Perspectives in Circulation Today

The Acute-Phase Proteins: A physiological role has been attributed to various members of the acute-phase proteins. Haptoglobin binds hemoglobin making its iron less available for bacteria. Ceruloplasmin oxidizes iron facilitating the binding of iron by ferritin again making it less available for bacteria. Mannose-binding protein, complement factors and serum amyloid A likewise have antibacterial actions. CRP is worth discusing in more detail.

CRP may have a special place in the innate immune system. Like IgG immunoglobulin, it activates complement, binds to Fc receptors and acts as an opsonin for various bacteria. The "Fc receptor", in turn, is a protein found on the surface of natural killer cells, macrophages, neutrophils, and mast cells . Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. (The former helpful actions... On the negative side is the ability of some viruses to use Fc receptors to help them infect cells.) CRP unlike IgG also recognizes necrotic or inflamed tissue including inflamed atherosclerotic plaque. The latter ability provides the clinician a means of detecting significant arteriosclerotic vascular disease in patients who are otherwise well. Thus, CRP is useful for its negative predictive value. A normal CRP rules out the possibility of an inflammatory or necrotic course. An elevated CRP is an indication of some problem somewhere. The name "CRP" iself bespeaks its diverse significance and dates back to the 1930's when it was first described by Tillet and Francis. The latter noted that sera of patients suffering from acute infection precipitated with a non-proteic pneumococcus extracts called C polysaccharide in the presence of calcium ions. They labeled the protein causing this reaction "C-reactive protein (CRP)". All acute inflammatory processes (infectious and non-infectious), and certain malignant conditions, result in rise in serum CRP as a non-specific phenomenon.The plasma levels of CRP in most healthy subjects is usually 1 mg/L with normal being defined as <10 mg/L. Plasma levels begin increasing within 4--6 hr after initial tissue injury and continue to increase several hundred fold within 24--48 hr. CRP remains elevated during the acute-phase response, and returns to normal with restoration of tissue structure and function. The rise in CRP is exponential, doubling every 8--9 hr. The half-life is less than 24 hr. CRP is a direct and quantitative measure of the acute phase reaction. Serial CRP measurements can be used as a diagnostic tool for infection, monitoring effect of treatment, or early detection of relapse. In the case of rheumatoid arthritis, an example of an inflammatory arthritis, both the ESR and CRP may be normal especially in the earliest stages of the disease. Negative tests, hence do not rule out the disease.

Atherosclerotic Risk Factors and the CRP, A Few Observations: In the Multi-Ethnic Study of Atherosclerosis (Majka DS et al 2008), race, gender and activity levels made some difference. Chinese had the lowest hs-CRP values and Blacks the highest. Moderate/vigorous physical activity was associated with lower levels (less so in women who had overall higher levels than men). The CRP level is affected by both drugs and life style. Anti-inflammatories and statins may lower levels. Obesity and lack of exercise, higher levels... but not the very high levels associated with an obvious inflammatory process. Teede et al (2008) found metformin to decrease and birth control pills to increase hs-CRP levels in patients with polycystic ovary syndrome. The addition of cod protein to the diet of type 2 diabetics may lower CRP levels (Ouellet V et al 2008). Lady chocolate addicts take note: One week of dark chocolate (very rich in flavonoids) ingestion improved lipid profiles, decreased platelet reactivity and reduced hs-CPR only in women(Hamed MS et al 2008). While oral steroids (e.g.1 mg dexamethasone twice daily) can lower CRP in normal healthy-appearing patients, the detrimental effects of such treatment likely outweighs any putative benefit in decreasing inflammation associated with atherosclerotic plaque. On the other hand, oral prednisone treatment has been reported to produce a striking reduction of clinical events and angiographic stenosis rate in patients with persistently high CRP concentrations (> 5 mg/l) after successful coronary artery stent implantation.

Osteomyelitis vs Cellulitis in the diabetic foot: In the presence of a diabetic foot infection, can the ESR signify the likelihood of osteomyelitis? Kaleta et al (2001) did a retrospective chart review of hospital patients admitted with cellulitis or osteomyelitis of the foot; they found that only the ESR among the various lab values differed between the two groups. A ESR above 70 mm/hr had a 100% specificity. a positive predictive value of 100% and a negative predictive value of 83%. Malabu UH et al (2007) have confirmed these observatons and point out the economic benefits of the test for less prosperous societies. It is to be noted that cellulitis alone in the foot may not greatly elevate the ESR or the white count. Lipodermosclerosis is another entity that is surprising in this regard; extensive lesions in the leg may elevate the ESR only to a minor degree.

Postoperative CRP rises in Orthopedic Surgery: As noted in the table above, the CRP does rise postoperatively and perhaps a little more so in patients with either a high normal or modestly elevated preoperative value due to rheumatoid athritis. In such patients, Laiho L et al (2001) found a peak median concentration (94 mg/l) on day one and two and found it took about a week to return to the preoperative value (13 mg/l). A more prolonged elevation signified a complication. Orthopedic procedures are not alone in elevating the CRP; cardiovascular procedures, general surgery etc do likewise.

CRP & Presence of Atherosclerotic Cardiovascular Disease and Mortality: An elevated CRP value may signify inflammatory atherosclerotic disease and a diminished prognosis for life and limb. Wang et al (2003)demonstrated an increased mortality rate among peritoneal dialysis patients who had a single random elevated high-sensitivity CRP (hs-CRP)determination. Gupta R et al (2008) found elevated levels of pre-procedural hs-CRP to be predictive of restenosis in patients receiving extra- or intracranial stenting procedures. Elevated hs-CRP has been found both in patients with known atherosclerotic cardiovascular disease and with conditions associated with it or promoting it such as diabetes, obesity (even in children and adolescents), coronary vasculitis (Kawasaki disease) and chronic heart failure. Again, compromise of the circulation as in patients with congenital heart disease associated with anoxia and increased brain natriuretic levels has been shown to have increased hs-CRP (Tomita H et al 2008). Ridker et al in studying 144 healthy physicians and an equal number of controls matched for age and smoking habits and followed for 5 years found that high baseline CRP levels predicted future development of symptomatic PAD independent of BMI, hypercholesterolemia, hypertension, diabetes and family history of premature PAD (Circulation 1998). Shankar et al (Am Heart J 2007) found the incidence of an ABI under 0.9 among 1611 apparently healthy subjects over age 39 to be associated with CRP in both sexes across the full range of CRP without an apparent threshold independent of smoking, BMI, waist circumference, total cholesterol, glycosylated hemoglobin and age. Vu JD et al found that the likelihood of PAD was significantly enhanced in American adults who had the metabolic syndrome and/or diabetes if their CRP levels were also elevated (Am J Cardiol 2005). Hozawa A et al include the Japanese elderly among the populations in who CRP appears to be an independent risk factor for PAD (Hyperten Res 2004). Daskalopoulou SS et al (Circ J 2008) found newly diagnosed intermittent claudication to be significantly associated with hs-CRP, LDL-cholesterol, serum creatinine, plasma fibrinogen, and diabetes; and they found treatment of lipids, blood pressure, diabetes and homocysteine had been suboptimal in most patients in their primary care setting. Hulthe J et al found both intima-media thickness and plaque occurrence in the femoral artery to be associated with CRP levels which in turn were independently related to abdominal obesity, smoking and antibody titers to oxidized low-density lipoprotein (Clin Sci 2001). Vainas T et al (2005) not only found that hs-CRP was associated with baseline and 12-month follow-up arm-brachial indices and vascular events independent of conventional risk factors but demonstrated CRP presence in all femoral plaques and its production in some. However, various authors have concluded that hs-CRP elevations are not independent of traditional risk factors. Khera et al (Dallas Heart Study,Circulation 2006) found that coronary artery calcifications (2726 patients) and aortic plaque (2393 patients) were associated with increased CRP levels that were not statistically significant when adjusted for BMI and estrogen and statin usage in a multivariate analysis. Again,Bo et al recently found hs-CRP associated with carotid-media thickness and the severity of peripheral atherosclerosis but not independent of the other risk factors measured in their lipid clinic (Bo M et al, Angiology 2008). In conclusion, an elevation of hs-CRP in an otherwise healthy person may signal the presence of asymptomatic vascular disease but not necessarily independent of conventional risk factors or having a pathological effect itself.

Research Opportunities

Perspectives in Circulation Today

Volume 3, Number 11