Falsely Elevated Thyroglobulin – HAMA

Serum Thyroglobulin (Tg) is the primary tumor marker measured postoperatively to monitor for recurrence of thyroid cancer.  Tg concentrations reflect the mass, or amount, of residual thyroid tissue — remnant or tumor.

An unexpected elevated Tg result which is not consistent with clinical findings and history is distressing for the patient and can lead to unnecessary costly or invasive actions or changes in therapy.  

The measurement of Tg is subject to interference from

  • Biotin
  • Thyroglobulin Antibodies (TgAbs)
  • Heterophile Antibodies (HAbs)
    – Human Antimouse Antibodies (HAMAs)
    – Rheumatoid Factor (RF)

It is recommended that any biotin-containing supplements be stopped for at least 72 hours before testing – longer for high doses (>5 mg/day).

Some Tg assays (tests) are more susceptible to interference from antibodies which can cause falsely increased or decreased levels of thyroglobulin. Checking for TgAbs then “reflexing” to LC-MS/MS, which is resistant to interference from TgAbs, is now common practice. 

 HAb or HAMA interference is much rarer than TgAb interference and generally causes falsely high results if not blocked. Different antibody blocking proteins are added by assay manufacturers; and may cause variations in test results when comparing those results using different assays, laboratories, facilities or assay manufacturers.

While HAMA interference is not common, a lab result that is inconsistent with expectations or clinical findings should be reviewed before action is taken based on that result. 

“One of the first things that can be done when faced with a clinical discordant result, is to double-check the sample name and specimen type, since a sample mix-up could’ve caused the unexpectedly high or low results.”
—David Lin, AACC
Once it’s been confirmed that it was the correct patient and sample, several steps can be taken to validate the results.

  • In–house lab procedures (dilution, rechecking analytes)
  • Retest the same or a new sample using a different assay
  • Test the same or a new sample for HAbs

Discordant or contradictory laboratory results should never be actionable without further validation. Test results can guide patient treatment but should not be the only driver.  An old adage of wise physicians is  “Treat the patient, not the numbers.”  While technology has brought monumental advances to medicine, it can not replace the wisdom of the human brain.  


 Heterophile Antibodies
Slide and transcript from AACC.org — technical, but quite understandable.
https://www.aacc.org/science-and-research/clinical-chemistry-trainee-council/trainee-council-in-english/pearls-of-laboratory-medicine/2017/heterophile-antibodies

Commentary on: Implications of Thyroglobulin Antibody Positivity in Patients with Differentiated Thyroid Cancer: A Clinical Position Statement
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783929/

Quest Diagnostics
https://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Thyroglobulin_HAMA.pdf

LabCorp
https://www.labcorp.com/tests/140657/human-antimouse-antibodies

Phantoms in the Assay Tube: Heterophile Antibody Interferences in Serum Thyroglobulin Assays
https://academic.oup.com/jcem/article/88/7/3069/2845219