C-Reactive Protein

Background

For many years, C-Reactive Protein (CRP) was known as a highly sensitive but non-specific marker for acute inflammation. It is produced in the liver and rises to very high levels within 4-6 hours following acute injurious conditions such as trauma, surgery, or infection. Levels as high as 1000 mg/L are not uncommon after severe trauma. Within the past 10 years, researchers have developed a high sensitivity immunoassay denoted hsCRP. These assays measure levels below 10 mg/L. At these levels, measurement of conditions indicative of chronic, low grade inflammation are now possible. With these new measurements, the CDC (Centers for Disease Control and Prevention) has determined 0.08-3.1 mg/L as a normal reference range for healthy persons. Dividing the lower limits of <10 mg/L for chronic inflammation has identified quartiles or quintiles that have shed light upon subgroups of patients who have an increased relative risk for cardiovascular disease (CVD).

Prior to these findings, cholesterol levels were the most significant biochemical alteration that was associated with CVD. Yet, the Framingham study still found 35% of CVD events occurred in patients with a total cholesterol <200 mg/dL, a level that is normal by established guidelines. A nested case-control study of 122 cases subjects and 244 control subjects from the Women's Health Study found hsCRP the strongest univariate predictor of the risk for CVD events. It is hypothesized that CRP is a marker for unstable atherosclerotic plaque. Patients with an increased level may be at greater risk for plaque rupture which may lead to an embolism. Other studies have found the risk of myocardial infarction is directly related to the increasing levels of CRP, a risk that was greater for elevated lipoprotein (a), homocysteine, total cholesterol, fibrinogen, and tissue Plasminogen activator.

OUTLINE

Measurement

Clinical Utility

Interference

Commonly Used Terms

Internet Links

REFERENCE METHODS CHARACTERIZATION

A two-site immunoradiometric assay for C-reactive protein in serum.

Shapiro D, Shenkin A.

Department of Pathological Biochemistry, Western Infirmary, Glasgow, Scotland, UK.
Clin Chim Acta 1989 Apr 14;180(3):285-92 Abstract quote
An immunoradiometric assay was developed for C-reactive protein in serum. The assay had a sensitivity of 5 micrograms/l and good precision.

Correlation with radial immunodiffusion (r = 0.916) and EMIT (r = 0.935) was close. A reference range for healthy adults of 0.05-4.0 mg/l was derived.

A rapid and sensitive automated light scattering immunoassay for serum C-reactive protein and the definition of a reference range in healthy blood donors.

Price CP, Calvin J, Walker SA, Trull A, Newman DJ, Gorman EG.

Department of Clinical Biochemistry, St Bartholomew's, London, UK.
Clin Chem Lab Med 1999 Feb;37(2):109-13 Abstract quote
The increasing interest in the measurement of serum C-reactive protein in relation to the risk stratification of patients with chest pain has demonstrated the need for more sensitive routine methods of measurement and an accurate definition of the reference range.

We report the determination of a reference range in serum samples from 491 blood donors using a particle enhanced turbidimetric immunoassay that has been modified to offer better imprecision within the reference range. The median values were found to be 2.40 and 2.20 mg/l for males and females, respectively with 95th percentile range of 1.20-5.20 and 0.40-5.40 mg/l, respectively.

Evaluation of a sensitive immunoluminometric assay for the determination of C-reactive protein (CRP) in serum and plasma and the establishment of reference ranges for different groups of subjects.
Wood WG, Ludemann J, Mitusch R, Heinrich J, Maass R, Frick U.

Institut fur Klinische Laboratoriumsdiagnostik, Klinikum der Hansestadt Stralsund, Germany.

Clin Lab 2000;46(3-4):131-40 Abstract quote
A sensitive immunoluminometric assay originally designed to measure C-reactive protein (CRP) in neonates and minimal serum volumes was adapted to measure this protein in a routine method without prior sample dilution. The concentration range covered without prior dilution was 10 micrograms/l to 20 mg/l using a sample volume of 5 microliters serum and a total assay time of less than 2 h.

Serum samples were assayed from participants in a community medicine programme (SHIP--Study of Health in Pomerania) of the University of Greifswald, Germany (n = 414), as well as from mother-child pairs at birth (n = 30) and women attending the infertility clinic (n = 36).

The validation of the assay was compared with a commercial latex-enhanced turbidimetric immunoassay (Roche Diagnostics--Integra 700) using routine serum samples (n = 60) from hospital patients. Comparison was made with the routine assay used in the SHIP study (Roche Diagnostics--Hitachi 717/Tina Quant). From 414 SHIP samples measured in the immunoluminometric assay, 289 were below the detection level in the turbidimetric (Tina Quant) assay. A significant positive correlation (p < 0.01) between log C-reactive protein concentration with age was found, both in the non-screened (all CRP values) (n = 414, r = 0.222) and selected (CRP < 5.00 mg/l = 90th percentile) (n = 370, r = 0.242) SHIP participants. Women were found to have significantly higher CRP levels than men (women: median age 47 a, median CRP 1.29 mg/l; men: median age 55 a, median CRP 1.00 mg/l--p = 0.016) in the non-selected SHIP participants. The situation was different in the selected group, (median age: men 54 a, women 48 a) where no significant difference in median CRP values between the sexes was seen (men: 0.874 mg/l, women 0.951 mg/l, p = 0.206). The distribution of CRP values in a "Normal Healthy Population" is skewed (mean/median--SHIP: all--2.08; selected--1.49). From the 414 SHIP samples measured in the immunoluminometric assay, 289 were below the detection level (2.5 mg/l) in the turbidimetric (Tina Quant) assay. From the 125 remaining samples the correlation between both methods was acceptable (r = 0.813), the regression line y = a + bx being: CRP (ILMA) = 1.83 + 0.842*CRP (Tina Quant).

The Tina Quant assay gave values significantly higher than the ILMA in the range 2.5-25 mg/l CRP (p < 0.001). The total information loss in 289/414 subjects with a CRP < 2.5 mg/l with the Tina Quant assay makes it no longer suitable for epidemiological studies in which CRP is to be studied as a risk factor for cardiovascular events. The comparison between the immunoluminometric assay and the latex-enhanced immunoturbidimetric assay (Roche Integra) was much better. The latter measured down to less than 0.3 mg/l, thus being more suitable for epidemiological studies than the Tina Quant assay from the same producer. The correlation and regression data between the ILMA (x) and the Roche Integra assay (y) were: r = 0.971; CRP (Roche Integra) = 0.635 + 0.984*CRP (ILMA); n = 50.10 sera with CRP levels between 25 and 460 mg/l showed no high-dose hook effect in either assay. The remaining 50 sera were measurable in both assays.

The turbidimetric assay gave rise to marginally but significantly higher values than the immunoluminometric assay (p = 0.004). The mothers at birth had a median CRP of 3.64 mg/l (range 1.49-12.6 mg/l), the neonates a median CRP of 34 micrograms/l (range 4-288 micrograms/l). All births were without complications, with gestational periods between 38 and 42 weeks. There was no correlation between maternal and neonatal CRP at birth. Mothers at birth had significantly higher CRP levels than healthy non-pregnant women (p < 0.001). Women attending the infertility clinic had CRP-values similar to age-matched healthy non-pregnant women (median 0.698 mg/l, range 0.05-9.97 mg/l). Interassay coefficients of variation at CRP concentrations of 0.85 and 7.9 mg/l were 8.99 and 7.93%, respectively, for the immunoluminometric

Evaluation of four automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications.

Roberts WL, Sedrick R, Moulton L, Spencer A, Rifai N.

Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
Clin Chem 2000 Apr;46(4):461-8 Abstract quote
BACKGROUND: C-reactive protein (CRP) can provide prognostic information about the risk of developing atherosclerotic complications in apparently healthy patients. This new clinical application requires quantification of CRP concentrations below those traditionally measured in the clinical laboratory.

METHODS: The Dade Behring BN II, the Abbott IMx, the Diagnostic Products Corporation IMMULITE, and the Beckman Coulter IMMAGE are four automated analyzers with high-sensitivity CRP (hs-CRP) methods. We evaluated these assays for precision, linearity, and comparability with samples from 322 apparently healthy blood donors.

RESULTS: The imprecision (CV) of the BN II, IMx, IMMULITE, and IMMAGE methods was < or = 7.6%, < or = 12%, < or = 9.8%, and < or = 9.7% at 3.5 mg/L, respectively. The BN II, IMx, IMMULITE, and IMMAGE methods were linear down to < or = 0.30, < or = 0.32, < or = 0.85, and 2.26 mg/L, respectively. CRP concentrations demarcating each quartile in a healthy population were method dependent. The IMx method gave results comparable to the BN II method for values in the reference interval. The IMMULITE method had a positive intercept compared with the BN II method. The IMMAGE method demonstrated more scatter and a positive intercept compared with the BN II method, which may reflect the fact that it is a less sensitive assay.

CONCLUSIONS: The four hs-CRP methods exhibited differences in results for a healthy population. Additional standardization efforts are required to ensure that hs-CRP results can be related to large-scale epidemiologic studies.

Immunoradiometric assay of circulating C-reactive protein: age-related values in the adult general population.

Hutchinson WL, Koenig W, Frohlich M, Sund M, Lowe GD, Pepys MB.

Immunological Medicine Unit, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.

Clin Chem 2000 Jul;46(7):934-8 Abstract quote
BACKGROUND: Increased values of C-reactive protein (CRP), the classical acute phase protein, within the range below 5 mg/L, previously considered to be within the reference interval, are strongly associated with increased risk of atherothrombotic events, and are clinically significant in osteoarthritis and neonatal infection.

METHODS:: A robust new polyclonal-monoclonal solid- phase IRMA for CRP was developed, with a range of 0.05-10.0 mg/L.

RESULTS:: Plasma CRP values in general adult populations from Augsburg, Germany (2291 males and 2203 females; ages, 25-74 years) and Glasgow, Scotland (604 males and 650 females; ages, 25-64 years) were very similar. The median CRP approximately doubled with age, from approximately 1 mg/L in the youngest decade to approximately 2 mg/L in the oldest, and tended to be higher in females.

CONCLUSION:: This extensive data set, the largest such study of CRP, provides valuable reference information for future clinical and epidemiological investigations.

CLINICAL UTILITY CHARACTERIZATION

CARDIAC

C-reactive protein and atherosclerosis of the thoracic aorta: a population-based transesophageal echocardiographic study.

Agmon Y, Khandheria BK, Meissner I, Petterson TM, O'Fallon WM, Wiebers DO, Christianson TJ, McConnell JP, Whisnant JP, Seward JB, Tajik AJ.

Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Arch Intern Med. 2004 Sep 13;164(16):1781-7. Abstract quote

BACKGROUND: An association between systemic inflammatory markers and the presence and severity of atherosclerotic plaques has not been demonstrated in a nonselected population. The purpose of this study was to examine the association of inflammatory markers with aortic atherosclerotic plaques in a sample of the general population and in a subgroup free of clinical vascular disease.

METHODS: Transesophageal echocardiography was performed in 386 subjects (median age, 66 years; 53% men). We examined the association between systemic inflammatory markers and aortic atherosclerotic plaques.

RESULTS: Aortic plaques were present in 267 subjects (69%). Plaques at least 4 and 6 mm thick and mobile debris were present in 114, 41, and 20 subjects, respectively. High-sensitivity C-reactive protein (hs-CRP) level was associated with the presence of aortic plaques, adjusting for age, sex, smoking status, and additional atherosclerosis risk factors. Among subjects with plaques, hs-CRP level was independently associated with plaques at least 6 mm thick; similar trends were observed for the associations of hs-CRP level with plaques at least 4 mm thick and mobile debris. In subjects with aortic plaques who were free of clinically apparent coronary artery or cerebrovascular disease, hs-CRP level was independently associated with plaques at least 6 mm thick.

CONCLUSIONS: Level of hs-CRP is independently associated with the presence and severity of aortic atherosclerotic plaques. These observations establish the association of systemic inflammation with anatomically defined atherosclerosis in the general population.

Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis.

deFilippi C, Wasserman S, Rosanio S, Tiblier E, Sperger H, Tocchi M, Christenson R, Uretsky B, Smiley M, Gold J, Muniz H, Badalamenti J, Herzog C, Henrich W.

Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
JAMA. 2003 Jul 16;290(3):353-9. Abstract quote
CONTEXT: Cardiac troponin T (cTnT) and C-reactive protein (CRP) are prognostic markers in acute coronary syndromes. However, for patients with end-stage renal disease (ESRD) the ability of combinations of these markers to predict outcomes, and their association with cardiac pathology, are unclear. O

OBJECTIVE: To investigate the association between levels of cTnT and CRP and long-term risk of cardiac pathology and death in patients with ESRD.

DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study initiated February through June 1998 and enrolling 224 patients with ESRD from 5 hemodialysis centers in the Houston-Galveston region of Texas. Levels of cTnT and CRP were analyzed at study entry in patients without ischemic symptoms.

MAIN OUTCOME MEASURES: All-cause mortality during a mean follow-up of 827 (range, 29-1327) days. Secondary outcomes in predefined substudies were coronary artery disease (CAD), decreased (< or =40%) left ventricular ejection fraction (LVEF), and presence of left ventricular hypertrophy (LVH).

RESULTS: One hundred seventeen (52%) patients died during follow-up. For levels of cTnT and CRP, progressively higher levels predicted increased risk of death compared with the lowest quartile (for cTnT quartile 2: unadjusted hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1; quartile 3: HR, 2.7; 95% CI, 1.5-4.9; quartile 4: HR, 3.0; 95% CI, 1.6-5.3. For CRP quartile 2: HR, 0.9; 95% CI, 0.5-1.6; quartile 3: HR, 1.8; 95% CI, 1.1-3.1; quartile 4: HR, 1.8; 95% CI, 1.1-3.2). Both cTnT and CRP remained independent predictors of death after adjusting for a number of potential confounders. The combination of cTnT and CRP results provided prognostic information when patients were divided into groups at or above and below the biomarker medians (high cTnT/high CRP levels vs low cTnT/low CRP levels for risk of death: HR, 2.5; 95% CI, 1.5-4.0). Elevated levels of cTnT, but not CRP, were strongly associated with diffuse CAD (n = 67; 0%, 25%, 50%, and 62% prevalence of multivessel CAD across progressive cTnT quartiles, P<.001). An LVEF of 40% or less was identified in 4 (9%), 3 (8%), 10 (27%), and 7 (19%) of patients across cTnT quartiles (P =.07). No trend for cTnT levels was found among patients with LVH (P =.45); similarly, no trend for CRP was found among patients with LVH (P =.65) or an LVEF of 40% or less (P =.75).

CONCLUSIONS: Among stable patients with ESRD, increasing levels of cTnT and CRP are associated with increased risk of death. Furthermore, higher levels of cTnT may identify patients with severe angiographic coronary disease.

C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.

Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB.

Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.

Circulation 1999 Jan 19;99(2):237-42 Abstract quote

BACKGROUND: Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events.

METHODS AND RESULTS: We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2. 17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2. 08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97).

CONCLUSIONS: These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.

CRP may predict heart disease survival
J Am Coll of Cardiol 2000;36:1774
CRP levels may be a better predictor of patients who will benefit from cholesterol lowering drugs (statins)

A study of 985 patients with severe coronary artery disease had levels of cholesterol and CRP followed for three years-109 patients died

Baseline cholesterol levels failed to predict which patients would die but CRP levels did with patients with the highest levels of CRP benefitting the most

C-reactive protein in patients with chronic stable angina: differences in baseline serum concentration between women and men.

Garcia-Moll X, Zouridakis E, Cole D, Kaski JC.

Coronary Artery Disease Research Unit, Cardiological Sciences, St. George's Hospital Medical School, London, U.K.

Eur Heart J 2000 Oct;21(19):1598-606 Abstract quote

AIMS: Serum C-reactive protein has prognostic significance in apparently healthy men and women and in men with coronary artery disease. Little is known regarding the predictive role of C-reactive protein in women with coronary heart disease. We assessed whether differences exist in C-reactive protein levels and their prognostic value in men compared with women. We also assessed whether C-reactive protein concentrations differed in women receiving hormone replacement therapy vs those on no hormone replacement therapy.

METHODS AND RESULTS: We prospectively studied 911 consecutive patients (327 women) with typical exertional angina. All patients underwent clinical, biochemical and angiographic characterization at study entry. Serum C-reactive protein was measured using a highly sensitive assay and correlated with clinical events during follow-up (from 1.0 to 3.7 years). C-reactive protein was significantly higher in women than men (3.0 mg. l(-1)[range 1.3-5.8] vs 2.1 mg. l(-1)[range 1.0-4.2], P<0.001), even after multiple regression adjustment for other risk factors. C-reactive protein was also significantly higher in women receiving hormone replacement therapy than in women not using hormone replacement therapy (P=0.001). C-reactive protein was an independent predictor of cardiovascular risk (logistic regression P=0.033) in the whole group but, despite higher C-reactive protein concentration, women had a similar rate of cardiac events compared to men.

CONCLUSIONS: Baseline C-reactive protein levels were higher in women than men but the event rate was similar in men and women. Women on hormone replacement therapy had significantly higher C-reactive protein than women not using hormone replacement therapy. In the group as a whole, increased C-reactive protein was associated with a higher cardiovascular risk.

Serum C-reactive protein and fibrinogen concentrations and self-reported angina pectoris and myocardial infarction: findings from National Health and Nutrition Examination

Survey III. Ford ES, Giles WH.

Division of Nutrition and Physical Activity and Division of Adult Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA.

J Clin Epidemiol 2000 Jan;53(1):95-102 Abstract quote

C-reactive protein may predict the risk of cardiovascular disease, but its association with angina pectoris in the general population has not been clearly established, however.

We used data from National Health and Nutrition Examination Survey III conducted from 1988-1994 to examine the associations between serum C-reactive protein and plasma fibrinogen concentrations and self-reported angina pectoris and myocardial infarction among 7,948 U.S. men and women aged 40 years and older. C-reactive protein and fibrinogen concentrations were moderately correlated (r = 0.43). After adjustment for age, sex, race or ethnicity, education, smoking status, systolic blood pressure, serum cholesterol, high-density lipoprotein cholesterol, history of diabetes mellitus, body mass index, and physical activity, fibrinogen (but not C-reactive protein) concentration was significantly associated with self-reported angina pectoris. Neither fibrinogen or C-reactive protein concentrations were significantly associated with angina pectoris when entered in the model simultaneously. C-reactive protein and fibrinogen concentrations were positively associated with myocardial infarction when entered separately into models, but only C-reactive protein concentration was significantly associated with myocardial infarction when both variables were entered simultaneously.

These cross-sectional data showed a significant positive association between C-reactive protein concentration and myocardial infarction but not self-reported angina pectoris in the U.S. population.

Cardiac troponin T and C-reactive protein as markers of acute cardiac allograft rejection.

Chance JJ, Segal JB, Wallerson G, Kasper E, Hruban RH, Kickler TS, Chan DW.

Department of Pathology, Johns Hopkins Hospital, 600 N. Wolfe Street/Meyer B-125, 21287-7065, Baltimore, MD, USA

Clin Chim Acta 2001 Oct;312(1-2):31-9 Abstract quote

Due to myocyte damage and an associated inflammatory response, it is possible that cardiac troponin T and C-reactive protein (CRP) concentrations may correlate with the histologic grade of rejection in endomyocardial biopsy samples obtained from patients who have received a heart transplant. In this study, 704 blood samples were obtained from 145 different heart transplant recipients just prior to endomyocardial biopsy. Plasma specimens were assayed for troponin T and CRP concentration and the results compared with the assigned International Society of Heart and Lung Transplantation (ISHLT) histologic grade. Rejection was defined as an ISHLT grade of 3A or higher. The negative predictive values were near 80% in all cases, and a statistically significant increase in median troponin T concentration was observed across ISHLT grades. After the first month posttransplantation, the specificity of the troponin T test (cutoff 0.1 ng/ml) was 95% and increased to 98% when false positives seen in renal disease patients were excluded. Both tests demonstrated poor sensitivity and positive predictive value for rejection. Neither CRP nor troponin T had sufficient sensitivity to serve as an alternative to endomyocardial biopsy in the diagnosis of acute cardiac allograft rejection. However, the troponin T test had a high specificity, especially when patients with renal insufficiency were excluded, and could serve as an adjunct test in this setting. When combined with a normal serum creatinine, a troponin T>/=0.1 ng/ml prior to endomyocardial biopsy correlated with graft rejection in almost all cases, making biopsy unnecessary.

Association of C-reactive protein with markers of prevalent atherosclerotic disease.

Folsom AR, Pankow JS, Tracy RP, Arnett DK, Peacock JM, Hong Y, Djousse L, Eckfeldt JH;

The Investigators of the NHBLI Family Heart Study. Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55454-1015, USA.

Am J Cardiol 2001 Jul 15;88(2):112-7 Abstract quote

Recent prospective studies have demonstrated that elevated C-reactive protein (CRP) is a marker of increased risk of atherothrombotic clinical events. We examined in a large, cross-sectional family-based study (n = 875 men, 948 women) whether serum CRP was associated with prevalent coronary heart disease (CHD), the ankle/brachial blood pressure index, or carotid intima-media thickness, an indicator of subclinical atherosclerosis as assessed by B-mode ultrasound.

CRP was associated with many other cardiovascular risk factors, particularly markers of obesity and insulin resistance, markers of inflammation and acute phase reaction, and hormone replacement therapy. Adjusted for age and family type, there was a weak positive association of CRP with carotid intima-media thickness in both genders and with prevalent CHD in women. However, adjustment for other risk factors completely eliminated the associations. For example, among women, the risk factor-adjusted mean values of intima-media thickness across quartiles of CRP were 0.76, 0.74, 0.75, and 0.76 mm (p >0.5). In men there was a weak inverse association between CRP and ankle/brachial blood pressure index, independent of other risk factors, but no such association in women. Our findings indicate that CRP is not strongly and independently associated with prevalent atherosclerosis. Because CRP has been associated with clinical events, it could be that elevated CRP may be a stronger marker of thrombotic risk than of the degree of atherosclerosis.

Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.

Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB, Ridker PM.

Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215-1204, USA.

JAMA 2002 Aug 28;288(8):980-7 Abstract quote
CONTEXT: Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown.

OBJECTIVES: To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk.

DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75 343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years.

MAIN OUTCOME MEASURE: Incidence of first myocardial infarction or death from CHD.

RESULTS: Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P<.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend =.002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP.

CONCLUSIONS: These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.

Ridker PM, Rifai N, Rose L, Buring JE, Cook NR.

Center for Cardiovascular Disease Prevention and the Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston 02215, USA.
N Engl J Med 2002 Nov 14;347(20):1557-65 Abstract quote
BACKGROUND: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol levels are elevated in persons at risk for cardiovascular events. However, population-based data directly comparing these two biologic markers are not available.

METHODS: C-reactive protein and LDL cholesterol were measured at base line in 27,939 apparently healthy American women, who were then followed for a mean of eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. We assessed the value of these two measurements in predicting the risk of cardiovascular events in the study population.

RESULTS: Although C-reactive protein and LDL cholesterol were minimally correlated (r=0.08), base-line levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for age, smoking status, the presence or absence of diabetes mellitus, categorical levels of blood pressure, and use or nonuse of hormone-replacement therapy, the relative risks of first cardiovascular events according to increasing quintiles of C-reactive protein, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses of each component of the composite end point and among users and nonusers of hormone-replacement therapy. Overall, 77 percent of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46 percent occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score.

CONCLUSIONS: These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.

COLON CANCER

C-reactive protein and the risk of incident colorectal cancer.

Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ.

Department of Medicine, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Md 21205, USA.

JAMA. 2004 Feb 4;291(5):585-90. Abstract quote

CONTEXT: Inflammation may play a role in the pathogenesis of colorectal cancer; however, epidemiological evidence supporting this hypothesis in average-risk persons is sparse.

OBJECTIVE: To determine the risk of incident colon and rectal cancer associated with elevated baseline plasma concentrations of C-reactive protein (CRP).

DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study of a cohort of 22 887 adults (>18 years and Washington County, Maryland, residents) enrolled between May and October 1989 and followed up through December 2000. A total of 172 colorectal cancer cases were identified through linkage with the Washington County and Maryland State Cancer registries. Up to 2 controls (n = 342) were selected from the cohort for each case and matched by age, sex, race, and date of blood draw.

MAIN OUTCOME MEASURE: Odds ratio (OR) of incident colon and rectal cancer.

RESULTS: Plasma CRP concentrations were higher among all colorectal cases combined than controls (median CRP, 2.44 vs 1.94 mg/L; P =.01). The highest concentration was found in persons who subsequently developed colon cancer vs matched controls (median CRP, 2.69 vs 1.97 mg/L; P<.001). Among rectal cancer cases, CRP concentrations were not significantly different from controls (median CRP, 1.79 vs 1.81 mg/L; P =.32). The risk of colon cancer was higher in persons in the highest vs lowest quartile of CRP (OR, 2.55; 95% confidence interval [CI], 1.34-4.88; P for trend =.002). In nonsmokers, the corresponding association was stronger (OR, 3.51; 95% CI, 1.64-7.51; P for trend<.001). A 1-SD increase in log CRP (1.02 mg/L) was associated with an increased risk of colon cancer after adjusting for potential confounders and excluding cases occurring within 2 years of baseline (OR, 1.35; 95% CI, 1.05-1.74) or excluding those with late-stage colon cancer at the time of diagnosis (OR, 1.38; 95% CI, 0.99-1.91).

CONCLUSIONS: Plasma CRP concentrations are elevated among persons who subsequently develop colon cancer. These data support the hypothesis that inflammation is a risk factor for the development of colon cancer in average-risk individuals.

HYPERTENSION

C-reactive protein and the risk of developing hypertension.

Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM.

Department of Medicine, Center for Cardiovascular Disease Prevention and the Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass 02215-1204, USA.

JAMA. 2003 Dec 10;290(22):2945-51. Abstract quote

CONTEXT: Although it has been hypothesized that hypertension is in part an inflammatory disorder, clinical data linking inflammation with incident hypertension are scarce.

OBJECTIVE: To examine whether C-reactive protein levels, a marker of systemic inflammation, are associated with incident hypertension.

DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study that began in 1992 of 20 525 female US health professionals aged 45 years or older who provided baseline blood samples with initially normal levels of blood pressure (BP) (systolic BP <140 mm Hg and diastolic BP <90 mm Hg, and no history of hypertension or antihypertensive medications) and then followed up for a median of 7.8 years for the development of incident hypertension. Plasma C-reactive protein levels were measured and baseline coronary risk factors were collected.

MAIN OUTCOME MEASURE: Incident hypertension, defined as either a new physician diagnosis, the initiation of antihypertensive treatment, or self-reported systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg.

RESULTS: During follow-up, 5365 women developed incident hypertension. In crude models, the relative risks (RRs) and 95% confidence intervals (CIs) of developing hypertension from the lowest (referent) to the highest levels of baseline C-reactive protein were 1.00, 1.25 (95% CI, 1.14-1.40), 1.51 (95% CI, 1.35-1.68), 1.90 (95% CI, 1.72-2.11), and 2.50 (95% CI, 2.27-2.75) (linear trend P<.001). In fully adjusted models for coronary risk factors, the RRs and 95% CIs were 1.00, 1.07 (95% CI, 0.95-1.20), 1.17 (95% CI, 1.04-1.31), 1.30 (95% CI, 1.17-1.45), and 1.52 (95% CI, 1.36-1.69) (linear trend P<.001). C-reactive protein was significantly associated with an increased risk of developing hypertension in all prespecified subgroups evaluated, including those with very low levels of baseline BP, as well as those with no traditional coronary risk factors. Similar results were found when treating C-reactive protein as a continuous variable and controlling for baseline BP.

CONCLUSION: C-reactive protein levels are associated with future development of hypertension, which suggests that hypertension is in part an inflammatory disorder.

RHEUMATOLOGIC

Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients.

Liou LB.

Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-yuan County, Taiwan.

Clin Exp Rheumatol 2001 Sep-Oct;19(5):515-23 Abstract quote

OBJECTIVE: To examine the correlation between C-reactive protein (CRP) and CRP-inducing cytokines (IL-1 beta, IL-6, TNF-alpha) and IL-1 receptor antagonist (IL-1ra), as well as to study their relationship with systemic lupus erythematosus disease activity (SLEDAI) in newly diagnosed, untreated lupus patients.

METHODS: Sera from newly diagnosed untreated lupus and rheumatoid arthritis (RA) patients were examined for CRP and cytokines. Data were compared among patient groups and correlated individually among the lupus group. Lupus monocytes and neutrophils were cultured in vitro to produce IL-1ra and experimental results were related to CRP levels and SLEDAI.

RESULTS: Within lupus, serum CRP, IL-6, IL-1 beta and TNF-alpha levels were significantly lower than those of RA (all p values were < 0.005) and generally higher than those in the controls (p = 0.002, < 0.001, > 0.2, and < 0.001, respectively). Except IL-1ra, which was correlated with CRP (p = 0.045), no substantial correlation was discovered between CRP and IL-6, IL-1 beta or TNF-alpha individually. Moreover, excluding IL-1ra (p = 0.024), there was no association between cytokines and SLEDAI. In vitro IL-1ra as secreted by monocytes correlated with serum CRP and SLEDAI.

CONCLUSION: In lupus patients, serum IL-1 beta, IL-6 or TNF-alpha levels failed to correlate with low CRP levels. This indicates a complicated CRP production process, which can not be explained solely by single cytokines as reported previously. Both serum and in vitro produced IL-1ra may be applied clinically as a surrogate CRP marker in untreated lupus patients as they are both correlated with serum CRP.

INTERFERING DISEASES OR SUBSTANCES THAT ALTER LEVELS CHARACTERIZATION

High intake of vitamin E reduces CRP levels especially among type II diabetic patients Free Radic Biol Med. 2000 Oct 15;29(8):790-2.

Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.

van Baal WM, Kenemans P, van der Mooren MJ, Kessel H, Emeis JJ, Stehouwer CD.

Institute for Cardiovascular Research-Vrije Universiteit (ICAR-VU), Department of Obstetrics and Gynaecology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.

Thromb Haemost 1999 Jun;81(6):925-8 Abstract quote

OBJECTIVE: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women.

DESIGN: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks.

RESULTS: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group.

CONCLUSION: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, Anderson PW.

Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

J Clin Endocrinol Metab 2000 Jan;85(1):214-8 Abstract quote

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women.

Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT.

We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.

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INTERFERING DISEASES OR SUBSTANCES THAT ALTER LEVELS	CHARACTERIZATION
High intake of vitamin E reduces CRP levels especially among type II diabetic patients	Free Radic Biol Med. 2000 Oct 15;29(8):790-2.
Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. van Baal WM, Kenemans P, van der Mooren MJ, Kessel H, Emeis JJ, Stehouwer CD. Institute for Cardiovascular Research-Vrije Universiteit (ICAR-VU), Department of Obstetrics and Gynaecology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.	Thromb Haemost 1999 Jun;81(6):925-8 Abstract quote OBJECTIVE: To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women. DESIGN: Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks. RESULTS: CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group. CONCLUSION: In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.
The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, Anderson PW. Brigham and Women's Hospital, Boston, Massachusetts 02115, USA	J Clin Endocrinol Metab 2000 Jan;85(1):214-8 Abstract quote C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.