A non-coronary syndrome cause of elevated troponin.
A 45-year-old woman presented to the emergency department (ED) with a chief complaint of substernal chest pain. The pain had been intermittent for the previous four days and was characterized as dull. The pain was exacerbated by exertion, position, and eating. The patient's physical examination was unremarkable with the exception of morbid obesity (body mass index 50.6). Her electrocardiogram (ECG) was within normal limits. Her troponin I returned 1.05 ng/mL (normal < 0.9 ng/ mL). A diagnosis of acute coronary syndrome (ACS) non-ST elevation myocardial infarction (NSTEMI) was made and American Heart Association/American College of Cardiology guidelines for ACS/NSTEMI were initiated. Subsequent troponin I levels returned 1.09 ng/mL, 1.09 ng/ mL, 1.1 ng/mL, 1.18 ng/mL, and 1.08 ng/mL at hours 9, 14, 36, 44, and 52 respectively. All serial CK-MB fractions returned normal. The patient was discharged in good condition. Coronary artery angiograms done later in the year revealed no significant pathology.
The patient presented to the ED 15 months after the above episode with similar symptoms. She had a normal ECG but her initial troponin level returned 2.28 ng/mL (normal < 0.9 ng/mL). The patient was again started on the ACS/NSTEMI protocol and admitted to the hospital. Serial troponin I assays returned 2.51 ng/mL, 2.52 ng/mL, and 2.35 ng/mL at hours 8, 18, and 52 respectively. Cardiology saw the patient in consultation and requested a repeat troponin level with and without the addition of ethylene glycol. The sample without the ethylene glycol returned 2.46 ng/ mL while the sample with the ethylene glycol returned 0.8 ng/mL,(normal < 0.9 ng/mL). Cardiology concluded that the patient had autoantibodies against the troponin assay resulting in a falsely elevated troponin.
Troponins are proteins that regulate striated and cardiac muscle contraction. There are three subunits in this protein complex-troponin C, troponin T, and troponin I. Troponin C binds to calcium ions, troponin T binds to tropomyosin facilitating muscle contraction, and troponin I binds to actin inhibiting actin-myosin interactions. The cardiac and skeletal muscle isoforms of troponin I and T are structurally different, thus antibodies produced to the cardiac forms do not react with the skeletal forms, making these two subforms ideal markers for myocardial injury. Skeletal and cardiac muscle troponin C isoforms are identical in structure, thus separate antibodies cannot be made to distinguish myocardial injury from skeletal muscle injury.
Troponin Elevations From Nonthrombotic Causes
Both troponin I and troponin T are sensitive and specific markers for myocardial cellular damage. Myocardial cellular damage does not always reflect myocardial ischemia related to an acute thrombotic coronary event. Numerous medical conditions are known to cause elevations in troponin. These conditions may be cardiac, pulmonary, renal, or systemic in nature. Table 1 lists these conditions and the probable mechanisms for the elevations. (1) Though not indicative of an acute thrombotic coronary event, these elevations do portend a worse prognosis in patients with these underlying diseases.
False Positive Troponins
In a small minority of patients elevated troponins may arise from problems with the assay itself and not be reflective of myocardial cellular damage. This would represent a false positive result (ie, an elevated troponin that is not really elevated). This was determined to be the case with our patient. Table 2 lists some causes for falsely positive cardiac troponins.
An understanding of the assay for troponins is necessary to understand false positives as well as false negatives. Troponin assays are sandwich-type immunoassays consisting of a capture protein and an immunofluorescent protein. The capture protein crosslinks with the troponin that is present in the sample and with an immunofluorescent protein. The sample is then read by a specialized reader that is sensitive to the amount of light being fluoresced by the captured sample. Some patients have heterophilic antibodies that have the potential to raise or even lower the reported troponin level, giving a false positive or a false negative result. Human anti-animal antibodies are known for their interference with "sandwich" immunoassays. Human anti-mouse antibodies (HAMA) have an increasing prevalence in the population secondary to the use of mouse monoclonal antibodies for imaging purposes and also for therapeutic purposes. (2) Melanson et al reported a case of falsely elevated cTnI in a patient with HAMAs presumed to be from rituximab therapy. (3) These antibodies having similar structure to the troponin protein, can bind with the capture protein and with the immunofluorescent tag giving a positive reading for troponin. It is estimated that the prevalence of heterophilic antibodies ranges between 0.17%-40% in the general population. (4) It should be noted that not all patients with heterophilic antibodies will have a false positive troponin. Both rheumatoid factor and fibrin can cause false positive results. The fibrin induced false positives can be eliminated by using plasma and not serum for the analysis. Figure 1 illustrates how a sandwich assay works and how these heterophilic antibodies and other proteins can interfere with the assay.
Manufacturers have placed agents in their assays that are designed to counteract and neutralize these interfering antibodies. Despite this there are still times when spurious results occur. If the clinician feels that the results contradict the clinical presentation, the Food and Drug Administration recommends that the clinician communicate with the laboratory asking the lab to rule out technical errors and analytical interfering factors. The clinician should then consider repeating the blood draw and review the clinical presentation while considering additional diagnostic testing. (5)
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In conclusion the diagnosis of NSTEMI/ACS is made on more data than an elevated cTn. Despite advances in modern technology, the total evaluation of the patient including chief complaint, present illness, past medical history, physical examination, and ECG are still essential in making the correct diagnosis of acute coronary syndrome.
(1.) Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med 2005;142:786-791.
(2.) Kricka LJ. Human anti-animal antibody interferences in immunological assays. Clin Chem 1999;45:942-956.
(3.) Melanson SE, Tanasijevic MJ, Jarolim P. Cardiac troponin assays: a view from the clinical chemistry laboratory. Circulation 2007;116:e501-504.
(4.) Roongsritong C, Warraich I, Bradley C. Common causes of troponin elevations in the absence of acute myocardial infarction: incidence and clinical significance. Chest 2004;125:1877-1884.
(5.) US Food and Drug Administration. Troponin: what laboratorians should know to manage elevated result. <http:// www.fda.gov/medicaldevices/safety/alertsandnotices/ tipsandarticlesondevicesafety/ucm109362.htm#fn19> (accessed 2009).
D. Shannon Howell, MD; J. Nelson Perret, MD; and Cris Mandry, MD
Dr. Howell is a second program year emergency medicine resident at LSUHSC/Earl K. Long Medical Center. Dr. Perret is clinical assistant professor in the Department of Medicine at Louisiana State University Health Sciences Center (LSUHSC) in New Orleans and Earl K. Long Medical Center in Baton Rouge. Dr. Mandry is chairman in the Department of Emergency Medicine and clinical associate professor in the Department of Medicine at LSUHSC/Earl K. Long Medical Center.
Table 1. Nonthrombotic causes of elevated troponins. (1) Disorder Explanation for elevation Cardiac Left ventricular Demand ischemia (subendocardial hypertrophy ischemia) Tachycardias Demand ischemia (supply/demand mismatch) Cardiac contusion Direct myocardial damage (trauma) Myocarditis Direct myocardial damage (inflammatory) Pericarditis Direct myocardial damage (inflammatory) Heart failure Myocardial strain (myocardial wall stretch) Infiltrative Direct myocardial damage (myocyte cardiac disease compression) Cardioversion Direct myocardial damage (trauma) Cardiac toxicity Direct myocardial damage (toxic) (eg chemotherapy) Cardiac Direct myocardial damage transplantation (inflammatory/immune) Hypertensive Myocardial strain (ventricular stretch) emergencies Pulmonary Acute pulmonary Myocardial strain (right ventricular embolism stretch) Pulmonary Myocardial strain (right ventricular hypertension stretch) Renal Chronic renal Unknown failure Systemic Disorders Sepsis Demand ischemia (supply/demand mismatch) Hypotension Demand ischemia (decreased perfusion pressure) Strenuous exercise Demand ischemia (supply demand mismatch) Adapted from Jeremias and Gibson. (1) Table 2. Possible causes of falsely positive troponins. Analyzer malfunction Autoantibodies Fibrin clot Human antianimal antibodies Human anti-mouse antibodies (HAMAS) Immunocomplex formation Microparticles in specimen Rheumatoid factor
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|Author:||Howell, D. Shannon; Perret, J. Nelson; Mandry, Cris|
|Publication:||The Journal of the Louisiana State Medical Society|
|Date:||Jul 1, 2011|
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