The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate because of evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine (¹³¹I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin levels greater than 10 ng/mL but no structurally evident disease were consecutively enrolled in 5 tertiary-care institutions. After the administration of 5.55 GBq of ¹³¹I, the risk of persistent, recurrent, or metastatic differentiated thyroid cancer (prmDTC) was compared with that before RAT. The causes of hyperthyroglobulinemia were explored-and the response to RAT assessed-6-12 mo after RAT. The change in suppressed thyroglobulin level was reported. Results: A cohort of 254 subjects with a median stimulated thyroglobulin level of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low, intermediate, and high risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT (P = 0.952). During the follow-up (median, 10.6 mo), hyperthyroglobulinemia was ultimately attributed to a thyroid remnant, biochemical disease, and structural or functional disease in 17.3%, 54.3%, and 28.4% of subjects, respectively. In addition, responses that were excellent, indeterminate, biochemically incomplete, and structurally or functionally incomplete were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, the distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the 3 postoperative risk groups. Suppressed thyroglobulin levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as being at intermediate to high risk, and RAT using 5.55 GBq of ¹³¹I reveals biochemical, functional, or structural disease and yields a non-structurally or -functionally incomplete response in more than 80% patients, suggesting that TT-DTC patients with unexplained hyperthyroglobulinemia are explicit candidates for RAT.

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