C-reactive protein

C-reactive protein (CRP) is an annular (ring-shaped), pentameric is_associated_with::protein found in is_associated_with::blood plasma, the levels of which rise in response to is_associated_with::inflammation (i.e., C-reactive protein is an is_associated_with::acute-phase protein of hepatic origin that increases following is_associated_with::interleukin-6 secretion from is_associated_with::macrophages and is_associated_with::T cells). Its physiological role is to bind to is_associated_with::lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the is_associated_with::complement system via the is_associated_with::C1Q complex.

CRP is synthesized by the is_associated_with::liver in response to factors released by is_associated_with::macrophages and fat cells (is_associated_with::adipocytes). It is a member of the is_associated_with::pentraxin family of proteins. It is not related to is_associated_with::C-peptide (insulin) or is_associated_with::protein C (blood coagulation). C-reactive protein was the first is_associated_with::pattern recognition receptor (PRR) to be identified.

History and nomenclature
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the is_associated_with::C-polysaccharide of is_associated_with::Pneumococcus.

Discovered by Tillett and Francis in 1930, it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer. The later discovery of hepatic synthesis demonstrated that it is a native protein.

Genetics and structure
The CRP gene is located on the first is_associated_with::chromosome (1q21-q23). It is a member of the small is_associated_with::pentraxins family. It has 224 amino acids, has a monomer molecular mass of 25106 Da, and has an annular pentameric discoid shape.

Function
CRP binds to the is_associated_with::phosphocholine expressed on the surface of dead or dying cells and some bacteria. This activates the is_associated_with::complement system, promoting is_associated_with::phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria.

This so-called is_associated_with::acute phase response occurs as a result of a rise in the concentration of IL-6, which is produced by is_associated_with::macrophages as well as is_associated_with::adipocytes in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of is_associated_with::interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.

CRP binds to is_associated_with::phosphocholine on microbes. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin-mediated phagocytosis), which express a receptor for CRP. It plays a role in is_associated_with::innate immunity as an early defense system against infections.

CRP rises within two hours of the onset of inflammation, up to a 50,000-fold, and peaks at 48 hours. Its half-life of 18 hours is constant, and therefore its level is determined by the rate of production and hence the severity of the precipitating cause. CRP is thus a screen for inflammation.

Diagnostic use
CRP is used mainly as a marker of inflammation. Apart from is_associated_with::liver failure, there are few known factors that interfere with CRP production.

Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. is_associated_with::ELISA, is_associated_with::immunoturbidimetry, rapid is_associated_with::immunodiffusion, and visual agglutination are all methods used to measure CRP.



A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser is_associated_with::nephelometry. The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L. The risk of developing cardiovascular disease is quantified as follows:


 * low: hs-CRP level under 1.0 mg/L
 * average: between 1.0 and 3.0 mg/L
 * high: above 3.0 mg/L

Normal concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with is_associated_with::aging. Higher levels are found in late pregnant women, mild is_associated_with::inflammation and is_associated_with::viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe is_associated_with::bacterial infections and is_associated_with::burns (>200 mg/L).

CRP is a more sensitive and accurate reflection of the acute phase response than the ESR (Erythrocyte Sedimentation Rate). ESR may be normal and CRP elevated. CRP returns to normal more quickly than ESR in response to therapy.

Several studies investigated differential diagnostic values of CRP in a series of inflammatory disease ( including inflammatory bowel disease, Intestinal Lymphoma, Intestinal Tuberculosis and Behcet's Syndrome), and compared CRP to other inflammatory biomarkers, such as ESR and WBC.

Cancer
The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed. While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.

In a 2004 is_associated_with::prospective cohort study on colon cancer risk associated with CRP levels, people with is_associated_with::colon cancer had higher average CRP concentrations than people without colon cancer. It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk.

Cardiovascular disease
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of is_associated_with::diabetes, is_associated_with::hypertension and is_associated_with::cardiovascular disease. A study of over 700 nurses showed that those in the highest is_associated_with::quartile of is_associated_with::trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate is_associated_with::ischemic is_associated_with::necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral is_associated_with::infarcts; so far, this has been demonstrated in animal models only.

It has been hypothesized that patients with high CRP levels might benefit from use of is_associated_with::statins. This is based on the is_associated_with::JUPITER trial that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins. A subsequent trial however failed to find that CRP was useful for determining statin benefit.

In a meta-analysis of 20 studies involving 1,466 patients with is_associated_with::coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.

To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.

Fibrosis and inflammation
is_associated_with::Scleroderma, is_associated_with::polymyositis, and is_associated_with::dermatomyositis elicit little or no CRP response. CRP levels also tend not to be elevated in SLE unless serositis or synovitis is present. Elevations of CRP in the absence of clinically significant inflammation can occur in renal failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease. Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.

Obstructive sleep apnea
C-reactive protein (CRP), a marker of systemic inflammation, is also increased in is_associated_with::obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects. Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.

Coronary heart disease risk
Arterial damage results from white blood cell invasion and is_associated_with::inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very is_associated_with::specific prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.

The is_associated_with::American Heart Association and U.S. is_associated_with::Centers for Disease Control and Prevention have defined risk groups as follows: But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, is_associated_with::triglycerides, and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.
 * Low Risk: less than 1.0 mg/L
 * Average risk: 1.0 to 3.0 mg/L
 * High risk: above 3.0 mg/L