DOI 10.1515/cclm-2013-0105 Clin Chem Lab Med 2013; 51(11): 2087–2097
Opinion Paper Giuseppe Lippi* and Mario Plebani
False myths and legends in laboratory diagnostics Abstract: Remarkable advances in understanding human biology in health and disease, propelled by technological innovations, have contributed to an increase in the number and quality of diagnostic tests. This evolving scenario has been accompanied by the proliferation of false myths and legends in laboratory diagnostics, consuming valuable human and economic resources and jeopardizing the clinical reasoning. The aim of this article is to provide a synthetic overview about some paradigmatic examples of false beliefs in laboratory diagnostics involving activated partial thromboplastin time (APTT), cardiospecific troponins, ischemia modified albumin (IMA), D-dimer, prostate specific antigen (PSA), dibucaine number, Bence Jones protein (BJP), lipoprotein(a), neutrophil gelatinaseassociated lipocalin (NGAL), potassium and reference ranges. Although the suggestive cases described in this article are not intended to be comprehensive, we hope that their description may help remove some mysticisms in laboratory diagnostics. Keywords: diagnostics; laboratory medicine; legends; myths; test. *Corresponding author: Prof. Giuseppe Lippi, Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Via Gramsci, 14, 43126 Parma, Italy, Phone: +39 0521 703050, Fax: +39 0521 703791, E-mail:
[email protected],
[email protected] Mario Plebani: Department of Laboratory Medicine, Academic Hospital of Padova, Padova, Italy
Introduction Laboratory diagnostics is an essential part of the clinical decision-making, providing valuable clues about screening, diagnosis, follow-up and therapeutic monitoring of most acute and chronic human disorders. Remarkable advances in our understanding of human biology in health and disease, propelled by exceptional technological innovations, have contributed to an increase in the number and quality of diagnostic tests over the past century. Under some circumstances, the expanded knowledge of biology in health and disease, as well as the increasing complexity
of in vitro diagnostics, have not proceeded in parallel with a mindful or appropriate use of old and innovative biomarkers, nor has the changing scenario of medicine and therapy been followed by a progressive demission of redundant or obsolete tests. It is also noteworthy that a sort of false belief has surrounded the use some specific laboratory analyses for years, for which a real clinical usefulness in some clinical settings has not been consistently proven. Even more paradoxically, some tests have been speculatively used ‘off-label’ in both research and clinics, i.e., for diagnosing or monitoring of conditions for which the test was not originally developed and without a credible scientific background [1]. The aim of this article is to provide a synthetic overview about some suggestive and paradigmatic examples of false myths and legends in laboratory diagnostics (Table 1).
Prolonged activated partial thromboplastin time and bleeding The activated partial thromboplastin time (APTT) is a global test of hemostasis, which is typically requested in combination with prothrombin time (PT) and fibrinogen for assessment of secondary hemostasis, also known as ‘blood coagulation’ [2]. Pathological derangements of the delicate hemostatic balance may alternatively expose the patient to ineffective coagulation and bleeding (i.e., hypofunction), or excess clotting and thrombosis (i.e., hyperfunction) [3]. Along with mounting evidences that shortened values of APTT may reflect a prothrombotic state [4], prolonged values have been historically associated with a potential hemorrhagic risk. Basically, an isolate prolongation of APTT mirrors the presence of plasma inhibitors and acquired or inherited deficiencies of coagulation factors of the intrinsic pathway, thus including von Willebrand factor, coagulation factors XII, XI, IX and VIII [5]. Although it is hence undeniable that an isolate prolongation of APTT, once preanalytical artifacts have been excluded [6, 7], may reflect life-threatening abnormalities of secondary hemostasis such as von Willebrand disease [8], hemophilia A (i.e., factor VIII deficiency), B
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2088 Lippi and Plebani: False myths and legends in laboratory diagnostics Table 1 Suggestive examples of false myths and unfounded beliefs in laboratory diagnostics. A prolonged activated partial thromboplastin time (APTT) is always associated with bleeding An increase value of cardiospecific troponin always reflects an acute myocardial infarction (AMI) The generation of ischemia modified albumin (IMA) only occurs in the presence of myocardial ischemia Increased D-dimer values are diagnostic of venous thromboembolism (VTE) Screening of prostate cancer with prostate specific antigen (PSA) is effective to decrease cancer-related mortality and increases quality of life Dibucain number must be systematically assessed as part of pre-anesthesia surgical screening Bence Jones protein (BJP) should be assessed before administration of contrast media Increased concentration of lipoprotein[a] [Lp(a)] is associated with enhanced risk of mortality Neutrophil gelatinase-associated lipocalin (NGAL) is the ‘troponin of the kidney’ Hyperkalemia is always a consequence of a metabolic disorder Laboratory values within the reference ranges are always normal and vice versa
(i.e., factor IX deficiency) and C (i.e., factor XI deficiency) [9], a variety of other conditions might cause abnormal prolongations. Among these, nearly half of the cases are represented by isolated factor XII deficiency (approx. 34% of cases) and the presence of lupus anticoagulant (LAC) (approx. 13% of cases) [10]. Although the former condition may be associated with remarkably prolonged clotting times, up to incoagulable APTTs, the clinical picture is not accompanied by a significant bleeding diathesis, even in patients homozygous for nearly complete factor XII deficiency (i.e., factor activity 70 is referred as normal, between 40 and 70 as intermediate (heterozygotes), and
