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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5871-5874
Copyright © 2003 by The Endocrine Society

COMMENT

No Increase of Blocking Type Anti-Thyrotropin Receptor Antibodies During Pregnancy in Patients with Graves’ Disease

Nobuyuki Amino, Yukiko Izumi, Yoh Hidaka, Keiko Takeoka, Yukiko Nakata, Ke-Ita Tatsumi, Atsuo Nagata and Toru Takano

Department of Laboratory Medicine (N.A., Y.I., Y.H., K.T., Y.N., K.-I.T., T.T.), Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and Diagnostic Department (A.N.), Yamasa Corporation, Tokyo 103-0014, Japan

Address all correspondence and requests for reprints to: Nobuyuki Amino, Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: namino{at}labo.med.osaka-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Serial changes in serum levels of anti-TSH receptor antibodies were examined during and after pregnancy in six patients with Graves’ disease receiving no or minimal maintenance doses of antithyroid drugs. During pregnancy, serum levels of TSH-binding inhibitory Igs (P < 0.001) and thyroid-stimulating antibodies (TSAbs) (P < 0.01) decreased gradually but increased after delivery in all patients. Activities of thyroid-stimulation blocking antibodies (TSBAbs) were lower than the cut-off value in early pregnancy, and values significantly decreased in four patients during pregnancy. The other two patients showed no significant change during pregnancy. In contrast, TSBAb levels increased significantly (P < 0.01) after delivery in all patients. We found that activities of TSH-binding inhibitory Igs, TSAb, and TSBAb decrease during pregnancy and increase after delivery, suggesting that amelioration of Graves’ disease during pregnancy is induced by decrease of TSAb but not by the appearance of TSBAb.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS WELL-ESTABLISHED that Graves’ thyrotoxicosis is ameliorated in the latter half of pregnancy but aggravates after delivery (1, 2). At first, it was simply supposed that gestational amelioration was induced by the suppression of activities of thyroid-stimulating antibodies (TSAbs) during pregnancy (2, 3). Later, Kung and Jones (4) reported that thyroid-stimulation blocking antibodies (TSBAbs) were increased, possibly because of a change from stimulatory to blocking antibody activity during pregnancy in Graves’ disease. Their hypothesis stemmed from the general belief that T helper cell 2 (Th)2-immune reaction was increased in pregnancy (5, 6).

Recently we clarified that both Th1 and Th2 immune reactions were suppressed in systemic immunity during pregnancy (7, 8). Moreover, our patients with Graves’ disease constantly showed decrease in TSH-binding inhibitory Ig (TBII) and TSAb activities during pregnancy, and these activities increased dramatically after delivery (9, 10).

In this study, we examined serial changes in serum activities of TBIIs, TSAbs, and TSBAbs in pregnancy to clarify whether the change from stimulatory to blocking antibody activity during pregnancy is a common phenomenon.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We examined six pregnant patients with Graves’ disease. To avoid the immunosuppressive effect of antithyroid drugs, we selected patients who were receiving no antithyroid drugs or minimum maintenance dose of thiamazole (5 mg or less per day) or propylthiouracil (50 mg or less per day). Two patients had received subtotal thyroidectomy and one patient had received total thyroidectomy because of large goiter and resistance to antithyroid drug, from 2 to 16 yr before pregnancy. Pertinent clinical data are summarized in Table 1Go. Patients 2 and 5 received T4 before pregnancy for treatment of hypothyroidism that developed after thyroidectomy. Patient 6 received a small dose of T4 in the second and third trimesters. The clinical course was examined in these patients during pregnancy and after delivery until 6 months postpartum. Physical examination and laboratory tests were performed every 1–2 months. Informed consent was obtained from all patients.


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  		TABLE 1. Clinical data in pregnant patients with Graves’ disease

 
TBII was measured by radioreceptor assay using a commercial kit (Cosmic Corp., Tokyo, Japan), and the results were expressed as percent inhibition of binding of labeled TSH, as described previously (11). The intra- and interassay coefficients of variation (CVs) were 2.5–8.9 and 7.5–17.3%, respectively. The cut-off value was 12% (11).

Bioassays of TSAbs and TSBAbs were performed as previously reported (12). As for TSAb assay, the polyethylene glycol (PEG 6000) 22.5% (final) precipitated fraction (crude IgG) from 0.25-ml aliquots of test serum was dissolved in the modified Hank’s buffer (salt-free) and then incubated with porcine thyroid cells in a total volume of 0.25 ml for 5 h at 37 C. Then cAMP production was assayed by RIA. TSAb was expressed as percentage increase in cAMP production, compared with normal IgG.

TSBAb activity was determined by the incubation of 200 µl patient IgG or normal IgG fraction with 25 µl of bovine TSH (100 mU/liter, final) in the modified Hank’s buffer. Patient IgG and normal IgG were the PEG 12.5% precipitated fraction from 0.25 ml of serum and normal human serum, respectively. TSBAb activity was expressed as percentage of inhibition of bovine TSH-stimulated cAMP production by testing IgG using the following method.

(1)
All experiments were performed in duplicate. Cut-off values of TSAbs and TSBAbs were 180 and 45%, respectively. To avoid the interassay variation, serum samples were stored at once at -20 C and TSAb and TSBAb were assayed at the same time. The intra- and interassay CVs of TSAb assay were 3.4–5.3% and 5.2–11.7%, respectively. The intra- and interassay CVs of TSBAb assay were 13.0 and 14.9%, respectively.

Antithyroid microsomal antibodies (MCHAs) were measured by agglutination assay using commercial kits (Fuji Rebio Co., Tokyo, Japan) (3).

Statistical analysis

Serial changes of TBII, TSAb, and TSBAb activities were analyzed by two-way ANOVA and/or Friedman test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Activities of TBIIs and TSAbs were positive in the first trimester in all six patients with Graves’ disease. As pregnancy progressed, these activities decreased consistently but increased significantly after delivery in all patients (TBII, P < 0.001; TSAb, P < 0.01) (Fig. 1Go). TSBAb activities were less than cut-off value (45%) at the first trimester in all patients, but values decreased, similarly to TBII activities, during pregnancy in four patients (Fig. 1Go). The other two patients showed no consistent change. Interestingly TSBAb values increased after delivery in all patients and two (patients 2 and 3) became positive at more than 45%.



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  		FIG. 1. Serial changes of serum TBII (%), TSAb (%), and TSBAb (%) activities during and after delivery in six patients with Graves’ disease. I, II, and III indicate the first, second, and third trimesters, respectively. PP, Postpartum period from 3 to 6 months after delivery. Dotted lines indicate the normal cut-off values.

 
After delivery, patient 1 relapsed into Graves’ thyrotoxicosis (TBII 55.0%, TSAb 605%, TSBAb 34.1%) (Table 1Go). Patients 2 and 3 showed increased TSBAb activities (59.0 and 48.8%, respectively) after delivery, but TSAb activities also increased (541 and 960%, respectively) and patients maintained euthyroid even after delivery (Table 1Go). Patient 4 showed aggravation of Graves’ thyrotoxicosis in association with increase of TSAbs (375%) after delivery. Patient 5 was treated with T4 for hypothyroidism during the observation period and showed clear decrease of TBII and TSAb activities during pregnancy and then increase after delivery (75.0 and 4270%, respectively, at postpartum evaluation). Patient 6 developed mild destructive thyrotoxicosis at 3 months postpartum, although TSAb slightly increased to 205% and TSBAb was -4.5%. Serum MCHA was positive in five patients, and titers decreased during pregnancy and increased after delivery, similar to changes of TBII, in all five patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
TSBAbs coexist with TSAbs in about 30% of patients with Graves’ disease (13, 14). Usually remission of Graves’ thyrotoxicosis is associated with decrease or disappearance of TSAbs (15). Although rare, some patients spontaneously recover into euthyroid or develop hypothyroidism because of the appearance of TSBAbs during the clinical course of Graves’ disease (16).

During pregnancy, serum levels of IgG (17) and titers of antithyroid microsomal and antithyroglobulin antibodies consistently decrease and then increase after delivery (18). Similar to these changes, serum levels of TBIIs and TSAbs also decrease during pregnancy and increase after delivery in association with postpartum relapse or aggravation with Graves’ thyrotoxicosis (2, 3). These changes were confirmed also in this study. Thus, amelioration or remission of Graves’ disease during pregnancy could be explained by these changes. In patients with subclinical autoimmune hepatitis, serum levels of anticytochrome 2D6 autoantibodies decrease during pregnancy and increase after delivery in association with the clinical onset of postpartum autoimmune hepatitis (19, 20). Considering these results, Th2-dependent humoral immunity is suppressed in human pregnancy. Our recent data on cytokine production strongly support this possibility because systemic levels of both Th1- and Th2-type cytokines decreased during pregnancy, although both immune reactions increased after delivery (8). In mice, Th2-type cytokines predominate at the local maternal-fetal interface (6, 21), but mRNA expression of both Th1- and Th2-type cytokines in peripheral blood T cells was suppressed in the latter half of pregnancy (6). Thus, during pregnancy in both humans and animals, systemic activities of Th1- and Th2-immune reactions might be suppressed, and increase in serum antibody activities during pregnancy rarely occurs.

Kung and Jones (4) also found a dramatic decrease of TSAb activities but did not find a decrease of TBII activities during pregnancy. Moreover, they found an increase of TSBAb activities during pregnancy. If the humoral immunity is suppressed during pregnancy in general, an increase of TSBAb activities is a very exceptional condition. However, in our study, TSBAb activities were also decreased during pregnancy, and they increased clearly after delivery. When TSAb activities were high, coexisting TSBAb could be detected only by TSBAb-specific radioreceptor assay (13) or conversion assay (14, 22). Conversely, TSBAb activities could be detected when TSAb activities became low (13, 14). In the study by Kung and Jones (4), this possibility may explain the increase of TSBAbs during pregnancy because TSAb activities remarkably decreased during pregnancy. However, they denied this possibility after examination of nonpregnant patients with Graves’ disease.

In this study, porcine thyroid cells were used for bioassay, but they used cultured human thyroid cells. However, species difference of TSH receptor (23) cannot explain the discrepancy between their results and ours. According to our experience, serum TBII activities consistently decrease during pregnancy (1, 9), and no change of TBII levels during pregnancy is a rather exceptional condition. Two other exceptional cases have been reported previously, and one of our patients had an increase of TBIIs during pregnancy (9). This could be explained by the effect of T4 therapy because the patient was diagnosed with marked hypothyroidism in early pregnancy. The other case was reported by Ueta et al. (24), and theirs showed increase of TBIIs during pregnancy in association with development of hypothyroidism.

Recently, Schwarz-Lauer et al. (25) pointed out the difficulty in interpreting concurrent TSAb and TSBAb activities in a serum as being caused by different antibodies. A weak agonist is also an antagonist. A TSAb with less intrinsic bioactivity than TSH will inhibit TSH action and demonstrate TSBAb activity. Therefore, the parallelism that we observed in TSAb and TSBAb activities during and after pregnancy could reflect changes in titers of the same antibody.

Although there are some exceptional cases, as shown above, both Th1- and Th2-immune reactions are suppressed during pregnancy, and activities of both TSAbs and TSBAbs are decreased during pregnancy. Increase of TSBAbs during pregnancy may not be the general phenomenon and amelioration of Graves’ disease could be induced by decrease of TSAbs rather than by the appearance of TSBAbs.


   Acknowledgments
 
We thank Ms. Rika Kamada for her skillful assistance.


   Footnotes
 
This work was supported by Grants-in-Aid for Scientific Research (14207107 and 15659135) (to N.A.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Health Science Grants from the Ministry of Health, Labor, and Welfare of Japan.

Abbreviations: CV, Coefficient of variation; MCHA, antithyroid microsomal antibody; TBII, TSH-binding inhibitory Ig; Th, T helper cell; TSAb, thyroid-stimulating antibody; TSBAb, thyroid-stimulation blocking antibody.

Received June 4, 2003.

Accepted August 28, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Tamaki H, Amino N, Aozasa M, Mori M, Tanizawa O, Miyai K 1987 Serial changes in thyroid-stimulating antibody and thyrotropin binding inhibitor immunoglobulin at the time of postpartum occurrence of thyrotoxicosis in Graves’ disease. J Clin Endocrinol Metab 65:324–330[Abstract/Free Full Text]
  2. Tamaki H, Itoh E, Kaneda T, Asahi K, Mitsuda N, Tanizawa O, Amino N 1993 Crucial role of serum human chorionic gonadotropin for the aggravation of thyrotoxicosis in early pregnancy in Graves’ disease. Thyroid 3:189–193[Medline]
  3. Hidaka Y, Tamaki H, Iwatani Y, Tada H, Mitsuda N, Amino N 1994 Prediction of post-partum Graves’ thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy. Clin Endocrinol 41:15–20[Medline]
  4. Kung AWC, Jones BM 1998 A change from stimulatory to blocking antibody activity in Graves’ disease during pregnancy. J Clin Endocrinol Metab 83:514–518[Abstract/Free Full Text]
  5. Wegmann TG, Lin H, Guilbert L, Mosmann TR 1993 Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14:353–356
  6. Delassus S, Coutinho GC, Saucier C, Darche S, Kourilsky P 1994 Differential cytokine expression in maternal blood and placenta during murine gestation. J Immunol 152:2411–2420[Abstract]
  7. Watanabe M, Iwatani Y, Kaneda T, Hidaka Y, Mitsuda N, Morimoto Y, Amino N 1994 Changes in T, B, and NK lymphocyte subsets during and after normal pregnancy. Am J Reprod Immunol 37:368–377
  8. Shimaoka Y, Hidaka Y, Tada H, Nakamura T, Mitsuda N, Morimoto Y, Murata Y, Amino N 2000 Changes in cytokine production during and after normal pregnancy. Am J Reprod Immunol 44:143–147
  9. Tamaki H, Amino N, Iwatani Y, Tachi J, Mitsuda N, Tanizawa O, Miyai K 1989 Discordant changes in serum anti-TSH receptor antibody and antithyroid microsomal antibody during pregnancy in autoimmune thyroid diseases. Thyroidology 2:73–77
  10. Amino N, Tada H, Hidaka Y, Izumi Y 2000 Postpartum autoimmune thyroid syndrome. Endocr J 47:645–655[CrossRef][Medline]
  11. Izumi Y, Hidaka Y, Tada H, Takano T, Kashiwai T, Tatsumi K, Ichihara K, Amino N 2002 Simple and practical parameters for differentiation between destruction-induced thyrotoxicosis and Graves’ thyrotoxicosis. Clin Endocrinol 57:51–58[CrossRef][Medline]
  12. Ochi Y, Yamashiro K, Takasu N, Kajita Y, Sato Y, Nagata A 2001 Sensitive assay to detect thyroid stimulating antibody (TSAb) in the presence of thyroid stimulation blocking antibody (TSBAb) in serum. Horm Metab Res 33:115–120[CrossRef][Medline]
  13. Tada H, Izumi Y, Watanabe Y, Takano T, Fukata S, Kuma K, Hidaka Y, Amino N 2001 Blocking type anti-TSH receptor antibodies detected by radioreceptor assay in Graves’ disease. Endocr J 48:703–710[CrossRef][Medline]
  14. Tada H, Mizuta I, Takano T, Tatsumi K, Izumi Y, Hidaka Y, Amino N 2003 Blocking-type anti-TSH receptor antibodies and relation to responsiveness to antithyroid drug therapy and remission in Graves’ disease. Clin Endocrinol 58:403–408[CrossRef][Medline]
  15. Kashiwai T, Hidaka Y, Takano T, Tatsumi K, Izumi Y, Shimaoka Y, Tada H, Takeoka K, Amino N 2003 Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves’ disease. Endocr J 50:45–49[CrossRef][Medline]
  16. Miyauchi A, Amino N, Tamaki H, Kuma K 1988 Coexistence of thyroid-stimulating and thyroid-blocking antibodies in a patient with Graves’ disease who had transient hypothyroidism. Am J Med 85:418–420[CrossRef][Medline]
  17. Amino N, Tanizawa O, Miyai K, Tanaka F, Hayashi C, Kawashima M, Ichihara K 1978 Changes of serum immunoglobulins IgG, IgA, IgM, and IgE during pregnancy. Am J Obstet Gynecol 52:415–420
  18. Amino N, Kuro R, Tanizawa O, Tanaka F, Hayashi C, Kotani K, Kawashima M, Miyai K, Kumahara Y 1978 Changes of serum anti-thyroid antibodies during and after pregnancy in autoimmune thyroid diseases. Clin Exp Immunol 31:30–37[Medline]
  19. Izumi Y, Kaneko A, Oku K, Kimura M, Tanaka S, Tada H, Tatsumi K, Takano T, Hidaka Y, Amino N 2002 Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases. J Intern Med 252:361–367[CrossRef][Medline]
  20. Izumi Y, Tanaka S, Hidaka Y, Shimaoka Y, Tatsumi K, Takano T, Kaneko A, Oku K, Amino N 2003 Relation between postpartum liver dysfunction and anti-cytochrome 2D6 antibodies. Am J Reprod Immunol 50:355–362[CrossRef]
  21. Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG 1993 Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol 151:4562–4573[Abstract]
  22. Amino N, Watanabe Y, Tamaki H, Iwatani Y, Miyai K 1987 In vitro conversion of blocking type anti-TSH receptor antibody to the stimulating type by anti-human IgG antibodies. Clin Endocrinol 27:615–624[Medline]
  23. Watanabe Y, Tahara K, Hirai A, Tada H, Kohn LD, Amino N 1997 Subtypes of anti-TSH receptor antibodies classified by various assays using CHO cells expressing wild-type or chimeric human TSH receptor. Thyroid 7:13–19[Medline]
  24. Ueta Y, Fukui H, Murakami H, Yamanouchi Y, Yamamoto R, Murao A, Santou Y, Taniguchi S, Mitani Y, Shigemasa C 1999 Development of primary hypothyroidism with the appearance of blocking-type antibody to thyrotropin receptor in Graves’ disease in late pregnancy. Thyroid 9:179–182[CrossRef][Medline]
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