Characterization of thyroid-stimulating blocking antibodies that appeared during transient hypothyroidism after radioactive iodine therapy.

Hypothyroidism after radioactive iodine (RAI) therapy for Graves' disease can be transient or permanent. The cause for early transient hypothyroidism is unknown. We evaluated 11 patients who developed transient hypothyroidism within 6 months of RAI and 12 who remained euthyroid after RAI. Approximately equal numbers of patients in each group had thyroid-stimulating antibody (TSAb) that increased cyclic adenosine monophosphate (cAMP) levels in Chinese hamster ovary (CHO) cells transfected with the recombinant human thyrotropin receptor (TSHR) (WT cells). Approximately equal numbers of patients from both groups had an increase in TSAb activity post-RAI. All TSAbs had their dominant functional epitope on the N-terminus of the TSHR extracellular domain, requiring residues 90-165 for activity because they, but not TSH, completely lost stimulating activity in a receptor chimera, wherein TSHR residues 90-165 were substituted by equivalent residues of the lutropin/choriogonadotropin receptor (LH/CGR). Although equal numbers of patients in both groups had thyrotropin-binding inhibiting immunoglobulin activity (TBII), as measured by radioreceptor assay before RAI, patients with transient hypothyroidism had a surge in TBII activity and all except one became positive for thyroid-stimulating blocking antibodies (TSBAb), as measured by inhibition of TSH-stimulated cAMP from WT cells. When immunoglobulin G (IgGs) were epitope-mapped using TSHR/LH-CGR chimeras with different substitutions, 8 hypothyroid subjects had TSBAbs directed against residues 90-165 of the TSHR, as well as TSHR residues 261-370. Two had functional epitopes directed at residues 9-89 as well as TSHR residues 261-370. None of the euthyroid control patients developed TSBAbs and their TBII activity decreased post-RAI. When patients with transient hypothyroidism reverted to a euthyroid state, TSAb was still detectable in 5; however, TBII was present in all and TSBAb, although decreased, was still positive in 9. In summary, RAI therapy was associated with a change in thyroid antibody characteristics in most patients. Additionally, patients with a surge in TBII and the appearance of TSBAb developed transient hypothyroidism after RAI.