Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocu lar muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye mu scle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been sh own to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrog enase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for crossr eactive human autoantibodies. Sera have been screened from patients with th yroid-associated ophthalmopathy classified according to activity and presen ce or not of eye muscle disease, and from those with Graves' hyperthyroidis m without eye involvement. Also examined were serum samples taken periodica lly from 20 patients with Graves' hyperthyroidism during 24 months of treat ment of their hyperthyroidism with antithyroid drugs. Four of these patient s had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did n ot develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopa thy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dys-function, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evid ent ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. S ignificantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who de veloped eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodi es were not detected in any of 6 patients who developed congestive ophthalm opathy without evidence of eye muscle damage or in 4 patients who did not d evelop any eye signs. In conclusion we have shown a close relationship betw een eye muscle disease and serum antibodies against the Fp subunit of succi nate dehydrogenase in patients with Graves' hyperthyroidism.