Serum Thyroglobulin (Tg) Monitoring of Patients with Differentiated Thyroid Cancer Using Sensitive (Second-Generation) Immunometric Assays Can Be Disrupted by False-Negative and False-Positive Serum Thyroglobulin Autoantibody Misclassifications

CONTEXT: Reliable thyroglobulin (Tg) autoantibody (TgAb) detection before Tg testing for differentiated thyroid cancer (DTC) is critical when TgAb status (positive/negative) is used to authenticate sensitive second-generation immunometric assay ((2G)IMA) measurements as free from TgAb interference and when reflexing "TgAb-positive" sera to TgAb-resistant, but less sensitive, Tg methodologies (radioimmunoassay RIA or liquid chromatography-tandem mass spectrometry LC-MS/MS). OBJECTIVE: The purpose of this study was to assess how different Kronus (K) vs Roche (R) TgAb method cutoffs for "positivity" influence false-negative vs false-positive serum TgAb misclassifications that may reduce the clinical utility of reflex Tg testing. METHODS: Serum Tg(2G)IMA, TgRIA, and TgLC-MS/MS measurements for 52 TgAb-positive and 37 TgAb-negative patients with persistent/recurrent DTC were compared. A total of 1426 DTC sera with TgRIA of ≥ 1.0 μg/L had false-negative and false-positive TgAb frequencies determined using low Tg(2G)IMA/TgRIA ratios (0.6 kIU/L K vs >40 kIU/L R) had unacceptably high false-negative frequencies (22%-32%), whereas false positives approximated 12%. Functional sensitivity cutoffs minimized false negatives (13.5% K vs 21.3% R, P < .01) and severe interferences (Tg(2G)IMA, <0.10 μg/L) (0.7% K vs 2.4% R, P < .05) but false positives approximated 23%. CONCLUSIONS: Reliable detection of interfering TgAbs is method and cutoff dependent. No cutoff eliminated both false-negative and false-positive TgAb misclassifications. Functional sensitivity cutoffs were optimal for minimizing false negatives but have inherent imprecision (20% coefficient of variation) that, exacerbated by TgAb biologic variability during DTC monitoring, could cause TgAb status to fluctuate for patients with low TgAb concentrations, prompting unnecessary Tg method changes and disrupting Tg monitoring. Laboratories using reflexing should limit Tg method changes by considering a patient's Tg + TgAb testing history in addition to current TgAb status before Tg method selection.