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Letters |
1 USA hCG Reference Service, Department of Obstetrics and Gynecology, University of New Mexico, 2211 Lomas Blvd., Albuquerque, NM 87131
aAuthor for correspondence. Fax 505-272-3576; e-mail Stephen{at}hcglab.com.
To the Editor:
The USA hCG Reference Service aids physicians in the interpretation of discordant or irregular human chorionic gonadotropin (hCG) results that do not concur with physical findings. The Service has now observed 24 cases of false-positive hCG results (14–571 IU/L). All have been cases erroneously diagnosed with choriocarcinoma or gestational trophoblast disease without demonstrable pregnancy or tumor (1)(2)(3)(4). Because of false-positive hCG results, patients have needlessly received chemotherapy, hysterectomy, and/or other surgery. The suspected cause for serum false-positive hCG is the presence of heterophilic antibodies that bind both capture and detection antibodies, effectively bridging them in the same way as the target antigen should in a standard ELISA format.
Until recently, we primarily demonstrated false-positive hCG by the following criteria: (a) more than fivefold variation in results from different hCG assays; (b) positive hCG test results for serum and not urine; and (c) positive values for urinary hCGß-core fragment in serum (not urine). Recently, however, we have added a test that includes a heterophilic antibody blocking agent [heterophilic blocking tube (HBT) blocking agent; Scantibodies Inc.] to our protocol for the detection of false-positive hCG. The HBT blocking reagent is a unique formulation of immunoglobulins targeted specifically against heterophilic antibodies to neutralize their interference in immunoassays (David Cantor, Office of Development, Scantibodies Laboratories Inc., San Diego CA, personal communication). In this study, serum samples (0.5 mL) were incubated in HBTs for 30 min before use (exactly as described by the manufacturer). They were then assayed in the same manner as untreated serum, in the usual hCG Reference Service hCG immunometric assay.
Here we present the prospective data from the nine most recent false-positive hCG cases where we used the HBT blocking agent and also from five retrospective, or previous, cases (from both stored frozen serum and subsequently provided serum samples) reassayed both with and without the HBT blocking agent (cases 10–14). Table 1
shows hCG values found in serum by the original referring laboratory, the hCG Reference Service hCG immunometric assay, and our assay again with the addition of the HBT blocking agent. In 12 of 14 cases, lower false-positive hCG concentrations were detected by the Reference Service ELISA than by the original laboratory’s test. Of the 11 samples that gave a positive result with the Reference Service assay, 9 were completely blocked by the addition of the HBT blocking agent and 2 were considerably reduced (>50%) by the HBT blocking agent. In the remaining 3 of the 14 cases, no hCG was detected by the Reference Service assay, and the effect of the HBT blocking agent could not be evaluated.
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The finding that the HBT blocking agent blocked all 11 serum samples that gave false-positive results confirms that heterophilic antibodies are the source of the assay interference. The reasons for the occurrence of heterophilic antibodies in healthy individuals are poorly understood (5). In one large study, the prevalence of heterophilic antibodies, at a concentration sufficient to produce discordant results, was estimated as 
3.4% of the population studied (6). It is clear that heterophilic antibodies present a real problem to immunoassay-generated results, a problem that is made more pertinent especially when serious therapies depend heavily on the results. The HBT blocking agent used here appears to be extremely effective in preventing false-positive hCG results. However, although we have demonstrated the efficiency with our immunometric assay, similar efficiency with other commercial immunometric assays should be individually confirmed.
References
The following articles in journals at HighWire Press have cited this article:
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  C. L Buckner, L. Wilson, and C. N. Papadea An Unusual Cause of Elevated Serum Total {beta}hCG Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 186 - 191. [Abstract] [Full Text] [PDF]
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 C. M. Preissner, L. A. Dodge, D. J. O'Kane, R. J. Singh, and S. K.G. Grebe Prevalence of Heterophilic Antibody Interference in Eight Automated Tumor Marker Immunoassays Clin. Chem., January 1, 2005; 51(1): 208 - 210. [Full Text] [PDF]
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P. von Lode, J. Rainaho, and K. Pettersson Quantitative, Wide-Range, 5-Minute Point-of-Care Immunoassay for Total Human Chorionic Gonadotropin in Whole Blood Clin. Chem., June 1, 2004; 50(6): 1026 - 1035. [Abstract] [Full Text] [PDF]
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J. F. Emerson, G. Ngo, and S. S. Emerson Screening for Interference in Immunoassays Clin. Chem., July 1, 2003; 49(7): 1163 - 1169. [Abstract] [Full Text] [PDF]
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 N. Esfandiari and J. M. Goldberg Heterophile Antibody Blocking Agent to Confirm False Positive Serum Human Chorionic Gonadotropin Assay Obstet. Gynecol., May 1, 2003; 101(5): 1144 - 1146. [Abstract] [Full Text] [PDF]
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S. A. Butler, L. A. Cole, T. G. Olsen, P. R. Hubert, L. R. Nycum, and C. B. Hammond Falsely Elevated Human Chorionic Gonadotropin Leading to Unnecessary Therapy Obstet. Gynecol., March 1, 2002; 99(3): 516 - 517. [Full Text] [PDF]
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R. Sapin and C. Simon False Hyperprolactinemia Corrected by the Use of Heterophilic Antibody-blocking Agent Clin. Chem., December 1, 2001; 47(12): 2184 - 2185. [Full Text] [PDF]
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