Various cases in the hospitalization of patients with elevated Troponins have revealed certain false positives and false negatives with current lab assays in the measurement of cardiac Troponins, a biomarker specific to myocardial injury. It is prudent to raise awareness in the understanding, investigation and management of such scenarios in the best interest of patient care.
One of the most common causes for false positives with cardiac Troponin I (cTnI) measurement happens to be heterophile antibodies, antibodies stimulated by exposure to a variety of antigens including transfused blood, vaccinations, therapeutic use of mouse monoclonal antibodies, autoimmune diseases (rheumatoid factor), and even dietary antigens. Heterophile antibodies, in essence are weak antibodies that form bridging complexes with assay specific antibodies, thereby confounding the presence of Troponin in a specimen[1][2]. While commercial assay manufacturers can use blocking antibodies to address this issue, clinicians can investigate with both Troponin I and T measurements since Troponin T measurements have not shown to be confounded by heterophiles antibodies.
Biotin, a B-vitamin found in many dietary supplements, is another known confounder for cardiac Troponin measurements. Biotin interferes with immunoassay function by saturating the assay binding sites, preventing the linking between analyte-antibody sandwich complex. This can lead to false low assay results in reporting Troponin. The FDA remains concerned[3] about troponin laboratory tests that have not addressed the risk of biotin interference. The agency has posted a webpage on Biotin Interference with Troponin Lab Tests – Assays Subject to Biotin Interference[4] to notify the public about troponin assays where the risk of biotin interference has not yet been addressed. Clinicians must proactively extract information from patients about exogenous consumption of any form of Biotin, Vitamin B7, multi-vitamin supplements during assessment for chest pain.
Another interesting observation is in Rhabdomyolysis, a life threatening condition involving severe skeletal muscle breakdown due to trauma, overxertion, dehydration or toxic drug abuse[5] can also lead to falsely elevated cardiac Troponin measurements, and a cause for concern in the emergency department[6]. While the causes for the elevation are debated, these increases could reflect re-expressed isoforms[7]. Clinicians need to be aware of the possibility that noncardiac increases in cardiac Troponins may occur and lead to a possible false-positive diagnosis of cardiac injury when skeletal muscle pathology is present.
Other analytical false positives with fibrin microclots are known to cause interference with assay measurements for Troponins[8]. Manufacturers must work closely with clinicians and the FDA in raising awareness for false positives in Troponin measurements.
Furthermore, close collaboration between laboratory medicine, emergency departments and cardiology will better enable identifying assay interference related false results vs pathophysiologic false positives of non-cardiac origins such as pulmonary embolism, sepsis, renal failure, aortic dissection, cocaine abuse, thyroid storm etc. When approaching any patient with a suspected false troponin result clinicians can probe for history of dietary supplement use, autoimmune phenomena, or other hints of potential heterophile antibody interference to develop better clinical context to patient assessment.
Sources:
- Lakusic N, Sopek Merkas I, Lucinger D, Mahovic D. Heterophile antibodies, false-positive troponin, and acute coronary syndrome: a case report indicating a pitfall in clinical practice. Eur Heart J Case Rep. 2021;5(2):ytab018. Published 2021 Feb 4. doi:10.1093/ehjcr/ytab018
- Zaidi A, Cowell R. False positive cardiac troponin elevation due to heterophile antibodies: more common than we recognise?. BMJ Case Rep. 2010;2010:bcr1120092477. Published 2010 Jul 15. doi:10.1136/bcr.11.2009.2477
- FDA (2019, November 5). UPDATE: The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety Communication. https://www.fda.gov/medical-devices/safety-communications/update-fda-warns-biotin-may-interfere-lab-tests-fda-safety-communication
- FDA (2019, November 5). Biotin Interference with Troponin Lab Tests – Assays Subject to Biotin Interference. https://www.fda.gov/medical-devices/in-vitro-diagnostics/biotin-interference-troponin-lab-tests-assays-subject-biotin-interference
- Egholm G, Pareek M. Drug-Induced Rhabdomyolysis with Elevated Cardiac Troponin T. Case Rep Med. 2015;2015:270204. doi: 10.1155/2015/270204. Epub 2015 Oct 8. PMID: 26557852; PMCID: PMC4617698.
- Li SF, Zapata J, Tillem E. The prevalence of false-positive cardiac troponin I in ED patients with rhabdomyolysis. Am J Emerg Med. 2005 Nov;23(7):860-3. doi: 10.1016/j.ajem.2005.05.008. PMID: 16291441.
- Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol. 2011 Oct 18;58(17):1819-24. doi: 10.1016/j.jacc.2011.08.026. Epub 2011 Sep 29. PMID: 21962825.
- Dimeski, Goce, Coogan, Melanie, Jones, Brock and Brown, Nigel. “Is the new Beckman AccuTnI+3 assay capable of producing false-positive troponin I results?” Clinical Chemistry and Laboratory Medicine (CCLM), vol. 53, no. 4, 2015, pp. e101-e103. https://doi.org/10.1515/cclm-2014-0616