The American Journal of Medicine
Volume 123, Issue 5 , Pages 393-399, May 2010

The Utility of Biomarkers in Sorting Out the Complex Patient

  • Christopher Moriates, MD
    • ,
  • Alan Maisel, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Alan Maisel, MD, San Diego VA Medical Center, Cardiology 111-A, 3350 La Jolla Village Dr., San Diego, CA 92116

Department of Medicine, Division of Cardiology, The University of California at San Diego and the San Diego Veterans Affairs Medical Center, San Diego, Calif

Article Outline

Abstract 

Today's patients present with a complexity of illness far more significant than ever before. Risk factors, in particular for cardiovascular, renal, and metabolic diseases, often interact with each other at core pathophysiological levels. Biomarkers are inexpensive tools that may help differentiate disease states in complex patients. Ideal biomarkers are both sensitive and specific to the disease state being examined. Natriuretic peptides are the prototype of ideal biomarkers and are adjuncts for the diagnosis and exclusion of heart failure in the dyspneic patient, especially those presenting with comorbidities such as lung disease. Just as natriuretic peptide levels can be considered the arbiter of congestive heart failure, cardiac troponins are decisive for myocardial necrosis. Novel assays with higher sensitivity will aid in earlier diagnosis, albeit with some decreased specificity. Nevertheless, the patient presenting with comorbidities and atypical symptoms of myocardial infarction will not be arbitrarily sent home. In the future, other novel biomarkers, such as neutrophil gelatinase-associated lipocalin for acute kidney injury, may come to the forefront for diagnosis of disease in the complex patient.

Keywords: Biomarkers, Complex patient

 

In medicine today, patients with few or no comorbidities are increasingly less frequent. Gone are the days when a visit to the family doctor meant a routine check of the blood pressure or a simple course of penicillin. Complex patients present with numerous risk factors for cardiovascular, renal, and metabolic diseases that interact with each other at core pathophysiological levels. Thus, this confluence of individual characteristics or variables with numerous disease states makes both diagnosis and treatment of the complex patient a tremendous challenge for health care professionals. Unfortunately, as the prevalence of complex patients is increasing,1, 2 so is our challenge of providing adequate care.

Clinical Significance

 


•Biomarkers are inexpensive tools that may help differentiate diseases in complex patients.

•Ideal biomarkers are both sensitive and specific to the disease state being examined.

•Natriuretic peptides and cardiac troponins are well-established markers for heart failure and infarction, respectively.

•Novel biomarkers, including highly sensitive troponins for ischemia, procalcitonin for bacterial pneumonia, and neutrophil gelatinase lipocalin for acute kidney injury, may move to the forefront of diagnosis in complex patients.

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The Increasing Prevalence of Complex Patients 

It is estimated that currently nearly one fourth of the US population has metabolic syndrome and that over 80 million American adults (1 in 3) have 1 or more types of cardiovascular disease.2 Of these Americans with cardiovascular disease, 38 million are estimated to be over 60 years old. Certainly, advances in modern medicine have allowed patients to live longer, illustrated by the increased survival in patients suffering acute myocardial infarction in the era of angioplasty and stent deployment. It is estimated, however, that 30%-50% of these patients will develop significant left ventricular dysfunction or heart failure as a result of the myocardial infarction.3

In the general population, 6.7 million older adults have both elevated C-reactive protein levels (≥2 mg/L) and low-density lipoprotein levels above their individual National Cholesterol Education Program goals.4 Thus, it is not at all uncommon for a typical complex patient to present to a physician's office with a history of obesity, hypertension, and cigarette smoking,5 with an active problem list that includes type 2 diabetes mellitus, coronary artery disease, congestive heart failure, renal insufficiency, chronic obstructive pulmonary disease, sleep apnea, and atrial fibrillation.

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The Importance of Differentiating Diseases in the Complex Patient 

Simply stated, patients do better when diagnosed and treated, immediately and effectively, for the complications with which they present. Take 2 examples:

•How many asymptomatic diabetic patients presenting with fatigue have died because they were sent home with an undiagnosed myocardial infarction? Indeed, missed diagnosis of acute coronary syndrome occurs in 2%-8% of patients presenting to an emergency department, resulting in dire consequences for both patients and physicians. Patients mistakenly discharged have approximately a 25% short-term mortality rate, which is at least twice what it would be if they were admitted, and missed myocardial infarctions are the number 1 cause of malpractice payouts.6

•How many patients with a history of chronic obstructive pulmonary disease (COPD) were never given life-saving medications for undiagnosed heart failure because their presentation with shortness of breath was treated with steroids and bronchodilators? Readmissions to the hospital for alternating diagnoses of pulmonary disease and heart failure are an all-too-common scenario, suggesting initial diagnosis ambiguity. A recent study of Medicare patients revealed that over 22% of patients admitted for COPD were readmitted to the hospital within 30 days, and that of these patients, 5.7% were admitted for heart failure.7 The use of B-type natriuretic peptide testing can decrease the number of readmissions that occur for presumably the wrong initial diagnose of heart failure or pulmonary disease.8

A significant challenge when targeting correct treatments is ensuring the correct diagnosis, however, acute problems can be difficult to diagnose with traditional tools alone.

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New Tools that Help Diagnose Patients With Complex Problems 

While expensive tests such as computed tomography and magnetic resonance imaging scans are used more frequently in this era of “defensive” medicine, the Obama administration's health task force made it evident that expensive tests need to be replaced by cheaper but effective means of diagnosis. Hence, the case for using effective biomarkers has never been so important.

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The Attributes that Comprise an Ideal Biomarker 

Ideal biomarkers are both sensitive and specific to the disease state being examined. They ideally define a disease (not necessarily a disease process), and potentially reflect on the underlying etiology that can be targeted for therapy. Clinical uses of biomarkers include diagnosis, risk stratification, screening, and guiding therapy.

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Promising Cardiac, Renal, and Metabolic Biomarkers Important in Diagnosis, Prognosis, and Management of Patients 

There are many emerging biomarkers currently under study, as well as a portfolio of established biomarkers that can bring immediate promise to understanding underlying etiologies of the complex patient (Figure 1). Several of these relevant biomarkers are included below with clinical examples.

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  • Figure 1. 

    Current and possible future biomarkers related to cardiac disease. IMA = ischemia-modified albumin; FABP = fatty acid binding protein; PIGF = placental growth factor; MPO = myeloperoxidase; TnI/TnT = troponin I/troponin T; Myo = myoglobin; CKMB = creatinine kinase MB isotype; CRP = C-reactive protein; TNFα = tumor-necrosis factor α; sCD40L = soluble CD40 ligand; ST2 = soluble ST2 receptor; PCT = procalcitonin; HgA1c = glycosylated hemoglobin; LDL = low-density lipoprotein; OxLDL = oxidized low-density lipoprotein; HCY = homocysteine; BNP = B-type natriuretic peptide; NT-proBNP = amino-terminal fragment of pro-B-type natriuretic peptide; MMP = metalloproteinases; MR-proANP = midregional pro-A-type natriuretic peptide; Gal-3 = galectin-3; GDF-15 = growth differentiation factor 15; NGAL = neutrophil gelatinase-associated lipocalin; Myo. ischemia = myocardial ischemia; LV = left ventricular.

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Natriuretic Peptides 

Natriuretic peptides, specifically B-type natriuretic peptide (BNP) and the amino-terminal fragment of proBNP (NT-proBNP), are well-established tools in the diagnosis and prognosis of patients with heart failure. Plasma natriuretic peptides (NPs) are released from the heart in response to volume overload, as well as serving as markers of elevated filling pressures, a finding that in many cases would otherwise be detectable only with invasive testing.9 Therefore, the use of NPs are an important adjunct to other diagnostic modalities.

Because BNP levels significantly aide in diagnosing or excluding heart failure in the complex patient with shortness of breath (dyspnea), it is the standard by which other biomarkers are being judged.10 The measurement of the inactive NT-proBNP also has become ingrained into standard clinical practice, and a single measurement of either NP for patients with dyspnea significantly aids in their diagnosis and management, resulting in shorter hospital stays and lower costs of hospitalization.11, 12

Consider a clinical case: An elderly patient with lung disease, hypertension, and renal insufficiency presents with dyspnea and a BNP level >500 pg/mL.

The elevated BNP level suggests that heart failure is likely, even in the presence of COPD exacerbation or pneumonia. Even a moderate elevation of creatinine would not account for the extent of elevation. Evaluating the BNP level in context of a pretest probability is an important diagnostic tool, as shown in Figure 2. Several studies suggest that BNP levels can subsequently be used to target treatment effectiveness such that the BNP level can be lowered gently to “dry” levels at the same time that the COPD exacerbation is treated with steroids, bronchodilators, and potentially, antibiotics.14

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  • Figure 2. 

    B-type natriuretic peptide (BNP) nomogram: using BNP values to determine confidence in the diagnosis of heart failure. A BNP nomogram can be used to determine the final probability of acute heart failure based on the initial clinical judgment (pretest probability) and the BNP level. A patient that has approximately a 50% pretest probability of having heart failure may have vastly different post-test probabilities based on the BNP level, as shown by the 3 different lines drawn on the nomogram.

Adapted from: McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106:416-422.13

As previously discussed, the BNP is a powerful tool for differentiating the underlying etiology of dyspnea, as illustrated in this clinical case: A 65-year-old man developed worsening dyspnea. He denied chest pain or nausea. He had a previous history of hypertension, COPD, and a myocardial infarction. Physical examination was significant for a jugular venous pressure of 14 cm, rhonchi and wheezing throughout all lung fields, and no gallops or edema. A bedside echocardiogram showed normal overall systolic function. This patient was diagnosed with COPD exacerbation, given the usual treatment, and discharged home at 8:00 pm. At 11:00 pm, he awoke with severe dyspnea and was transported via ambulance back to the same hospital. This time the BNP level was obtained; it was 900 pg/mL.

This patient had COPD with underlying diastolic dysfunction (also known as heart failure with preserved ejection fraction). Diastolic dysfunction is very common in the emergency department and is often more difficult to diagnose than systolic dysfunction. However, even in diastolic dysfunction heart failure, the BNP is elevated and is very reliable in separating patients with COPD exacerbation from those with congestive heart failure (CHF).15 In 1 study of 250 patients presenting to an emergency department with symptoms of dyspnea, 30 patients were initially misdiagnosed by the emergency physician, however, in these patients, if a BNP level was used, with a cutoff of 80 pg/mL, 29 of the 30 patients would have been correctly diagnosed (Figure 3).16

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  • Figure 3. 

    Missed diagnosis of congestive heart failure (CHF) in the emergency department in a study of 250 patients. In a study of 250 patients presenting to the emergency department with symptoms of dyspnea, 15 patients were diagnosed with having CHF by emergency physicians when they actually had other causes of dyspnea, while another 15 patients that ultimately did have CHF were misdiagnosed by emergency physicians. The B-type natriuretic peptide levels between these 2 groups differed significantly and if a cutoff B-type natriuretic peptide level of 80 pg/mL was used for diagnosis, 29 of the 30 initially misdiagnosed patients would have been correctly identified.

Adapted from: Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37:379-385.16

Consider a final case: a middle-aged female patient presenting with acute shortness of breath and a creatinine level of 3.2 mg/dL.

The elevated creatinine suggests renal dysfunction, a well-documented confounder of natriuretic peptide levels. Nevertheless, BNP is only partially influenced by renal function, and moreover, is considerably less impacted when compared with NT-proBNP.17 Thus, knowledge of baseline BNP level in this clinical scenario is valuable, and can often be a useful guide to treatment. If we consider that the baseline BNP level for this patient is ∼200 pg/mL and that the current BNP level is ∼1200 pg/mL, then heart failure is clearly present. Some worsening of renal function also is likely present but should improve as the heart failure is treated (ie, type I cardio-renal syndrome). On the other hand, if the presenting BNP level was only slightly above baseline (ie, ∼400 pg/mL) with a higher creatinine than normal, then worsening renal function likely led to marginal volume increase and dyspnea.

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Newer Diagnostic and Prognostic Markers of Heart Failure 

Arrays of biomarkers that will likely prove useful in heart failure are on the horizon. The mid-regional pro-A-type natriuretic peptide assay is a newer addition to the existing panel of hemodynamic stress heart failure markers. Mid-regional pro-A-type natriuretic peptide has been found to have diagnostic value comparable to BNP and NT-proBNP, as shown in Figure 4, and even has been shown to have independent prognostic power.19 Less specific markers also have emerged as possible adjunctive measures in a multimarker approach to heart failure. Growth differentiation factor 15 levels are abnormally high in heart failure and provide independent prognostic power beyond that of established clinical and biochemical markers.20, 21 Galectin-3, produced by activated cardiac macrophages, is elevated in patients with acute heart failure, providing independent prognostic information.22 The soluble ST2 receptor (ST2) appears to be transcriptionally induced by mechanical strain of the heart and can be detected in the serum.23 ST2 levels appear to correlate with severity of heart failure, left ventricular ejection fraction, and creatinine clearance, as well as with the levels of BNP, NT-proBNP, and C-reactive protein.24 High ST2 levels also can serve as an independent predictor of cardiovascular death and heart failure following ST-elevation myocardial infarction.25

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  • Figure 4. 

    The sensitivity and specificity of natriuretic peptides for the diagnosis of acute destabilized heart failure in short-of-breath patients presenting to an emergency department. The natriuretic peptides—BNP, NT-proBNP and the more novel MR-proANP—have similar sensitivities and specificities for the diagnosis of acute heart failure at different cut-points. BNP = B-type natriuretic peptide; NT-proBNP = amino-terminal fragment of pro-B-type natriuretic peptide; MR-proANP = midregional pro-A-type natriuretic peptide.

Data from: Gegenhuber A, Struck J, Poelz W, et al. Midregional pro-A-type natriuretic peptide measurements for diagnosis of acute destabilized heart failure in short-of-breath patients: comparison with B-type natriuretic peptide (BNP) and amino-terminal proBNP. Clin Chem. 2006;52:827-831.18

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Diagnosing Pneumonia in Patients With Underlying Heart Failure 

A relatively common diagnostic dilemma is a patient with underlying heart failure who presents with acute dyspnea, representing most likely either an acute exacerbation of heart failure or possibly pneumonia. This is especially important because patients with heart failure are actually more prone to lower respiratory tract infections. A biomarker that can effectively identify bacterial infections in these patients would be extremely valuable. Procalcitonin (PCT) has been studied as a marker of bacterial infection and has been found to be markedly elevated in cases of infection.26 PCT has been suggested as a guide for differentiating those patients with COPD exacerbations who would benefit from antibiotic treatment from those who would not, and has been found to reduce antibiotic use without any change in clinical outcomes or forced expiratory volume1 between groups.27 The current established cutoffs indicate that a procalcitonin level of <0.1 μg/L suggests the absence of bacterial infection, 0.1-0.25 μg/L indicates that a bacterial infection is unlikely, 0.26-0.5 μg/L indicates a possible bacterial infection, and >0.5 μg/L strongly suggests the presence of bacterial infection.28

Consider the following clinical case: A 57-year old obese man with a history of COPD and heart failure presents to an emergency department with an acute worsening of dyspnea. The patient has diffuse wheezing and rales on lung examination and mildly worsened lower-extremity edema. A BNP level was obtained and found to be 250 pg/mL. A PCT level also was obtained and found to be 0.6 μg/L.

This patient initially presented with dyspnea that may have been due to an acute exacerbation of COPD or CHF. Because the patient's baseline BNP is unknown, it is unclear at this point whether the BNP represents an acute elevation, however, the PCT level >0.5 μg/L indicates that this patient likely has an underlying bacterial pneumonia and would clearly benefit from antibiotic treatment at this time.

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Troponins 

Just as BNP levels can be considered the arbiter of CHF, cardiac troponins (troponin I/troponin T) are decisive for myocardial necrosis. Because myocardial necrosis, whether associated with a coronary occlusion or subendocardial ischemia, is prognostic, a true elevation often leads to commencement of a cardiac-specific treatment.

Consider the following case: A woman with a history of diabetes and reflux disease, as well as a left anterior descending stent placed 2 weeks prior now presents to the triage area of the emergency department with vomiting. Her vital signs are within normal range and the electrocardiogram has an underlying paced rhythm, precluding the detection of ischemic changes.

The triage nurse in the past would likely have discharged the patient with prescribed antinausea medication. However, symptoms of vomiting can be part of the constellation of acute coronary syndrome, especially in women and diabetics. Thus, an immediate troponin test should be ordered and, if positive, could lead to lifesaving therapy in the catheterization laboratory, where acute stent thrombosis could be diagnosed and treated.

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The Next Generation “Highly Sensitive” Troponin Assays 

Cardiac troponin is the preferred biomarker for the detection of myocardial necrosis based on its high clinical sensitivity and absolute near specificity for myocardial tissue.29 The introduction of novel assays with even higher clinical sensitivity, detecting troponin levels at nanogram quantities, suggests even earlier diagnosis of acute myocardial infarction and identification of patients at substantial risk postinfarction.30 However, very low levels of troponin elevation, especially when not undergoing dynamic changes, will account for a potential decrease in specificity. Low levels of troponin can be seen in multiple comorbid disease states such as renal insufficiency and heart failure. Thus, clinicians will be faced with increased challenges in deciphering whether these “low levels” truly reflect transient ischemic etiology.

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Providing Additional Information to the Supersensitive Troponins 

Additional markers that have reasonable specificity for acute coronary syndrome might consequently offer additive value in further elucidating small, and perhaps rising, levels of troponin. Markers of oxidative stress, such as myeloperoxidase (MPO), may serve this important role. MPO may contribute to several phases of atherothrombosis, from the initial insult to the vascular endothelium, to development of the atheroma, to rupture of the vulnerable plaque and its clinical manifestation as acute coronary syndrome. MPO has shown prognostic utility in predicting long-term adverse events postinfarction at 30 days and at 6 months.31

The ability to diagnose ischemia before irreversible necrotic damage may revolutionize the management of patients with acute coronary syndrome. Along with high-sensitivity troponins, other potential markers of ischemia currently under investigation include BNP, whole blood choline, placental growth factor, heart-type fatty acid binding protein, and ischemia-modulated albumin.

Figure 5 displays an array of biomarkers that are emerging as important indicators of different stages of cardiac disease.

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  • Figure 5. 

    List of important biomarkers that may aid in the diagnosis and prognosis at various stages of coronary artery disease. MPO = myeloperoxidase; CRP = C-reactive protein; HCY = homocysteine; CD40L = CD40 ligand; OxLDL = oxidized low-density lipoprotein; MCP-1 = monocyte chemotactic protein-1; MMPs = matrix metalloproteinases; IL-6 = interleukin-6; IMA = ischemia-modified albumin; FABP = fatty acid binding protein; MDA-LDL = malondialdehyde-modified low-density lipoprotein; FFA = free fatty acids; BNP = B-type natriuretic peptide; Myo = myoglobin; CKMB = creatinine kinase MB isotype; TnI/TnT = troponin I/troponin T; NT-proBNP = amino-terminal fragment of proBNP.

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Neutrophil Gelatinase-Associated Lipocalin for Acute Kidney Injury 

Neutrophil gelatinase-associated lipocalin (NGAL) is one of the earliest and most robustly induced genes and proteins in the kidney after ischemic or nephrotoxic injury. Elevations are detectable within hours of acute kidney injury, whereas corresponding creatinine elevations lag 1 to 3 days behind.32 Studies have already demonstrated its usefulness as a diagnostic biomarker in the complex patient undergoing cardiopulmonary bypass, angiography with contrast administration, and diarrhea-associated hemolytic uremic syndrome.33, 34, 35 Recent studies suggest that elevated NGAL levels connote a more rapid decrease in renal function in those patients who already have the diagnosis of chronic kidney disease.36

Consider the following clinical case: An obese patient with COPD, heart failure, and renal insufficiency presents with acute dyspnea. The BNP level is 900 pg/mL and the creatinine is 2.1 mg/dL.

A normal urinary NGAL level suggests that while chronic kidney disease is present, no acute injury is involved. NGAL has a very high sensitivity and specificity for acute kidney injury, as shown in Figure 6.

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  • Figure 6. 

    The sensitivity and specificity of urine NGAL and creatinine for the diagnosis of acute kidney injury. Urine NGAL at a cut-point of 85 μg/g has sensitivity equal to a creatinine level of 1.4 mg/dL (93%), but has a much greater specificity (98% vs. 75%) at these cut-points. Urine NGAL may prove to be a more reliable marker for acute kidney injury than the current standard, creatinine. Urine NGAL = urine neutrophil gelatinase-associated lipocalin.

Data from: Nickolas TL, O'Rourke MJ, Yang J, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008;148:810-819.37

Continuing with the case: Subsequent to parenteral diuretic treatment, the BNP decreased to 600 pg/mL, and the patient was negative 2 L of urine. The NGAL level hadn't spiked. However, the following day, with another 2 L negative, the BNP was down to 400 pg/mL, and the NGAL level markedly increased, even though the creatinine level remained unchanged.

This likely means that the patient has reached his optimum dry weight BNP level, and as such, further aggressive diuretic treatment could lead to worsening renal function, likely evidenced by rising creatinine levels in subsequent 1-2 days.

Thus, NGAL might be able to help regulate appropriate diuretic treatment, probably even shorten the length of stay and help ensure that patients are discharged with lowest BNP levels while maintaining an optimal outpatient diuretic dose.

Figure 7 demonstrates where a paradigm using BNP, NGAL, and creatinine can help determine the volume status of the patients, and perhaps mitigate or prevent the worsening renal dysfunction that is so often seen in heart failure.

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  • Figure 7. 

    Hypothetical paradigm whereby the combination of BNP, NGAL, and serum creatinine could help determine the euvolemic state in patients treated for acute decompensated heart failure, avoiding or mitigating the worsening renal function that often occurs in this setting. BNP = B-type natriuretic peptide; NGAL = neutrophil gelatinase-associated lipocalin.

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Conclusion 

The increasing prevalence of obesity, cardiovascular disease, diabetes, metabolic syndrome, and chronic kidney disease collectively contributes to an increased prevalence of complex patients. Complex patients are difficult to diagnosis with traditional tools alone, and in this new era of affordable health care, less expensive tools are actively being sought as a way to improve patient care. Cardiac, renal, and metabolic biomarkers play a critical role in diagnosis, prognosis, and treatment management of complex patients. Novel biomarkers are expected to further elucidate underlying pathologies and allow for earlier detection of disease onset using multimarker panels of blood and urine that will directly improve clinical care for the complex patient.

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 Funding: None.

 Conflict of Interest: Christopher Moriates: no conflicts of interest. Alan Maisel: Consultant for Inverness. Research support from BRAHMS, Abbott, Inverness, Roche, Critical Diagnostics. Advisory board for Critical Diagnostics.

 Authorship: All authors had access to the data and a role in writing the manuscript.

PII: S0002-9343(09)01103-6

doi:10.1016/j.amjmed.2009.07.034

The American Journal of Medicine
Volume 123, Issue 5 , Pages 393-399, May 2010

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