Ebook Laboratory medicine - The diagnosis of disease in the clinical laboratory (2/E): Part 2

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Part 2 book "Laboratory medicine - The diagnosis of disease in the clinical laboratory" includes contents: The heart, diseases of red blood cells, bleeding and thrombotic disorders, transfusion medicine, diseases of white blood cells, lymph nodes and spleen, the respiratory system, the gastrointestinal tract, the liver and biliary tract, pancreatic disorders, the kidney, male genital tract, female genital system, breast, the endocrine system.

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C H A P T E R The Heart Fred S. Apple 9 LEARNING OBJECTIVES 1. Learn the diﬀerential diagnosis of ischemic chest pain and the laboratory tests used in the assessment of myocardial injury, including acute myocardial infarction. 2. Learn the clinical features of congestive heart failure (CHF) and the laboratory tests useful in ruling in and ruling out CHF and monitoring and risk outcomes assessment of patients with this disorder. CHAPTER OUTLINE Introduction 209 Orders for Serial Cardiac Troponin Acute Myocardial Infarction 209 Testing 215 Description 209 High-sensitivity Cardiac Troponin Diagnosis 210 Assays 215 Cardiac Troponin 212 Congestive Heart Failure 216 Analytical Methods for Measuring Description 216 Cardiac Troponin 213 Diagnosis 216 99th Percentile Reference Value as Implications for Therapy Using Test Results a Cutoff for Diagnosis of Acute for Natriuretic Peptides 218 Myocardial Infarction 214 Biological Variability 218 Role of Cardiac Troponin for Risk Novel Biomarkers for Heart Failure Risk Outcomes Assessment 214 Assessment 218 INTRODUCTION There are many forms of cardiac disease. This chapter briefly covers the role of biomarkers in acute myocardial infarction (AMI) and congestive heart failure (CHF). The large numbers of other cardiac diseases are not discussed in this chapter because of the relatively minor role of diagnostic clinical laboratory tests in these disorders. ACUTE MYOCARDIAL INFARCTION Description The term AMI is defined as an imbalance between myocardial oxygen supply (ischemia) and demand, resulting in injury to and the eventual death of myocytes. AMI should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Such necrosis is most often associated with a thrombotic occlusion superimposed on coronary atherosclerosis. It is now apparent that the process of plaque rupture and thrombosis is 1 of the ways in which coronary atherosclerosis progresses. Total loss of coronary blood flow 209
210 CHAPTER 9 The Heart results in a clinical syndrome associated with an ST-segment elevation MI (STEMI). Partial loss of coronary perfusion, if severe, can lead to necrosis as well, which is generally less severe and is known as non-ST-segment elevation MI (NSTEMI). Both STEMI and NSTEMI are considered type 1 MIs. In instances of myocardial injury with necrosis with a condition other than coro- nary artery disease (CAD), which contributes to an imbalance between oxygen supply and/or demand (eg, coronary endothelial dysfunction, respiratory failure, hypotension, etc), this MI is a type 2 MI that is secondary to ischemic imbalance. Other ischemic events of lesser severity without myocardial necrosis are designated as angina, which can range from stable to unstable. About 1.7 million patients are hospitalized each year in the United States with an acute coro- nary syndrome (ACS). Approximately 700,000 patients suffer from an initial AMI annually and another 500,000 from a recurrent AMI. Coronary heart disease causes 20% of all deaths and cardiovascular diseases up to 40%. Historically, most deaths caused by ischemic heart disease have been acute, but as our therapeutic abilities have improved, the disease is slowly becoming a more chronic one. In many patients with AMI, no precipitating factor can be identified. The clinical history remains of substantial value in establishing a diagnosis. A prodromal history of angina can be elicited in 40% to 50% of patients with AMI. Of the patients with AMI presenting with prodromal symptoms, approximately one third have had symptoms from 1 to 4 weeks before hospitalization; in the remaining two thirds, symptoms predate admission by a week or less, with one third hav- ing had symptoms for 24 hours or less. The pain of AMI is variable in intensity, and the discom- fort is described as a squeezing, choking, vise-like, or heavy pain. It may also be characterized as a stabbing, knife-like, boring, or burning discomfort. Often the pain radiates down the left arm. In some instances, the pain of AMI may begin in the epigastrium and simulate a variety of abdominal disorders, which often causes AMI to be misdiagnosed as indigestion. In other patients, the discomfort of AMI radiates to the shoulders, upper extremities, neck, and jaw, again usually favoring the left side. Diagnosis The ideal biomarker of myocardial injury should 1) provide early detection of myocardial injury, 2) provide rapid, sensitive, and specific diagnosis for an AMI, 3) serve as a risk stratification tool in ACS patients, 4) assess the success of reperfusion after thrombolytic therapy, 5) detect reocclusion and reinfarction, 6) determine the timing of an infarction and infarct size, and 7) detect procedural-related perioperative MI during cardiac or noncardiac surgery. In reality, no 1 biomarker is able to 100% cover all these areas. However, cardiac troponin (cTn) does provide the power to be utilized in the majority of these clinical areas. Ruling in AMI requires a test with high diagnostic sensitivity (preferred by the ER physician in the urgent care, emergency setting as to not send anyone home with an AMI), whereas ruling out AMI requires a test with high diagnostic specificity (preferred by the cardiologist following admission to avoid excessive and costly diagnostic evaluations in the non-AMI patient). It is the function of the laboratory to provide advice to physicians about cardiac biomarker/troponin characteristics. An updated 2012 “Global Until 2000, the diagnosis of AMI established by the World Health Organization (WHO) Task Force for the Third required at least 2 of the following criteria: 1) a history of chest pain, 2) evolutionary changes Universal Definition of MI” on the ECG, and/or 3) elevations of serial cardiac biomarkers (total creatine kinase [CK] and has codified the role of CKMB). It was rare for a diagnosis of AMI to be made in the absence of biochemical evidence of biomarkers. The advocate myocardial injury. A 2000 ESC/ACC consensus conference, updated in 2007 and most recently that the diagnosis be made from evidence of in 2012 by the “Global Task Force for the Third Universal Definition of MI,” has codified the myocardial injury based role of biomarkers. The advocate that the diagnosis be made from evidence of myocardial injury on biomarkers of cardiac based on biomarkers of cardiac damage, preferably cTnI or cTnT, in the appropriate clinical damage, preferably situation of ischemic symptoms (Table 9–1). This guideline does not suggest that all increases cardiac troponin (cTn) of cTn should elicit a diagnosis of AMI, but only those associated with the appropriate clinical, I or T, in the appropriate ECG, and imaging findings. When cTn increases that are not caused by acute ischemia occur, clinical situation of the clinician is obligated to search for another etiology for the elevation, a number of which ischemic symptoms. are shown in Table 9–2. The initial ECG is diagnostic of AMI in about 30% of AMI patients.
CHAPTER 9 The Heart 211 TABLE 9–1 Criteria for Diagnosis of Acute Myocardial Infarction The term acute myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any 1 of the following criteria meets the diagnosis for MI: • Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin [cTn]) with at least 1 value above the 99th percentile upper reference limit (URL) and with at least 1 of the following: ° Symptoms of ischemia ° New or presumed new significant ST-segment T-wave (ST-T) changes or new left bundle branch block (LBBB) ° Development of pathological Q waves in the ECG ° Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality ° Identification of an intracoronary thrombus by angiography or autopsy • Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased • Percutaneous coronary intervention (PCI)-related MI is arbitrarily defined by elevation of cTn values (>5 × 99th percentile URL) in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, i) symptoms suggestive of myocardial ischemia, ii) new ischemic ECG changes, iii) angiographic findings consistent with a procedural complication, or iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required • Stent thrombosis associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least 1 value above the 99th percentile URL • Coronary artery bypass grafting (CABG)-related MI is arbitrarily defined by elevation of cardiac biomarker values (>10 × 99th percentile URL) in patients with normal baseline cTn values (≤99th percentile URL). In addition, i) new pathological Q waves or new LBBB, ii) angiographically documented new graft or new native coronary artery occlusion, or iii) imaging evidence of new low of viable myocardium or new regional wall motion abnormality are required TABLE 9–2 Diagnoses of Increased Cardiac Troponin: Elevation of Cardiac Troponin Values Because of Myocardial Injury Injury related to primary myocardial ischemia Plaque rupture Intraluminal coronary artery thrombus formation Injury related to supply/demand imbalance of myocardial ischemia Tachyarrhythmias/bradyarrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolemic, or septic shock Severe respiratory failure Severe anemia Hypertension with or without LVH Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction without significant CAD Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotoxic agents, for example, anthracyclines, Herceptin Multifactorial or indeterminate myocardial injury Heart failure Stress (takotsubo) cardiomyopathy Severe pulmonary embolism or pulmonary hypertension Sepsis and critically ill patients Renal failure Severe acute neurological diseases, for example, stroke, subarachnoid hemorrhage Infiltrative diseases, for example, amyloidosis, sarcoidosis Strenuous exercise
212 CHAPTER 9 The Heart TABLE 9–3 Universal Classification of Different Types of Myocardial Infarction Type 1: spontaneous myocardial infarction Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, assuring erosion, or dissection with resulting intraluminal thrombus in 1 or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD but on occasion nonobstructive or no CAD. These are either an ST-segment elevation MI (STEMI) or non-STEMI (NSTEMI) Type 2: myocardial infarction secondary to an ischemic imbalance In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, for example, coronary endothelial dysfunction, coronary embolism, tachyarrhythmias/bradyarrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without LVH Type 3: myocardial infarction resulting in death when biomarker values are unavailable Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected Type 4a: myocardial infarction related to percutaneous coronary intervention (PCI) Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values 5 × 99th percentile URL in patients with normal baseline values (20% if the baseline values are elevated and are stable or falling. In addition, i) symptoms suggestive of myocardial ischemia, ii) new ischemic ECG changes or new LBBB, iii) angiographic loss of patency of a major coronary artery or side branch or persistent slow- or no-flow or embolization, or iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required Type 4b: myocardial infarction related to stent thrombosis Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarkers values with at least 1 value above the 99th percentile URL Type 5: myocardial infarction related to coronary artery bypass grafting (CABG) Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10 × 99th percentile URL in patients with normal baseline cTn values (
CHAPTER 9 The Heart 213 cytoplasmic fraction (3%–6%). cTn subunits I and T have different amino acid sequences encoded by different genes allowing for their cardiac tissue specificity. Following myocardial injury, multiple forms are elaborated both in tissue and in blood. The multiple forms of Troponin is a complex cTnI include the T–I–C ternary complex, IC binary complex, and free I. Multiple chemical of 3 protein subunits, modifications of these 3 forms can occur, involving oxidation, reduction, phosphorylation troponin C (the calcium- and dephosphorylation, and both C- and N-terminal degradation. The conclusions from binding component), these observations are that cTn immunoassays need to be developed in which the antibodies troponin I (the recognize epitopes in the stable region of cTnI and, ideally, demonstrate an equimolar response inhibitory component), to the different cTnI forms that circulate in the blood. and troponin T (the tropomyosin-binding component). Over the Analytical Methods for Measuring Cardiac Troponin past 20 years, numerous manufacturers have Over the past 20 years, numerous manufacturers have developed monoclonal antibody-based developed monoclonal diagnostic immunoassays for the sensitive measurement of cTnI and cTnT. Assay times range antibody-based from 5 to 30 minutes. Table 9–4 shows analytical characteristics of representative assays approved diagnostic immunoassays by the FDA for patient testing. In clinical practice, 2 obstacles limit the ease for switching from for the measurement of 1 cTnI assay to another. First, there is currently no primary reference cTnI material available for cTnI and cTnT. manufacturers to use for standardizing assays. Second, concentrations fail to agree because of the different epitopes recognized by the multiple, different antibodies used in different assays. Therefore, standardization of cTnI assays remains elusive. For cTnT, there is only 1 manufacturer. Therefore, there are no standardization problems. In 2012, the IFCC Task Force on Clinical Appli- cations of Cardiac Biomarkers readdressed quality specification aspects for cTn assays. These specifications were intended for use by the manufacturers of commercial assays and by clinical TABLE 9–4 Analytical Characteristics of Representative Contemporary Sensitive, and High-sensitivity (hs), Point-of-care Cardiac Troponin Assays Epitopes Recognized by Company/Platform/ 99th Percentile 10% CV Capture (C) and Detection (D) Assay LoD (μg/L) (μg/L) (μg/L) Antibodies Abbott ARCHITECT 0.009 0.028 0.032 C: 87-91, 24-40; D: 41-49 Abbott i-STAT (POC) 0.02 0.08 0.10 C: 41-49, 88-91; D: 28-39, 62-78 Alere Triage (POC) 0.05
214 CHAPTER 9 The Heart laboratories using cTn assays to establish uniform criteria so that all assays could be evaluated objectively for their analytical qualities and clinical performance. Factors addressed included: antibody selection, calibration materials, imprecision characteristics at clinical decision values, effects of storage time and temperature, glass versus plastic tubes versus gel separator tubes, the influence of anticoagulants, and whole blood measurements. 99th Percentile Reference Value as a Cutoff for Diagnosis of Acute Myocardial Infarction The Global Task Force’s 2012 “Third Universal Definition of Myocardial Infarction” guideline was predicated on cTn monitoring, with detection of a rising and/or falling cTn, and with at least 1 value above the 99th percentile value. Using the 99th percentile value (compared with the older WHO criteria) has demonstrated an increase in the number of MIs in day-to-day clinical practice, EDs, epidemiologic studies, and clinical trials. The data suggest that the more analyti- cally sensitive cTn tests result in greater rates of MI diagnosis and greater rates of cTn positivity compared with the older biomarker CKMB. Milder and smaller MIs are detected. Clinical cases prior to 2007 that were earlier classified as unstable angina are given a diagnosis of MI because of an increased and rising cTn. Further, procedure-related troponin increases (ie, following angio- plasty) will be labeled MI (Table 9–3). The importance of small troponin increases has been confirmed by their association with a poor prognosis. Several markers should Several biomarkers should no longer be used to evaluate cardiac disease. They include no longer be used to aspartate aminotransaminase (AST), total CK activity, CKMB isoforms, myoglobin, total evaluate cardiac disease. lactate dehydrogenase (LD), and LD isoenzymes. These markers have poor specificity for the They include aspartate detection of cardiac injury because of their wide tissue distribution. Further, CKMB is no longer a aminotransaminase (AST), recommended biomarker, and is suggested for clinical use only when cTn assays are not available. total CK activity, CKMB CKMB offers no additional diagnostic value to aid in the timing of the onset of myocardial injury, isoforms, myoglobin, total infarct sizing, or determination of reinfarction. There is no evidence to support dual testing for lactate dehydrogenase cTn and CKMB. (LD), and LD isoenzymes. Role of Cardiac Troponin for Risk Outcomes Assessment Patients With Ischemia In the environment of preventive and evidence-based medicine, the use of cTnI or cTnT mea- sured in patients with ischemia will allow clinicians to use biomarkers as both exclusionary and prognostic indicators. The results will assist in determining who is more at risk for AMI and death, and thereby determine who may benefit from early medical or surgical intervention. Such patients benefit from the use of anticoagulant therapy and the use of platelet antagonists, and an early invasive strategy. The goal of monitoring cardiac biomarkers in patients suggestive of ACS with and without AMI would be to effectively identify patients with unstable coronary disease and triage them to an appropriate therapeutic regimen. Optimal use of this strategy requires at least 2 blood samples for cTn measurement. General population screening of hospitalized patients with cTnI or cTnT is not recommended at present. Patients With Nonischemic Presentations Clinicians are often confronted with a clinical history of a patient without overt CAD and a low probability of myocardial ischemia. However, as a precautionary measure, serial cTns are ordered. A typical serial order set to rule in or rule out an AMI would include blood draws at 0 hour (presentation), 3, 6, and 9 to 12 hours. When 1 or 2 of the serial cTn concentrations are found to be increased, the clinician would likely be confronted with the following concerns: 1) What does the increase mean in the clinical setting of a nonischemic patient? 2) Is the increase a false-positive finding resulting from an analytical error? 3) Why was the test ordered in the first place? As cTn assays with increasing low-end analytical sensitivity (high-sensitivity [hs] cTn assays) have been developed (currently not FDA cleared for use in the United States), the ability to detect minor degrees of myocardial injury in a variety of clinical conditions has widened and has led to a better understanding that cTn is not just a biomarker for MI, but a sensitive biomarker
CHAPTER 9 The Heart 215 for myocardial injury. The 20% of suspected ACS patients who clinically do not rule in for MI, but display an increased cTn, represents patients with nonischemic pathologies (Table 9–2) in whom the mechanisms of injury are well defined (such as myocarditis, blunt chest trauma, and chemotherapeutic agents), and patients with increased cTn, in whom the mechanism of injury is not clear. Orders for Serial Cardiac Troponin Testing Blood samples should be drawn at presentation (0 hour) to the hospital (often this is hours after the index clinical symptom onset) and at least once more at 6 to 9 hours later. As noted, a typical serial order set to rule in or rule out an AMI would include blood draws at 0 hour (presentation), 3, 6, and 9 to 12 hours. Occasionally a patient may require a 12- to 24-hour sample, if the earlier measurements are normal, but the clinical suspicion of AMI is high. As the cTn concentration may remain increased 3 to 12 days after an AMI, after 2 positive values with a rising pattern, it does not appear cost-effective to continually monitor cTn once a diagnosis is established. In patients where recurrent MI is suspected from clinical signs or symptoms following the initial MI, an immediate remeasurement at the time of a suspicious new event (0) and 3-, 6-, and 9-hour serial blood samples are recommended. It is reasonable to suspect recurrent infarction if there is a >20% increase in the second value as long as it exceeds the 99th percentile. High-sensitivity Cardiac Troponin Assays It is important to understand that the term “high sensitivity” (hs) reflects the assay’s character- istics and does not refer to a difference in the form of cTn being measured. There is a need for a consensus on defining what nomenclature should be used for an hs assay. Several names have been used in the literature for these assays, but the term “high sensitivity” has been recommended by expert opinion. This term, however, begs the question: how does one define an hs assay? In a scorecard concept (Table 9–5), an assay is designated hs if it meets 2 basic criteria. First, the total imprecision (CV) at the 99th percentile value should be ≤10%. Second, measurable concentra- tions below the 99th percentile (the upper limit of normal) should be attainable with an assay at a concentration value above the assay’s limit of detection for at least 50% of healthy individuals. None of the current US-marketed assays for both central laboratory and point-of-care testing meet the 2-fold hs criteria. Concentrations for hs assays are expressed in nanograms per liter instead of the commonly published units of micrograms per liter. For deriving normal reference 99th percentile cutoffs for cTn assays, it is recommended that inclusion criteria be based on data obtained from an interview for a history of medications and known underlying disease, as well as a blood measurement of a natriuretic peptide (NP; N-terminal pro–B-type natriuretic peptide [NT-proBNP] or B-type natriuretic peptide [BNP]), interpreted vis-à-vis a cutoff value for the exclusion of ventricular dysfunction to serve as a TABLE 9–5 Scorecard Designations of cTn Assays Acceptance Designation Total Imprecision at the 99th Percentile (CV%) Guideline acceptable ≤10 Clinically usable >10 to ≤20 Not acceptable >20 Assay Designation Measurable Normal Values Below the 99th Percentile (%) Level 4 (third generation, hs) ≥95 Level 3 (second generation, hs) 75 to
216 CHAPTER 9 The Heart surrogate biomarker for underlying myocardial dysfunction, and an estimated GFR to exclude renal disease. In addition, the groups should be split equally by sex and include a diverse racial and ethnic mix. Literature now supports reporting of gender-specific cutoffs for hs assays, as men demonstrate approximately 2-fold higher 99th percentiles compared with women. With improved analytical sensitivity, hs assays have been shown to provide an earlier diag- nosis, with the ability to rule in and rule out by 3 hours instead of 6 hours with contemporary assays. However, with increased clinical sensitivity, with the ability to detect smaller myocardial injuries from multiple, pathological etiologies, decreased clinical specificity, below 80%, occurs. Early studies have now demonstrated that the use of a delta change in cTn concentration over a 0- to 3-hour serial time window allows for the ability to separate acute injury, that is, AMI, from a chronic injury, such as heart failure, with improved clinical specificity up to 95%. This will be an important tool to use for clinical care when hs assays are cleared for use in the United States some time in 2014. CONGESTIVE HEART FAILURE Description CHF is a condition in which there is ineffective pumping of the heart leading to an accumulation of fluid in the lungs. Typically, it results from a loss of cardiac tissue and subsequent function. It is defined as the pathophysiological condition in which an abnormality of cardiac function CHF is a condition is responsible for the failure of the heart to pump sufficient blood to satisfy the requirements in which there is of the metabolizing tissues. In the United States, CHF is the only cardiovascular disease with ineffective pumping of an increasing incidence. The National Heart, Lung, and Blood Institute estimates that current the heart leading to an prevalence is about 5 million Americans with CHF, with an incidence of approximately 400,000 accumulation of fluid in new cases each year. CHF is the leading cause of hospitalization in individuals 65 years and older. the lungs. Two biomarkers Current prognosis is dependent on disease severity, but overall it is poor. The 5-year mortality have been well studied is approximately 10% in mild CHF, 20% to 30% in moderate CHF, and up to 80% in end-stage to assist in these disease. clinical settings: B-type natriuretic peptide (BNP, pharmacologically active Diagnosis hormone) and N-terminal proBNP (NT-proBNP, not Natriuretic Peptides in Monitoring CHF pharmacologically active Two biomarkers have been well studied to assist in these clinical settings: BNP (pharmacologically peptide). active hormone) and NT-proBNP (not pharmacologically active peptide). Both blood peptides are derived from cleavage of the myocardial proBNP peptide following myocardial stress and/or fluid overload. In general, the clinical evidence for utilization of either biomarker is very similar, but each has subtle analytical and physiological differences, depending on the pathophysiology of an individual patient. In the course of this chapter, both NPs are used interchangeably unless specifically noted. The ACC/AHA practice guidelines for the evaluation and management of CHF indicate that the role of NP in the identification of CHF patients remains to be clarified. In contrast, the ESC has incorporated monitoring NPs into their practice algorithm at the time of patient presentation alongside the clinical history, physical examination, ECG, and chest x-ray. An abnormal NP find- ing would trigger an echocardiogram or other imaging modality. NP concentrations in patients diagnosed with CHF are substantially increased (>1000 ng/L for BNP or >1800 NT-proBNP) when compared with patients who have minor increases (
CHAPTER 9 The Heart 217 Importantly, NPs are not 100% specific for CHF. Increases have been described for other non-CHF etiologies involving filling pressure defects, including LV hypertrophy, inflammatory cardiac diseases, systemic arterial hypertension, pulmonary hypertension, acute and chronic renal failure, liver cirrhosis, and several endocrine disorders (eg, hyperaldosteronism and Cush- ing syndrome). In CHF patients presenting to the ED, patients admitted tend to have higher BNP concentrations (>500 ng/L) versus those who are discharged (mean
218 CHAPTER 9 The Heart Reference Intervals: Medical Decision Cutoff Values A number of clinical factors affect the BNP and NT-proBNP concentrations, most importantly age, gender, obesity, and renal function. Significant differences are observed between men and women (higher), and there are increasing concentrations with age by decade. For BNP and NT-proBNP, the significance of the results for these assays in relation to the degree of left ventricle dysfunction remains a debate. For both analytes, there is an inverse relationship between values and body mass index. For NT-proBNP, establishing reference intervals has been challenging. Review of both the FDA-approved US package insert and the European assay package insert reveals substantial differences in what concentrations are considered normal by age and sex. For BNP, a cutoff of 100 ng/L has been endorsed as demonstrating optimal sensitivity and specificity. For NT-proBNP, the FDA-approved package insert describes a 2-tier cutoff by age at 75 years: 450 ng/L. However, more evidence-based cutoffs have been derived from the PRIDE/ICON studies based on age and renal function, and are recommended as follows—age 450 ng/L; age ≥50 years: >900 ng/L; all ages: best negative predictive value 60 mL/min: 900 pg/mL, and eGFR ≤60 mL/min: 1800 ng/L. Implications for Therapy Using Test Results for Natriuretic Peptides The utility of serial measurements of NPs in guiding therapy for chronic heart failure has been the subject of numerous randomized controlled trials reported in the literature since 2000. The existing trial data suggest that adjustment of treatment in chronic heart failure according to NP measurements, used in conjunction with established clinical treatments, is likely to reduce car- diac mortality and hospital admissions with heart failure, at least in patients with systolic heart failure who are younger than 75 years and relatively free of comorbidities. Biological Variability As BNP and NT-proBNP become more widely used to monitor CHF patients following therapy, questions have addressed the usefulness of serial monitoring in assisting the success of drug ther- apy. In a study of 11 patients with CHF, the biological variation for BNP and NT-proBNP was evaluated using 4 different assays. The findings indicated that a change of 130% for BNP and 90% for NT-proBNP is necessary before results of serially collected data can be considered clinically and statistically significant. For example, these findings imply that a decrease from approximately 500 to 250 ng/L would be necessary for a clinician to conclude that therapy was successful in improving CHF features. Clinicians without this knowledge may inappropriately assume that a decrease from an admission BNP value of 500 ng/L to a 24-hour post-admission value of 400 ng/L may have been a result of successful patient management. It has been suggested that following the admission BNP value, a second BNP value be obtained within 24 hours of discharge to optimize the diagnostic utility of BNP in the overall assessment of patients with CHF. Novel Biomarkers for Heart Failure Risk Assessment In addition to the advances in the understanding of established NP biomarkers in HF, there is an increased study of the elucidation of novel biomarkers potentially useful for the evaluation and management of patients with HF, and the growing understanding of important and relevant comorbidities in HF. Literature on candidate biomarkers from a number of classes will be growing over the next several years and include: a) myocyte stretch (with assays for ST2, GDF-15), b) myocyte necrosis (with hs-cTn assays), c) systemic inflammation (with assays for LP-PLA2), d) oxidative stress (with assays for MPO), e) extracellular matrix turnover (with assays for collagen propeptides), f) neurohormones (with assays for chromogranin A), and g) biomarkers of extracardiac processes, such as renal function (with assays for NGAL).
CHAPTER 9 The Heart 219 REFERENCES Apple FS. Opinion: a new season for cardiac troponin assays: its time to keep a scorecard. Clin Chem. 2009;55:1303–1306. Apple FS. High-sensitivity cardiac troponin for screening large populations of healthy people: is there risk? Clin Chem. 2011;57:537–539. Apple FS, Collinson PO; IFCC Task Force on Clinical Applications of Cardiac Biomarkers. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem. 2012;58:54–61. Apple FS, et al. Quality specifications for B-type natriuretic peptide assays. Clin Chem. 2005;51:486–493. Apple FS, et al. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage laboratory medicine practice guidelines: analytical issues for biomarkers of heart failure. Circulation. 2007;116:e95–e98. Apple FS, et al. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage laboratory medicine practice guidelines: analytical issues for biomarkers of acute coronary syndromes. Clin Chem. 2007;53:547–551. Apple FS, et al. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem. 2012;58:1574–1581. Katus HA, et al. Interpreting changes in troponin—clinical judgment is essential. Clin Chem. 2012;58:39–44. Kavsak PA, et al. Cardiac troponin testing in the acute care setting: ordering, reporting, and high sensitivity assays—an update from the Canadian Society of Clinical Chemists (CSCC). Clin Biochem. 2011;44:1273–1277. McFalls EO, et al. Long-term outcomes of hospitalized patients with a non-acute syndrome diagnosis and an elevated cardiac troponin level. Am J Med. 2011;124:630–635. Morrow DA, et al. National Academy of Clinical Biochemistry practice guidelines: clinical characteristics and utilization of biomarkers in acute coronary syndromes. Clin Chem. 2007;53:552–574. Peacock WF, et al; for the ADHERE Scientific Advisory Committee Study Group. Cardiac troponin and heart failure outcome in acute heart failure. N Engl J Med. 2008;358:2117–2126. Tang WHW, et al. National Academy of Clinical Biochemistry practice guidelines: clinical utilization of cardiac biomarker testing in heart failure. Circulation. 2007;116:e99–e109. Thygesen K, et al; Writing Group on Behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598. Van Kimmenade RRJ, Januzzi JL Jr. Emerging biomarkers in heart failure. Clin Chem. 2012;58:127–138. Wu AHB, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: use of cardiac troponin and B-type natriuretic peptide or N-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure. Clin Chem. 2007;53:2086–2096.
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C H A P T E R Diseases of Red Blood Cells Daniel D. Mais 10 LEARNING OBJECTIVES 1. Learn the diﬀerent causes of anemia and their pathophysiology. 2. Learn how to identify the speciﬁc cause of anemia in a particular patient. 3. Learn the causes of erythrocytosis and how to distinguish among them. CHAPTER OUTLINE Anemia 221 Glucose-6-phosphate Dehydrogenase Definition 221 (G6PD) Deficiency 246 Differential Diagnosis 222 Pyruvate Kinase (PK) Deficiency 246 Acute Blood Loss 235 Paroxysmal Nocturnal Hemoglobinuria 247 Iron Deficiency Anemia 236 Sideroblastic Anemia 247 Anemia of Chronic Disease (ACD) 237 Pure Red Cell Aplasia 247 Thalassemia 238 Erythrocytosis 248 Folate Deficiency 239 Definition 248 Vitamin B12 Deficiency 239 Differential Diagnosis 248 Lead Poisoning (Plumbism) 240 Polycythemia Vera 248 Sickle Cell Anemia and Other Methods 249 Hemoglobinopathies 241 Red Cell Indices 249 Hereditary Spherocytosis 242 Reticulocyte Counting 250 Hereditary Elliptocytosis (HE) 243 Hemoglobin Electrophoresis 250 Autoimmune Hemolytic Anemia 243 Screening Tests for Sickle Hemoglobin 251 Hemolytic Disease of Osmotic Fragility Test 251 the Newborn (HDN) 245 Direct Antiglobulin Test (Coombs Test) 251 Microangiopathic Hemolytic Anemias 245 Kleihauer–Betke Test 251 ANEMIA Definition Anemia refers to a deficiency in red blood cells (RBCs) and implies a decline in oxygen-carrying capacity. The complete blood count (CBC) provides several measures of red cell quantity, includ- ing RBC count, hemoglobin (Hb) concentration, and hematocrit (Hct) (see description of RBC indices later in this chapter). Hb concentration is the parameter most widely used to diagnose anemia, based on 1967 World Health Organization (WHO) recommendations (Table 10–1). This definition is not universally accepted, and numerous alternatives have been proposed over the years, usually suggesting slightly higher values and race-specific values. It is important to remem- ber also that the normal ranges for Hb and Hct are different for infants, children, adult men, Anemia refers to a adult women, pregnant women, and the elderly. Attention to age- and gender-appropriate normal deficiency in red blood ranges is important in the evaluation of anemia. cells (RBCs) and implies Anemia may present with pallor, fatigue, dyspnea, or evidence of poor tissue oxygen- a decline in oxygen- ation (chest pain due to poor cardiac oxygenation, altered mental status due to poor cerebral carrying capacity. 221
222 CHAPTER 10 Diseases of Red Blood Cells TABLE 10–1 WHO Definition of Anemia Group Hemoglobin (g/dL) Infants and children, 6 months to 6 years
CHAPTER 10 Diseases of Red Blood Cells 223 TABLE 10–3 Classification of Anemia by Mean Corpuscular Volume (MCV) and Red Blood Cell Distribution Width (RDW) Normal RDW High RDW Low MCV Anemia of chronic disease Iron deficiency anemia Thalassemia Sickle cell disease Hemoglobin E Normal MCV Acute blood loss Early nutritional (iron, B12, folate) deficiency Anemia of chronic disease Sickle cell disease Low erythropoietin states (renal failure) High MCV Aplastic anemia Folate and B12 deficiency Liver disease Myelodysplasia Alcohol abuse Reticulocytosis (eg, hemolysis) Microcytic anemia Reticulocyte count Hypo-regenerative Hyper-regenerative microcytic anemia microcytic anemia Serum ferritin Spherocytosis Serum iron % Transferrin saturation Yes No Test results Test results are low are normal Direct Inherited antiglobulin membrane test or enzyme defects Probable Hemoglobin iron deficiency electrophoresis Positive Negative Sideroblastic anemia Immune Thalassemia Hereditary Anemia of hemoglobin E hemolytic spherocytosis chronic disease anemia FIGURE 10–1 Diagnostic algorithm for microcytic anemia.
224 CHAPTER 10 Diseases of Red Blood Cells Normocytic anemia Reticulocyte Multiple cytopenias: Reticulocyte count count normal Myelodysplasia increased Bone marrow infiltration Aplastic anemia Isolated anemia: No blood loss: Anemia of chronic disease Probable hemolysis Early iron deficiency Early folate/B12 deficiency Medication effect If all excluded: Pure red cell aplasia Myelodysplasia Paroxysmal nocturnal Hemoglobinuria FIGURE 10–2 Diagnostic algorithm for normocytic anemia. Macrocytic anemia Reticulocyte count low Reticulocyte count high No hypersegmented Macrocytosis due to Hypersegmented neutrophils and reticulocytosis neutrophils and MCV < 115: (anemia probably due MCV > 115: Liver disease to hemolysis or blood Probable B12 Hypothyroidism loss) or partially treated or folate deficiency Down syndrome hypo-regenerative Medication effect macrocytic anemia Low B12 and All excluded Normal B12 folate confirms and folate deficiency Probable myelodysplasia FIGURE 10–3 Diagnostic algorithm for macrocytic anemia.
CHAPTER 10 Diseases of Red Blood Cells 225 Suspected hemolytic anemia (reticulocytosis, increased LDH): Exclude splenic enlargement and occult bleed Perform: Peripheral smear Bilirubin Haptoglobin Urine hemoglobin Urine hemosiderin Urine urobilinogen Schistocytes Spherocytes, spur cells, bite cells, etc. Bilirubin normal to increased Bilirubin increased (especially indirect) Haptoglobin decreased or absent Haptoglobin normal to decreased Urine hemoglobin positive Urine hemoglobin absent Hemosiderinuria present Hemosiderinuria absent Urobilinogen absent Urobilinogen increased Intravascular hemolysis Extravascular hemolysis Microangiopathic: DIC, TTP, HUS, Membrane defects: eg, HS, HE HELLP (clinical presentation) (peripheral smear) Mechanical hemolysis, eg, heart Pyruvate kinase deficiency (PK) valve (note history) (peripheral smear, PK assay) Toxins, eg, venoms (note history) Hemoglobinopathy (hemoglobin Infections, eg, malaria, babesia, electrophoresis) clostridium (peripheral smear, history) Thalassemia (red cell indices, Oxidant stress, eg, some cases of hemoglobin electrophoresis) G6PD deficiency (G6PD assay) Hemolytic transfusion reaction: Hemolytic transfusion reaction, eg, eg, Rh, Duffy (history) ABO incompatibility (history) Oxidant stress, eg, some cases of Paroxysmal nocturnal hemoglobinuria G6PD deficiency (G6PD assay) (Ham’s test, flow cytometry) Paroxysmal cold hemoglobinuria (detect anti-P antibody) FIGURE 10–4 Diagnostic algorithm for suspected hemolytic anemia. DIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; HELLP, hemolysis, elevated liver function tests, and low platelets; HS, hereditary spherocytosis; HE, hereditary elliptocytosis; G6PD, glucose-6-phosphate dehydrogenase.
226 CHAPTER 10 Diseases of Red Blood Cells TABLE 10–4 Morphologic Findings in Red Cells Finding Definition Associated Conditions Basophilic stippling Small blue dots in red cells, due to clusters of Hemolytic anemias ribosomes Lead poisoning Thalassemia Pappenheimer Larger, more irregular, and grayer than Asplenia bodies basophilic stippling, due to iron-containing Sideroblastic anemia mitochondria Heinz bodies Heinz bodies: gray-black round inclusions, Oxidative injury as found in Bite cells seen only with supravital stains (crystal G6PD deficiency or with unstable violet). Bite cells: sharp bite-like defects in red hemoglobins cells where a Heinz body has been removed in the spleen. Both are due to denatured hemoglobin Howell–Jolly bodies Howell–Jolly body: dot-like, dark purple Asplenia Cabot rings inclusion. Cabot ring: ring-shaped dark purple inclusion. Both represent a residual nuclear fragment Target cells Red cells with a dark circle within the Thalassemia central area of pallor, reflecting redundant Hemoglobin C membrane Liver disease Schistocytes Fragmented red blood cells, with forms such Microangiopathic hemolytic as helmet-shaped cells, due to mechanical red anemias (MHA): DIC, TTP, HUS, HELLP. cell fragmentation Mechanical heart valves Dacrocytes Teardrop or pear-shaped erythrocytes Can be seen in thalassemia and (teardrop cells) megaloblastic anemia Often seen in myelophthisis Echinocytes Red blood cells that have circumferential Uremia (burr cells) undulations or spiny projections with Gastric cancer pointed tips Pyruvate kinase deficiency Acanthocytes Red blood cells that have circumferential Liver disease (spur cells) blunt and spiny projections with bulbous tips Abetalipoproteinemia McLeod phenotype Spherocytes Red cells without central pallor due to Immune hemolytic anemia decreased red cell membrane Hereditary spherocytosis Elliptocytes Red cells twice as long as they are wide Iron deficiency Hereditary elliptocytosis Stomatocytes Red cells whose area of central pallor is Alcohol abuse elongated in a mouth-like shape Dilantin exposure Rh null phenotype (absence of Rh antigens) Hereditary stomatocytosis DIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; HELLP, hemolysis, elevated liver function tests, and low platelets. See Figures 10–5 to 10–18 for peripheral smears with abnormal red blood cell morphology. to low reticulocyte count. Such hyporegenerative anemias include iron deficiency anemia, anemia of chronic disease (ACD), lead poisoning, folate deficiency, B12 deficiency, myelodys- plastic syndrome, aplastic anemia, and pure red cell aplasia. Regardless of the morphology or red cell size, anemia that is accompanied by reticulocytosis suggests either hemolysis or hemorrhage. Some exceptions should be noted. One is a partially treated production defect, such as in the early treatment of iron, folate, or B12 deficiency, in which one may find persistent anemia with reticulocytosis. Second, both hemolytic and blood-loss ane- mia may eventually lead to depletion of iron, folate, or B12, and they can present as a produc- tion defect. Lastly, paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia that may transform to aplastic anemia.
CHAPTER 10 Diseases of Red Blood Cells 227 FIGURE 10–5 Peripheral blood smear with acanthocytes. FIGURE 10–6 Peripheral blood smear with the basophilic stippling. FIGURE 10–7 Peripheral blood smear with dacrocytes. FIGURE 10–8 Peripheral blood smear with echinocyte. Hemolytic anemias are those in which red cell survival, normally 120 days, is shortened. The premature destruction of erythrocytes may occur within the bloodstream (intravascular hemolysis) or within the reticuloendothelial system (eg, extravascular hemolysis). Intravas- cular hemolysis is caused by mechanical red cell trauma (microangiopathic hemolytic anemia [MHA] from mechanical heart valve), complement fixation on the red cell surface (eg, ABO incompatibility), paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobin- uria (PCH), snake envenomation, and infectious agents (eg, malaria, babesiosis, Clostridium). Extravascular hemolysis is much more common and is typical for all remaining causes of hemo- lysis. The causes of hemolysis may be inherited or acquired. Inherited forms of hemolytic anemia usually, but not always, present in early childhood (Table 10–5).
228 CHAPTER 10 Diseases of Red Blood Cells FIGURE 10–9 Peripheral blood smear from a patient with hemoglobin C disease. FIGURE 10–10 Peripheral blood smear showing a Howell–Jolly body.