Investigating unexpectedly positive hCG test results

In February, I wrote about interfering antibodies being the cause of false-positive hCG results from blood samples.  As a follow-up, I thought it would be a good idea to talk about what the lab can do to investigate the potential problem.

As a reminder: false-positive hCG results are often attributed to the presence of an interfering antibody in the blood sample.  Such was the case with Jennifer Rufer who was misdiagnosed with cancer due to a false-positive hCG blood test.  It's important to know that laboratories are likely not able to independently identify when an interfering antibody is present.  An interfering antibody should be suspected whenever the clinical picture of the patient fails to match the laboratory (in this case, hCG) results.  When laboratorians are asked to investigate the possibility of a false-positive hCG result there are several ways to do so but the key piece of information to note is that the lab has to be notified that there is the suspicion of an erroneous hCG result.  This is because the laboratory is nearly always unaware of the clinical picture of the patient.  We need to rely on our clinical colleagues to alert us to the possibility that an hCG test result is potentially incorrect.

So, what can the lab do when asked if an hCG blood test result is falsely increased?  There are several approaches the lab can take to investigate:

  1. Perform an hCG test on a urine sample obtained from the patient.  Because hCG is excreted in the urine, the detection of hCG in a urine sample indicates that the result from the blood sample is likely accurate.  Interfering antibodies aren't excreted into the urine and so if hCG is detected in the urine then the blood test result is probably really due to the presence of hCG.
  2. Perform a dilution of the blood sample.  Because interfering antibodies are reactive against the hCG assay reagents, the expected response to sample dilution is typically not observed.  That is, if the sample is diluted by a factor of 1:2, the hCG concentration should decrease by a factor of 2 if the hCG molecule is truly present.  Failure to observe the expected decrease in concentration supports the presence of an interfering antibody.
  3. Repeat the hCG test using a different method.  Interfering antibodies may be reactive against antibodies derived from a specific animal species (e.g. against mouse antibodies).  If the hCG test is repeated using a different method and the results are considerably different then that can suggest the presence of an interfering antibody.  Importantly, the alternative method selected should be one that uses antibodies derived from a different species of animal than the test in question.
  4. Treat the sample with blocking agents.  Blocking agents are commercially available that can be used to remove (by adsorption) potentially interfering antibodies from the sample.  If the hCG results after treatment is considerably different from the result of the untreated sample, then interfering antibodies may be present.  The definition of considerably different is not well defined although many labs use a difference of 50% to alert them to the possibility that interfering antibodies are present.

I recommend that laboratories use more than one of these investigations rather than rely on a single one.  As the Rufer case so clearly demonstrates, erroneous laboratory results can result in serious harm to patients.  Together with our clinical colleagues, it our responsibility to do all that we can to assure that laboratory test results can be correctly interpreted.

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