Pathophysiology of Graves' ophthalmopathy

Abstract

Pathohistological characteristics of Graves' ophthalmopathy (GO) include glycosaminoglycan deposition in the orbit, active inflammatory process, fibrosis of the extra-ocular muscles and fat accumulation within the orbit. These processes lead to the clinical manifestations of proptosis, chemosis, periorbital edema, and altered ocular motility. Current evidence demonstrates that GO is not a result of hyperthyroidism but rather represents a second target of the underlying autoimmune process. The candidate orbital autoantigens and the cells involved in the development and progression of GO are reviewed. The initiation and propagation of the autoimmune process against such antigens involves a complex action of lymphocytes and auto-antibodies. At least three cell types are involved in the unique remodeling of orbital tissues of GO patients: T cells, orbital fibroblasts, and B cells through the production of autoantibodies. These are further discussed in this review. In Graves' hyperthyroidism, autoantibodies to TSH receptors (TSH-R) may affect thyroid function by stimulating TSH-R, promoting excessive thyroid growth, hormone production and secretion receptor which stimulates TSH receptor mRNA and expression. The correlation of TSH-Abs levels with GO activity is used clinically as a marker of disease activity, to aid prediction of the disease course, and to support GO diagnosis in patients with no clinically significant thyroid disease. Several future specific therapies under investigation are mentioned. These are aimed against the autoantibodies, the orbital fibroblasts or the peroxisome proliferator-activated receptor gamma (PPARgamma), which regulates fatty acid storage and glucose metabolism.