Review
The Utility of Biomarkers in Sorting Out the Complex Patient

https://doi.org/10.1016/j.amjmed.2009.07.034Get rights and content

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.

Section snippets

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

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

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.

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.

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.

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

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

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

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

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

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

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

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

References (37)

  • D. Bolignano et al.

    Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage

    Am J Kidney Dis

    (2008)
  • E.S. Ford et al.

    Increasing prevalence of the metabolic syndrome among U.S. adults

    Diabetes Care

    (2004)
  • W. Rosamond et al.

    Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee

    Circulation

    (2008)
  • G.C. Fonarow

    Identifying and managing post-myocardial infarction patients with left ventricular dysfunctionMedscape Cardiology

  • J. Coresh et al.

    Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000

    J Am Soc Nephrol

    (2005)
  • K.J. Greenlund et al.

    Prevalence of multiple cardiovascular disease risk factors among women in the United States, 1992 and 1995: the Behavioral Risk Factor Surveillance System

    J Womens Health

    (1998)
  • T.H. Lee et al.

    Evaluation of the patient with acute chest pain

    N Engl J Med

    (2000)
  • S.F. Jencks et al.

    Rehospitalizations among patients in the Medicare fee-for-service program

    N Engl J Med

    (2009)
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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.

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