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C Reactive Protein High Sensitivity

Historically, C-reactive protein (CRP) has been used clinically to monitor inflammatory disease activity, detect postoperative and neonatal infections and assess transplant rejection. Generally, a CRP level above 1.0 mg/dL indicates significant inflammatory disease. Traditional CRP assays were designed to measure CRP levels between 0.2 and 100 mg/dL. Recently, more sensitive methods for measurement of CRP have become available. They have been referred to as high-sensitivity CRP (hs-CRP) because they can accurately measure very low levels of CRP that fall within the traditional assay's normal range (< 0.6 mg/dL).

Current evidence indicates that inflammation plays a central role in the pathogenesis of atherosclerosis and thrombosis and that hs-CRP is a marker of low-grade vascular inflammation that is predictive of future cardiovascular events. All prospective studies reported to date have indicated that basal hs-CRP values in the highest quartile or quintile of data are associated with a 2.3 to 4.8-fold increased relative risk of developing cardiovascular disease. These studies have convincingly demonstrated that hs-CRP is a risk factor for future myocardial infarction, ischemic stroke, peripheral arterial disease and coronary heart disease mortality in apparently healthy men and women. In addition, elevated hs-CRP is predictive of cardiac complications in patients with unstable angina or myocardial infarction. Increased hs-CRP is additive to the predictive value of total and HDL cholesterol in determining cardiovascular risk.

Aspirin decreases the relative risk of future myocardial infarction most effectively in patients in the highest hs-CRP quintile. This observation raises the possibility that the beneficial effect of aspirin is due to its anti-inflammatory effect rather than its anti-platelet effect. Pravastatin has also been shown to reduce the relative risk of recurrent coronary events most effectively in patients with the highest hs-CRP levels. Statin drugs may have anti-inflammatory as well as lipid-lowering properties. In contrast, estrogen replacement therapy, which is associated with increased risk of thrombosis, increases hs-CRP levels, suggesting that it may promote pro-inflammatory events. Overweight (BMI 25-29) and obese (BMI >30) men and women have higher hs-CRP values than normal-weight (BMI < 25) individuals.

The following table correlates hs-CRP levels with cardiovascular risk.

Quintile

hs-CRPRange (mg/dL)

CV Risk Estimate

1

<0.06

Low

2

0.06 - 0.09

Mild

3

0.10 - 0.16

Moderate

4

0.17 - 0.32

High

5

>0.32

Highest

Hs-CRP should only be ordered for cardiovascular risk assessment. This assay is not useful for monitoring patients with clinically apparent inflammatory and infectious disorders. Traditional CRP should be ordered in these circumstances.

Data from both the Physician's Health Study and the Women's Health Study have demonstrated that the combined result of high sensitivity (hs) CRP and lipid screening has greater predictive power than either of these risk factors alone. Risk prediction models that incorporate the total cholesterol:HDL cholesterol ratio (TC:HDL-C) are significantly better than those based on hs-CRP alone.

Each individual's TC:HDL-C ratio and hs-CRP values should be classified into a quintile using the following table.

Quintile

hs-CRP

(mg/dL)

TC:HDLC

Women

TC:HDLC

Men

1

<0.06

<3.4

<3.4

2

0.06 - 0.09

3.4 - 4.0

3.4 - 4.0

3

0.10 - 0.16

4.1 - 4.6

4.1 - 4.6

4

0.17 - 0.32

4.7 - 5.8

4.7 - 5.5

5

>0.32

>5.8

>5.5

Then, the relative risk for future cardiovascular events can be estimated by plotting TC:HDL-C and hs-CRP quintiles in the following table.

TC:HDL-C Quintile
 

hs-CRP Quintile

1

2

3

4

5

1

1.0

1.4

2.0

2.9

4.2

2

1.2

1.7

2.5

3.5

5.0

3

1.4

2.1

2.9

4.2

6.0

4

1.7

2.5

3.5

5.1

7.2

5

2.2

3.0

4.2

6.0

8.7

The relative risk of first coronary events in persons in the fifth quintile for both hs-CRP and TC:HDL-C ratio is eight to nine fold higher than those in the first quintile. Hs-CRP should only be ordered for cardiovascular risk assessment. It should not be ordered if a patient has had recent inflammation, infection or trauma. A period of 2 weeks is usually adequate for hs-CRP concentrations to return to basal levels. The predictive value of hs-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 >0.5 mg/dL to avoid misclassification because of clinically silent infection.

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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