 ± 0.74 for left eye) had no significant difference in delta proptosis. One patient in FLD, 8 patients in FHD, and 2 patients in CD groups had at least 2 mm increase in proptosis (P = 0.01).
Similarly CAS was increased more dramatically in FHD group (0.34 ± 0.6) compared with other groups (P = 0.008). Using post hoc analysis, mean delta CAS was significantly higher (P = 0.006) in FHD group (0.34 ± 0.6) compared with CD group (−0.03 ± 0.4). Furthermore, mean delta CAS was 0.14 ± 0.35 in FLD group and −0.03 ± 0.4 in CD group (P = 0.08). CAS was increased at least 1 point in 13.8% (4/29) of the patients in FLD, 34.4% (11/32) of patients in FHD, and 6.4% (2/31) of patients in CD (P = 0.01). Worsening of CAS occurred in 25% of smokers and 17.5% of nonsmoker patients (P = 0.68). Proptosis increased in the right eye with an average of 1.0 ± 1.2 mm in smokers and 0.45 ± 0.86 mm in nonsmokers (P = 0.15). In the left eye, it was 0.91 ± 1.37 mm in smokers and 0.41 ± 0.72 mm in nonsmokers (P = 0.24).
This is the first report of the effect of radioiodine dose on ophthalmic complications. Our study showed that ophthalmic complications were dependent on the radioiodine dose. It is higher in patients who received high fixed dose of 131I compared with other methods. In the meantime, CD of 5.55 MBq/g (thyroid weight) was as effective as fixed high dose of 555 MBq in the treatment of GD with remarkably lower amount of administered 131I and fewer ophthalmic complications and may be considered as the preferred method of radioiodine therapy.
Radioiodine Dose and Response to Therapy
Although radioactive iodine is frequently used in treatment of GD and is considered as the first line of treatment in some parts of the world, there is no consensus on the optimal dose of radioiodine. Different dose strategies of fixed versus CD (based on thyroid radioiodine uptake and thyroid volume) have been used interchangeably in the last few decades.14 Furthermore, both of these strategies can be applied using either low or high doses of radioiodine.6 In the low fixed dose method, usually a dose of 185 to 370 MBq has administered, whereas higher doses of 555 to 800 MBq has been administered in the high fixed dose methods.15–17 On the other hand, in CD strategies, a dose range of 2.9 to 11.1 MBq/g (80–300 μCi/g) of 131I has been used.3,18
In a large study in 316 patients with GD, a response rate of 93.3% was obtained after RIT with 7.4 MBq/g of thyroid weight.19 This is concordant with the 12 months response rate of 92.9% in our patients who were treated with 5.55 MBq/g.
In another study, the response rate 3 months after radioiodine therapy was 60% for a fixed dose of 185 MBq and 65% for a CD of 185 to 370 MBq, which was very similar to our result (58.6 and 66.7%, respectively) 6 months after therapy.20
Lewis et al21 reported a response rate of 89% to a fixed dose of 550 MBq of 131I 1 year after therapy, which was concordant with our results (94.4%) in FHD group who received 555 MBq of 131I.
However, many studies releveled no association between administrated dose and received thyroid dose in fixed dose strategies, and recommended CD strategy for RIT of GD.22,23 Furthermore, RIT of GD with individual CDs could provide the availability of treatment with lower doses compared with fixed dose method.24 This is consistent with our findings that the lowest mean administered activity was in CD group compared with other fixed dose methods. Furthermore, the lowest administered dose with successful result of therapy was 74 MBq in one of the patients who was treated with calculated methodology in our study.
We compared the CD strategy (mean dose, 240.5 MBq) with 2 different fixed doses (259 MBq or 555 MBq). Although the mean radioiodine dose was similar in FLD and CD groups, the response rate was 8.10%, higher in the CD group compared with the FLD group after 6 months. This superiority reached 26% after 12 months and became statistically significant. Our study indicate that the administration of 5.55 MBq/g of 131I is more effective compared with low fixed dose of 259 MBq and as effective as high fixed dose of 555 MBq, whereas the mean administered activity (240.5 MBq) was lower than both. According to the ALARA (as low as reasonably achievable) principle, the goal is achieving cure for the hyperthyroidism of GD, with the lowest radiation burden to the patient as well as to the society. Considering the ALARA principle, our study confirmed that the treatment with calculated method could treat patients with lower doses and higher success rate, and is the preferred method of radioiodine therapy.
The opponents of calculated strategy accept that this method could treat patients with lower doses of 131I; however, they discuss that this method is costly and the result of treatment is not different in fixed versus CD strategies.4,25 Our study, however, showed that CD strategy is not only the most appropriate method according to ALARA principle but also is associated with lower ophthalmic complications.
Radioiodine Dose and Ophtalmopathy
Radioiodine therapy is a safe treatment with no increased mortality or increased risk of cancer.8 However, it is associated with small risk of worsening of GO, when glucocorticoids was not administered concomitantly with 131I.8 Although thyroid-associated ophthalmopathy occurs in 20% to 25% of patients with GD, only 5% of patients have moderate to severe GO.1 Clinical activity score was used for categorization of severity of ophthalmopathy. When CAS is equal to 3 or more, it is considered as an active disease and concomitant corticotherapy is recommended.1 We studied patients with inactive GO, which include the majority of patients with GD.
Our study revealed that there was no change in visual acuity 6 months after treatment, whereas proptosis and CAS increased significantly after treatment. CAS was increased after RIT much more commonly in FHD group (34.4% or 11/32) compared with FLD group (13.8% or 4/29) and CD group (6.4% or 2/31) (P = 0.01). In addition, mean delta proptosis and mean delta CAS of both eyes were significantly higher in FHD compared with FLD and CD groups. This finding suggests more effective and well-controlled thyroid ablation and restricted release of antigens after RIT in patients treated with CD of 131I. This hypothesis that controlled radiation will result in restricted release of antigens, and limited immune reaction needs to be confirmed by measuring serial antibody levels in another study. This new hypothesis may be applied to other radionuclide treatment applications too and underscore the importance of dosimetry-based treatment.
Overall, increment of ≥2 mm in proptosis was noted in 12% of our patients, which was again more prevalent in FHD group compared with FLD and CD groups. Another study in 76 patients treated with 7.4 MBq/g reported increase in proptosis of ≥2 mm in 39% of patients.26 The thyroid volume was estimated by palpation in that study, which usually overestimate the thyroid size.26 This may explain the difference between 2 studies; anyhow, it is consistent with our findings that the severity of ophthalmic complications is dose dependent.
It is suggested that thyroid surgery after radioiodine ablation of thyroid remnant may be helpful to complete elimination of antigens and prevent ophthalmopathy flare up.27,28 The idea of “antigen deprivation” by ablative doses of radioactive iodine has also been mentioned previously.29 Interestingly, a systematic review on GO including 10 randomized trials with 1136 patients showed that ATD therapy is associated with lower rate of GO than RIT or surgery, whereas RIT and surgery was not significantly different. This finding suggest that anti-inflammatory effect of ATD seems to play a role in prevention of worsening GO. Similarly, the addition of corticosteroids was highly effective in the prevention of progression of GO in patients with preexisting GO.30 We have not administered glucocorticoids to any of our patients.
It is well known that smoking increase the rate of GO and it is worsening after RIT.9,31 In our study, the number of smokers in the 3 groups was the same and worsening of GO was not different in 3 groups. Anyhow, there was a trend that smokers have more increase in proptosis after RIT than nonsmokers.
Our study is the first prospective study on the effect of radioactive iodine dose on GO and showed that worsening of GO is dose dependent, and fixed high dose of 131I (555 MBq) is associated with higher rate of worsening of GO.
Calculated dose strategy is preferable to fixed dose methods and could treat patients more effectively with lower doses of 131I. Furthermore, worsening of GO is dose dependent, and treatment of patient with 5.55 MBq/g of thyroid weight is associated with lower eye complications compared with fixed dose of 555 MBq of 131I.
This research was a part of the thesis of the first author for the degree of nuclear medicine specialty and financially supported by a grant from research deputy of Mashhad University of Medical Sciences.
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