Evolution of C-Reactive Protein as a Cardiac Risk Factor

Paula J. D'Amore, PhD, D(ABMLI)


Lab Med. 2005;36(4):234-238. 

In This Article

C-Reactive Protein

C-reactive protein, an acute phase reactant produced in the liver, is a non-specific marker of acute inflammation diseases, infections, and neoplastic diseases. C-reactive protein is a member of the pentraxin family of proteins that binds to the C-polysaccharide of Streptococcus pneumoniae. As a participant in the innate immune response, CRP binds phosphocholines and other ligands resulting in the activation of complement via the classical pathway. It is believed that in addition to being a marker of inflammation, CRP plays an integral part in the inflammatory process of atherosclerosis. High concentrations of CRP mRNA have been demonstrated to be present in atherosclerotic plaques.[8] C-reactive protein has been shown to possess some proatherogenic properties that may influence the progression of atherosclerosis. A direct pro-inflammatory effect on endothelial cells has been described whereby CRP stimulates other cells including endothelial cells to elaborate chemokines (MCP-1), pro-inflammatory cytokines (IL-1, IL-6, TNF-α), and adhesion molecules such as intercellular adhesion molecule (ICAM-1) and VCAM-1 that will attract monocytes to the site of injury.[9,10] Macrophages are then able to adhere more readily to the endothelial cells. C-reactive proteins activate macrophages to secrete tissue factor, a powerful procoagulant.[11] C-reactive protein may play a role in the decreased expression of nitric oxide in endothelial cells. Nitric oxide inhibits platelet aggregration, decreases vasoconstriction and the proliferation of smooth muscle cells.[12] C-reactive protein, present in atherosclerotic plaques, binds to oxidized LDL and enhances the ability of macrophages to phagocytsize LDL and form foam cells through the CRP receptor CD32.

The traditional CRP assay, using a polyclonal antibody, has a lower limit of detection of 3 mg/L. The assay detects acute infection and other inflammatory processes. C-reactive protein levels in acute inflammation usually are in the range of 40 to 200 mg/L or greater.[13] However, the assay is not sensitive enough to detect variations in CRP levels associated with sub-clinical chronic inflammation present in vascular events occurring in atherosclerosis. The high-sensitivity CRP (hsCRP) assay was developed to detect these lower levels with an analytical sensitivity down to 0.1 to 0.2 mg/L. Most laboratories use commercial nephelometry assays with a monoclonal CRP antibody coated to a latex particle or immunoturbidmetric assays. High-sensitivity CRP should be measured only in the absence of overt inflammatory processes. Results greater than 10 mg/L suggest the presence of an acute inflammatory process.

Although there is no circadian rhythm to the production of CRP, overnight fasting before specimen collection is recommended to avoid turbidity due to lipemia. Lipidemia would interfere with the actual nephelometry testing. Testing can be performed on serum or plasma (collected in heparin or EDTA). In a CDC Phase 1 study, Certified Reference Material 470 (CRM470), a reference material preparation distributed by the Institute for Reference Materials and Measurements (IRMM), was found to perform better than other materials for standardizing hsCRP assays.[14] The inter-assay differences of CRM470 is currently being evaluated by the CDC. Also, the College of American Pathologists (CAP) introduced the first proficiency program for hsCRP assays in 2002. C-reactive protein levels are stable over time. Two measurements should be made at least 2 weeks apart.


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