Studies on the Pathogenesis of the Ophthalmopathy of Graves' Disease1

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Abstract
Ophthalmometry and determinations of serum levels of long acting thyroid stimulator globulin (LATS), pituitary thyrotropin (TSH) and antithyroglobulin (anti-TG) antibody were performed in previously untreated hyperthyroid patients before and after administration of therapeutic doses of I131-iodide. LATS was detected in the sera of 10 of 38 patients prior to treatment, including 7 of the 9 patients presenting with ophthalraopathy. The mean exophthalmometric reading of patients who were seropositive for LATS was more than 3 mm higher than of those who were sero-negative. Observations have been made on 24 patients followed for 6 months or longer after radioiodide treatment. Most patients with LATS-negative sera remained seronegative following treatment; this group showed a mean slight but clinically unimportant increase in proptosis. In 3 patients LATS was first detected in the serum several months after treatment at a time when the subjects were clinically euthyroid. In each case the appearance of LATS in the circulation shortly preceded or coincided with the onset of an ophthalmopathy, which was severe in 2 of the subjects. Antibodies to thyroglobulin or to thyroid cell components were detected in the pretreatment sera of each of the patients who were destined to develop ophthalmopathy. Post-treatment rises in serum tlters of anti-TG antibody were observed which occurred later than the first detection of circulating LATS and after the onset of ophthalmopathy. TSH was detected in none of the sera obtained from untreated thyrotoxic patients, nor was it detected at any time after treatment in the sera of the patients who developed severe ophthalmopathy. Serum TSH was detected in 16 of the 24 patients as they became euthyroid or hypothryoid and subsequently was reduced when desiccated thyroid or thyroxine therapy was given. A concept of the pathogenesis of Graves'' disease and its complications is presented which emphasizes the probable antibody nature of LATS and the role that antecedent thyroid injury plays an initiating LATS production and in influencing the biological effect of this globulin. In this context, thyroidal 1131 is viewed as an agent of physical injury which can lead to extrathyroidal anamnestic antibody synthesis and important clinical consequences.