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A Possible Role of Immunoglobulin E in Patients with Hyperthyroid Graves’ Disease

Department of Medicine (A.S., Y.T.), Dokkyo Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Saitama 343-8555, Japan; Department of Medicine (T.Y., H.O., H.S., Y.M., A.T., S.O., K.J., A.K., Y.N., E.T., Y.I., K.K.), Kashiwa City Hospital, Kashiwa, Chiba 277, Japan; Department of Gerontology (T.A.), Endocrinology and Metabolism, Shinshu University School of Medicine, Matsumoto, Nagano 390, Japan

Address correspondence and requests for reprints to: Akira Sato, M.D., Department of Medicine, Dokkyo Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Saitama 343-8555, Japan.

	Abstract

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To investigate the possible participation of immunoglobulin E (IgE) in the autoimmune process of Graves’ disease, incidence of elevation of serum IgE level, TSH receptor antibody (TRAb), and thyroid status were studied in 66 patients with hyperthyroid Graves’ disease, 54 patients with Hashimoto’s thyroiditis, 19 patients with bronchial asthma, and 15 patients with pollen allergy. In hyperthyroid Graves’ patients, elevation of serum IgE levels (170 U/mL) was found in 19 of 66 patients (29%), 11 of whom had hereditary and/or allergic conditions. Elevations of serum IgE levels were found in 63% of patients with bronchial asthma and in 40% of patients with pollen allergy. Mean values of serum IgE were the same in patients with hyperthyroid Graves’ disease and with bronchial asthma. During methimazole treatment TRAb decreased without fluctuation of IgE levels in both groups. The decrease in TRAb was significantly greater in patients with normal IgE than in patients with IgE elevation. After prednisone administration, reduction in TRAb was greater in patients with normal IgE than that in patients with IgE elevation.

High incidence of IgE elevation in hyperthyroid Graves’ disease and slower reduction in TRAb in association with IgE elevation suggest a difference in the autoimmune processes in Graves’ disease with and without elevation of IgE.

	Introduction

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IT IS widely believed that hyperthyroid Graves’ disease is an autoimmune disorder characterized by the presence of circulating TSH receptor antibody (TRAb) (1, 2, 3). The majority of activity of TRAb is in the immunoglobulin G (IgG) class (4). However, there may be a role of other immunoglobulins. For instance, immunoglobulin E (IgE) deposits in the thyroid (5) and ocular muscles of hyperthyroid Graves’ disease (6, 7). Recently, it has been noted that recurrence of Graves’ disease can be induced by pollen allergy (8, 9). Because pollen allergy is one of the most common diseases associated with the synthesis of IgE (10), IgE therefore might play a role in the induction and maintenance of hyperthyroid Graves’ disease.

To evaluate this potential relationship, we first studied the incidence of elevation of serum IgE among hyperthyroid Graves’ disease, Hashimoto’s thyroiditis, bronchial asthma, and pollen allergy. Second, in regard to pollen allergy and bronchial asthma, we analyzed the past, present and family histories in patients with hyperthyroid Graves’ disease. In addition, a possible presence of circulating antibodies against 16 antigens was studied. Thirdly, the effects of antithyroid drug and glucocorticoid on thyroid function and serum IgE levels were studied in hyperthyroid Graves’ disease.

	Materials and Methods

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Sixty-six patients (15 males and 51 females, ages 15–67 yr) with hyperthyroid Graves’ disease, 54 patients (3 males and 51 females, ages 11–87 yr) with Hashimoto’s thyroiditis, 19 patients (11 males and 8 females, ages 17–70 yr) with bronchial asthma, and 15 patients (7 males and 8 females, ages 41–70 yr) with pollen allergy due to Japanese cedar were examined in this study. The diagnosis of hyperthyroid Graves’ disease was made on the basis of clinical features such as diffuse goiter, exophthalmos, tachycardia, tremor and sweating, and laboratory data such as undetectable serum TSH, elevated levels of serum thyroxine (T₄), and TRAb. Hyperthyroid patients were treated with methimazole (20–30 mg/day) (12) and visited the outpatient clinic once a month for laboratory examinations (serum levels of TSH, T₄, and TRAb) and for adjustment of the doses of methimazole for maintaining euthyroidism. Serum level of IgE was measured every two months. The diagnosis of Hashimoto’s thyroiditis was made on clinical features such as diffuse and firm goiter and laboratory data such as the presence of thyroid microsomal and/or thyroglobulin autoantibodies, normal or reduced levels of serum T₄, and normal or elevated levels of serum TSH. Thyroid microsomal and thyroglobulin autoantibodies were measured by the tanned red cell hemagglutination technique using commercially available kits (Fuji-Zoki Co., Tokyo, Japan). The autoantibodies were considered to be present when a positive reaction was obtained in the presence of dilute serum (dilution x 100 or more). Diagnosis of bronchial asthma was made on the basis of clinical findings such as intermittent reversible episodes of bronchospasm associated with cough, wheezing, and dyspnea alternating with periods of remission, and decreased pulmonary function tests in peak flow rate and forced expiratory flow rate within the past 6 yr. Pollen allergy due to Japanese cedar was diagnosed on the basis of rhinitis and conjunctivitis that occurred in early spring and on positive radioallergosorbent assay against Japanese cedar within the past 6 yr. Blood was obtained at their first visit, and serum IgE level was determined. Serum levels of T₄, TSH, and TRAb were measured as reported previously (11). The normal ranges were 5–11 µg/dL for T₄, 0.5–5 mU/L for TSH, and less than 15% for TRAb, respectively. The data of IgE were analyzed with logarithmically transformed values because serum IgE concentrations follow a logarithmic-normal distribution. Normal value for serum IgE was below 170 U/mL, because mean serum IgE level was 61.66 U/mL (mean ± SD; 27.54 138.34 U/mL) obtained from 43 normal subjects without history of allergic diseases and negative for specific antibodies against 16 common antigens (13), and because IgE level 170 U/mL could discriminate possible high IgE. IgE and antibodies against 16 antigens were determined by Mitsubishi-Kagaku Bio-Clinical Laboratories, Inc. of Tokyo, Japan, using the method reported by Nakagawa et al (14). Informed consent was obtained from all subjects.

Statistical analysis was made by the two-tailed paired and unpaired Student’s t tests and by Fisher’s exact test where appropriate. A P value less than 0.05 was considered statistically significant.

	Results

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Incidence and mean serum levels of elevated IgE in thyroid diseases, bronchial asthma, and pollen allergy

The incidence and mean levels of serum elevated IgE in patients with hyperthyroid Graves’ disease, Hashimoto’s thyroiditis, bronchial asthma, and pollen allergy are shown in Table 1. Elevation in serum IgE (>170 U/mL) was found in 6 of 54 (11%) patients with Hashimoto’s thyroiditis and in 1 of 41 (2%) control subjects. In contrast, elevation in serum IgE was found in 19 of 66(29%) patients with untreated hyperthyroid Graves’ disease. The incidence of elevation of serum IgE was significantly greater in patients with hyperthyroid Graves’ disease than in control subjects (P = 0.006). As expected, elevation in serum IgE was found more frequently in patients with bronchial asthma (63%) and with pollen allergy (40%). The mean serum values of elevated IgE were the same in hyperthyroid Graves’ disease and in bronchial asthma. In addition, the mean serum values of elevated IgE of Graves’ disease and bronchial asthma were significantly greater than those of Hashimoto’s thyroiditis and pollen allergy. In contrast, nonelevated serum IgE values were the same in hyperthyroid Graves’ disease, bronchial asthma, pollen allergy, Hashimoto’s thyroiditis, and control subjects. Analysis indicated that no relationship was found between serum levels of IgE and other thyroid parameters (serum levels of T₄, TSH, and TRAb).

In 19 hyperthyroid patients with IgE elevation, 11 patients had the positive history and/or the family history for asthma or pollen allergy. One patient had suffered from asthmatic attacks for a couple of years and had a positive family history for asthma. Three patients had had asthmatic attacks in their childhood and had relatives with asthma. Another 3 patients had relatives with asthma. As for pollen allergy, 2 patients had pollen allergy and a positive family history for pollen allergy. Two patients had relatives with pollen allergy. However, 8 patients had neither the personal history nor the family history for allergic disorders. A possible presence of antibodies against 16 antigens (Penicillium Cladosporium, Candida, Alternaria, Aspergillus, House dust, Dermatophagoides, Egg white, Cat, Dog, Soybean, Ragweed, Mugwort, Timothy, Sweet vernal and Japanese cedar) was studied in 7 hyperthyroid patients with high IgE elevation (>1000 U/mL) and in 7 hyperthyroid patients with normal IgE (<169 U/mL). The highly positive antibodies (>20.1 lumi-count x 100) against 1–6 overlapped antigens were found in all 7 patients with IgE elevation. In contrast, 7 patients with normal IgE were negative for these antigens (<4.40 lumi-count x 100).

Effect of methimazole treatment on serum levels of IgE and thyroid parameters

Before treatment with methimazole, serum levels of T₄ were the same in 19 patients with IgE elevation and in 47 patients with normal IgE. During methimazole treatment, serum levels of T₄ decreased progressively but variably in both groups (Fig. 1-A). Before methimazol treatment, serum levels of TRAb were slightly but insignificantly greater in elevated IgE group than in the normal IgE group. During methimazole treatment, serum levels of TRAb decreased progressively in both groups, but a decrease was significantly greater in normal IgE group than in elevated IgE group (Fig. 1-B). In patients with or without IgE elevation, serum IgE levels did not fluctuate markedly during methimazole treatment (Fig. 1-C).

View larger version (44K): [in this window] [in a new window]   Figure 1. Changes in serum levels of T4, TRAb, and IgE after methimazole treatment in hyperthyroid Graves’ disease patients with IgE elevation and with normal IgE, according to the length of time. Panels A, B, and C show changes in serum levels of T4, TRAb, and IgE, respectively. Serum levels of T4, TRAb, and IgE were measured every 2 months. Data represents mean ± SD. IgE was analyzed with logarithmically transformed data. Hatched bars, patients with hyperthyroid Graves’ disease with IgE elevation; open bars, patients with hyperthyroid Graves’ disease with normal IgE.

During methimazole treatment, 30 mg prednisone in three divided doses was administered daily for 2 weeks in 6 hyperthyroid patients with IgE elevation and in 8 patients without IgE elevation. Eight hours after the last dose of glucocorticoid, blood was obtained to measure thyroid hormones and other parameters. As shown in Table 2, the patients were euthyroid at the start of glucocorticoid administration, as evidenced by normal levels of serum T₄ and TSH. After glucocorticoid administration, serum levels of T₄ decreased similarly in both groups. Tg decreased significantly in the group with normal IgE (P < 0.05) but not in the group with elevated IgE. TRAb decreased in response to glucocorticoid, but the magnitude of decrease was greater in patients with normal IgE than in patients with elevated IgE (P < 0.0001). Serum levels of IgE increased slightly in 4 of 6 patients with IgE elevation and in 3 of 8 patients without IgE elevation.

	Discussion

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We therefore studied the relation with the most common allergic diseases, bronchial asthma and pollen allergy, which induce elevation of serum IgE. We found that 11 of 19 patients with IgE elevation had the present, past, and/or family histories of bronchial asthma or pollen allergy. We further found, in the absence of clinical and historical overt symptoms, that a number of specific high titer antibodies were present in patients with IgE elevation but not in patients without IgE elevation. This suggests that one third of hyperthyroid Graves’ patients had hereditary and atopic allergic states when judged by the family history, IgE elevation, and 16 IgE antibody analyses.

We next made a study to determine whether IgE elevation was just incidental or had some linkage with hyperthyroid Graves’ disease. Serum IgE level did not dramatically fluctuate during methimazole treatment. A decrease in TRAb during methimazole treatment was examined to see if the recovery phase of Graves’ disease was different between elevated and non-elevated IgE groups. As shown in Fig. 1, decreases in serum T₄ levels in response to methimazole were the same in both groups. Under this condition, however, a decrease in TRAb was significantly smaller in patients with IgE elevation than in patients without IgE elevation. This suggests that the recovery phase of Graves’ disease is retarded in patients with IgE elevation. In addition, we found that reduction in levels of TRAb and Tg in response to glucocorticoid was smaller in patients with IgE elevation than in patients with normal levels of serum IgE. This again suggests that autoimmune processes are somewhat different in patients with and without IgE elevation. In order for IgE to play a pathogenetic role, these antibodies must be shown to have activity targeting the TSH receptor or recently characterized eye muscle antigens. However, IgE antibodies against any recognized orbital or thyroid autoantigen have not been shown. Furthermore, because allergies are common in the community and because of the well-known association between autoimmunity, immunodeficiency, and allergy, the effect of allergy on the autoimmune process, the stress of asthma and other allergic reactions may all play a role in the participation of thyroid autoimmunity rather than its pathogenesis.

Recently, it has been noted that recurrence of hyperthyroid Graves’ disease can be induced by pollen allergy (8, 9). Because pollen allergy is the well-known disease that induces IgE elevation, recurrence of hyperthyroid Graves’ disease may coincide with IgE elevation. Unfortunately, however, this suggested sequence of events was not studied in a sufficient number of patients (8, 9). Our present study indicated that no recurrence of hyperthyroid Graves’ disease was found in any of 66 patients with or without IgE elevation during maintenance dose of methimazole treatment. Thus, the linkage between pollen allergy with IgE elevation and recurrence of hyperthyroid Graves’ disease could not be ascertained.

Received October 13, 1998.

Revised May 4, 1999.

Revised June 16, 1999.

Accepted June 23, 1999.

	References

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