Abstract
Graves’ orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways.
Highlights
Graves’ orbitopathy (GO) or thyroid eye disease is the most common overt thyroidal manifestation of Graves’ disease (GD) with substantial morbidity and socioeconomic impact [1–4]
The increased adipogenesis has been demonstrated by using in vitro cultures of human fibroblasts and analysis of ex vivo samples from patients with GO [21]. By using both in vitro lineage specific differentiation protocols and flow cytometry, studies have indicated that orbital fibroblasts (OF) possess mesenchymal stem cell (MSC) properties including positivity for Thy-1 (CD90) which is a marker of MSC [22–25]
In cells with low levels of thyrotropin receptor (TSHR) expression, homo-heterodimer formation is less likely. This may change during adipogenesis, as TSHR expression increases, and may lead to activation of different signaling cascades from that predominating in orbital fibroblasts
Summary
Graves’ orbitopathy (GO) or thyroid eye disease is the most common overt thyroidal manifestation of Graves’ disease (GD) with substantial morbidity and socioeconomic impact [1–4]. Extensive orbital tissue remodelling in GO is mainly shown as adipose tissue expansion and tissue edema via increased adipogenesis and hyaluronan production, respectively. These pathogenetic processes produce disfiguring proptosis and underpin all GO signs and symptoms. There is a close clinical and temporal association between GD and GO suggesting an autoimmune response to common antigen/s in the orbit and thyroid gland. The thyrotropin receptor (TSHR) is expressed in orbital adipose tissue (OAT) [5–8] and virtually all patients with hyperthyroid GO have thyroid stimulating antibodies (TSAB). The incidence of GO is estimated to be 16/100,000 in females and 2.9/100,000 in males [11]. The prevalence estimate is about 10/10,000 [12].
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