C-Reactive Protein, High Sensitivity

                                                    Shown to Predict Future Atherosclerotic Events

Introduction

C-Reactive protein (CRP) consists of five identical, nonglycosylated polypeptide subunits that are noncovalently linked to form a disc-shaped pentamer with a molecular weight of ~125,000. CRP is synthesized in the liver. It can bind to polysaccharides. In the presence of calcium ions it can also bind phosphorylcholine, phosphatidylcholine, and polyanions such as nucleic acids. In the absence of calcium ions, CRP binds polycations such as histones. Once complexed with one of these other molecules, CRP activates the classical complement pathway.

Clinical Significance

CRP is a nonspecific marker of inflammation. A variety of conditions can lead to elevated serum concentrations of CRP, including inflammation, infection, and malignancy. Recent evidence gathered in apparently healthy adults using high sensitivity CRP (hs-CRP) methods indicates that CRP is a strong independent risk factor for subsequent development of stroke, myocardial infarction, and peripheral vascular disease. Apparently healthy individuals with hs-CRP results in the highest quartile (the upper 25%) have 2 to 4 times the risk of developing subsequent atherosclerotic disease compared with those in the lowest quartile. Simultaneous measurements of hs-CRP and lipids (total and HDL cholesterol) predict future vascular risk better than lipid measurements alone.

Medications can alter hs-CRP results. CRP levels are increased in postmenopausal women taking hormone replacement therapy. Administration of both aspirin and pravastatin can reduce CRP concentrations. These latter two agents may have clinical benefits as a result of reducing chronic, low grade inflammation associated with the atherosclerotic process. Other agents like nonsteroidal antiinflammatory drugs and glucocorticoids may also reduce CRP concentrations.

When using CRP to assess the risk of cardiovascular and peripheral vascular disease, measurements should be compared to previous values. Recent medical events resulting in tissue injury, infections, or inflammation (which may cause elevated CRP levels) should also be considered when interpreting results.

Laboratory Diagnosis

Of the major inflammatory markers, only CRP has an established World Health Organization standard. Commercial hs-CRP assays now provide reliable results. Several prospective studies of hs-CRP have shown a consistent relation between baseline CRP levels and future risk of atherosclerotic complications. Most of these studies examined risk for atherosclerosis for patients with hs-CRP values in the highest quartile or quintile (top 25 or 20%, respectively). The relative risk for these subjects compared with those in the lowest quartile or quintile is two- to fourfold higher. hs-CRP is independent of other risk factors. Cutoff values for the top quintile are typically 2.5 mg/L; although, in postmenopausal women on hormone replacement therapy the cutoff is about 5 mg/L. The basal CRP concentration of an individual remains stable over long periods of time.

Methodology

ARUP뭩 high sensitivity CRP assay is a latex particle enhanced turbidimetric immunoassay. Latex particles coated with antibody specific to human CRP aggregate in the presence of CRP from the patient sample forming immune complexes. The immune complexes cause an increase in light scattering that is proportional to the concentration of CRP in the sample. The light scattering is quantified optically by measuring turbidity.

Appropriate Use of Test

hs-CRP has been consistently shown to predict future atherosclerotic events in several prospective studies. It also adds to the predictive value of lipid testing alone. hs-CRP may be appropriate as an addition to the routine assessment of atherosclerotic risk. It can be considered a marker of existing arterial disease, as opposed to a primary risk factor leading to future disease.

Methodology:

Immunoturbidimetric Assay

Specimen Required:

Collect: One 7 mL red top or SST tube. Separate ASAP.
Transport
: Refrigerated or frozen.
Stability: 7 days at 2-8℃; 1 year -20℃

Reference Interval:

0-2.5 mg/L

Interpretive Data

The upper limit of the reference interval for high sensitivity C-reactive protein (hs-CRP) is 2.5 mg/L. This corresponds to the 80th percentile of an apparently healthy group of adult males and females. Patients with results above this limit are 2 to 4 times more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease. Simultaneous measurements of CRP and lipids predict future vascular risk better than lipid measurements alone (Circulation 1998; 97:2007-2011). In women, hs-CRP concentrations may be influenced by hormonal status. CRP is a nonspecific marker of inflammation, and a variety of conditions other than atherosclerosis may cause elevated levels.

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Nader Rifai and Paul M. Ridker
High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease
Clin Chem 2001 47: 403-411. [Abstract] [Full Text]

Nader Rifai and Paul M. Ridker
Proposed Cardiovascular Risk Assessment Algorithm Using High-Sensitivity C-Reactive Protein and Lipid Screening. Clin Chem 2001 47: 28-30. [Full Text]

Nader Rifai, Russell P. Tracy, and Paul M. Ridker
Clinical Efficacy of an Automated High-Sensitivity C-Reactive Protein Assay
Clin Chem 1999 45: 2136-2141. [Abstract] [Full Text]

William L. Roberts, Linda Moulton, Terence C. Law, Genesis Farrow, Margaret Cooper-Anderson, John Savory, and Nader Rifai
Evaluation of Nine Automated High-Sensitivity C-Reactive Protein Methods: Implications for Clinical and Epidemiological Applications. Part 2
Clin Chem 2001 47: 418-425. [Abstract] [Full Text]

Ira S. Ockene, Charles E. Matthews, Nader Rifai, Paul M. Ridker, George Reed, and Edward Stanek
Variability and Classification Accuracy of Serial High-Sensitivity C-Reactive Protein Measurements in Healthy Adults. Clin Chem 2001 47: 444-450. [Abstract] [Full Text]

William L. Roberts, Rachel Sedrick, Linda Moulton, Anthony Spencer, and Nader Rifai
Evaluation of Four Automated High-Sensitivity C-Reactive Protein Methods: Implications for Clinical and Epidemiological Applications. Clin Chem 2000 46: 461-468. [Abstract] [Full Text]

Wolfgang Koenig
C-Reactive Protein and Cardiovascular Risk: Has the Time Come for Screening the General Population?  Clin Chem 2001 47: 9-10. [Full Text]

Hans K. Meier-Ewert, Paul M. Ridker, Nader Rifai, Nick Price, David F. Dinges, and Janet M. Mullington
Absence of Diurnal Variation of C-Reactive Protein Concentrations in Healthy Human Subjects
Clin Chem 2001 47: 426-430. [Abstract] [Full Text]

Nader Rifai, Rana Joubran, Harry Yu, Mohamad Asmi, and Mohidien Jouma
Inflammatory Markers in Men with Angiographically Documented Coronary Heart Disease
Clin Chem 1999 45: 1967-1973. [Abstract] [Full Text]

Winston L. Hutchinson, Wolfgang Koenig, Margit Fröhlich, Malte Sund, Gordon D.O. Lowe, and Mark B. Pepys
Immunoradiometric Assay of Circulating C-Reactive Protein: Age-related Values in the Adult General Population
Clin Chem 2000 46: 934-938. [Abstract] [Full Text]
Robbert J. de Winter, Johan Fischer, Radha Bholasingh, Jan P. van Straalen, Thyra de Jong, Jan G.P. Tijssen, and Gerard T. Sanders
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Clin Chem 2000 46: 1597-1603. [Abstract] [Full Text]

Axel Stachon, Andreas Böning, Heike Weisser, Axel Laczkovics, Guido Skipka, and Michael Krieg
Prognostic Significance of Low Serum Cholesterol after Cardiothoracic Surgery
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Robert H. Christenson and Hassan M. E. Azzazy
Biochemical markers of the acute coronary syndromes
Clin Chem 1998 44: 1855-1864. [Abstract] [Full Text]

James K. Liao
Endothelium and acute coronary syndromes
Clin Chem 1998 44: 1799-1808. [Abstract] [Full Text]

Julie Wilkins, J. Ruth Gallimore, Edwin G. Moore, and Mark B. Pepys
Rapid Automated High Sensitivity Enzyme Immunoassay of C-Reactive Protein
Clin Chem 1998 44: 1358-1361. [Full Text]

Elizabeth M. Macy, Timothy E. Hayes, and Russell P. Tracy
Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications
Clin Chem 1997 43: 52-58. [Abstract] [Full Text]

Raffaele Pezzilli, Antonio Maria Morselli-Labate, Rita Miniero, Bahjat Barakat, Manuela Fiocchi, and Onda Cappelletti
Simultaneous Serum Assays of Lipase and Interleukin-6 for Early Diagnosis and Prognosis of Acute Pancreatitis. Clin Chem 1999 45: 1762-1767. [Abstract] [Full Text]

Raymond Gambino
C-Reactive Protein—Undervalued, Underutilized. Clin Chem 1997 43: 2017-2018. [Full Text]

Yuzuru Takemura, Haku Ishida, Yuji Inoue, Hiroyuki Kobayashi, and J. Robert Beck
Opportunistic Discovery of Occult Disease by Use of Test Panels in New, Symptomatic Primary Care Outpatients: Yield and Cost of Case Finding
Clin Chem 2000 46: 1091-1098. [Abstract] [Full Text]