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Serum Antibodies against the Flavoprotein Subunit of Succinate Dehydrogenase Are Sensitive Markers of Eye Muscle Autoimmunity in Patients with Graves’ Hyperthyroidism¹

Department of Medicine (K.G., S.K., J.S., J.R.W.), Allegheny University Hospitals, Allegheny General, Pittsburgh, Pennsylvania 15212-4772; Institute of Endocrinology (A.D.B., A.Be., A.A.S.), 2nd University of Naples, Naples, Italy; Endocrine Research Laboratory (S.W.), Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; Department of Veterans Affairs Medical Center and Department of Biochemistry and Biophysics (B.C., B.A.C.A.), University of California at San Francisco, California 94121; Cattedra di Endocrinologia (M.S.), Universita di Parma, Parma, Italy; and Department of Clinical and Experimental Medicine "F Magrassi" (A.Bi.), 2nd University of Naples, Naples, Italy

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves’ hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, 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 cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves’ hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves’ hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not 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 ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves’ hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves’ hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves’ hyperthyroidism.

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