Reply: RA Highly Sensitive Thyroglobulin Assay Has Superior Diagnostic Sensitivity for Recurrence of Differentiated Thyroid Cancer in Patients Undergoing TSH Suppression

REPLY: We greatly appreciate the comments of Dr. Zöphel et al. concerning the sensitivity of enzyme-linked immunosorbent assay (ELISA), the occurrence of high-dose hook effects, and recovery testing for serum thyroglobulin measurement. They noted that the high-dose hook effects in 2-step ELISA for thyroglobulin assays occurred theoretically but not in daily routine (1), as was supported by the report that the high-dose hook effects occurred in only 1 of 356 consecutive differentiated thyroid carcinoma (DTC) patients in the whole study population (2). Furthermore, they speculated that recovery testing could reveal a falsely low thyroglobulin concentration leading to a false sense of safety in patient management. Generally, we agree with their comments. No current thyroglobulin method is perfect. There can be a 4-fold between-method variability that precludes the use of different thyroglobulin methods for serial monitoring of DTC patients (3). Therefore, the functional sensitivity of thyroglobulin methods, including ELISA, is reported differently. We also acknowledge that the retrospective study by Zöphel et al. (n = 126) suggests that serial measurements of low levels of thyroglobulin by ELISA in treated patients with DTC enable detection of recurrence (without using thyroid-stimulating hormone stimulation) 6−12 mo earlier than would be possible using a conventional thyroglobulin immunoradiometric assay (4). However, as the authors put it, a prospective study is now needed to confirm their observations. According to the abstract of the paper by Görges et al. (5), we cannot identify the immunoenzymatic assay as ELISA. As for recovery testing for serum thyroglobulin measurement, recently it was reported that the potential for thyroglobulin autoantibody (TgAb) interference is only weakly related to the TgAb concentration, and even low levels have the potential to interfere (6–8). Therefore, guideline 46 of the National Academy of Clinical Biochemistry states that “recovery tests do not reliably detect TgAb and should be discouraged and eliminated” (6). Although TgAb interference with serum thyroglobulin measurements, especially when made by immunometric assay methodology, is likely to remain a problem for the foreseeable future, serial TgAb concentrations are, fortunately, a useful surrogate tumor marker test for monitoring the disease status of TgAb-positive DTC patients (9).