The correct answer is: E. False positive assay related to interfering antibodies

DISCUSSION

In this case, there was no rise or fall in the cTnI values, and there were no other objective findings consistent with ACS, making MI an unlikely diagnosis.

Myocarditis is a frequent cause of non-ACS related cTn elevations; however, the symptoms were atypical for myocarditis, and in combination with the cardiac MRI results, make this unlikely.

Pulmonary embolism is a potentially life threatening cause of cardiac troponin (cTn) elevations. cTn elevations usually arise from significant right ventricular ischemia related to the hemodynamic stress of the pulmonary embolism. However, the patient was relatively asymptomatic, right ventricular size and function were normal, as was the arterial blood gas, making a hemodynamically significant pulmonary embolism unlikely.

cTn elevations can be seen in patients with chronic renal failure, although are much more common with cTnT than cTnI. Given the CrCl of 80 ml/min, renal failure as an etiology appears unlikely.

The most likely cause for the elevated cTn is related to assay interferences leading to elevations (Choice E).

There are a number of substances that can interfere with current troponin assays that clinicians should be aware of. The first is fibrin or microclots.¹ This can occur in samples that are hemolyzed, and can usually be eliminated by using serum instead of plasma, or having hemolyzed samples spun prior to analysis.

Antibodies to cTn can produce a result of either a decreased troponin concentration (by blocking an epitope recognized by a reagent antibody) or an increased troponin value that appears to reflect the presence of increased cTn concentration is another possibility.²

Another source is endogenous anti-bodes such as heterophile antibodies, which can interfere with immunoassay measurements.¹ Current cTn assays are enzyme-linked immunoassays which have both a capture antibody and a conjugate antibody. Linkage of both with troponin results in the detection of a positive result. However, heterophile antibodies can occur as a result of incidental exposure to foreign proteins, at times bind to the cTn assay, mimicking a positive result. This has been seen with a number of animal proteins, most commonly mouse, although others can also cause false positive results. This can also occur with rheumatoid factor antibodies as well,^{3, 4} although results may vary by assay,⁵ and may be less common with newer assays.

Circulating immunoglobulins complexed with enzymes and other proteins that are measured in the diagnostic laboratory have been recognized for many years. Typically, small changes would not be clinically important or detected in most clinical immunoassays, but because of the critical importance of cTn for the diagnosis of MI, even minor elevations become clinically important. Because even small increases in cTn will be identified as abnormal, increased values due to interfering proteins are important to recognize, given their potential to lead to unnecessary interventions, particularly for future evaluations.

Keys to diagnosis include a high index of suspicion, particularly in a patient in whom the clinical scenario does not appear consistent with ACS, and subsequent diagnostic tests are negative (as seen in the current case). In addition, serial sampling of cTn will not demonstrate a significant change. Continuing sampling for longer periods than usual MI exclusion protocols (i.e., up to 24-48 hrs) can be helpful for demonstrating their continued detection. For high cTn values, as was seen in this case, measuring CK-MB can be helpful, as significant Tn values should also lead to elevated CK-MB values.

A number of strategies are available for inactivating the antibodies and preventing interference. One is to use specialized tubes, in which the sample is analyzed after being placed in a tube that contains heterophile blocking agents.

In this case, the samples were rechecked after using heterophile blocking agents, which resulted in undetectable cTn values.

References

1. McNeil A. The trouble with Troponin. Heart Lung Circ 2007;16 Suppl 3:S13-6.
2. Plebani M, Mion M, Altinier S, Girotto MA, Baldo G, Zaninotto M. False-positive troponin I attributed to a macrocomplex. Clin Chem 2002;48:677-679.
3. Fitzmaurice TF, Brown C, Rifai N, Wu A, Yeo KTJ: False increase of cardiac troponin I with heterophilic antibodies. Clin Chem 1998;44:2212–2214.
4. Katwa G, Komatireddy G, Walker SE. False positive elevation of cardiac troponin I in seropositive rheumatoid arthritis. J Rheumatol 2001;28:2750–2751.
5. Kenny PR, Finger DR. Falsely elevated cardiac troponin-I in patients with seropositive rheumatoid arthritis. J Rheumatol 2005;32:1258–1261.