Two Graves' disease patients who spontaneously developed hypothyroidism after antithyroid drug treatment: Characteristics of epitopes for thyrotropin receptor antibodies

Few reports have identified blocking thyrotropin receptor antibodies (TSHRAbs) as a pathogenic mechanism explaining spontaneous hypothyroidism after antithyroid drug (ATD) treatment of Graves' disease. Here we report 2 Graves' patients who showed different courses of hypothyroidism after ATD treatment. The first patient had Graves' hyperthyroidism and was treated with ATD for 1 year. After a short period of euthyroidism, she developed permanent hypothyroidism with blocking TSHRAb. The second patient became euthyroid after 1 year of ATD treatment. After 3 years, however, she presented with hypothyroidism with blocking TSHRAb activity. Her hypothyroidism was transient, and restoration of euthyroidism was followed by disappearance of blocking TSHRAb. Blocking and stimulating TSHRAbs activities of these 2 patients were serially measured using Chinese hamster ovary (CHO) cells transfected with wild-type human TSHR (CHO-hTSHR) and 2 TSHR chimeras with residues 8-165 (Mc1+2) or 90-165 (Mc2) substituted by equivalent residues of the luteinizing hormone/chorionic gonadotropin receptor (LH/CGR). During their hypothyroid phases, blocking TSHRAbs activities were positive in all 3 kinds of assays and stimulating TSHRAbs activities were negative in CHO-hTSHR or in Mc1+2 assay. Mc2 stimulating TSHRAb activity was detected in sera of hypothyroid phase of the second patient who had transient hypothyroidism but not in the first whose hypothyroidism was permanent. In these 2 cases, we demonstrate the causative role of blocking TSHRAb in the development of hypothyroidism after ATD treatment in Graves' patients. Interestingly, the difference in the course of blocking TSHRAb-induced hypothyroidism was associated with the difference in epitope reactivities of TRAb during hypothyroid phase that developed after ATD treatment of Graves' disease.