The pathogenesis and treatment of Graves' ophthalmopathy.

Abstract

Graves' ophthalmopathy (GO) is probably an autoimmune condition although the pathogenesis is still not fully understood. GO is frequently, though not invariably, associated with Graves' disease and it may in fact be a separate disease entity. Ophthalmopathy is commonest in the 30 to 50 age group,2'3 and is more common in women (2:1, female:male), although the female preponderance is not so marked as in Graves' disease where the ratio is 6:1.4,5,6 A family history of autoimmune thyroid disease is frequently present which may or may not be accompanied by ophthalmopathy. The pattern of inheritance is not a simple one and no single gene appears to be implicated. In Graves' disease it is likely that the genes conferring susceptibility are associated with the major histocompatibility genes and expression of major histocompatibility antigens B8 and DR3 confers an increased risk for Graves' disease.4'7 The most striking pathological feature ofGO is the marked increase in muscle bulk. The eye muscles show lymphocytic infiltration and have increased intercellular spaces with mucopolysaccharide and water. The structure ofthe muscle is usually normal although there may be swelling ofthe fibres and loss ofstriations and in more severe cases fibre atrophy and disordered muscle structure. The retrobulbar connective tissue also contains numerous lymphocytes and fibroblasts and there is proliferation of the connective tissue with newly formed collagen. The spaces between the collagen fibres contain amorphous material, mainly hyaluronic acid and other glycosaminoglycans which increase the osmotic pressure and trap water. The main result of all these changes is an increase in the total orbital contents. The presence ofimmune response cells in the orbit, the deposition of immunoglobulins on orbital tissues and the association with autoimmune thyroid disease suggests that the underlying mechanism is an autoimmune process. Cell-mediated immune responses and antibodies against eye muscle antigens have been identified but it is not known whether the damage results from cell-mediated immunity, circulating immune complexes or pathogenic antibodies. Cellmediated immunity has been clearly demonstrated with the production of macrophage migration inhibition factor (MIF) by sensitized T lymphocytes in response to retro-orbital antigens using both crude orbital antigens consisting of muscle and fat' and retro-orbital muscle.9 Attempts to purify the antigen from retro-orbital tissue suggested that thyroglobulin or a derivative was responsible,'0 although there has been no confirmatory evidence for this. T cell subsets have not been studied extensively inGO but two cases with abnormal helper:suppressor T cell ratios and increased circulating activated T cells have been described. Lymphocytes from patients with GO have been shown to induce lysis in eye muscle cells'2 and lymphocytes incubated with fibroblasts provoke an increase in glycosaminoglycans.'3 Antibodies, termed ophthalmic immunoglobulins, have been described in the serum of patients with GO which bind specifically to eye muscle membranes.'4 The specific nature of ophthalmic immunoglobulins was shown by failure to neutralize binding to eye muscle by pre-incubation of serum with membrane preparations from other tissues. Pre-incubation of thyrotrophin-binding-inhibiting immunoglobulin (TBII) with eye muscle membranes did not result in loss of thyroid stimulating hormone (TSH) binding inhibition. There was no correlation ofophthalmic immunoglobulins with microsomal antibody, thyroglobulin antibody, or TBII in serum of patients with Graves' disease.' While thyroid-stimulating antibody (TSAb) is responsible for the hyperthyroidism of Graves' disease it does not appear to cause the ophthalmopathy. There is a dissociation clinically between GO and hyperthyroidism,15 a lack of correlation between long-acting thyroid stimulator (LATS), TBII, or TSAb activity and eye disease, a poor correlation between TBII and ophthalmic immunoglobulins, and pre-incubation of LATS or TBII with eye muscle membranes or other