The pathophysiology of thyroid-associated ophthalmopathy.

TAO is an inflammatory disease of the orbital tissues. The effects of inflammation, mediated through cytokine release, include proliferation of fibroblasts, increased deposition of extracellular matrix, and adipocyte differentiation and proliferation. As a result, edema, enlargement of the extraocular muscles, and increased volume of the orbital soft tissues occur with ensuing exophthalmos and, in some patients, compression of the optic nerve. Edema, inflammation, and late fibrosis, account for the decreased function of the extraocular muscles, despite relative preservation of the fibers themselves. The recruitment of T cells to the orbits of these patients may result from the expression of the target of the aberrant immune response in Graves' disease, the TSH receptor, in the orbits of patients with TAO. The orbital fibroblasts, especially those present within patients with TAO, may be more sensitive to the effects of cytokines, accounting for the frequent, and relatively selective, involvement of the orbit in Graves' disease. Insight into the cellular and molecular pathways proposed in this cascade introduces potential sites for new therapeutic approaches and understanding of the mechanisms of current treatments. Corticosteroids, used frequently in the treatment of TAO, have a detectable effect at the molecular level. While glucocorticoids do not directly influence extracellular matrix production [62] or baseline proliferation of orbital fibroblasts [27] they do attenuate the effect of several cytokines on inducing proliferation of these fibroblasts or extracellular matrix production, and this influence is greater in fibroblasts from TAO patients [27,36]. The consistent observation of early inflammation suggests that immunomodulation early in the course of the disease should be a primary goal of management of TAO. The elucidation of the specific cytokines that are released and active in the orbits of patients with TAO may aid in the development of more specific immunomodulatory therapies. Improved understanding of the pathophysiology of TAO may also help identify more rational approaches to treatment. For example, identification of the molecules involved in the inflammatory cascade which results in TAO may help predict progression of disease and identify specific treatment modalities which may benefit individual patients [11,70].