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C Reactive Protein and High Sensitivity C Reactive Protein

C reactive protein (CRP) is an acute phase reactant that plays a role in innate immunity. CRP acts as an opsonin by binding to bacterial or damaged human cells and the immunoglobulin receptors on phagocytes, thereby promoting phagocytosis. CRP also binds C1q and activates the classical complement cascade.

CRP is synthesized in hepatocytes and alveolar macrophages in response to cytokines, particularly IL-6. It is a general marker of inflammation that begins to rise four to six hours after tissue injury.  This is much earlier than other acute phase reactants, which do not begin to increase until 24 hours or more. CRP also increases to much higher levels than other acute phase proteins, making it the most sensitive indicator of small inflammatory stimuli. CRP concentration peaks at 48 hours and then decreases with a half-life of 48 hours.

Historically, CRP has been used clinically to monitor inflammatory disease activity, detect postoperative and neonatal infections and assess transplant rejection. When using CRP to evaluate infection, inflammation or tissue injury, a CRP level less than 5 mg/L is considered negative and a value greater than 10 mg/L is considered positive. The upper limit of quantification is approximately 500 mg/L. Sequential measurement of CRP is important for effective monitoring of inflammation.

More sensitive CRP assays, called high-sensitivity CRP (hs-CRP), have been developed to detect lower levels of inflammation that accompany cardiovascular disease. HS-CRP assays reliably measure levels between 1.0 mg/L and 10.0 mg/L. The coefficient of variation for hsCRP assays should be 10% of less near the medical decision point of 1.0 mg/L. The lower limit of quantification should be significantly below 1.0 mg/L.

Current evidence indicates that inflammation plays a central role in the pathogenesis of atherosclerosis and thrombosis and that CRP is a marker of low-grade vascular inflammation that is predictive of future cardiovascular events. In 2009, the U.S. Preventive Services Task Force concluded that there was strong evidence that CRP is associated with cardiovascular disease events (Buckley DI, et al. Ann Emer Med. 2009;151:483-495). They also concluded that there was moderate evidence for using CRP to further stratify the risk of patients with intermediate risk (10-20%) of having a cardiovascular event in the next decade. Increased CRP is additive to the predictive value of total and HDL cholesterol in determining cardiovascular risk.

Many factors can influence baseline CRP levels including ethnicity, age, gender, body weight and smoking status. Median CRP levels increase with age. Individuals 80 years and older have CRP levels that are almost two times higher than individuals in their 40s. Median CRP levels are lower in men than in women. Estrogen replacement therapy increases CRP levels. Overweight (BMI 25-29) and obese (BMI >30) men and women have higher CRP values than normal-weight (BMI <25) individuals. Smokers have higher levels of CRP due to inflammation.

CRP should not be ordered for cardiac risk assessment if a patient has had recent inflammation, infection or trauma. A period of 2 weeks is usually adequate for CRP concentrations to return to basal levels. The predictive value of CRP is greatly improved if two measurements are made approximately 1 month apart and the lowest of these values is used to determine the appropriate quintile for cardiovascular risk assessment. It is especially important to repeat CRP values >5 mg/L to avoid misclassification because of clinically silent infection. 

The biggest challenge to interpreting CRP elevation is the large variability in measurement that occurs in following an individual over time. The intraindividual coefficient of variation (CV) can vary as much as 46% over a 2 to 3 week period.

Risk assessment guidelines are listed in the following table.

Interpretation

CRP (mg/L)

Low cardiac risk

<1.0

Average cardiac risk

1.0 – 3.0

High cardiac risk

>3.0

Infection or Inflammation

>10

Specimen requirement is a minimum of 0.5 mL of serum (one SST tube). Gross lipemia or hemolysis interferes with this test.

 

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