Editorials

The renaissance of C reactive protein

It may be a marker not only of acute illness but also of future cardiovascular disease

C reactive protein (CRP) has traditionally been used as an acute phase marker of tissue injury, infection, and inflammation, but the use of high sensitivity assays has recently shown that increased C reactive protein values predict future cardiovascular disease.

The C reactive protein response has no diagnostic specificity, but serial measurements can be helpful in clinical management. It is a powerful screening test for organic disease and is useful in monitoring known infectious or inflammatory diseases and their response to treatment.¹ Although a high value is unequivocal evidence of tissue damaging disease, C reactive protein values (unlike most other clinical laboratory tests) can really only be interpreted when all other clinical and laboratory information is available. Nevertheless, serial measurements of C reactive protein, added to the full clinical picture, contribute usefully to diagnosis, prognosis, and management.¹

C reactive protein is a trace protein in healthy subjects, with a median concentration of around 1 mg/l, but values can exceed 400 mg/l in the acute phase response. Routine applications in adult medicine require measurement above 5-10 mg/l, but the development of high sensitivity assays has recently allowed clinicians to explore the role of C reactive protein in atherosclerotic disease.

Predictor of coronary events
Increased C reactive protein values significantly predict coronary events in outpatients with stable or unstable angina² and in hospital patients with severe unstable angina³ and predict outcome after coronary angioplasty.⁴ Even in healthy asymptomatic people in the general population individuals with baseline C reactive protein values in the top third of the distribution (geometric mean 2.4 mg/l) have twice the future risk of a coronary event than with those with values in the bottom third (mean 1.0 mg/l).⁵ Similar relationships exist for stroke and peripheral vascular disease.

A pathogenetic role?
C reactive protein selectively binds to low density lipoprotein, particularly the partly degraded low density lipoprotein found within atherosclerotic plaques, and is generally present together with it, and activated complement, within such plaques. ^{7 8} Bound C reactive protein activates complement, is proinflammatory, and may thus contribute to atherogenesis. C reactive protein may also increase macrophage production of tissue factor,⁹ the coagulation initiator responsible for occlusive thrombotic events. However, it will be possible to test whether C reactive protein has a pathogenetic role only when drugs are developed that selectively inhibit C reactive protein production or binding. Meanwhile, it is of interest that statins lower C reactive protein values,¹⁰ suggesting that some of their protective effects may be mediated through suppression of inflammation or cytokines.

A spur to research
Routine empirical measurement of C reactive protein is a valuable aid to patient management across a broad range of clinical practice. Sensitive C reactive protein assay may become a new risk assessment marker for cardiovascular disease, and guidelines for its application are under discussion. While the potential management implications of a raised C reactive protein value in asymptomatic subjects are not yet clear, in those with active coronary disease a raised value definitely identifies a high risk group likely to require interventions. The possibility that C reactive protein may contribute to pathogenesis of atherothrombosis, and the fact that it increases ischaemic myocardial injury, should spur the development of specific drugs to inhibit C reactive protein.

Department of Medicine, Royal Free and University College Medical School, London NW3 2PF

Abi Berger, science editor. 

BMJ

Footnotes

   MBP has received fees for speaking and consulting about C reactive protein from Abbott Laoratories and for speaking from Dade-Behring and has collaborated on C reactive protein testing with Roche Diagnostics.