Synonyms:

• Human Thyroid Stimulator (HTS)
• Long-acting Thyroid Stimulator (LATS)
• Thyretain™
• Thyroid-stimulating Antibody (TSAb)
• TSI

 

Use:

Thyroid-stimulating immunoglobulins (TSI) can be detected in the majority of patients (77.8%) with Graves’ disease.¹ These antibodies have also been associated with a small portion (15.9%) of patients with toxic multinodular goiter.¹ It has also been reported that TSI measurement can be used to predict relapse or remission when methimazole² or radioiodine^3,4 is used to treat Graves’ disease. These assays have also been advocated for use in patients with subclinical Graves’ hyperthyroidism or patients with unilateral ophthalmopathy.⁵

Additional Information:

The clinical utility of measuring TSI for the prediction of neonatal hyperthyroidism in the children of mothers with Graves’ disease has been well documented.^5-8 This syndrome is caused by the transfer of maternal IgG across the placenta, resulting in transient fetal hyperthyroidism. Generally, the titers of thyroid autoantibodies tend to drop during pregnancy, due to the presence of immunosuppressive trophoblastic factors;⁵ however, persistent elevation of TSI titers, especially during the third trimester, is associated with increased risk of neonatal hyperthyroidism. This form of hyperthyroidism tends to correct itself within four months of life. Measurement of TSI in the mother or the child can also be useful in distinguishing this transient autoimmune form of neonatal hyperthyroidism from other nonimmune forms of congenital hyperthyroidism.^6-8

Background. The hyperthyroidism of Graves’ disease is caused by thyrotropin receptor autoantibodies.⁹ These antibodies mimic the TSH that normally binds to the receptor and stimulate the thyroid to produce thyroid hormone. These antibodies are generally detected by two types of assays.¹⁰ One type of assay measures the ability of IgG to inhibit binding of TSH to solubilized TSH receptor in an enzyme immunoassay format (TRAb or TBII). The other type of assay is more of a bioassay in that it measures the ability of the patient’s IgG (or serum) to stimulate cyclic AMP production in tissue cultures of various kinds. It is clear from the literature that the solublized receptor binding assays are not clinically interchangeable with the functional bioassays because the populations of antibodies measured by each assay are not completely concordant.^11,12 This results, in part, due to the fact that not all TSH receptor binding immunoglobulins are stimulatory. Some of the receptor-binding antibodies are inhibitory and have been implicated in cases of Hashimoto thyroiditis.

The nomenclature used in the literature for the various TSH receptor assays is inconsistent and confusing. Assays that measure binding of TSH to solubilized receptor are often referred to as TRAb (thyroid receptor antibody), TBII (TSH-binding inhibitor immunoglobulin), or LATS (long-acting thyroid stimulator) assays. Assays that measure the ability of IgG to bind to TSH receptor on cells and stimulate adenylate cyclase production have generally been referred to as TSI (thyroid-stimulating immunoglobulin) assays. Traditional TSI assays have used either a rat thyroid cell line, FRTL-5,¹³ or a Chinese hamster ovary (CHO) cell line transfected with the human TSH receptor.¹⁴ TSH receptor binding immunoglobulin in the patient sample is allowed to bind to the receptors on the cell surfaces in these cultures. The TSH receptor mediates its function through the production of cyclic AMP within the cell cytosol. An immunoassay is used to measure the increases in cyclic AMP concentration that results from adding the patient immunoglobulin to the cells in culture. These assays have been reported to have sensitivities of about 80% but concordance of only 70%.¹⁴

Footnotes:

1. Macchia E, Concetti R, Borgoni F, et al, “Assays of TSH-Receptor Antibodies in 576 Patients With Various Thyroid Disorders: Their Incidence, Significance and Clinical Usefulness,” Autoimmunity, 1989, 3(2):103-12. PubMed 2577491

2. Wortsman J, McConnachie P, Tahara K, et al, “Thyrotropin Receptor Epitopes Recognized by Graves’ Autoantibodies Developing Under Immunosuppressive Therapy,” J Clin Endocrinol Metab, 1998, 83(7):2302-8. PubMed 9661599

3. Murakami Y, Takamatsu J, Sakane S, et al, “Changes in Thyroid Volume in Response to Radioactive Iodine for Graves’ Hyperthyroidism Correlated With Activity of Thyroid-Stimulating Antibody and Treatment Outcome,” J Clin Endocrinol Metab, 1996, 81(9):3257-60. PubMed 8784079

4. Chiovato L, Fiore E, Vitti P, et al, “Outcome of Thyroid Function in Graves’ Patients Treated With Radioiodine: Role of Thyroid-Stimulating and Thyrotropin-Blocking Antibodies and of Radioiodine-Induced Thyroid Damage,” J Clin Endocrinol Metab, 1998, 83(1):40-6. PubMed 9435414

5. Davies TF, Roti E, Braverman LE, et al, “Thyroid Controversy – Stimulating Antibodies,” J Clin Endocrinol Metab, 1998, 83(12):377-81 (review). PubMed 9814446

6. Polak M, “Hyperthyroidism in Early Infancy: Pathogenesis, Clinical Features and Diagnosis With a Focus on Neonatal Hyperthyroidism,” Thyroid, 1998, 8(12):1171-7 (review). PubMed 9920374

7. Glinoer D, “Thyroid Hyperfunction During Pregnancy,” Thyroid, 1998, 8(9):859-64 (review). PubMed 9777758

8. Krude H, Biebermann H, Krohn HP, et al, “Congenital Hyperthyroidism,” Exp Clin Endocrinol Diabetes, 1997, 105(Suppl 4):6-11 (review). PubMed 9439907

9. Orgiazzi J, “Anti-TSH Receptor Antibodies in Clinical Practice,” Endocrinol Metab Clin North Am, 2000, 29(2):339-55 (review). PubMed 10874533

10. Rees Smith B, McLachlan SM, Furmaniak J, “Autoantibodies to the Thyrotropin Receptor,” Endocr Rev, 1988, 9(1):106-21 (review). PubMed 3286231

11. Di Cerbo A, Di Paola R, Bonati M, et al, “Subgroups of Graves’ Patients Identified on the Basis of the Biochemical Activities of Their Immunoglobulins,” J Clin Endocrinol Metab, 1995, 80(9):2785-90. PubMed 7673424

12. Watanabe Y, Tahara K, Hirai A, et al, “Subtypes of Anti-TSH Receptor Antibodies Classified by Various Assays Using CHO Cells Expressing Wild-Type or Chimeric Human TSH Receptor,” Thyroid, 1997, 7(1):13-9. PubMed 9086564

13. Vitti P, Rotella CM, Valente WA, et al, “Characterization of the Optimal Stimulatory Effects of Graves’ Monoclonal and Serum Immunoglobulin G on Adenosine 3′,5′ Monophosphate Production in fRTL-5 Thyroid Cells: A Potential Clinical Assay,” J Clin Endocrinol Metab, 1983, 57(4):782-91. PubMed 6136523

14. Vitti P, Elisei R, Tonacchera M, et al, “Detection of Thyroid-Stimulating Antibody Using Chinese Hamster Ovary Cells Transfected With Cloned Human Thyrotropin Receptor,” J Clin Endocrinol Metab, 1993, 76(2):499-503.PubMed 8094393