Thyroid-stimulating Immunoglobulin (TSI)

The measurement of thyroid stimulating autoantibodies, in conjunction with other clinical and laboratory findings, is used as an aid in the diagnosis of patients suspected of having Graves' disease.1

Heterophilic antibodies in human serum can react with the immunoglobulins included in the assay components causing interference with in vitro immunoassays. For diagnostic purposes, the results obtained from this assay should be used in combination with the clinical examination, patient medical history, and other findings.

Graves' disease (GD) is an autoimmune disorder and the most common cause of hyperthyroidism.2-7 In GD, thyroid stimulating immunoglobulins (TSI) bind to the TSH receptor (TSHR) and mimic TSH stimulation of the thyroid gland. Because TSI induced thyroid hormone secretion is not controlled by negative feedback, such stimulation causes uncontrolled hyperthyroidism.8 Extrathyroidal manifestations of GD include endocrine exophthalmos, pretibial myxedema. GD is characterized thyroid acropachy, i.e., the soft-tissue swelling of the hands and clubbing of the fingers. Radiographic imaging of affected extremities typically demonstrates periostitis, most commonly the metacarpal bones. TSI are IgG antibodies that can cross the placental barrier and cause neonatal thyrotoxicosis in newborns delivered by mothers with GD.9,10

The TSH receptor contains a large extracellular domain that presents epitopes for a variety of autoantibodies, including TSI and Thyroid Blocking Immunoglobulins TBI.11-13 In contrast to TSI, TBI bind to the TSH receptor and inhibit TSH stimulation of thyroid cells, leading to hypothyroidism. Commonly used Thyrotropin Receptor Autoantibody (TRAb) assays do not distinguish between TSI and TBI. The IMMULITE 2000 TSI assay utilizes recombinant human TSH receptors (hTSHR) for the specific detection of thyroid stimulating autoantibodies.1

The clinical utility of TSI measurement includes a determination of the autoimmune etiology of thyrotoxicosis,2-7 monitoring GD patient therapy,14 prediction of remission or relapse,15 confirmation of Graves' ophthalmopathy,16 and prediction of hyperthyroidism in neonates.9,17,18 TheTSI test is used for the differential, diagnosis of etiology of thyrotoxicosis in patients with ambiguous clinical signs or indeterminate thyroid radioisotope scans.3 TSI can also be of value in determining the risk of neonatal thyrotoxicosis in a fetus of a pregnant female with active or past GD and the differential diagnosis of gestational thyrotoxicosis versus first-trimester manifestation or recurrence of GD.9,10 TSI can also be ordered to assess the risk of GD relapse after antithyroid drug treatment.

Several published studies have evaluated the sensitivity and specificity of the Siemens TSI assay for diagnosing GD patients and discriminating them from patients with other thyroid diseases.19-22 Kembel and coworkers23 evaluated three commercially available anti-TSHR autoantibody measurement methods and found equivalent performance in patients with untreated GD. However, discordant results were observed when testing specimens collected from patients undergoing treatment for GD. In these patients, the Siemen TSI assay more frequently generated results consistent with clinical history, results of other laboratory tests, and imaging studies than the TSI bioassay and Roche TRAb assay. In the validation for FDA submission,11 serum samples from 361 treated and untreated hyperthyroid Graves' disease patients, and 404 individuals with other thyroid or autoimmune diseases were evaluated. The TSI values for patients without GD with other thyroid or autoimmune diseases had an upper limit of 0.39 IU/L. At the 0.55 IU/L cut-off, the clinical sensitivity and specificity for GD were 98.6% and 98.5%, respectively.

1. Thyroid Stimulating Immunoglobulin (TSI) on Siemens Immulite 2000; PIL2KTSID-8, 2016-03-09.

2. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906-918. PubMed 27038492

3. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421. PubMed 27521067

4. Smith TJ, Hegeds L. Graves' Disease. N Engl J Med. 2016 Oct 20;375(16):1552-1565. PubMed 27797318

5. Burch HB, Cooper DS. Management of Graves Disease: A Review. JAMA. 2015 Dec 15;314(23):2544-2554. PubMed 26670972

6. Menconi F, Marcocci C, Marin M. Diagnosis and classification of Graves' disease. Autoimmun Rev. 2014 Apr-May;13(4-5):398-402. PubMed 24424182

7. Bartalena L, Tanda ML. Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009 Mar 5;360(10):994-1001. PubMed 19264688

8. Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev. 1998 Dec;19(6):673-716. PubMed 9861544

9. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017 Mar;27(3):315-389. PubMed 28056690

10. Bucci I, Giuliani C, Napolitano G. Thyroid-stimulating hormone receptor antibodies in pregnancy: Clinical Relevance. Front Endocrinol (Lausanne). 2017 Jun 30;8:137. PubMed 28713331

11. McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: Potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 2013 Jan;23(1):14-24. PubMed 23025526

12. Evans M, Sanders J, Tagami T, et al. Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrin (Oxf). 2010 Sep;73(3):404-12. PubMed 20550534

13. Morgenthaler NG, Ho SC, Minich WB. Stimulating and blocking thyroid-stimulating hormone (TSH) receptor autoantibodies from patients with Graves' disease and autoimmune hypothyroidism have very similar concentration, TSH receptor affinity, and binding sites. J Clin Endocrinol Metab. 2007 Mar;92(3):1058-1065. PubMed 17179194

14. Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling M, Lundell G, Torring O. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol. 2008 Jan;158(1):69-75. PubMed 18166819

15. Giuliani C, Cerrone D, Harii N, et al. A TSHR-LH/CGR chimera that measures functional thyroid-stimulating autoantibodies (TSAb) can predict remission or recurrence in Graves' patients undergoing antithyroid drug (ATD) treatment. J Clin Endocrinol Metab. 2012 Jul;97(7):E1080-1087. PubMed 22492869

16. Eckstein AK, Plicht M, Lax H, et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab. 2006 Sep;91(9):3464-3470. PubMed 16835285

17. Bjrgaas MR, Farstad H, Christiansen SC, Blaas HG. Impact of thyrotropin receptor antibody levels on fetal development in two successive pregnancies in a woman with Graves' disease. Horm Res Paediatr. 2013;79(1):39-43. PubMed 23154300

18. American College of Obstetricians and Gynecologists. Practice Bulletin No. 148: Thyroid disease in pregnancy. Obs