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Horm Metab Res 2025; 57(02): 79-87
DOI: 10.1055/a-2498-8050
Review

Clinical Application of Thyrotropin Receptor Antibodies

Yang Yang 
1   Department of Endocrinology and Metabolism, Lanzhou University Second Clinical Medical School, Lanzhou, China (Ringgold ID: RIN74713)
,
Hui Chen
1   Department of Endocrinology and Metabolism, Lanzhou University Second Clinical Medical School, Lanzhou, China (Ringgold ID: RIN74713)
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Abstract

Thyrotropin receptor antibodies (TRAb) are specific for Graves’ disease (GD) and play a crucial role in the pathogenesis of GD. TRAb assays have recently been greatly improved. This review discusses the clinical application of TRAb in the differential diagnosis of hyperthyroidism, the prognosis of GD, GD in gestation and pediatrics, and GD related ophthalmopathy (GO). In addition to the classical competition and bioassays, a new bridging assay has emerged for TRAb assays. TRAb is the main pathogenic mechanism of hyperthyroidism in GD. Treated GD still has a high rate of recurrence and even a short-term surge of TRAb, leading to rapid deterioration of GO. Fetal goiter may be associated with elevated maternal TRAb during pregnancy, overtreatment may lead to fetal hypothyroidism. Pediatric patients with GD have high TRAb, poor remission from treatment, and insignificant manifestations of GO. TRAb is significantly correlated with GO activity and severity. Currently, TRAb assay has high specificity and sensitivity and can be used directly to identify the cause of hyperthyroidism. TRAb can be used to predict recurrence of drug treated GD or progression of GO after RAI therapy. TRAb should be measured regularly for GD in gestation to guide anti-thyroid medication to avoid thyrotoxicosis or hypothyroidism in the fetus. Monitoring TRAb in pediatric GD may help control the progression of GO. TRAb assay is an important guide for the treatment of GO.

Keywords

Graves’ disease - TRAb - diagnosis - prognosis


Publikationsverlauf

Eingereicht: 25. Oktober 2024

Angenommen nach Revision: 09. Dezember 2024

Accepted Manuscript online:
09. Dezember 2024

Artikel online veröffentlicht:
10. Februar 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Wiersinga WM, Poppe KG, Effraimidis G. Hyperthyroidism: aetiology, pathogenesis, diagnosis, management, complications, and prognosis. Lancet Diabetes Endocrinol 2023; 11: 282-298
    CrossrefPubMedSuche in Google Scholar
  • 2 Davies TF, Andersen S, Latif R. et al. Graves’ disease. Nat Rev Dis Primers 2020; 6: 52
    CrossrefPubMedSuche in Google Scholar
  • 3 Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med 2016; 375: 1552-1565
    CrossrefPubMedSuche in Google Scholar
  • 4 Brandt F, Thvilum M, Almind D. et al. Graves’ disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish populationbased register study. Thyroid 2013; 23: 408-413
    CrossrefPubMedSuche in Google Scholar
  • 5 Dekkers OM, Horváth-Puhó E, Cannegieter SC. et al. Acute cardiovascular events and allcause mortality in patients with hyperthyroidism: a populationbased cohort study. Eur J Endocrinol 2017; 176: 1-9
    CrossrefPubMedSuche in Google Scholar
  • 6 Biondi B, Kahaly GJ, Robertson RP. Thyroid dysfunction and diabetes mellitus: two closely associated disorders. Endocr Rev 2019; 40: 789-824
    CrossrefPubMedSuche in Google Scholar
  • 7 Bolf EL, Sprague BL, Carr FE. A linkage between thyroid and breast cancer: a common etiology?. Cancer Epidemiol Biomarkers Prev 2019; 28: 643-649
    CrossrefPubMedSuche in Google Scholar
  • 8 Lillevang-Johansen M, Abrahamsen B, Jørgensen HL. et al. Excess mortality in treated and untreated hyperthyroidism is related to cumulative periods of low serum TSH. J Clin Endocrinol Metab 2017; 102: 2301-2309
    CrossrefPubMedSuche in Google Scholar
  • 9 Adams DD, Purves HD. Abnormal responses in the assay of thyrotropins. Proc Univ Otago Med School 1956; 34: 11-12
    PubMedSuche in Google Scholar
  • 10 Martin A, Barbesino G, Davies TF. T-cell receptors and autoimmune thyroid disease--signposts for T-cell-antigen driven diseases. Int Rev Immunol 1999; 18: 111-140
    CrossrefPubMedSuche in Google Scholar
  • 11 Chen CR, Pichurin P, Nagayama Y. et al. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J Clin Invest 2003; 111: 1897-1904
    CrossrefPubMedSuche in Google Scholar
  • 12 Sanders J, Chirgadze DY, Sanders P. et al. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 2007; 17: 395-410
    CrossrefPubMedSuche in Google Scholar
  • 13 Sanders P, Young S, Sanders J. et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 2011; 46: 81-99
    PubMedSuche in Google Scholar
  • 14 Morshed SA, Latif R, Davies TF. Characterization of thyrotropin receptor antibody-induced signaling cascades. Endocrinology 2009; 150: 519-529
    CrossrefPubMedSuche in Google Scholar
  • 15 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; 23: 14-24
    CrossrefPubMedSuche in Google Scholar
  • 16 Morshed SA, Davies TF. Graves’ disease mechanisms: the role of stimulating, blocking, and cleavage region TSH receptor antibodies. Horm Metab Res 2015; 47: 727-734
    Thieme ConnectPubMedSuche in Google Scholar
  • 17 Morshed SA, Ando T, Latif R. et al. Neutral antibodies to the TSH receptor are present in Graves’ disease and regulate selective signaling cascades. Endocrinology 2010; 151: 5537-5549
    CrossrefPubMedSuche in Google Scholar
  • 18 Stassi G, De Maria R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2002; 2: 195-204
    CrossrefPubMedSuche in Google Scholar
  • 19 Ovčariček PP, Görges R, Giovanella L. Autoimmune thyroid diseases. Semin Nucl Med 2024; 54: 219-236
    CrossrefPubMedSuche in Google Scholar
  • 20 Tozzoli R, Bagnasco M, Giavarina D. et al. TSH receptor autoantibody immunoassay in patients with Graves’ disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis. Autoimmun Rev 2012; 12: 107-113
    CrossrefPubMedSuche in Google Scholar
  • 21 Barbesino G, Tomer Y. Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013; 98: 2247-2255
    CrossrefPubMedSuche in Google Scholar
  • 22 Smith BR, Bolton J, Young S. et al. A new assay for thyrotropin receptor autoantibodies. Thyroid 2004; 14: 830-835
    CrossrefPubMedSuche in Google Scholar
  • 23 Schott M, Hermsen D, Broecker-Preuss M. et al. Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves’ disease (GD): an international multicentre trial. Clin Endocrinol (Oxf) 2009; 71: 566-573
    CrossrefPubMedSuche in Google Scholar
  • 24 Hinds WE, Takai N, Rapoport B. et al. Thyroid-stimulating immunoglobulin bioassay using cultured human thyroid cells. J Clin Endocrinol Metab 1981; 52: 1204-1210
    CrossrefPubMedSuche in Google Scholar
  • 25 Lytton SD, Ponto KA, Kanitz M. et al. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab 2010; 95: 2123-2131
    CrossrefPubMedSuche in Google Scholar
  • 26 Gao YM, Qiu L, Yu SL. et al. Thyroid stimulating receptor autoantibodies. Clin Chim Acta 2024; 559: 119700
    CrossrefPubMedSuche in Google Scholar
  • 27 Frank CU, Braeth S, Dietrich JW. et al. Bridge technology with TSH receptor chimera for sensitive direct dDetection of TSH receptor antibodies causing Graves’ disease: analytical and clinical evaluation. Horm Metab Res 2015; 47: 880-888
    Thieme ConnectPubMedSuche in Google Scholar
  • 28 Ehlers M, Schott M, Allelein S. Graves’ disease in clinical perspective. Front Biosci 2019; 24: 35-47
    CrossrefPubMedSuche in Google Scholar
  • 29 Kim JJ, Jeong SH, Kim B. et al. Analytical and clinical performance of newly developed immunoassay for detecting thyroid-stimulating immunoglobulin, the Immulite TSI assay. Scand J Clin Lab Invest 2019; 79: 443-448
    CrossrefPubMedSuche in Google Scholar
  • 30 Allelein S, Diana T, Ehlers M. et al. Comparison of a bridge immunoassay with two bioassays for thyrotropin receptor antibody detection and differentiation. Horm Metab Res 2019; 51: 341-346
    Thieme ConnectPubMedSuche in Google Scholar
  • 31 Kahaly GJ, Bartalena L, Hegedüs L. The American thyroid association/American association of clinical endocrinologists guidelines for hyperthyroidism and other causes of thyrotoxicosis: a European perspective. Thyroid 2011; 21: 585-591
    CrossrefPubMedSuche in Google Scholar
  • 32 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; 26: 1343-1421
    CrossrefPubMedSuche in Google Scholar
  • 33 Zöphel K, Roggenbuck D, Schott M. Clinical review about TRAb assay’s history. Autoimmun Rev 2010; 9: 695-700
    CrossrefPubMedSuche in Google Scholar
  • 34 Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/l: a prospective study. Clin Endocrinol (Oxf) 2010; 72: 685-688
    CrossrefPubMedSuche in Google Scholar
  • 35 Laurberg P, Wallin G, Tallstedt L. et al. 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; 158: 69-75
    CrossrefPubMedSuche in Google Scholar
  • 36 Piantanida E, Lai A, Sassi L. et al. Outcome prediction of treatment of Graves’ hyperthyroidism with antithyroid drugs. Horm Metab Res 2015; 47: 767-772
    Thieme ConnectPubMedSuche in Google Scholar
  • 37 Dwivedi SK, Kalaria T, Buch H. Thyroid autoantibodies. J Clin Pathol 2023; 76: 19-28
    CrossrefPubMedSuche in Google Scholar
  • 38 Kotwal A, Stan M. Thyrotropin receptor antibodies – an overview. Ophthalmic Plast Reconstr Surg 2018; 34: S20-S27
    CrossrefPubMedSuche in Google Scholar
  • 39 Chaker L, Cooper SD, Walsh JP. et al. Hyperthyroidism. Lancet 2024; 403: 768-780
    CrossrefPubMedSuche in Google Scholar
  • 40 Kahaly GJ. Management of Graves thyroidal and extrathyroidal disease: an update. J Clin Endocrinol Metab 2020; 105: 3704-3720
    CrossrefPubMedSuche in Google Scholar
  • 41 Lee SY, Pearce EN. Testing, monitoring, and treatment of thyroid dysfunction in pregnancy. J Clin Endocrinol Metab 2021; 106: 883-892
    CrossrefPubMedSuche in Google Scholar
  • 42 Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol 2013; 1: 238-249
    CrossrefPubMedSuche in Google Scholar
  • 43 Lee SY, Pearce EN. Assessment and treatment of thyroid disorders in pregnancy and the postpartum period. Nat Rev Endocrinol 2022; 18: 158-171
    CrossrefPubMedSuche in Google Scholar
  • 44 Wang MT, Lee WJ, Huang TY. et al. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol 2014; 78: 619-629
    CrossrefPubMedSuche in Google Scholar
  • 45 Suzuki N, Noh JY, Hiruma M. et al. Analysis of antithyroid drug-induced severe liver injury in 18,558 newly diagnosed patients with Graves’ disease in Japan. Thyroid 2019; 29: 1390-1398
    CrossrefPubMedSuche in Google Scholar
  • 46 Andersen SL, Olsen J, Wu CS. et al. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013; 98: 4373-4381
    CrossrefPubMedSuche in Google Scholar
  • 47 Nguyen CT, Mestman HJ. Graves’ hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes 2019; 26: 232-240
    CrossrefPubMedSuche in Google Scholar
  • 48 Kobaly K, Mandel SJ. Hyperthyroidism and pregnancy. Endocrinol Metab Clin North Am 2019; 48: 533-545
    CrossrefPubMedSuche in Google Scholar
  • 49 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; 27: 315-389
    CrossrefPubMedSuche in Google Scholar
  • 50 Quintanilla-Dieck L, Khalatbari HK, Dinauer CA. et al. Management of pediatric Graves disease: a review. JAMA Otolaryngol Head Neck Surg 2021; 147: 1110-1118
    CrossrefPubMedSuche in Google Scholar
  • 51 van der Kaay DC, Wasserman JD, Palmert MR. Management of neonates born to mothers with Graves’ Disease. Pediatrics 2016; 137: e20151878
    CrossrefPubMedSuche in Google Scholar
  • 52 Obeid R, Obeid R, Kalra VK. et al. Neonatal thyrotoxicosis presenting as persistent pulmonary hypertension. BMJ Case Rep 2012; bcr0220125939
    PubMedSuche in Google Scholar
  • 53 Regelmann MO, Sullivan CK, Rapaport R. Thyroid “vise” in an infant with neonatal Graves’ disease. Pediatrics 2013; 132: e1048-e1051
    CrossrefPubMedSuche in Google Scholar
  • 54 Kaplowitz PB, Vaidyanathan P. Update on pediatric hyperthyroidism. Curr Opin Endocrinol Diabetes Obes 2020; 27: 70-76
    CrossrefPubMedSuche in Google Scholar
  • 55 Banigé M, Estellat C, Biran V. et al. Study of the factors leading to fetal and neonatal dysthyroidism in children of patients with Graves Disease. J Endocr Soc 2017; 1: 751-761
    CrossrefPubMedSuche in Google Scholar
  • 56 De Luca F, Alessi L, Bruno E. et al. Graves’ disease in childhood: new epidemiological, pathophysiological and therapeutic insights. Minerva Pediatr 2016; 68: 66-69
    PubMedSuche in Google Scholar
  • 57 Wiersinga W, Žarković M, Bartalena L. et al. Predictive score for the development or progression of Graves’ orbitopathy in patients with newly diagnosed Graves’ hyperthyroidism. Eur J Endocrinol 2018; 178: 635-643
    CrossrefPubMedSuche in Google Scholar
  • 58 Taylor PN, Zhang L, Lee RWJ. et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol 2020; 16: 104-116
    CrossrefPubMedSuche in Google Scholar
  • 59 Rotondo DG, Torregrossa L, Caturegli P. et al. Association of T and B cells infiltrating orbital tissues with clinical features of Graves orbitopathy. JAMA Ophthalmol 2018; 136: 613-619
    CrossrefPubMedSuche in Google Scholar
  • 60 Pawlowski P, Reszec J, Eckstein A. et al. Markers of inflammation and fibrosis in the orbital fat/connective tissue of patients with Graves’ orbitopathy: clinical implications. Mediators Inflamm 2014; 412158
    PubMedSuche in Google Scholar
  • 61 Cao J, Su Y, Chen Z. et al. The risk factors for Graves’ ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 2022; 260: 1043-1054
    CrossrefPubMedSuche in Google Scholar
  • 62 Zhang L, Grennan-Jones F, Draman MS. et al. Possible targets for nonimmunosuppressive therapy of Graves’ orbitopathy. J Clin Endocrinol Metab 2014; 99: E1183-E1190
    CrossrefPubMedSuche in Google Scholar
  • 63 Krieger CC, Place RF, Bevilacqua C. et al. TSH/IGF-1 receptor cross talk in Graves’ ophthalmopathy pathogenesis. J Clin Endocrinol Metab 2016; 101: 2340-2347
    CrossrefPubMedSuche in Google Scholar
  • 64 Krieger CC, Neumann S, Place RF. et al. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J Clin Endocrinol Metab 2015; 100: 1071-1077
    CrossrefPubMedSuche in Google Scholar
  • 65 Bartalena L, Tanda ML. Current concepts regarding Graves’ orbitopathy. J Intern Med 2022; 292: 692-716
    CrossrefPubMedSuche in Google Scholar
  • 66 Ryder M, Wentworth M, Algeciras-Schimnich A. et al. Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, Graves’ disease, and Graves’ ophthalmopathy. Thyroid 2021; 31: 1597-1602
    PubMedSuche in Google Scholar
  • 67 Furmaniak J, Sanders J, Sanders P. et al. TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves' disease and Graves’ orbitopathy – results from a phase I clinical trial. Clin Endocrinol (Oxf) 2022; 96: 878-887
    CrossrefPubMedSuche in Google Scholar