Pathophysiology of Graves’ Ophthalmopathy: The Cycle of Disease

Extract

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 protein-coupled 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.