False-Positive hCG Assay Results Leading to Unnecessary Surgery and Chemotherapy and Needless Occurrences of Diabetes and Coma

Much concern has been raised by the unraveling at the hCG Reference Service of six cases of persistent phantom human chorionic gonadotropin (hCG). These are false-positive hCG results, which are likely attributable to human anti-mouse IgG or to heterophilic antibodies (1)(2)(3). The hCG Reference Service, started in January 1998 to aid with the interpretation of irregular or discordant hCG immunoassay results, requests parallel serum and urine samples. Each is tested in four separate two-step microtiter plate ELISAs (assay 1 detects intact hCG, assay 2 detects nonnicked or bioactive hCG only, assay 3 detects the hCG free β-subunit only, and assay 4 detects the hCG β-core fragment only) at three different concentrations (undiluted, a 1:2 dilution, and a 1:5 dilution). From the data, inferences are made about the nature (nonnicked or nicked hCG, free β-subunit, and β-core fragment) and likely source (trophoblast disease, pituitary hCG, cancer, or phantom hCG) of the hCG immunoreactivity. In all six cases of phantom hCG tested by the service, increased hCG concentrations were detected in serum samples (Table 1), but no detectable hCG, free β-subunit, or β-core fragment was found in the parallel urine samples (40 quantitative hCG test sold in the US (4), is particularly prone to false-positive results. Laboratory directors and managers need to be aware of this potential problem, especially if they are performing the AxSym or IMx hCGβ type test. They need to be available to help physicians quickly exclude or identify phantom hCG, which can be done by simply running quantitative urine hCG tests. In phantom hCG cases, no hCG immunoreactivity may be detected (<5 IU/L) in urine samples. Other simple methods to exclude phantom hCG are to test serum samples with competitive hCGβ RIAs (which do not detect phantom hCG), or to demonstrate nonlinearity in dilutions of the serum samples in an hCG immunoassay (phantom hCG may give grossly nonlinear results). Alternatively, help can be sought from the hCG Reference Service.