A false positive case of cardiac troponin I: Which diagnostic approach?

Abstract

The finding of elevated cardiac troponin levels (i.e. values above the99thpercentilevalueofthereferencepopulation)notrelatedtoischemicmyocardial injury in patients admitted to the emergency department(ED) with suspected acute myocardial infarction (AMI), represents arelevant clinical problem, increasingly observed in the last few years,following the implementation of cardiac troponin (cTnI, cTnT) measure-ment with high-sensitivity immunoassays [1]. Indeed, the majority ofpatients (up to 70%) admitted to the ED with more than one elevatedtroponin level may actually have myocardial injury unrelated to acutecoronary syndrome (ACS), especially when they have an age of morethan 70 years, heart failure, and/or other comorbidities [2,3]. In suchpatients, the incidence of “falsepositive”cases,i.e.the findingof troponinelevations in the absence of clinically documented myocardial injury, isactually unknown. Clinical observation however suggests that the per-centage of “false positive” troponin elevations is extremely low.Inapaperrecentlypublishedinthejournal[4],aclinicalcaseofapa-tient presenting to the ED with suspicion of AMI and non-diagnosticECG that shows a false positive cTnI result due to the presence in theblood sample of an analytical interference caused by heterophilic anti-bodies,hasbeenpublished.Theauthorssuggesttheadoptionofanalgo-rithm that allows the prompt detection of the supposed false-positiveresult. The described protocol considers the systematic measurementof CK-MB reflex testing in all troponin-positive samples as a reliabletool for the identification of biological and analytical interference. Thisreflextestingisbasedontheuseofawellknownbutoutdatedbiomark-erwhichlackssensitivityandspecificityforthedetectionofmyocardialinjury when compared with cardiac troponin. In addition the Authorsseemtoignorecurrentinternationalguidelines[5],whichbasethediag-nosis of myocardial infarction, along with the documentation of objec-tive evidence of myocardial ischemia, on the correct interpretation ofserialcardiactroponintesting.Infacttheanalysisofthereleasekineticsof troponin may permit the distinction between myocardial damagecaused by myocardial ischemia from myocardial injury caused byother factors and, possibly, from “false positive” troponin elevations[5,6]. According to these criteria, the detection of a rise and/or fall pat-tern of troponin with at least one value above the 99th percentileupper reference limit, is needed to make the diagnosis. It is well know,instead, that theinterference ofaheterophilicantibodytypically causesa constant (chronic) increase in troponin values, which cannot beconfused with the typical kinetic of the biomarker in AMI patients.Therefore, the interference by heterophilic antibodies should be differ-entiated from the huge number of clinical conditions which can causea chronic increase in troponin levels [5].Reflex testing is usually per-formed when the result of a first screening test is positive, in order toimprovethespecificity,althoughatthecostoflowersensitivity.Thisdi-agnostic strategy, therefore, should be adopted in clinical laboratorypractice to improve specificity employing a second text more specific(but more expensive and time consuming) than the screening text.Inthe case of the proposed reflex testing [4], the cardiac specificity of thesecond test (i.e. CK-MB) is significantly lower than the specificity ofthe screening test (i.e. cardiac troponin) and significantly less sensitivefor cardiac damage. As a consequence, the potential clinical advantageof using a very sensitive and cardio-specific screening test, such as thecardiactroponins, appearsto be, intheproposed “reflextesting” strate-gy, completely lost. A huge number of clinical studies have definitivelydemonstrated that cardiac troponins (particularly when assayed withhigh-sensitivity methods) represent a more cardiac-specific and sensi-tive biomarker than CK-MB in cardiovascular risk stratification, both inthe general population as well as in patients with cardiac disease [1,7]confirmingthatthemeasurementof CK-MBisnowobsolete.Moreover,considering that the incidence of heterophilic antibodies in the generalpopulationvariesgreatlyindifferentstudies(from0.17to40%)[8,9]thereflextestingproposed,ifappliedsystematicallyinallpatientsadmittedto the ED with increased troponin values, may allow the detection of