Pathology Associates Of Lexington, P.A.

High-Sensitive CRP Testing

As a Marker of Coronary Heart Disease

[NewsPath, April 2003, Dr. John Carter]

For many years C-reactive protein levels have been useful as a biochemical marker of inflammatory disorders, abnormally elevated CRP levels particularly being a good indicator of post-operative infections. More recently technologic improvements have permitted precise measurements of C-reactive protein levels <3.0 mg/L, with studies noting the potential clinical significance in variations of low CRP levels ranging from 1.0-3.0 mg/L. These highly sensitive tests for C-reactive protein (hs-CRP) levels have been advertised in numerous publications, both in professional and public media, as potential markers for the micro-inflammatory foci within arterial walls in atherosclerotic cardiovascular disease, especially coronary atherosclerosis.

Anticipating clinical interest in the use of hs-CRP testing, we incorporated this test in our routine lab service in June 2001. With the realization, however, that CRP is an acute-phase reactant, responsive to a wide variety of inflammatory stimuli, we had reservations as to the specificity of this test as an indicator of coronary heart disease (CHD), hence did not actively advertise or promote its use, preferring to await a thorough evaluation in the medical literature.

A recent publication (Circulation. 2003; 107:499-511 -- copy available @ 936-8226) summarizes an American Heart Association conference (CDC/AHA Workshop on Inflammatory Markers in Cardiovascular Disease) held in Atlanta on March 14-15, 2002. The major conclusions of this workshop are summarized below:

1. hs-CRP testing is precise down to or below 0.3 mg/L. Results within these lower and previously "normal" ranges seem to have predictive potential for cardiovascular disease. (The new study recommends reporting hs-CRP results in units of mg/L, so that the result "number" will now be 10X greater than previous results which were reported as mg/dl.)

2. Many studies have shown a gradation of increasing CHD risk with higher hs-CRP levels.

3. Population studies comparing "well persons" in the lower third of hs-CRP levels with those in the upper third show a twofold increase in risk of CHD with the higher levels. This predictive value seems to be limited to Caucasian and Japanese-American male populations. (Data thus far are limited for persons of African, South Asian or Native American descent.)

4. While the technical variability of hs-CRP assays is generally precise, <10% in the 0.3-10.0 mg/L range, there is considerable within-person variability of hs-CRP levels. Thus, as with serum cholesterol levels, at least two separate measurements of hs-CRP are necessary to classify a person’s risk level, to account for within individual variability. There seems to be minimal seasonal or diurnal variation of hs-CRP levels.

5. Individuals with evidence of active infection, systemic inflammatory processes, or recent trauma should not be tested with hs-CRP levels for CHD risk until these conditions have clearly normalized.

6. Numerous clinical conditions are associated with elevations of hs-CRP levels, including hypertension, elevated body mass index, cigarette smoking, diabetes mellitus, low HDL/high triglyceride levels, hormonal supplements, chronic infections and chronic inflammatory disorders. Many of these conditions, in themselves, are recognized as heightened CHD risk situations.

7. The degree of elevation of hs-CRP level does not appear to correlate well with the extent of angiographically defined atherosclerosis. In other words, higher hs-CRP levels do not necessarily reflect more extensive atherosclerosis.

8. Relative coronary heart disease risk categories relative to hs-CRP levels:

1.Low-risk: <1.0 mg/L

2.Average risk: 1.0-3.0 mg/L

3.High risk: >3.0 mg/L

AHA recommendations for use of hs-CRP in clinical practice:

There were no universal clinical practice situations where hs-CRP levels should always be performed.
Consensus opinion, however, did reflect that:

The entire adult population should not be screened with hs-CRP levels for CHD risk assessment.
Other inflammatory markers also should not be used for this purpose.
Secondary CHD prevention measures should not depend on hs-CRP results.
Management guidelines for acute coronary syndromes should not be dependent on hs-CRP levels.
Serial testing of hs-CRP should not be used to monitor effects of treatment.

Consensus opinion, with some conflicting evidence, favors use of hs-CRP testing as an independent marker of cardiac risk in persons judged to be at intermediate risk by global assessment measures and in patients with known but apparently (10-20% ten year) stable CHD. Benefits of therapy based on this strategy remain uncertain.

Conflicting opinions regarding hs-CRP testing, with less well-established efficacy, include:

Use of hs-CRP levels as an independent risk factor, as part of a global coronary risk assessment, in adults without known coronary heart disease.
Use of hs-CRP levels as a motivating factor to improve patient’s lifestyle behavior.

In summary, the AHA/CDC conference recommends limiting current assays of hs-CRP as an adjunct to established risk factors in intermediate risk patients projected to have a 10-20% ten year risk of CHD. (Patients can visit the AHA website at http://www.americanheart.org, then click on "health tools" and calculate a ten year risk.) The finding of a high risk level of hs-CRP (>3.0 mg/L) may allow for intensification of medical therapy and possibly motivate some patients to improve their lifestyle and/or medication compliance. Individuals globally at a low risk for CHD will be unlikely to have a higher risk identified through hs-CRP testing.

In patients with stable coronary disease or acute coronary syndromes, hs-CRP measurement may be useful as an independent marker for assessing the possibility of recurring events; however, secondary preventative interventions should not be dependent on hs-CRP levels. Also serial testing of hs-CRP should not be used to monitor effects of treatment. These recommendations reflect that scientific evidence is not fully adequate at present. A long list of this CDC/AHA report’s recommendations for further necessary research reflects the need to clarify numerous issues.

(posted 4/30/03)