J Korean Endocr Soc.  2008 Jun;23(3):179-185. 10.3803/jkes.2008.23.3.179.

Clinical Usefulness of the Second Generation TSH-Binding Inhibitory Immunoglobulin Assay Using Recombinant Human TSH Receptor in Patients with Graves' Disease

• Huh JE
• Suk JH
• Kim MK
• Choi IJ
• Son SM
• Kim IJ
• Kim YK

• KMID: 1479204
• DOI: http://doi.org/10.3803/jkes.2008.23.3.179

Abstract

BACKGROUND AND AIM: Detection of TSH receptor antibody in patients with Graves' disease (GD) has been widely used in clinical practice. This has been performed mostly by commercial radio-receptor assays that measure TSH-binding inhibitory immunoglobulin (TBII) with using porcine TSH receptor as the ligand. To increase the sensitivity of the assay, many research groups have tried to replace the porcine source of TSH receptor with recombinant human TSH receptor. In this study we evaluated the clinical usefulness of the second generation TBII assay, which uses recombinant human TSH receptor, for making the diagnosis of GD, as compared to the conventional TBII assay.
MATERIALS AND METHODS
We obtained sera from 76 patients with newly diagnosed or relapsing GD without or with less than 4 weeks of antithyroid drugs, and 54 patients with Hashimoto's thyroiditis who had not received thyroid hormone treatment or quit thyroid hormone more than 3 months before. TBII was measured by using both the conventional porcine TBII assay (pTBII) and the human recombinant TBII assay (hTBII). TBII was also measured in the sera from 66 healthy controls.
RESULTS
The cut-off values of the pTBII and hTBII assay were defined as two geometric standard deviations from the geometric mean of the values in healthy controls, and these values were 10.8 IU/L and 1.0 IU/L, respectively. The sensitivity was 62% (47/76) for pTBII, as compared to 100% (76/76) for the hTBII, for diagnosing GD. Of the 54 patients with Hashimoto's thyroiditis, 3 (5.6%) and 7 (13.0%) patients had positive pTBII and positive hTBII, respectively.
CONCLUSION
These data showed that the hTBII assay was a comparable method in terms of the sensitivity for the diagnosis of GD, as compared to the pTBII assay. It can be suggested that this new hTBII assay, rather than the pTBII assay, should be more widely used as the first line diagnostic test for GD.

Keyword

Graves' disease; sensitivity; TSH-binding inhibitory immunoglobulin

MeSH Terms

Antithyroid Agents
Diagnostic Tests, Routine
Graves Disease
Humans
Immunoglobulins
Immunoglobulins, Thyroid-Stimulating
Receptors, Thyrotropin
Thyroid Gland
Thyroiditis
Thyrotropin Alfa
Antithyroid Agents
Immunoglobulins
Immunoglobulins, Thyroid-Stimulating
Receptors, Thyrotropin
Thyrotropin Alfa

Figure

• 

  Figure 1 Cut-off value for pTBII (A) and hTBII (B) calculated from normal healthy controls. Cut-off value was defined as a geometric mean plus twice of a geometric standard deviation in healthy control. The cut-off values of pTBII and hTBII were 10.8 IU/L and 1.0 IU/L, respectively. Straight lines showed geometric mean of pTBII and hTBII, respectively. Dotted lines showed cut-off value of pTBII and hTBII, respectively.

• 

  Figure 2 Comparison between pTBII and hTBII in patients with untreated Graves' disease.

• 

  Figure 3 Distribution of (A) pTBII or (B) hTBII titer in patients with Hashimoto's thyroiditis without medication according to serum TSH level. Of 54 patients with Hashimoto's thyroiditis, 3 patients had positive TBII titers using pTBII and 7 patients had positive TBII titers using hTBII.

Reference

1. Rees SB, McLachlan SM, Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr Rev. 1988. 9:106–121.

2. Zakarija M, McKenzie JM. The spectrum and significance of autoantibodies reacting with the thyrotropin receptor. Endocrinol Metab Clin North Am. 1987. 16:343–363.

3. Weetman AP, McGregor AM. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev. 1994. 15:788–830.

4. Shewring G, Smith BR. An improved radioreceptor assay for TSH receptor antibodies. Clin Endocrinol (Oxf). 1982. 17:409–417.

5. Ilicki A, Gamstedt A, Karlsson FA. Hyperthyroid Graves' disease without detectable thyrotropin receptor antibodies. J Clin Endocrinol Metab. 1992. 74:1090–1094.

6. Costagliola S, Swillens S, Niccoli P, Dumont JE, Vassart G, Ludgate M. Binding assay for thyrotropin receptor autoantibodies using the recombinant receptor protein. J Clin Endocrinol Metab. 1992. 75:1540–1544.

7. Costagliola S, Morgenthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglöner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G, Usadel KH. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves' disease. J Clin Endocrinol Metab. 1999. 84:90 –97.

8. R Development Core Team. R: A language and environment for statistical computing. 2007. Accessed December 5. . Vienna, Austria: R Foundation for Statistical Computing;Available from: http://www.R-project.org.

9. Paunkovic J, Paunkovic N. Does autoantibody-negative Graves' disease exist? A second evaluation of the clinical diagnosis. Horm Metab Res. 2006. 38:53–56.

10. Villalta D, Orunesu E, Tozzoli R, Montagna P, Pesce G, Bizzaro N, Bagnasco M. Analytical and diagnostic accuracy of "second generation" assays for thyrotrophin receptor antibodies with radioactive and chemiluminescent tracers. J Clin Pathol. 2004. 57:378–382.

11. Pedersen IB, Knudsen N, Perrild H, Ovesen L, Laurberg P. TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays. Clin Endocrinol (Oxf). 2001. 55:381–390.

12. Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab. 2000. 85:1038–1042.

13. Kim TY, Park YJ, Park DJ, Chung HK, Kim WB, Kohn LD, Cho BY. Epitope heterogeneity of thyroid-stimulating antibodies predicts long-term outcome in Graves' patients treated with antithyroid drugs. J Clin Endocrinol Metab. 2003. 88:117–124.

14. Gerding MN, van der, Broenink M, Bakker O, Wiersinga WM, Prummel MF. Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy. Clin Endocrinol (Oxf). 2000. 52:267–271.

15. Chiovato L, Vitti P, Bendinelli G, Santini F, Fiore E, Capaccioli A, Tonacchera M, Mammoli C, Ludgate M, Pinchera A. Detection of antibodies blocking thyrotropin effect using Chinese hamster ovary cells transfected with the cloned human TSH receptor. J Endocrinol Invest. 1994. 17:809–816.

16. Cho BY, Kim WB, Chung JH, Yi KH, Shong YK, Lee HK, Koh CS. High prevalence and little change in TSH receptor blocking antibody titres with thyroxine and antithyroid drug therapy in patients with non-goitrous autoimmune thyroiditis. Clin Endocrinol (Oxf). 1995. 43:465–471.

17. Kraiem Z, Lahat N, Glaser B, Baron E, Sadeh O, Sheinfeld M. Thyrotrophin receptor blocking antibodies: incidence, characterization and in-vitro synthesis. Clin Endocrinol (Oxf). 1987. 27:409–421.

18. Takasu N, Yamada T, Katakura M, Yamauchi K, Shimizu Y, Ishizuki Y. Evidence for thyrotropin (TSH)-blocking activity in goitrous Hashimoto's thyroiditis with assays measuring inhibition of TSH receptor binding and TSH-stimulated thyroid adenosine 3',5'-monophosphate responses/cell growth by immunoglobulins. J Clin Endocrinol Metab. 1987. 64:239–245.

19. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf). 2003. 58:138–140.