Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment

Abstract

Purpose: To review current concepts regarding the pathogenesis of Graves ophthalmopathy (GO). We have presented this information in the context of potential target sites for novel disease therapies.

Design: Review of recent literature.

Methods: Synthesis of recent literature.

Results: Enlargement of the extraocular muscle bodies and expansion of the orbital fatty connective tissues is apparent in patients with GO. These changes result from abnormal hyaluronic acid accumulation and edema within these tissues and expanded volume of the orbital adipose tissues. Recent studies have suggested that the increase in orbital fat volume is caused by stimulation of adipogenesis within these tissues. The orbital fibroblast appears to be the major target cell of the autoimmune process in GO. A subset of these cells is capable of producing hyaluronic acid and differentiating into mature adipocytes, given appropriate stimulation. In addition, orbital fibroblasts from patients with GO have been shown to display immunoregulatory molecules and to express both thyrotropin receptors (TSHRs) and insulin-like growth factor 1 receptors (IGF-1Rs). Increased TSHR expression in the GO orbit appears to be the result of stimulated adipocyte differentiation. The activation of IGF-1R on orbital fibroblasts by immunoglobulins from GO patients results in increased production of both hyaluronic acid and molecules that stimulate the infiltration of activated T cells into areas of inflammation.

Conclusions: Potential targets for novel therapeutic agents to be used in GO include blocking T-cell costimulation, depleting B cells, inhibiting cytokine action, targeting the IGF-1R or the TSHR, and preventing connective tissue remodeling.

FIGURE 1

Computed tomographic scan of a 50-year-old woman with congestive Graves ophthalmopathy (GO) shows mild enlargement of extraocular muscles and expansion of orbital fat compartment. (Top) Axial view. (Bottom) Coronal view.

FIGURE 2

Computed tomographic scan of a 43-year-old woman with Graves ophthalmopathy (GO) and marked proptosis related to expansion of the retrobulbar fat compartment shows minimal enlargement of the extraocular muscles. Each optic nerve is “straightened.” (Top) Axial view. (Bottom) Coronal view.

FIGURE 3

Computed tomographic scan of a 58-year-old woman with profound visual loss from optic neuropathy in association with Graves ophthalmopathy (GO) shows massive enlargement of all extraocular muscles and apical compression of the optic nerves. Minimal fat is visible. (Top) Axial view. (Bottom) Coronal view.

FIGURE 4

Proposed targets for agents of potential benefit in the treatment of Graves ophthalmopathy (GO) include (1) blocking T-cell costimulation, (2) depleting B cells, (3) inhibiting cytokine action, (4) targeting the insulin-like growth factor 1 (IGF-1) receptor or the thyrotropin (TSH) receptor, and (5) preventing connective tissue remodeling. IL-1, interleukin 1; TNF-α, tumor necrosis factor α.