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Thyrotropin Receptor Antibodies and Graves’ Disease, a Side-Effect of ¹³¹I Treatment in Patients with Nontoxic Goiter¹

Department of Internal Medicine and Endocrinology, Herlev Hospital (B.N., J.H.K., J.E.M.H.), Herlev; the Department of Internal Medicine and Endocrinology, Odense University Hospital (L.H.), Odense; and the Department of Clinical Physiology and Nuclear Medicine, Holbæk Hospital (A.V.C.S.), Holbæk, Denmark

Address all correspondence and requests for reprints to: Birte Nygaard, M.D., Department of Internal Medicine and Endocrinology F 112, Herlev Hospital, Herlev Ringvej, DK-2730 Herlev, Denmark.

	Abstract

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The use of ¹³¹I treatment in patients with benign nontoxic goiter is increasing, and the described side-effects are few. In this paper we describe appearance of TSH receptor antibodies (TRAb) and concomitant development of hyperthyroidism as a side-effect of ¹³¹I treatment in patients with nontoxic goiter. In this retrospective study, 191 consecutive patients with ¹³¹I-treated nontoxic goiter are described. Nine patients (5%) developed hyperthyroidism 3 months after ¹³¹I treatment, and 5 patients (3%) developed radiation thyroiditis within the first month. Frozen sera were analyzed for thyroid peroxidase antibodies (anti-TPO) in 130 patients before ¹³¹I treatment. In 21% of these, serum levels of anti-TPO were over 200 U/mL. The complication frequency of Graves’-like hyperthyroidism and hypothyroidism was 51% in patients with elevated anti-TPO (n = 27) and 15% in patients with normal serum anti-TPO levels (P < 0.00005). TRAb, anti-TPO, and thyroglobulin were followed in patients developing hyperthyroidism or radiation thyroiditis and in 10 control patients remaining euthyroid. At the time of ¹³¹I treatment, all patients had serum TRAb values within the normal range. Three months after administration of ¹³¹I, the patients developing hyperthyroidism had a transient extensive rise in serum TRAb and anti-TPO levels parallel to a rise in the serum free T₄ index. In patients developing radiation thyroiditis, serum TRAb values were normal. In control patients, serum TRAb and anti-TPO values were both within the normal range throughout the observation period.

In conclusion, hyperthyroidism can be triggered by ¹³¹I in patients with nontoxic goiter, not only related to radiation thyroiditis but also as a Graves’-like hyperthyroidism induced by TRAb. Elevated anti-TPO pretreatment is a marker of an increased risk of side-effects to ¹³¹I treatment in nontoxic goiter.

	Introduction

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RADIATION thyroiditis is a well known complication when thyroid diseases are treated with radioiodine (¹³¹I). Manifestations usually commence a few days after ¹³¹I treatment and consist of neck pain, dysphagia, thyroid tenderness, and transient hyperthyroidism (1, 2). In a few patients with toxic multinodular goiter, the appearance of TSH receptor antibodies (TRAb) and the onset of hyperthyroidism after ¹³¹I treatment, have been described (3, 4, 5, 6). TRAb are seen in about 85% of patients with Graves’ disease and are thought to be involved in the initiation of hyperthyroidism in Graves’ disease (7). TRAb have also been reported in patients with other thyroid diseases, but are uncommon in nontoxic goiter (7).

¹³¹I therapy is increasingly used in patients with benign nontoxic goiter (8, 9, 10, 11, 12, 13, 14). Therefore, we found it pertinent to describe the occurrence of hyperthyroidism in patients with nontoxic goiter, not as a result of radiation thyroiditis, but most likely caused by TRAb production triggered by ¹³¹I treatment.

	Subjects and Methods

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Patients

The study was retrospective, comprising 191 consecutive ¹³¹I-treated patients with nontoxic goiter (21 men and 170 women; median age, 52 yr; range, 30–83 yr). We have previously described the first 69 patients (8). Nontoxic goiter was defined as the presence of a goiter combined with free T₄ index (FT₄I) and free T₃ index (FT₃I) within the normal range; no discrimination was made between patients with or without thyroid autoantibodies. The patients were evaluated before and 1, 3, 6, and 12 months after treatment, and TSH, T₃, T₄, and T₃ uptake ratio were determined.

In patients developing hyperthyroidism (patients 1–9); in patients developing radiation thyroiditis defined as neck pain, dysphagia, thyroid tenderness, and transient hyperthyroidism (patients 10–14), and in 10 randomly selected control patients with normal FT₄I and FT₃I, we measured thyroid peroxidase antibodies (anti-TPO), TRAb, and thyroglobulin (Tg) for 12–24 months after ¹³¹I treatment. Patient data are given in Table 1. The results of thyroid scintiscans before ¹³¹I treatment are shown in Table 1. [Scintiscan at the time of hyperthyroidism was performed in only one patient (no. 5), and this demonstrated unaltered heterogeneous uptake.] None of the patients had eye symptoms related to the hyperthyroid phase.

Frozen (-20 C) sera from consecutive patients treated with ¹³¹I for nontoxic goiter were analyzed. Thyroid function was evaluated by measuring serum levels of T₄, T₃, and TSH and T₃ uptake ratio. Free T₄ and T₃ indexes were calculated by multiplying the T₄ level by the result of the T₃ uptake test. Details of the methods have been described previously (8). TRAb were determined by a receptor assay (TRAk-assay, Henning Berlin, Berlin, Germany; normal range, <9 U/L; interassay variation, 7%). Anti-TPO were measured by the LUMI-test from Henning Berlin (normal range, <200 U/mL; interassay variation, 10%). Tg was measured by the Dynotest Tg from Henning Berlin (normal range, 2–70 ng/mL; interassay variation, 3%).

¹³¹I was given at a dose of 3.7 megabecquerels/g total thyroid mass [evaluated by ultrasound (15)], corrected to a 100% 24-h ¹³¹I uptake. The maximum dose given was 740 megabecquerels. Before treatment, a ^99mTc thyroid scan was performed in all patients with a -camera.

For statistical evaluation, Mann-Whitney’s test, Fisher’s exact test, and Wilcoxon’s test were used. P < 0.05 was considered statistically significant.

	Results

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FT₄ index

All patients had normal FT₄I and FT₃I at the time of treatment. In five patients, classical symptoms of radiation thyroiditis were seen within 1 month (patients 10–14). The levels of FT₄ ranged from 150–233 arbitrary units after 1 month in four patients. In patient 11, no blood samples were obtained after 1 month, but the described symptoms were classic. FT₄ levels were normalized after 3 months in all five patients.

Nine patients (no. 1–9) had normal FT₄ concentrations 1 month after ¹³¹I treatment, but developed hyperthyroidism after 3 months. Symptoms of hyperthyroidism were minor in seven patients (no. 2, 3, and 5–9) and severe in two patients (no. 1 and 4).

Two patients became hyperthyroid and resolved spontaneously without therapy in 15–18 months (no. 2 and 5), five patients were given antithyroid drugs and remained euthyroid off medication 6–18 months after ¹³¹I treatment (no. 3 and 6–9), one patient’s hyperthyroidism was treated with a second dose of ¹³¹I (no. 1), and one patient had a subtotal thyroidectomy (no. 4).

Figure 1 shows changes in serum FT₄I related to ¹³¹I treatment in patients 1–6 and in 10 control patients. Data from patients 1, 3, 4, and 5 are shown at 18 and 24 months. Patients 7–9 are not illustrated in Figs. 1–4 because of some missing data.

View larger version (46K): [in this window] [in a new window]   Figure 1. Changes in serum FT4I related to time after 131I treatment of nontoxic goiter in 6 patients (no. 1–6) developing hyperthyroidism (median, black line; range, ) and range of FT4I in 10 control patients (.. .. .. .. ...).

View larger version (56K): [in this window] [in a new window]   Figure 2. Changes in serum TRAb concentration related to time after 131I treatment of nontoxic goiter in 6 patients (no. 1–6) developing hyperthyroidism (median, black line; range, ) and range of serum TRAb in 10 control patients (.. .. .. .. ...). A logarithmic scale was used.

View larger version (82K): [in this window] [in a new window]   Figure 3. Changes in serum anti-TPO values related to time after 131I treatment of nontoxic goiter in 6 patients (no. 1–6) developing hyperthyroidism (median, black line; range, ) and range of serum anti-TPO in 10 control patients (.. .. ...). A logarithmic scale was used.

View larger version (76K): [in this window] [in a new window]   Figure 4. Changes in serum Tg level related to time after 131I treatment of nontoxic goiter in 6 patients (no. 1–6) developing hyperthyroidism (median, black line; range, ) and serum Tg in 10 control patients (median, gray line; range, .. .. ..).

Changes in serum TRAb levels in patients 1–6 and the 10 control patients are shown in Fig. 2. TRAb values in patients developing hyperthyroidism were, although within the normal range, significantly higher (median, 5 U/L; range, 3–7) than those in the control patients (median, 1 U/L; range, 0–4; P < 0.001). Three months after ¹³¹I treatment there was a considerable increase in serum TRAb values. Serum TRAb values decreased during a period of 18 months, with a slightly slower decrease in the 2 patients who did not receive antithyroid drugs (no. 2 and 5). Patient 1, who received a second ¹³¹I treatment, showed a secondary rise in serum TRAb levels, but this was not followed by recurrence of hyperthyroidism. In patient 7, the serum TRAb value measured before and 1 month after treatment was 4 U/L; again after 12 months of treatement, it was 38 U/L. In patients 10–14, serum TRAb concentrations were within the normal range.

Anti-TPO

Serum anti-TPO levels were measured to evaluate changes in another thyroid autoantibody. Changes in serum anti-TPO values were parallel those in serum TRAb, i.e. no changes after 1 month, a considerable increase after 3 months, and no changes in the control group (Fig. 3). Of the patients developing radiation thyroiditis, two had normal anti-TPO values without any changes after ¹³¹I treatment, and three had elevated values with an increase after 3–6 months of treatment.

To evaluate whether there was a correlation between positive anti-TPO and development of side-effects to ¹³¹I treatment, anti-TPO were measured before treatment. Blood samples were available in 130 patients. Anti-TPO levels less than 200 U/mL were found in 103 patients (79%; only 2 patients had values between 100–200 U/mL). In patients with positive anti-TPO levels, 6 of 27 (22%) developed Graves’-like hyperthyroidism compared to 2 of 103 patients (2%) with normal anti-TPO levels (P = 0.002). Eight of 27 with positive anti-TPO levels developed hypothyroidism requiring L-T₄ (29%) compared to 13 of 103 (13%) without anti-TPO (P = 0.08). Three of 27 with positive anti-TPO developed radiation thyroiditis (11%) compared to 2 of 103 (2%) without these antibodies (P = 0.12).

Tg

Figure 4 shows changes in serum Tg concentrations. There was a significant increase (P = 0.04) in serum Tg levels 1 month after treatment in the patients who developed hyperthyroidism, but due to the wide range in the control group (8- 500 ng/mL), no difference between these patients and the control group was seen. Median Tg levels in the control group increased during the first 3 months, but the changes were not statistically significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
¹³¹I therapy has recently been described as an attractive alternative to surgery in the treatment of benign nontoxic goiter leading to an approximately 50% reduction in thyroid volume within 1–2 yr (8, 9, 10, 11, 12, 13, 14). In view of this, we found it pertinent to focus attention on possible side-effects of this treatment. In the present paper we describe 9 patients from a consecutive group of 191 patients (5%) who had normal serum TRAb values at the time of ¹³¹I treatment as well as 1 month later, but increased serum TRAb values and hyperthyroidism after 3 months. Similar findings were reported by Kay et al. in a study of 14 patients (16). Furthermore, a Graves’-like hyperthyroidism commencing several months after radioiodine therapy for toxic nodular goiter associated with appearance of TRAb has recently been described in a few patients (3, 4, 5, 6).

When Graves’ disease is treated with ¹³¹I, a transient rise in TRAb levels is seen after approximately 3 months. Also, an increase in serum levels of TgAb and microsomal antibodies has been described (7, 17, 18). These observations have been interpreted as an immunological response caused by the release of thyroid antigens from destroyed follicular cells (7). The increase in circulating antigens cannot be measured, but is believed to correspond to changes in serum Tg levels after ¹³¹I therapy. Therefore, we measured serum Tg as a marker of antigen release. We have previously seen a significant increase in serum Tg in the first days after ¹³¹I treatment of nontoxic goiter (unpublished data). In the present study we did not measure serum Tg until 1 month after treatment. Therefore, we may have overlooked a larger early increase in serum Tg. No obvious differences between serum Tg in the control group and the patients developing hyperthyroidism could be demonstrated.

In this retrospective study we did not measure cAMP production from thyroid tissue, but only TRAb, and we only had the possibility to obtain a thyroid scan in one patient to be completely sure that we were dealing with a Graves’-like disease. However, the concomitant increase in FT₄I and TRAb first seen 3 months after ¹³¹I treatment, the fact that hyperthyroidism in some patients persisted for over a year, and the different antibody profile seen in patients with a classical radiation thyroiditis make this explanation plausible. The fact that TRAb values were significantly higher, although within the normal range, in the patients developing hyperthyroidism could indicate that these patients had minimal preexisting Graves’ disease that was aggravated by ¹³¹I.

Other environmental factors that cause destruction of the follicular cells have been described as leading to development of Graves’ disease, i.e. external radiation for nonthyroidal disease (19), surgical manipulation of the thyroid during parathyroidectomy (20), or subacute thyroiditis (21). Such cases are rare and may be coincidental, or it could be the environmental influence that triggers a Graves’-like autoimmune response to the TSH receptor.

Thyroid autoantibodies have previously been described as a risk factor for the development of hypothyroidism after ¹³¹I therapy for single hot thyroid nodules (22). Correspondingly, we found that Graves’-like hyperthyroidism and hypothyroidism after ¹³¹I treatment were more likely to appear in patients with an elevated serum anti-TPO level (51%) than in those without (15%). Although we do not have a histological diagnosis, these patients with elevated anti-TPO could be suffering from Hashimoto’s thyroiditis. We, therefore, suggest that ¹³¹I treatment should only be used in highly selected patients with elevated anti-TPO.

Although Graves’ disease has an autoimmune origin, the pathogenesis of toxic nodular goiter is believed to be of nonautoimmune origin. Progression from nodular nontoxic goiter to hyperthyroidism is thought to be caused by an increasing autonomy in the multinodular goiter (23). However, in the present study we have described a Graves’-like hyperthyroidism based on autoimmune phenomena in patients with typical nodular nontoxic goiter.

In conclusion, treatment with ¹³¹I in patients with nontoxic goiter does not usually lead to increased serum TRAb levels. In some predisposed individuals, an immunological response, probably triggered by the release of Tg or other antigens from the thyroid, causes a transient (months) rise in TRAb and a concomitant hyperthyroidism starting 3 months after ¹³¹I treatment. This condition is different from the radiation thyroiditis, which can be observed during the first month after ¹³¹I without detectable TRAb in serum. When treating nontoxic goiter with ¹³¹I, one should be aware of this possible side-effect. Patients with high serum anti-TPO levels seem to be at an increased risk and require frequent evaluation.

	Footnotes

 
¹ This work was supported by grants from Agnes and Knut Mørks Foundation. The data were published in part as an abstract in Eur J Endocrinol 130(Suppl 1):7, 1994.

Received March 17, 1997.

Revised May 14, 1997.

Accepted June 3, 1997.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nygaard, B. Articles by Mølholm Hansen, J. E. Search for Related Content PubMed PubMed Citation Articles by Nygaard, B. Articles by Mølholm Hansen, J. E.