Is C-Reactive Protein a Valid Biomarker?

C-reactive protein, an indicator of acute inflammation, is the subject of considerable controversy as an important biomarker of cardiovascular health.

It is important to recognize that CRP levels are not specific to any area of inflammation and that there are many conditions that may cause inflammation and stimulate elevation of circulating CRP several times that above normal. There are also numerous non-inflammatory processes that cause local release and systemic exposure to inflammatory mediators, such as CRP.

CRP is produced by the liver and vascular endothelial cells, such those that line the arterial walls of major blood vessels of the heart and other vital organs. This protein is produced whenever an inflammatory process is initiated in the body and under normal physiological conditions, such as everyday stress, pregnancy, and aging.

Many clinical conditions contribute to the elevation of CRP. The classic work by Gabay and Kushner (1999) has enhanced our understanding of the role of CRP in acute inflammatory processes. For example, heart attack, unstable angina (recurring chest pain), rheumatic fever, rheumatoid arthritis, cancer, post-operative infection and healing, general trauma, hypertension, diabetes, and even obesity are associated with elevated CRP levels. Factors associated with cardiovascular risk, such as smoking, aging, and body mass index are also associated with elevated CRP.

There are also factors that may interfere with the significance of CRP assessment. These include diet, stress, exercise, some medications, and pregnancy. Healthy physical activity and emotional stress can also lead to increased CRP levels.

In 2003, the American Heart Association and the Centers for Disease Control and Prevention issued guidelines for measuring inflammatory markers such as CRP in assessing the risk of cardiovascular disease (http://circ.ahajournals.org/cgi/content/full/107/3/499). These guidelines stem from the vital need to identify better biomarkers that assess clinical risk that are based on many factors, including epidemiological studies and utilization of other markers to predict health outcomes. Plasma cholesterol concentration, lipoprotein profile, and homocysteine levels are a few of the other markers currently incorporated into the toolbox for assessment of the risk of coronary artery disease.

The emerging understanding of the atherosclerotic process and the development of atherosclerotic plaque that leads to endothelial injury and subsequent production of inflammatory substances contributed to the issuance of these guidelines. Yet, these markers cannot and should not be accepted as stand-alone indicators of risk. In this case, CRP is not a golden marker for inflammation, even though the Multiple Risk Factor Intervention Trial (Kuller et al., 1996) and Physicians’ Health Study (Ridker et al., 1997) reported a higher increase of cardiac mortality and incidence of myocardial infarction among men in the highest quartile of CRP.

It is interesting to note that scripted cholesterol-reducing medications, such as the statins, and over-the-counter anti-inflammatory/anti-platelet aggregation medications, such as aspirin, a COX-1 inhibitor, are considered the first line of treatment or prophylactic agents for individuals with hypercholesterolemia. These medications can inhibit or reduce the inflammatory process and thus reduce blood levels of CRP. In many cases, however, cardiac disease risk factors are reduced with appropriate weight reduction and dietary management, as indicated in guidelines from the National Cholesterol Education Program (http://hin.nhlbi.nih.gov/ncep.htm).

A careful evaluation of the epidemiological data indicates that small changes in a single biomarker do not necessarily establish the existence of an inflammatory process. In fact, a minimal response of an indicator, such as CRP, may only reflect normal fluctuations in non-inflammatory processes, and possibly other chronic conditions or lifestyle, including aging (Kushner, 2001).

by Roger Clemens, Dr.P.H.,
Contributing Editor
Director, Analytical Research, Professor, Molecular Pharmacology & Toxicology, USC School of Pharmacy, Los Angeles, Calif.
[email protected]

by Peter Pressman, M.D.,
Contributing Editor
Attending Staff, Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif.
[email protected]

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