Thyrotropin receptor antibodies and Graves’ orbitopathy

Abstract

Context and purpose The thyrotropin receptor (TSHR) is the key autoantigen in Graves’ disease (GD) and associated orbitopathy (GO). Antibodies targeting the TSHR (TSHR-Ab) impact the pathogenesis and the course of GO. This review discusses the role and clinical relevance of TSHR-Ab in GO. Methods Review of the current and pertinent literature. Results GO is the most common extrathyroidal manifestation of GD and is caused by persistent, unregulated stimulation of TSHR-expressing orbital target cells (e.g. fibroblasts and pre-adipocytes). Serum TSHR-Ab and more specifically, the stimulatory Ab (TSAb) are observed in the vast majority of patients with GD and GO. TSHR-Ab are a sensitive serological parameter for the differential diagnosis of GO. TSHR-Ab can be detected either with conventional binding immunoassays that measure binding of Ab to the TSHR or with cell-based bioassays that provide information on their functional activity and potency. Knowledge of the biological activity and not simply the presence or absence of TSHR-Ab has relevant clinical implications e.g. predicting de-novo development or exacerbation of pre-existing GO. TSAb are specific biomarkers of GD/GO and responsible for many of its clinical manifestations. TSAb strongly correlate with the clinical activity and clinical severity of GO. Further, the magnitude of TSAb indicates the onset and acuity of sight-threatening GO (optic neuropathy). Baseline serum values of TSAb and especially dilution analysis of TSAb significantly differentiate between thyroidal GD only versus GD + GO. Conclusion Measurement of functional TSHR-Ab, especially TSAb, is clinically relevant for the differential diagnosis and management of GO.

Type 1 diabetes and associated autoimmune diseases

“…Hashimoto’s thyroiditis (HT) was defined as a hypoechoic appearance on thyroid ultrasound, an elevated serum level of anti-thyroid peroxidase-Ab, with or without increased serum concentration of anti-thyroglobulin-Ab and euthyroidism or hypothyroidism[ 51 ]. TSHR-Ab are either acting as an agonist and stimulate unregulated thyroid growth as well as thyroid hormone production, or as an antagonist, blocking the activity of the natural ligand thyrotropin[ 45 , 52 - 55 ]. TSHR-stimulating Ab (TSAb), activating the TSHR causing an unregulated stimulation of thyroid cells, lead to GD[ 56 ].…”

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

“…ATDs and Tx per se do not modify the natural history of mild GO (53,54,168), although RCTs on moderate-to-severe GO are lacking. Long-term ATD treatment is beneficial for GO due to normalization of thyroid function and associated decline of TSHR-Ab serum levels (169), which are a biomarker for GO (43,170). Avoiding iatrogenic hypothyroidism in treating patients with GD/GO (Figures 1-4) is an important principle of medical management.…”

Epidemiology, Natural History, Risk Factors, and Prevention of Graves’ Orbitopathy

“…Most patients affected with GO are hyperthyroid (1), but a substantial proportion, ranging from 0.2 to 11% in different studies (35,(39)(40)(41), are euthyroid or subclinical/overt hypothyroid. TSH-receptor antibodies (TRAbs) are the ultimate responsible for hyperthyroidism due to Graves' disease (42), but they also strongly correlate with the clinical activity and severity of GO (3,4,43). But, in a series of 700 unselected patients with chronic autoimmune thyroiditis, overt GO was present in 44 (6%): among them TRAb bioassay for stimulating activities tested positive in 30/44 (68%) patients with GO vs. 36/656 (5.5%, p <0.001) patients without GO (44).…”

“…The close link of GO with thyroid autoimmune disorders, mainly Graves' disease, underpin the hypothesis that GO is triggered by immune reactions against one or more antigens shared by thyroid and orbit. The thyrotropin (TSH) receptor is the most likely culprit, supporting an important role of TSH receptor antibodies (TRAbs) in the pathogenesis and course not only of thyroid disease, but also of orbital disease (3,4). The insulin-like growth factor-1 (IGF-1) receptor seems also to be involved, which may explain the recent promising results obtained by treating patients with active, moderate-to-severe GO with an IGF-1 receptor antagonist monoclonal antibody, teprotumumab (5,6).…”