Phantom hCG
Yasodah Jayamohan, MD
CAP Chemistry Resource Committee
A recent phenomenon of the false-positive “phantom” hCG has been noted in
both laboratory and clinical medicine. These false-positive results have led to
confusion and unwarranted treatment for suspected diagnoses of abnormal
pregnancy and gestational trophoblastic disease. It is now known that the false-
positive hCG is a consequence of interference of heterophil antibodies with
standard assays for hCG.
Heterophil antibodies are human antibodies that have the capability to bind to
other species’ immunoglobulins. Thus, they can cause significant interference in
commercial kits that employ nonhuman immunoglobulins such as rabbit, mouse,
goat, horse or sheep antibodies.1-3 These antibodies can be categorized into
three major groups.
The first category includes polyspecific/multispecific antibodies that have a weak
to moderate affinity to various antigens. These antigens can be either auto-
antigens or animal antigens, and can be detected in about 40% of the normal
population.2 Since they are detected in low titers and have very low affinity,
most do not cause interference in immunoassays. The second category consists
of anti-immunoglobulin antibodies that cross react with animal immunoglobulins.
These are also weak in nature and have multispecific activities. Rheumatoid
factor is the classic example in this category that may cause interference in
immunoassays.2,6 The third, and most important category, consists of high-
affinity, high-specificity antibodies, which are produced against well-defined
animal antigens. These are encountered in individuals who have had prior
sensitization to an animal species. The sensitization may occur as a result of
occupational animal exposure, animal products in diet or therapeutic intervention
with animal proteins found in some therapeutic or imaging agents.2,3,6 These
antibodies are commonly referred to as human anti-animal antibodies (HAAA).1-
3,6 The commonly encountered human anti-mouse antibodies (HAMA) belong to
this category.
The problem of “phantom” hCG was identified in the early 1970s when classic
competitive immunoassays were in use.1 Similar interference can be noted even
in some older radioimmunoassays. In recent years, different hCG assays have
been marketed to measure serum hCG, which vary in their response to human
anti-animal antibodies and heterophil antibodies. Heterophil antibodies and, more
