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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 8 2775-2778
Copyright © 2000 by The Endocrine Society

Original Studies

An Elevation of Serum Immunoglobulin E Provides a New Aspect of Hyperthyroid Graves’ Disease

Takashi Yamada, Akira Sato, Ichiro Komiya, Takeo Nishimori, Yoshiharu Ito, Akira Terao, Sumiya Eto and Yoshiya Tanaka

Department of Medicine, Kashiwa City Hospital (T.Y., T.N., Y.I., A.T.), Kashiwa, Chiba 277; Department of Medicine, Dokkyo Koshigaya Hospital, Dokkyo University School of Medicine (A.S.), Koshigaya, Saitama 343-8555; Second Department of Medicine, Faculty of Medicine, University of the Ryukyus (I.K.), Nishihara, Okinawa 903-0215; and First Department of Medicine, University of Occupational and Environmental Health (S.E., Y.T.), Yawatanishiku, Kitakyushu 807-8555, Japan

Address all 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. E-mail: asato{at}dokkyomed.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In hyperthyroid Graves’ disease, short-term methimazole is sufficient to induce lasting remission in some patients, but even long-term treatment fails to do so in others. We have evaluated the role of autoimmune abnormalities in the helper T cell type 2 (TH2)-interleukin-13 (IL-13)-TSH receptor system in maintaining hyperthyroidism by comparing IgE levels in patients with various thyroid diseases.

One hundred and ninety-three patients with hyperthyroid Graves’ disease were treated with methimazole, and blood samples were obtained to measure serum levels of T4, T3, TSH, thyroglobulin, antimicrosomal antibody, TSH binding inhibitory Ig (TBII), thyroid-stimulating antibody, thyroid stimulation-blocking antibody, IgE, interferon-{gamma}, IL-4, and IL-13. Elevation of serum IgE (>=170 U/mL) was found in 35.5% of patients with hyperthyroid Graves’ disease, and serum levels of T4, T3, antimicrosomal antibody, and TBII were significantly greater in patients with IgE elevation than in those with normal serum IgE. During methimazole treatment, there was a parallel decrease in the serum T4 concentration in the presence or absence of an IgE elevation. However, there was a significantly smaller decrease in TBII in patients with elevated IgE than in those with normal IgE. As a result, the remission rate was significantly greater in patients with normal IgE than in those with IgE elevation. Serum levels of IL-13 were elevated in 64.7% of patients with IgE elevation in the absence of detectable TH1 marker, interferon-{gamma}.

These findings suggest that in one third of patients with hyperthyroid Graves’ disease, TH2 cells are stimulated and secrete excess amounts of IL-13, which subsequently stimulates B cells to synthesize more TSH receptor antibody and IgE, so that during methimazole treatment TBII decreases less in patients with IgE elevation, producing a lower remission rate.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GRAVES’ DISEASE is an autoimmune disorder of the thyroid characterized by the production of autoantibodies against TSH receptor (TRAb) (1, 2, 3). TRAb, composed of thyroid-stimulating antibody (TSAb), TSH binding inhibitory Ig (TBII), and thyroid stimulation-blocking antibody (TSBAb), is in the IgG class (4, 5) and is pathogenic for the disease, with stimulating effect, where hyperthyroidism is the result of TSH receptor stimulation (1, 2, 3). The etiology of Graves’ disease as an autoimmune disorder, however, is multifactorial on the basis of genetic susceptibility interacting with environmental and endogenous factors (3). Several lines of evidence suggest a relationship between thyroid autoimmunity and the allergic responses. First, IgE as well as IgG and IgM deposit in some Graves’ thyroid tissue (6) and ocular muscles of hyperthyroid Graves’ disease (7, 8). Second, associations have recently been reported between recurrence of hyperthyroid Graves’ disease and allergic rhinitis of pollen allergy (9, 10), one of the most common diseases associated with the synthesis of IgE (11). Third, the presence of IgE class thyroid peroxidase autoantibodies has been reported in some patients with Graves’ disease and Hashimoto’s thyroiditis (12). Finally, we reported the high incidence of IgE elevation in hyperthyroid Graves’ disease and a lesser reduction of TRAb in association with IgE elevation (13). IgE, therefore, might play a role in the induction and maintenance of hyperthyroid Graves’ disease. Less is known, however, about the role of IgE, because limitation in obtaining the sufficient amount of IgE has hampered examination of the nature of IgE class autoantibodies in TRAb activity.

We thus searched for the circulating levels of cytokines, including interferon-{gamma} (IFN{gamma}), interleukin-4 (IL-4), and IL-13, that participate in the production and secretion of Igs. We also studied the decay of TBII and remission rate from hyperthyroid Graves’ disease with or without elevated levels of IgE during methimazole treatment. Here we report the association of Graves’ disease with IgE and IL-13, suggesting the link between autoimmune thyroid disease and immune responses involving TH2 cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
One hundred ninety-three patients (29 males and 164 females, aged 15–69 yr) with hyperthyroid Graves’ disease, 72 patients (5 males and 67 females, aged 22–69 yr) with Hashimoto’s thyroiditis, 40 patients (2 males and 38 females, aged 13–69 yr) with simple goiter, and 39 patients (1 male and 38 females, aged 20–81 yr) with nodular goiter were in this study. Forty-two normal subjects (2 males and 40 females, aged 18–63 yr) served as controls. The diagnosis of Graves’ disease was based on clinical features such as diffuse goiter, exophthalmos, tachycardia, tremor, and sweating and laboratory data such as undetectable serum TSH and elevated levels of serum T4, T3, and TRAb (TSAb and TBII). Hyperthyroid patients were treated with methimazole (20–30 mg/day) (14, 15, 16, 17) and visited the out-patient clinic once a month for laboratory examinations [serum levels of TSH, T4, T3, TSAb, TBII, thyroglobulin (Tg), and IgE]. Three to 4 months after the initiation of methimazole, blood was obtained to measure TSBAb, IFN{gamma}, IL-4, and IL-13.

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 antimicrosomal antibody (MCHA), normal or reduced levels of serum T4 and T3, and normal or elevated levels of serum TSH. MCHA was measured by the tanned red cell hemagglutination technique using a commercially available kit (Fiji Zoki, Tokyo, Japan). MCHA was considered positive when a positive reaction was obtained in the presence of dilute serum (dilution, x100 or more).

The diagnosis of simple goiter was made on clinical features such as small, soft, and diffuse goiter and laboratory data such as normal serum levels of T4, T3, and TSH and the absence of MCHA. The diagnosis of nodular goiter was made on clinical and laboratory findings such as nontoxic goiter in the absence of circulating autoantibodies and nonmalignant histology on aspiration biopsy.

Serum levels of T4, T3, TSH, Tg, and TBII were measured as reported previously (14, 15, 16, 17). TSAb (18) and IgE (19) were measured by Mitsubishi Kagaku Bio-Clinical Laboratory, Inc. (Tokyo, Japan). TSBAb was measured by Yamasa Shoyu Laboratory (Choshi, Chiba, Japan) (18). The normal ranges were 5–11 µg/dL for T4, 78–190 ng/dL for T3, 0.1–5 µU/mL for TSH, 3–42 µg/mL for Tg, less than 15% for TBII, less than 180% for TSAb, and less than 30% for TSBAb, respectively. The data for IgE and MCHA were analyzed statistically with logarithmically transformed values and then converted to antilogarithmic values. Normal values for IgE were below 170 U/mL as reported previously (13). IFN{gamma} (enzyme-linked immunosorbent assay; Bender MedSystems, Vienna, Austria), IL-4 (Cytoscreen US, ultrasensitive for human IL-4, Biosource Technologies, Inc., Camarillo, CA), and IL-13 (IL-13 enzyme-linked immunosorbent assay, Bender MedSystems) were also measured by Mitsubishi Kagaku Bio-Clinical Laboratories, Inc.

Statistical analyses were made using two-tailed unpaired Student’s t test and Fisher’s exact test where appropriate. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Incidence of IgE elevation in various thyroid diseases

As shown in Table 1Go, 44 of 124 patients with Graves’ disease (35.5%) had an elevation of IgE (>=170 U/mL), and this incidence was significantly higher than that of other thyroid disorders. IgE elevation was also found in 15 of 72 patients with Hashimoto’s thyroiditis (20.8%). The difference in incidence between Graves’ disease and Hashimoto’s thyroiditis was statistically significant (P < 0.05). In patients with simple goiter and nodular goiter, the incidence of IgE elevation was low (5.0% and 5.1%, respectively) and comparable to that in normal subjects (2.4%).


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  		Table 1. Various thyroid parameters in patients with or without IgE elevation

 
Thyroid parameters in patients with or without IgE elevation

As expected, serum levels of T4 and T3 were significantly elevated, and TSH was undetectable in patients with untreated hyperthyroid Graves’ disease (Table 1Go). TBII, TSAb, and MCHA were higher in hyperthyroid patients with than in those without IgE elevation; the differences, except for TSAb, were statistically significant. In patients with simple goiter, Hashimoto’s thyroiditis, and nodular goiter, there was no significant difference in any of the parameters (TBII, TSAb, MCHA, T4, T3, and TSH) between IgE elevated and IgE normal groups.

Incidence of TSBAb in Graves’ disease with or without IgE elevation

Three to 4 months after the initiation of methimazole treatment, the presence or absence of TSBAb was examined in 59 patients with Graves’ disease. TSBAb was detected in 4 of 15 patients with IgE elevation (26.7%), whereas it was detected in 3 of 44 patients without IgE elevation (6.8%). However, the difference was not statistically significant (P = 0.0985).

Detection of IL-13 in sera of hyperthyroid patients with IgE elevation

The presence of circulating cytokines (IFN{gamma}, IL-4, and IL-13) was evaluated in 25 patients without and 17 patients with IgE elevation 3–4 months after methimazole treatment (Table 2Go). In the 25 patients without IgE elevation, IFN{gamma} and IL-4 were undetectable, whereas IL-13 was detected in 3. In contrast, IL-13 was detected in 11 of 17 patients with IgE elevation, but there was no correlation between the levels of IL-13 and IgE. IFN{gamma} was detected in 3 of 17 patients with IgE elevation, but IL-4 was not found in these 17 patients.


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  		Table 2. Circulatory cytokines in patients with hyperthyroid Graves’ disease with or without IgE elevation

 
Change in TBII and IgE during methimazole treatment in patients with hyperthyroid Graves’ disease

In 61 patients with normal IgE and 28 patients with IgE elevation, serum levels of T4, TBII, and IgE were followed for 8–10 months during methimazole treatment. As shown in Table 3Go, T4 decreased similarly in both groups. TBII also decreased progressively during methimazole treatment, but the decrease was significantly greater in those with normal than in those with elevated IgE. IgE decreased slightly during methimazole treatment in the IgE elevated group, but was stable in the IgE normal group.


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  		Table 3. Changes in serum levels of T4, TBII, and IgE during methimazole treatment

 
Remission rate in hyperthyroid patients with IgE elevation in response to methimazole treatment

Ninety patients with hyperthyroid Graves’ disease were treated with methimazole for 1.5 yr, and the treatment was discontinued when serum levels of T4, T3, TBII, and Tg were normalized (16). We designated these patients as the remission group. As shown in Fig. 1Go, 31 of the 90 patients had elevated levels of serum IgE at the initiation of methimazole treatment; 11 of these patients (35.5%) underwent remission. In contrast, 38 of 59 patients with normal IgE levels (64.4%) had a remission, a significantly greater remission rate than that in the IgE elevated group (P < 0.002).



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  		Figure 1. Two-year follow-up of methimazole-treated patients with hyperthyroid Graves’ disease after discontinuation of methimazole. The P value was calculated by two-tailed Fisher’s exact test.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
With the increase in numbers of patients with Graves’ disease, we reached the same results as those from the previous report that found that serum levels of IgE were significantly elevated in one third of patients with Graves’ disease and a lesser reduction in TRAb in patients with elevated IgE levels than in patients with normal IgE (13). The incidence of IgE elevation in Hashimoto’s thyroiditis (20.7%) is smaller than that in Graves’ disease (35.5%), and this difference is significant, suggesting that the autoantibody system of Graves’ disease is more affected by IgE elevation than that of Hashimoto’s thyroiditis. The decrease in TRAb in Graves’ disease during methimazole treatment was significantly smaller in the elevated IgE group than in normal IgE group.

If it were the case that TRAb synthesis is increased when IgE synthesis is stimulated, the remission rate should be lower in the elevated IgE than in the normal IgE group. Supporting this hypothesis is the significant difference in remission rate between IgE elevated and IgE normal groups of Graves’ disease; with the criteria for remission (normal serum levels of T4, T3, TSH, TBII, and Tg) reported previously (17), patients with IgE elevation had a significantly lower remission rate (35.5%) than those with normal IgE (64.4%). The elevated levels of IgE remained relatively stable during this study.

We then next made a study of cytokines relevant to T helper cell function because T helper cells have been considered to play an important role in autoimmune thyroid disease (3). IL-13 enhances the production of IgM, IgG, and IgA (20) and is the dominant IgE-inducing cytokine that is produced early and for a prolonged time by T cells in situations where IL-4 is absent or present at low levels (21, 22). In this study there was an elevation of IL-13, but not of IL-4, in 64.7% of patients with IgE elevation, but not in patients without IgE elevation. There was no elevation of IL-10 or differences between patients with and without IgE elevation (data not shown). The TH1 cell marker, IFN{gamma} (22), was not increased in the presence of a significant elevation of IL-13. It thus seems that TH2 cells are stimulated in hyperthyroid Graves’ disease (23, 24) to secrete excess IL-13. One possibility is that this IL-13, in turn, stimulates B cells to secrete MCHA, TSAb, TSBAb, and IgE (21). The finding, however, that one third of patients with Graves’ disease and one fifth of patients with Hashimoto’s thyroiditis have elevated IgE raises the possibility that many of the phenomena described here may be epiphenomena of other immunoregulatory and inflammatory defects and that an underlying state of autoimmune thyroid disease may be a permissive factor for IgE elevation and excess IL-13. Although there is an association between IgE elevation and thyroid autoantibodies, the exact mechanism underlying the relationship is not apparent with this study and remains to be determined.


   Acknowledgments
 
We are deeply indebted to Dr. Monte A. Greer for useful suggestions in the preparation of this manuscript.

Received October 19, 1999.

Revised April 21, 2000.

Accepted April 30, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Weetman AP, McGregor AM. 1984 Autoimmune thyroid disease: developments in our understanding. Endocr Rev. 5:309–355.[Medline]
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  5. Kriss JP, Pleshakov V, Chien JR. 1964 Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxoedema. J Clin Endocrinol Metab. 24:1005–1028.
  6. Werner SC, Wegelius O, Fierer JA, Hsu KC. 1972 Immunoglobulins (E, M, G) and complement in the connective tissues of the thyroid in Graves’ disease. N Engl J Med. 287:421–425.
  7. Raikow RB, Dalbow MH, Kennerdell JS, et al. 1990 Immunohistochemical evidence for IgE involvement in Graves’ orbitopathy. Ophthalmology. 97:629–635.[Medline]
  8. Talstedt L, Norberg R. 1988 Immunohistochemical staining of normal and Graves’ extraocular muscle. Invest Ophthalomol Vis Sci. 29:175–184.[Abstract/Free Full Text]
  9. Hidaka Y, Amino N, Iwatani Y, Itoh E, Matsunaga M, Tamaki H. 1993 Recurrence of thyrotoxicosis after attack of allergic rhinitis in patients with Graves’ disease. J Clin Endocrinol Metab. 77:1667–1670.[Abstract]
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  11. Ishizaka K. 1976 Cellular events in the IgE antibody response. Adv Immunol. 23:1–75.[Medline]
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  14. Yamada T, Takasu N, Sato A, Aizawa T, Koizumi Y. 1982 Pituitary-thyroid feedback regulation in patients with Graves’ disease during antithyroid drug therapy. J Clin Endocrinol Metab. 54:83–88.[Abstract]
  15. Yamada T, Koizumi Y, Sato A, et al. 1984 Reappraisal of the 3,5,3'-triiodothyronine-suppression test in the prediction of long term outcome of antithyroid drug therapy in patients with Graves’ disease. J Clin Endocrinol Metab. 58:676–680.[Abstract]
  16. Murakami M, Koizumi Y, Aizawa T, et al. 1988 Studies of thyroid function and immune parameters in patients with hyperthyroid Graves’ disease in remission. J Clin Endocrinol Metab. 66:103–108.[Abstract]
  17. Aizawa T, Ishihara M, Koizumi Y, et al. 1990 Serum thyroglobulin concentration as an indicator for assessing thyroid stimulation in patients with Graves’ disease during antithyroid drug therapy. Am J Med. 89:175–180.[CrossRef][Medline]
  18. Takasu N, Oshiro C, Akamine H, et al. 1997 Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves’ patients and in 688 normal subjects. J Endocrinol Invest. 20:452–461.[Medline]
  19. Shimazu S, Enomoto M. 1995 Serum IgE levels in healthy children. Allergol Immunol. 2:62–67 (in Japanese).
  20. Zurawski G, de Vries JE. 1994 Interleukin 13, interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 15:19–26.[CrossRef][Medline]
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