Clinical review 157: Pathophysiology of Graves' ophthalmopathy: the cycle of disease.

Abstract

Hyperthyroidism in Graves’ disease is due to the binding of stimulatory autoantibodies to the TSH receptor (TSHr) on thyroid follicular cells. The stimulation of this G proteincoupled receptor by autoantibodies leads to excessive and uncontrolled production of thyroid hormone. Our understanding of Graves’ disease has increased remarkably after the cloning in 1989 of TSHr (1–3). This achievement led to insights regarding TSHr biology, including the unique two-subunit structure of this receptor that may render it especially prone to autoimmune attack (4). In contrast, the pathophysiology of Graves’ ophthalmopathy (GO) and thyroid-associated pretibial dermopathy (PTD) is less well understood. However, studies by several groups have begun to unravel the many complex factors contributing to development of these ocular and dermal manifestations of Graves’ disease. The progression of GO and PTD from initiation to subclinical disease to fully developed ocular and dermal manifestations appears not to be a linear process. It seems rather to be a positive feedback cycle composed of mechanical, immunological, and cellular processes (Fig. 1). In this review each of the major components of this disease cycle will be examined with an eye toward understanding the limitations of current therapy and identifying targets for future therapy. Mechanical contributions to GO pathogenesis Many of the clinical symptoms and signs of GO can be explained on a mechanical basis by the increase in volume of intraorbital tissues characteristic of the disease (5). Although most individuals with GO have evidence of both extraocular muscle and orbital adipose tissue enlargement, some exhibit a predominance of either muscle or fat expansion (6). Individuals younger than 40 yr of age are considerably more likely to exhibit orbital fat expansion in the absence of muscle enlargement, whereas patients over 70 yr are more prone to severe, fusiform muscle enlargement without significant changes in orbital adipose tissue volume (7). Proptosis, the forward displacement of the globe, stems from this increase in orbital tissue volume within the unyielding confines of the bony orbit. Extraocular muscle dysfunction is caused, early in the disease, by swelling of the muscle bodies. Enlargement of the muscles at the apex of the orbit may lead to compressive optic neuropathy and visual loss. In later stages the extraocular muscles may become fibrotic and atrophic as a result of chronic inflammation and compression of the muscle fibers. Chemosis and periorbital edema appear to be caused primarily by decreased venous and lymphatic drainage from the orbit secondary to compression of these channels. Similarly, patients with severe PTD have compromise of low pressure lymphatics in the lower extremities (8), which probably contributes to the dependent edema seen in this condition. Histological examination of orbital adipose and extraoc