The Tale of Radioiodine and Graves' Orbitopathy

Abstract

Background:

Autoimmunity against the thyrotropin receptor (TSH-R) is a key pathogenic element in Graves' disease (GD) and the autoimmune aberration may be modified by antithyroid treatment. An association between radioactive iodine (RAI) therapy for GD and the development or worsening of Graves' orbitopathy (GO) is widely quoted. RAI-associated leakage of thyroid antigen(s) leads to an increased production of TSH-R antibodies that may initiate the eye injury.

Summary:

RAI therapy leads to prolonged worsening of autoimmunity against the TSH-R, and the number of patients entering remission of TSH-R autoimmunity is considerably lower than with other antithyroid therapies. Scientific evidence has indicated that RAI treatment for GD is associated with increased risk of occurrence or progression of GO compared with antithyroid drugs (ATD) and thyroid surgery. The risks of developing new GO or worsening of preexisting GO is around 20% after RAI and around 5% after ATD. The risk of developing severe GO after RAI is around 7%. Smoking, high levels of pretreatment serum triiodothyronine, and post-RAI hypothyroidism are associated with increased risk of GO, whereas a high TSH-R autoantibody titer is an independent risk factor for the progression of GO. In patients with mild preexisting GO, steroid prophylaxis is effective in preventing deterioration of GO. Also, routine use of prophylactic oral steroids with RAI therapy should be considered in GD patients without overt GO, but even more so in those at higher risks of eye complications such as smokers, old men, and those with severe hyperthyroidism or high TSH-R antibody titers.

Conclusion:

In contrast to ATD, remission of TSH-R autoimmunity after RAI therapy is less common, and RAI for GD is associated with definite increased risk of GO. Oral steroids are beneficial for patients with preexisting GO, particularly smokers.

Radioiodine and Thyroid Autoimmunity

G raves' disease (GD) is a common autoimmune disorder with various clinical manifestations (1). The cause for the most prevalent abnormality, hyperthyroidism, are the thyrotropin-receptor (TSH-R)-stimulating autoantibodies (2). These antibodies are also believed to cause the diffuse, hypervascular goiter observed in many patients. The exact mechanism leading to Graves' orbitopathy (GO) is not firmly established, but there is a correlation between disease activity and TSH-R antibodies (TRAb) (3 –5). GD patients with the extrathyroidal manifestations of orbitopathy, dermopathy, and acropachy have severe systemic disease with high circulating levels of TRAb (5 –8). It is well established that the therapy of hyperthyroidism may influence disease activity. During prolonged follow-up, TRAb tend to disappear from serum after all types of therapy for hyperthyroidism. The hypothesis that antithyroid drugs (ATD) may interfere with the immune system by reducing thyroid autoantigen availability and presentation is the one that provides the best explanation for the fall in serum TRAb levels observed in patients with GD during ATD treatment. Administration of ATD is in fact associated with a decrease in serum TSH or TRAb levels, respectively, leading to reduced thyroid stimulation (1,9).

Radioactive iodine (RAI) is routinely used as the definitive treatment of choice in most patients with Graves' hyperthyroidism (10). After a single RAI administration, patients may become hypothyroid, euthyroid, or remain hyperthyroid. Biological effects of RAI include necrosis and impaired replication of nondestroyed follicular cells, atrophy, fibrosis, and a chronic inflammatory response, which may ultimately result in permanent thyroid failure. Changes in thyroid histology are associated with a reduction in thyroid volume, which reflects thyroid damage. RAI treatment for GD is also followed by changes in thyroid autoimmunity, which may result in a transient increase of TRAb with thyroid-stimulating antibody activity (11,12). Further, there are several reports suggesting that GO may worsen after therapeutic procedures associated with the leakage of antigens from the thyroid, such as RAI (4,13,14). It has been claimed that after thyroid injury, there is liberation of thyroid antigen(s), leading to an increased production of autoantibodies, such as TSH-R, thyroglobulin, and thyroid peroxidase antibodies. This, in turn, may initiate the eye injury. RAI might worsen GO not only by activation of the autoimmune thyroid disease by release and presentation of antigen or destruction of radiosensitive suppressor T lymphocytes, but also by inducing hypothyroidism (2,10). Thus, the stimulation of thyroid cells through the TSH-R either by high TSH (due to hypothyroidism) or by an increase of TRAb (due to RAI) might result in a pathogenic signal leading to an exacerbation of eye disease (3). Further, TSH and TSH-R-stimulating antibodies both enhance the gamma-interferon-dependent human leukocyte antigen–DR locus (HLA-DR) expression by thyroid cells as well as increase the synthesis and expression of thyroid peroxidase by thyrocytes (14).

The surge of TRAb after RAI administration was also observed in clinical trials (15 –19). In a 5-year prospective study, patients with newly diagnosed Graves' hyperthyroidism aged 20–55 years were randomized to medical therapy, thyroid surgery, or RAI therapy (19). Thyroxine (T4) was added to therapy as appropriate to keep patients euthyroid (Table 1). TRAb were measured before and for 5 years after the initiation of therapy. Medical therapy and surgery were followed by a gradual decrease of TRAb in serum, with the disappearance of TRAb in 70%–80% of the patients after 18 months. In contrast, a considerable increase in TRAb was observed immediately after RAI therapy with maximal value at 3 months. This was associated with a 1 year worsening of autoimmunity against the TSH-R. Moreover, the number of patients entering remission of TSH-R autoimmunity with the disappearance of TRAb from serum during the following years was significantly lower than with the other types of therapy (p < 0.003). In the RAI group, average TRAb values were highly above the normal reference throughout the 5 years of follow-up. In a further prospective study (18), hyperthyroid patients with GD were randomly assigned to receive RAI alone or RAI plus pretreatment with ATD (methimazole, 30 mg/day). In the RAI group, TRAb levels increased significantly 1 month after RAI administration (45–78 U/L, 73%) reaching their highest levels at 3 months (225 U/L, 400%). In comparison, the mean serum TRAb levels before RAI was significantly lower in patients pretreated with methimazole (81 vs. 48 U/L, p < 0.05) and slightly increased after RAI (48–60 U/L, 19%).

Table 1.

Radioiodine Therapy for Graves' Disease and the Effect on Thyrotropin-Receptor Autoantibodies

References	Groups	Dose RAI (MBq)	Serum T3 levels (nmol/L) before therapy (normal range)	TRAb levels (U/L) before therapy (cut off )	TRAb (U/L) after therapy	TRAb positive (n, %) before therapy	TRAb positive (n, %) after therapy
(16)	RAI: n = 23	350	T3: 5.2 ± 0.9 (1.1–3.2)	10 ± 9; mean: 10 (<3)	3 months: increase from 10 to 42 U/L (p < 0.005), values remained elevated until month 9 (p < 0.05)	14 (61)	17 (74)
	RAI + ATD: n = 17	350	T3: 3.5 ± 2.0 (1.1–3.2)	20 ± 45 mean: 24 (<3)	Decrease from 24 to 2 U/L after 12 months (not statistically significant)	10 (59)	12 (71)
	RAI + betamethasone^a n = 20	350	T3: 3.1 ± 0.4 (1.1–3.2)	30 ± 12 (<3)	Increased levels after 3 and 6 months (p < 0.05), exact values not mentioned	14 (70)	12 (90)
(36)	RAI: n = 20	350	T3: 6.4 ± 0.4 (1.1–3.2)	22 ± 3 (<5)	Increase after 3 months (significant change [p < 0.05]; no exact values mentioned)	16 (80)	19 (95)
	RAI + betamethasone^a n = 20	350	T3: 5.3 ± 0.3 (1.1–3.2)	21 ± 4 (<5)	Increase after 6 months (significant change [p < 0.05]; no exact values mentioned)	17 (85)	18 (90)
(17)	RAI: n = 57	234 ± 139	T3: 4.7 ± 2.2 (reference values not mentioned)	Mean: 24 (U/L; range: <5–112) (cut off not mentioned)	Transient rise (significance of changes and exact values not mentioned)	Not determined	Not determined
	RAI + ATD: n = 57	188 ± 112	T3: 5.5 ± 2.8 (reference values not mentioned)	9 (<5–309) (cut off not mentioned)	No change (statistically significant [p < 0.05]; exact values not mentioned)
(18)	RAI: n = 32	393 ± 211	T3: 8.0 ± 3.8 (1.19–2.8)	Median: 62.2 (U/L; range: 11–407) (<11)	Significant increase from 45.0 to 225 U/L after 3 months, then progressive decrease to baseline levels (40.0 U/L) at 12 months (p < 0.05)	30 (94)	Not determined
	RAI + ATD: n = 29	330 ± 170	T3: 3.8 ± 1.9 (1.19–2.8)	77.5 (12–311) (<11)	During pretreatment with ATD decrease from 80.5 to 48.8 U/L. After RAI increase to 99.9 U/L. After month 12 decrease to baseline values (47.6 U/L). p < 0.05, respectively	Before randomization: 29 (100), after ATD, before RAI: 22 (75)
(19)	Group 1: < 35 years				Decrease to the upper level of the normal reference (significance and exact values not mentioned)	Not determined	Not determined
	ATD: n = 30	—	T3: 6.3 ± 2.0 (1.1–2.5)	38 ± 26 (cut off not mentioned)
	Surgery: n = 30	—	T3: 5.6 ± 1.8 (1.1–2.5)	35 ± 23 (cut off not mentioned)
	Group 2: ≥35 years				Decrease to the upper level of the normal reference (significance of changes and exact values not mentioned)
	ATD: n = 41	—	T3: 5.4 ± 1.7 (1.1–2.5)	31 ± 23 (cut off not mentioned)
	Surgery: n = 37	—	T3: 5.4 ± 1.9 (1.1–2.5)	26 ± 20 (cut off not mentioned)
	RAI: n = 41	Based on thyroid size	T3: 5.3 ± 1.7 (1.1–2.5)	34 ± 21(cut off not mentioned)	Increase after 3 months, decrease to baseline after 12 months (significance of changes and exact values not mentioned)

Starting 3 weeks before RAI with 6 mg/day for 1 week; tapered down until week 7.

RAI, radioiodine; ATD: antithyroid drugs; T3, triiodothyronine; TRAb, thyrotropin-receptor antibodies.

RAI Therapy and GO

An association between worsening of GO and RAI treatment was reported originally in 1967 (20). In this report, the onset of GO coincided with the appearance of long-acting thyroid stimulatory immunoglobulins in the serum of three patients with GD. This observation has been confirmed subsequently by other authors (13,14,21 –23). However, in a retrospective analysis of 573 patients with GD, there were no differences in the occurrence of posttreatment GO in patients who did not have overt eye disease before treatment among those who received a variety of treatments for their hyperthyroidism (24). The worsening of GO was more frequent in patients who had ocular signs before treatment, but the rate of progression was similar in the three (RAI, surgery, and ATD) treatment groups. In contrast, a careful review of the records of 89 patients with GD treated with RAI could indeed demonstrate progression of GO in one-third of patients with ocular symptoms before treatment (21). Even Graves' subjects without overt eye signs before RAI administration developed GO posttherapy. Among the 30 patients with initially present GO, 7 (23.3%) developed severe GO and significant increase of proptosis (p < 0.05). In addition, 5 (16.7%) of them required immediate special treatment for eye disease. Thus, the latter data suggest that hyperthyroid patients with pretreatment GO are at risk for developing severe GO after RAI treatment. On the other hand, the discrepant data in the literature might be attributed, at least in part, to the fact that reports were mainly retrospective. In addition, measurements of ocular parameters were often lacking and GO was evaluated too long after RAI treatment. This made it difficult to evaluate a possible relation between RAI administration and the outcome of eye disease.

The Italian trials

To address this problem, a randomized study (25,26) was performed in Pisa, Italy, in which hyperthyroid GD patients who had slight or no signs of GO and no change in their ocular status for at least 3 months before treatment were randomly assigned to a group treated with RAI alone (RAI group) or to a second group concomitantly treated with RAI and systemic steroids (SS) (RAI+SS group). The dose was 0.4–0.5 mg prednisone/kg body weight (BW) for 1 month, with subsequent tapering and withdrawal after 3 months. Before treatment, 10 patients in the RAI group and 5 in the RAI +SS group had no evidence of GO. Ocular symptoms did not occur in any of them after RAI therapy. Among the patients in the RAI group with clinical evidence of GO before therapy, ocular disease worsened in 9 of 16 (56%) and did not change in 6 of 16 (44%). In contrast, GO improved in 11 of 21 (52%) and did not change in 10 of 21 (48%) in the RAI+SS group. In this study worsening of GO occurred within 6 months of RAI in most patients, and was persistent. Soft tissue changes and extraocular muscle function were the parameters mostly involved. In four patients in the RAI group, the exacerbation was such as to require treatment with high doses of systemic glucocorticoids. The outcome of RAI therapy was similar in the two groups. The prevalence of hypothyroidism was about 30% at the end of the 18-month study period, and no relationship was noted between the development of hypothyroidism and the worsening of GO. The findings that GO was unchanged before RAI therapy, that exacerbation mostly occurred within 6 months after treatment, and that worsening did not occur in any patient receiving glucocorticoids concomitantly with RAI strongly suggest that the exacerbation of eye disease was related to RAI treatment (Table 2).

Table 2.

Radioiodine Therapy for Graves' Disease and the Effect on Graves' Orbitopathy

References	Groups	Dose RAI (MBq)	Smoking (n, %)	Preexisting GO (n, %)	New-onset GO (n, %)	Exacerbation of GO (n, %)	Regression of GO (n, %)
(25)	RAI: n = 26	Median: 355 (range: 222–555)	Not determined	16 (62)	0	9 (56)	0
	RAI + prednisone^a: n = 26	363 (203–592)		21 (81)	0	0	11 (52)
(27)	RAI: n = 150	407 ± 112 (mean ± SD)	82 (55)	72 (48)	6 (8)	17 (24)	0
	RAI + prednisone^a: n = 145	444 ± 136	87 (60)	75 (52)	0	0	50 (67)
	ATD: n = 148	—	84 (57)	74 (50)	1 (2)	3 (4)	3 (4)
(29)	Group 1: <35 years:
	ATD: n = 27	—	12 (44)	4 (15)		4 of 27 (15)	3 of 4 (75)
	Surgery: n = 27	—	14 (52)	0		3 of 27 (11)	0
	Group 2: ≥35 years:
	ATD: n = 38	—	15 (39)	5 (13)		4 of 38 (10)	3 of 5 (60)
	Surgery: n = 37	—	16 (43)	6 (16)		6 of 37 (16)	3 of 6 (50)
	RAI: n = 39	Based on thyroid size	22 (56)	7 (18)		13 of 39 (33)	4 of 7 (57)
(31)	Group 1: <35 years:			Not determined		Not determined	Not determined
	ATD: n = 30	—	14 (50)
	Surgery: n = 30	—	18 (60)
	Group 2: ≥35 years:					Not determined
	ATD: n = 41	—	18 (44)
	Surgery: n = 37	—	19 (51)
	RAI: n = 41	Based on thyroid size	23 (33)			15 (40)
(32)	RAI: n = 163	(23.4 × thyroid mass [g] + 120 [Gy])/(est. uptake [0 h; %] + effective half-life [days])	52 (32)	22 (13)	53 (38)	9 (41) + 1 (5) who had initially improved	10 (45), 1 (5) had subsequent deterioration
	ATD: n = 150	—	59 (62)	19 (13)	23 (18)	7 (37) + 2 (11) who had initially improved	10 (53), 2 (11) had subsequent deterioration
(17)	RAI: N = 57	234 ± 139	Not determined	16 (28)	11 (27)	2 (12)	3 (19)
	RAI + ATD: n = 57	188 ± 112		19 (33)	10 (26)	4 (21)	2 (11)

Oral prednisone, 0.4–0.5 mg/kg body weight starting 1–3 days after RAI; for 1 month, then tapered down for 3 months.

GO, Graves' orbitopathy; SD, standard deviation; est., estimated.

The same working group conducted a randomized, single-masked, controlled study (27,28) and concluded that the development of or worsening of GO occurred more frequently in patients treated with RAI alone but not in those treated with RAI and prednisone. Patients treated with methimazole alone did not have worsening GO. GO was transient in the majority of their patients but persisted and required immunosuppression in a few patients. In detail, they studied 443 patients with Graves' hyperthyroidism and mild or no GO. The former were defined as <22 mm of proptosis, intermittent or no diplopia, no optic neuropathy, and mild conjunctival and periorbital inflammation. All patients were treated with methimazole for 3–4 months. Patients were randomly assigned to one of three treatment arms. The first was RAI at a dose of 120–150 μCi/g of thyroid tissue. The second was RAI followed by a 3-month course of prednisone at a dose of 0.4–0.5 mg/kg of BW for 2–3 days followed by a taper over 2 months, and the last was methimazole for 18 months. Patients were evaluated at intervals of 1–2 months for 12 months for changes in function and appearance of the thyroid and progression of GO. Hypothyroidism and persistent hyperthyroidism were promptly corrected within 2–3 weeks by the administration of T4 or methimazole, respectively. A second dose of RAI was administered to patients who had persistent hyperthyroidism at the end of the follow-up. The authors defined the appearance, progression, or improvement of GO according to major and minor criteria. The major criteria included a variation of 2 mm or more in exophthalmometry measurements and lid fissure width and appearance or disappearance of diplopia. It also included variations of two or more points in the GO activity score. In this system a grade of one point was assigned for each of seven symptoms or signs. These were spontaneous retrobulbar pain, pain with eye movement, eyelid edema, eyelid erythema, conjunctival injection and chemosis, swelling of the caruncle, and changes of 1/10 or more in visual acuity. Minor criteria were variations in soft tissue or in the patients' assessment of his or her disease. Of the 150 patients treated with RAI alone (17 of 72 with preexisting GO and 6 of 78 without GO), GO developed or worsened in 23 (15%) patients from 2 to 6 months after treatment. The eye changes were transient in 15 patients and persistent in 5. Of the 145 patients treated with RAI and prednisone, 50 (67%) patients of the 75 with GO at baseline had improvement and no patient had progression. The remaining 95 patients had no change. No patients had worsening GO in this group. Of the 148 patients treated with ATD, 3 (2%) with GO at baseline improved, 4 (3%) had worsening of GO, and the remaining 141 patients had no change. The effects of RAI on thyroid function were similar in the patients treated with RAI regardless of whether they did or did not receive prednisone.

The Swedish trials

Similar data as the Italian trials were published from Sweden (Table 2). In their first report, Tallstedt et al. (29) studied 168 patients with Graves' hyperthyroidism stratified into two age groups. These were those 20–34 years of age (54 patients, group YOUNG) and 35–55 years of age (114 patients, group OLDER). The patients in group YOUNG were randomly assigned to treatment with methimazole or subtotal thyroidectomy. Those in group OLDER were assigned to one of these two treatments or to RAI therapy. All patients received T4 to avert hypothyroidism except those treated with RAI. Those treated with RAI received T4 when hypothyroidism developed. The duration of follow-up was at least 24 months. Twenty-two patients had infiltrative GO at randomization. During follow-up, GO developed for the first time in 22 patients (13%) and worsened in 8 patients (5%). The frequency of the development and/or worsening of GO was similar among the patients in group YOUNG (ATD, 4 of 27 patients, 15%, and surgery, 3 of 27 patients, 11%). In group OLDER, GO developed or worsened in 4 of the 38 (11%) treated medically, 6 of the 37 patients (16%) treated surgically, and 13 of the 39 patients (33%) given RAI (p = 0.02). The relative risk (RR) of GO associated with RAI treatment was 4.1 (95% confidence interval [CI] = 1.7–8.2, p = 0.002). The development or worsening of GO increased as pretreatment serum triiodothyronine (T3) concentrations increased (p = 0.002). As noted, patients who received RAI were treated with T4 only when biochemical hypothyroidism developed. This may have affected the outcome. It was later demonstrated in a retrospective analysis of 492 subjects with GD that early administration of L-T4 reduced the occurrence of GO (30). In this study, 248 patients received L-T4 when the serum concentration of TSH and/or T4 indicated hypothyroidism (group A). In the following years 244 patients were all given 0.05 mg of L-T4 daily, starting 2 weeks after RAI therapy and 0.1 mg after a further 2 weeks (group B). With a follow-up of 18 months, 45 patients (18%) in group A and 27 patients (11%) in group B developed GO or had deterioration of their GO when it was present (p = 0.03, RR = 1.64, 95% CI = 1.05–2.55). Twenty-six patients in group A required specific therapy for the ophthalmopathy compared to 11 patients in group B (p = 0.02, RR = 2.33, 95% CI = 1.18–4.60). To further analyze the benefits and risks of the three common antithyroid treatments, 179 patients with GD were randomly assigned to several groups by these authors (31). The risk of relapse of hyperthyroidism was highest in the medically treated group (42%), followed by those treated with RAI (21%) and then those in the surgically treated group (8%). Development or worsening of GO was not associated with relapse per se. Fifteen (38.5%) of 39 patients who received RAI experienced worsening GO. In those treated with RAI, a high serum T3 level was associated with adverse effects in terms of GO. The risk for developing or worsening of GO was 22% for a patient with serum T3 levels above 5 nmol/L compared to only a 2% risk if T3 levels were below 5 nmol/L. RAI further increased the risk from 10% to 58% for these respective T3 levels.

Recently, the same group published the results of a further randomized trial with a follow-up of 4 years (32). In this intention-to-treat study, patients with a recent diagnosis of Graves' hyperthyroidism were randomized to treatment with RAI (n = 163) or 18 months of ATD treatment (n = 150). Early substitution with L-T4 was given in both groups. As the main outcome measure, worsening or development of GO was significantly more common in the RAI treatment group (n = 63, 38.7%) compared with the ATD group (n = 32, 21.3%), p < 0.001. The risk for de novo development of GO was greater (p < 0.001) in patients treated with RAI (53 of 141, 38%) than in those treated with ATD treatment (23 of 131, 17.5%). Steroid treatment for GO was required in more patients in the RAI group (n = 15, 9.2%) than in the ATD group (n = 4, 2.7%). Smoking was shown to influence the risk of worsening or development of GO (p < 0.001), and smokers treated with RAI had the overall highest risk for GO. Cox regression analysis identified four risk factors associated with worsening or development of GO with and without set criteria for worsening or development of GO: RAI versus ATD (odds ratio [OR] = 7.72, 95% CI = 2.31–25.75, p < 0.001), current smoking (OR = 9.80, 95% CI = 2.75–34.90, p < 0.001), higher serum-free T4 (OR = 1.03, 95% CI = 1.01–1.04, p < 0001), and RAI in smokers (OR = 0.14, 95% CI = 0.11–0.74, p = 0.007). The authors concluded that RAI treatment is a significant risk factor for development of GO in Graves' hyperthyroidism.

Systematic review of randomized controlled trials

A systematic review of randomized controlled trials was recently undertaken to assess whether RAI for GD is associated with increased risk of GO compared with ATD or surgery (33). Random effects meta-analyses were used to combine the study data. Ten randomized trials involving 1136 patients permitted 13 comparisons. RAI was associated with an increased risk of GO compared with ATD (RR = 4.23, 95% CI = 2.04–8.77, p = 0.0001). GO developed in 36 out of 189 patients who received RAI compared with 8 out of 186 patients who received ATD. The risk of severe GO was also increased with RAI compared with ATD (RR = 4.35, 95% CI = 1.28–14.73, p = 0.02). Fourteen patients out of 189 in the RAI group developed severe GO compared with 3 patients out of 186 in the medical group. The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO. A pretreatment serum T3 level of >5 nmol/L was associated with increased risk of developing or worsening GO after RAI therapy compared with levels <5 nmol/L (RR = 5.8, 95% CI = 1.5–22.8) in two randomized trials (29 –31). Posttreatment hypothyroidism (both raised TSH and low T4) was positively associated with GO in one randomized trial (34). Also, a positive correlation with smoking and GO was noted (35). Finally, in four randomized studies it was observed that the peak incidence of GO after RAI was at 6 months. GO developed from 1 to 24 months after RAI, however. The authors concluded that RAI for GD is definitely associated with an increased risk of developing GO or worsening of preexisting GO as compared to ATD treatment.

RAI Therapy for GD with Versus Without Steroid Prophylaxis

Numerous prospective studies have reported a beneficial effect of steroid prophylaxis for GO in Graves' patients receiving RAI. Three randomized trials performed in Italy (25 –27) used prednisone after RAI treatment. The dose was 0.5 mg/kg BW/day for 1 month and then tapered over 2 months (Table 2). Two randomized studies from Sweden (16,36) used betamethasone for 7 weeks (6 mg/day for 5 days and then tapered weekly by 1.5–0.5 mg). Patients underwent RAI therapy 3 weeks after betamethasone was commenced and were receiving betamethasone 3 mg daily. In all trials, steroid prophylaxis was highly effective in preventing worsening of eye disease in patients with preexisting GO compared with RAI therapy without prednisone. GO worsened in 26 patients out of 88 patients with preexisting eye disease who received RAI alone. None of the 96 patients with preexisting eye disease who received steroid prophylaxis developed worsening GO (RR = 0.03, 95% CI = 0.00–0.24, p = 0.0007). In patients with no preexisting GO, eye disease developed in 6 out of 88 subjects in the RAI group compared with none in the steroid group of 75 patients (RR = 0.09, 95% CI = 0.00–1.49, p = 0.09). No significant side effects were observed due to SS therapy apart from transient “Cushingoid features” in one trial (27). In contrast, in a nonrandomized study of hyperthyroid GD patients with inactive and pretreated GO, there was no worsening of eye disease after RAI (37).

Dose of steroid prophylaxis

Since the optimal doses and schedules for prednisone treatment have not been defined, a retrospective matched cohort study at a university center was conducted recently (38). Of 111 RAI-treated Graves' patients with mild or no GO, 35 received no steroid prophylaxis, 28 received low-dose prednisone (starting dose, 0.16–0.27 mg/kg BW, group 1), and 48 received higher doses (group 2). Among the latter, 28 taking a starting dose, 0.32–0.56 mg/kg BW, were matched with group 1 using several relevant parameters. Prednisone was started 1 day after RAI and withdrawn after 6 weeks. Two of 35 patients not receiving steroid prophylaxis (6%) developed mild-to-moderate GO after RAI. No patients in groups 1 and 2 had progression of GO. Side effects were very mild and inconstant, although more frequent in group 2. Both groups showed an increase in BW, but this increase was greater in group 2. Thus, lower doses of oral prednisone (0.2 mg/kg BW) are as effective as the previously employed higher doses (0.3–0.5 mg/kg BW). A shorter treatment period of 6 weeks seems to be sufficient. However, a recent retrospective study has shown that in a minority of GD patients, high doses of intravenous methylprednisolone were required to adequately treat severe post-RAI activation of GO (39).

Toxicity of intravenous high-dose steroids

In this respect, the risk–benefit ratio for intravenous high-dose (0.5–1 g) glucocorticoids in patients with active disease of only moderate severity who might do equally well with oral steroids or even careful observation and frequent reassessment should be weighted toward the side of high or unacceptable risk (40). Although the frequency of hepatotoxicity appears to be very low, 7 of ∼800 GO patients treated in Italy with intravenous high-dose steroids suffered severe liver damage, of whom three died (41). Because no case of liver failure has been reported in GO patients receiving oral steroids or a cumulative dose of <8 g intravenous methylprednisolone, intravenous high-dose steroids should only be administered in centers experienced in this therapy.

Steroid prophylaxis and the efficacy of RAI in treating hyperthyroidism

In a prospective study of 40 patients with GD, betamethasone, given for 3 weeks before and 4 weeks after RAI, delayed, but did not abolish, the RAI-associated rise in thyroid autoantibody levels (36). At the end of the 12-month follow-up period, 9 out of 20 (45%) betamethasone-treated patients and 17 out of 20 (85%) placebo-treated patients developed hypothyroidism. In contrast, in a study of 31 GD patients who received RAI therapy, no differences in the thyroid function outcome of treatment were observed in the subgroup of patients treated with glucocorticoids after RAI administration compared with patients not receiving steroid treatment (42). Moreover, in a large randomized trial, the prevalence of permanent hypothyroidism after RAI therapy was similar in patients treated with RAI alone (62%) or with RAI followed by glucocorticoid coverage (66%) (27). Likewise, treatment failure, that is, persistent hyperthyroidism, was similar in the two groups (14% and 12%, respectively). Therefore, available data suggest that post-RAI treatment with glucocorticoids, usually given to prevent GO progression, does not affect the outcome of RAI therapy for hyperthyroidism (43 –45). Accordingly, no increase in the dose of RAI is required. Conversely, pretreatment with glucocorticoids may reduce the effectiveness of RAI therapy and should, therefore, be avoided.

In conclusion, numerous studies (25 –28,33,37,46 –48) indicate that steroid prophylaxis is effective in preventing GO progression after RAI and is safe. With low doses of oral prednisone for a short period it can be employed in daily clinical practice. As recommended in a recently published consensus statement of the European Group of Graves' Orbitopathy “EUGOGO” in this journal (49), glucocorticoids can be safely administered without any fear of compromising the outcome of RAI therapy (Fig. 1). This should be given foremost consideration in smokers with preexisting GO and those with severe hyperthyroidism or high TRAb titers (Table 3).

FIG. 1.

Steroids for radioiodine therapy of Graves' disease—when and how. RAI, radioiodine; yrs., years; mg/kg BW, milligram per kilogram body weight; TSH-R, thyrotropin receptor.

Table 3.

Personalized Medicine Factors Relating to Graves' Disease in Patients Treated with Radioiodine

Condition	Risk factors
GO	History of smoking
	High levels of TSH-R autoantibodies
	High pretreatment T3 levels
	Prolonged hypothyroidism after radioiodine
	Age (over 60 years)^a
	Male sex
	Genetic risk?

According to References (33,50,51).

In contrast, a foremost mild course of orbitopathy is observed in pediatric patients with Graves' disease (51).

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

Portions of this review were presented at the Spring 2010 Meeting of the American Thyroid Association, “Thyroid Disorders in the Era of Personalized Medicine,” Minneapolis, MN, May 13–16, 2010.

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