False positive troponin: A true problem

J Med Biochem 2013; 32 (3) DOI: 10.2478/jomb-2013-0021 UDK 577.1 : 61 ISSN 1452-8258 J Med Biochem 32: 197–206, 2013 Review article Pregledni ~lanak FALSE POSITIVE TROPONIN – A TRUE PROBLEM LA@NO POZITIVNI TROPONIN – ISTINIT PROBLEM Goran Kora}evi}1, Vladan ]osi}2, Ivana Stojanovi}3 1Clinic for Cardiovascular Diseases, Clinical Centre, Ni{ 2Centre for Medical Biochemistry, Clinical Centre, Ni{, 3Institute of Biochemistry, Faculty of Medicine, University of Ni{, Ni{, Serbia Summary: Cardiac troponins have a crucial role in diag- nosing acute myocardial infarction, but have been considered by some authors to have a high false positive rate. Such opinions may decrease the confidence in troponin with important clinical consequences. The aim of the paper is to analyze three different meanings of the phrase »false positive troponin«: A) analytic (technical) false positive, with no real myocardial damage; B) false positive considering AMI: cardiac injury is present, but there is no AMI; C) false positive considering CAD: there is myocardial damage, but no CAD. The most frequent and the most important source of misunderstanding is the confusion between aspects A) and B). Namely, there has been a relatively small percentage of false positive troponin elevations due to analytic reasons. On the contrary, there has been a relatively large percentage of »false positive« results in patients with myocardial necrosis due to causes other than AMI; for them – instead of »FP troponin elevation« – another phrase ought to be used, e.g., »non-AMI troponin elevation« until the etiopathogenesis in an individual patient is recognized. The phrase »false positive troponin« should be restricted to the artificial increase in troponin due to preanalytic and analytic reasons. By doing so, we may decrease the degree of confusion about troponin and increase the confidence in this highly specific marker of myocardial injury. The possibility of an analytic false positive result should always be kept in mind when one interprets elevated troponin. Kratak sadr`aj: Sr~ani troponini imaju klju~nu ulogu u dijagnostici akutnog infarkta miokarda, uprkos mi{ljenju nekih autora da imaju visoku stopu la`no pozitivnih (LP) rezultata. Takvi stavovi mogu smanjiti poverenje u troponin, {to mo`e da ima va`ne klini~ke posledice. Cilj ovog rada je da se analiziraju tri razli~ita zna~enja izraza »LP troponin«: A) analiti~ki (tehni~ki) LP, bez pravog o{te}enja miokarda; B) LP uzimaju}i u obzir akutni infarkt miokarda (AIM) – sr~ano o{te}enje je prisutno, ali se ne radi o AIM; C) LP u odnosu na koronarnu bolest (KB) – prisutno je o{te}enje miokarda, ali bez KB. Naj~e{}i i najva`niji izvor nesporazuma je zabuna izme|u aspekata A) i B). Naime, relativno je mali procenat LP troponina zbog analiti~kih razloga. Suprotno tome, relativno je veliki procenat »LP« rezultata u pacijenata sa nekrozom miokarda zbog uzroka druga~ijih od AIM; za njih – umesto »LP pove}anja troponina« – drugi izraz treba da se koristi, na primer »ne-AIM pove}anje troponina« – dok se ne otkrije uzrok u pacijenta. Fraza »LP troponin« trebalo bi da bude ograni~ena na artificijelno povi{enje koncentracije troponina zbog preanaliti~kih i analiti~kih razloga. Na taj na~in mo`emo smanjiti konfuziju oko troponina i pove}ati poverenje u ovaj visokospecifi~an marker o{te}enja miokarda. Mogu}nost analiti~ki pozitivnog rezultata treba imati na umu kada se interpretira povi{ena vrednost troponina. Klju~ne re~i: troponin, la`no pozitivan, infarkt miokarda, akutni koronarni sindrom Keywords: troponin, false positive, myocardial infarction, acute coronary syndrome Address for correspondence: Prof. dr Goran Kora}evi} Clinic for Cardiovascular Diseases Clinical Centre Ni{ Bul. Dr. Zorana \in|i}a 48 18000 Ni{, Serbia e-mail: gkoracevicªyahoo.com …they have confirmed what clinicians see and struggle with every day – that is, the assays they believe they are supposed to rely on – do not work in the way that the experts suggest they should (1). 198 Kora}evi} et al.: False positive troponin – a true problem Introduction Cardiac troponin I (cTnI) and T (cTnT) have a central place in the definition of (acute) myocardial infarction (AMI) and consequently crucial medical and scientific as well as high social and legal significance (1, 2). The high sensitivity of cTn has greatly improved the detection of AMI and thus (recognition of) its incidence increased substantially. Due to high cardiac specificity, cTn also revolutionized the confirmation of myocardial necrosis in the laboratory. Troponin serves as a basis for risk stratification in many diseases, including acute coronary syndrome – ACS (unstable angina versus AMI) and AMI itself, heart failure (both acute and chronic), renal failure, etc. Furthermore, the approach toward invasive diagnostics and therapy in ACS as well as the usage of some drugs (e.g. platelet GP IIb/IIIa inhibitors, low-molecular-weightheparins – LMWH) all depend on cTn values (3, 4). Thus, it is of great importance to avoid cTn misinterpretation, which may lead to wrong (and even dangerous) clinical decisions (5–6). However, it is sometimes difficult to explain positive cTn, because many diseases can increase it. The differential diagnosis has become extensive and troublesome (2, 3, 7). It produced the feeling that cTn testing has gotten out of hand (8). Due to complaints of false positive (FP) cTn measurements, the U.S. Food and Drug Administration issued a Medical Device Safety Report (9). For sure, not all colleagues are quite familiar with the terms: »positive predictive value« (PPV), »false positive«, etc. Even if one is, he/she might get confused by different meanings of the same phrase. Namely, there have been three different »standards« as references to calculate cTn sensitivity, specificity, etc: A) myocardial damage; B) AMI and C) coronary artery disease (CAD). Accordingly, there are three possible different meanings of the phrase »FP cTn« in contemporary medical literature and practice: A) Analytic (technical) FP, with no real myocardial damage; B) FP considering AMI: cardiac injury is present, but there is no AMI; C) FP considering CAD: there is myocardial damage, but no CAD (angiographically). A) Analytic (technical) FP, with no actual myocardial damage What are the causes of analytic, no actual myocardial damage FP cTn? Preanalytic and analytic problems can induce elevated and reduced values of cTn (10). There is a group of clinical conditions and no obvious myocardial diseases, like: sepsis /critically ill patients, hypovolemia, cerebrovascular accidents, acute cholecysti- tis (11) with potentially FP cTn. However, some of these case reports cannot exclude the influence of analytic interference on cTn values. A great deal of evidence showed trouble with FP cTnT in renal failure and in different skeletal muscle diseases and seriously reduced diagnostic significance of this biomarker (12). For example, there are forms in the d (...truncated)