CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus
pneumoniae, was the first acute-phase protein to be described and is an exquisitely
sensitive systemic marker of inflammation and tissue damage (1). The acute-phase response comprises the nonspecific physiological and biochemical responses of endothermic animals to most forms of tissue damage, infection, inflammation, and malignant neoplasia. In particular, the synthesis of a number of proteins is rapidly upregulated, principally in hepatocytes, under the control of cytokines originating at the site of pathology. Other acute- phase proteins include proteinase inhibitors and coagulation, complement, and transport proteins, but the only molecule that displays sensitivity, response speed, and dynamic range comparable to those of CRP is serum amyloid A protein (SAA) (Table 1) (1). Plasma CRP is produced only by hepatocytes, predominantly under transcriptional control by the cytokine IL-6, although other sites of local CRP synthesis and possibly secretion have been suggested. De novo hepatic synthesis starts very rapidly after a single stimulus, serum concentrations rising above 5 mg/l by about 6 hours and peaking around 48 hours. The plasma half-life of CRP is about 19 hours and is constant under all conditions of health and disease, so that the sole determinant of circulating CRP concentration is the synthesis rate (3), which thus directly reflects the intensity of the pathological process(es) stimulating CRP production. When the stimulus for increased production completely ceases, the circulating CRP concentration falls rapidly, at almost the rate of plasma CRP clearance. In unselected general populations of ostensibly healthy subjects, the median CRP value is slightly higher than among blood donors and tends to increase with age, presumably reflecting the increasing incidence of subclinical pathologies (4). However, surprisingly in view of the sensitivity, speed, and range of the CRP response, subjects in the general population tend to have stable CRP concentrations characteristic for each individual, apart from occasional spikes presumably related to minor or subclinical infections, inflammation, or trauma. Importantly, acute-phase CRP values show no diurnal variation and are unaffected by eating. Liver failure impairs CRP production, but no other intercurrent pathologies and very few drugs reduce CRP values unless they also affect the underlying pathology providing the acute-phase stimulus. The CRP concentration is thus a very useful nonspecific biochemical marker of inflammation, measurement of which contributes importantly to (a) screening for organic disease, (b) monitoring of the response to treatment of inflammation and infection, and (c) detection of intercurrent infection in immunocompromised individuals, and in the few specific diseases characterized by modest or absent acute-phase responses (Table 3) (1). It is not known why systemic lupus erythematosus and the other conditions listed with it in Table 2 fail to elicit major CRP production despite evident inflammation and tissue damage, nor why the CRP responses to intercurrent infection are apparently intact in patients with such conditions.
CRP belongs to the pentraxin family of calcium-dependent ligand-binding plasma proteins, the other member of which in humans is serum amyloid P component (SAP). The human CRP molecule (Mr115,135) is composed of five identical nonglycosylated polypeptide subunits (Mr 23,027), each containing 206 amino acid residues. The protomers are noncovalently associated in an annular configuration with cyclic pentameric symmetry (6) (Figure 1). Each protomer has the characteristic "lectin fold," composed of a two-layered sheet with flattened jellyroll topology. http://www.jci.org/articles/view/18921#SEC1
C-reactive protein Email this page to a friendShare on facebookShare on twitterBookmark & SharePrinter-friendly version C-reactive protein is produced by the liver. The level of CRP rises when there is inflammation throughout the body. This article discusses the blood test done to measure the amount of CRP in your blood. How the Test is Performed A blood sample is needed. This is usually taken from a vein. The procedure is called a venipuncture. How to Prepare for the Test No preparation is necessary for this test. How the Test Will Feel When the needle is inserted to draw blood, some people feel moderate pain, while others feel only a prick or stinging sensation. Afterward, there may be some throbbing. Why the Test is Performed The CRP test is a general test to check for inflammation in the body. It is not a specific test. That means it can reveal that you have inflammation somewhere in your body, but it cannot pinpoint the exact location. Your doctor may order this test to: Check for flare-ups of inflammatory diseases such as rheumatoid arthritis, lupus, or vasculitis Determine if anti-inflammatory medicine is working to treat a disease or condition However, a low CRP level does not always mean that there is no inflammation present. Levels of CRP may not be increased in people with rheumatoid arthritis and lupus. The reason for this is unknown. A more sensitive CRP test, called a high-sensitivity C-reactive protein (hs-CRP) assay, is available to determine a person's risk for heart disease. Many consider a high CRP level to be a risk factor for heart disease. However, it is not known whether CRP is merely a sign of cardiovascular disease or if it actually plays a role in causing heart problems. Normal Results Normal CRP values vary from lab to lab. Generally, there is no CRP detectable in the blood. Your doctor may also use a highly sensitive test called hs-CRP to help determine your risk of heart disease. According to the American Heart Association: You are at low risk of developing cardiovascular disease if your hs-CRP level is lower than 1.0mg/L You are at average risk of developing cardiovascular disease if your levels are between 1.0 and 3.0 mg/L You are at high risk for cardiovascular disease if your hs-CRP level is higher than 3.0 mg/L Note: Normal value ranges may vary slightly among different laboratories. Talk to your doctor about the meaning of your specific test results. The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens. What Abnormal Results Mean A positive test means you have inflammation in the body. This may be due to a variety of different conditions, including: Cancer Connective tissue disease Heart attack Infection Inflammatory bowel disease (IBD) Lupus Pneumococcal pneumonia Rheumatoid arthritis Rheumatic fever Tuberculosis This list is not all inclusive. Note: Positive CRP results also occur during the last half of pregnancy or with the use of birth control pills (oral contraceptives). Risks Veins and arteries vary in size from one patient to another and from one side of the body to the other. Obtaining a blood sample from some people may be more difficult than from others. Other risks associated with having blood drawn are slight but may include: Excessive bleeding Fainting or feeling light-headed Hematoma (blood accumulating under the skin) Infection (a slight risk any time the skin is broken) Alternative Names CRP; High-sensitivity C-reactive protein; hs-CRP http://www.nlm.nih.gov/medlineplus/ency/article/003356.htm
13.0 C-Reactive Protein The main biologic sign of inflammation is an increase in the erythrocyte sedimentation rate (ESR). In addition an increase in plasma concentrations of a group of proteins known as acute-phase proteins is a good indicator of local inflammatory activities and tissue damage. The acute phase proteins include C-reactive protein (CRP), inflammatory mediators (e.g. complement components c3 and c4, fibrinogen, etc. CRP is prominent among the acute-phase proteins because it provides fast and adequate information of the actual clinical situation; as a result CRP is a direct and quantitative measure of the acute-phase reactions. Measures of CRP add to the diagnostic procedure in selected cases (e-g. in the differentiation between a bacterial and a viral infection). An extremely elevated CRP is suggestive of a possible bacterial infection. The CRP level may be useful also for monitoring the effect of treatment and for early detection of postoperative complications or intercurrent infections. The CRP is a parameter for inflammatory activity. CRP is a method of choice for screening for inflammatory and malignant diseases and monitoring therapy in inflammatory disease. Elevations of CRP occur in nearly to diseases states, including bacterial infection, viral infections, myocardial infraction specificity rules out CRP as a definitive diagnostic tool. CRP levels rise following the tissue injury or surgery. In uncomplicated cases the level of CRP peaks about 2 days postoperatively and gradually returns to normal levels within 7 to 10 days. CRP is synthesized more rapidly than other acute Tests for CRP Rapid latex agglutination test Principle: The test is based on the reaction between patient serum containing CRP as the antigen & the corresponding antibody coated to the treated surface of latex particle. The coated particles enhance the detection of an agglutinate reaction when antigen is present in the serum being tested. Specimen- Serum Reagent & materials required CRP latex reagent Glycine saline buffer Capillary pipette Applicator sticks Glass slide Serologic pipettes & rubber bulb
Reporting Positive reaction agglutination Negative reaction absence of agglutination
CRP is an extremely sensitive, nonspecific, acute-phase reactant produced in response to most forms of tissue injury, infection, and inflammation and regulated by cytokines, including interleukin-6, interleukin- 1, and tumor necrosis factor-. 38 Although reportedly expressed by some mononuclear populations, these cells do not secrete CRP, and circulating CRP is exclusively produced by hepatocytes. 3940 The stimuli responsible for the generally modest elevations in plasma CRP predictively associated with coronary events are not known. They may arise in the atheromatous lesions themselves and reflect the extent of atherosclerosis and the local inflammation that predisposes to plaque instability, rupture, and occlusive thrombosis. On the other hand, increased CRP production may result from inflammation elsewhere in the body that is somehow proatherogenic and procoagulant. Chronic low-grade infections may be associated with increased risk of CHD, 41
42 as is the chronic inflammation of rheumatoid arthritis. 43 Many coagulation proteins, including fibrinogen, are acute-phase reactants; elevation of fibrinogen is a well-recognized risk factor for coronary events, 4 and increased CRP values may just be a signal of the acute-phase response in general. However, there is substantial evidence that CRP may contribute directly to the pathogenesis of atherothrombosis. CRP is a ligand binding protein that binds to the plasma membranes of damaged cells. 44
45 Aggregated but not soluble native CRP selectively binds LDL and VLDL from whole plasma and, as we have previously proposed, could thereby participate in their atherogenic accumulation. 46 Complexed CRP also activates complement and can be proinflammatory, 47 whereas CRP has recently been found to be a potent stimulator of tissue factor production by macrophages in vitro. 48 Tissue factor is the main initiator of coagulation in vivo, and its local concentration in the arterial wall is clearly related to coronary thrombotic events. 49
50
51 There are conflicting reports about the presence of CRP in atheromatous lesions, 52
53
54 and claims that CRP affects platelet function are also controversial. 55 However, the capacity of CRP to enhance tissue factor production suggests a possible causative link between increased CRP values and coronary events. Although the number of cases was relatively small, results of the present prospective study of a large cohort of initially healthy middle-aged men indicate that modest elevations in serum CRP concentration significantly predict future coronary events. These observations strengthen the association between low- grade inflammation and the progression and complications of atherosclerosis. Further work is required to clarify the underlying pathophysiological mechanisms, but modulation of the acute-phase response generally and/or the functions of specific acute-phase proteins specifically, especially CRP, already constitutes novel potential therapeutic https://circ.ahajournals.org/content/99/2/237.fullc targets in CHD.
The Role of C-Reactive Protein M. Saljoughian, PharmD, PhD Department of Pharmacy Services Alta Bates Summit Medical Center Berkeley, California
7/18/2008 US Pharm. 2008;33(7):HS12-HS15.
The human body responds to injury and infection by a process called inflammation. During an inflammatory process in the body, the levels of C-reactive protein (CRP), a pro-inflammatory cytokine, rise dramatically. It has been suggested that testing CRP levels in the blood may be an additional way to assess cardiovascular disease risk. Laboratory findings from clinical and research studies also suggest that inflammation is an important factor in atherosclerosis. This is the process in which fatty deposits build up in the inner lining of arteries. 1
The American Heart Association and the Centers for Disease Control and Prevention published a joint scientific statement in 2003 on the use of inflammatory markers in clinical and public health practice. 2 This statement was developed after systematically reviewing the evidence of association between inflammatory markers (mainly CRP) and coronary heart disease and stroke. A more sensitive CRP test, called a high-sensitivity C-reactive protein (hs- CRP) assay, is available to determine heart disease risk more accurately. 1
In 1930, Tillett and Francis originally discovered CRP as a substance in the serum of patients with acute inflammation that reacted with the C-polysaccharide of pneumococcus. Initially, it was thought that CRP might have a pathogenic role, as it was elevated in people with a variety of illnesses, but discovery of its hepatic synthesis and secretion closed that debate. Measuring and charting CRP values can prove useful in determining disease progression or the effectiveness of treatments. CRP is used mainly as a marker of inflammation. 3
Various analytic methods are available for CRP determination, such as enzyme-linked immunosorbent assay (ELISA), immunoturbidimetry, rapid immunodiffusion, and visual agglutination. In general, both the CRP test and another test, called the erythrocyte sedimentation rate (ESR), measure the increase in inflammatory generated proteins. The CRP test is a direct measurement of C-reactive protein, while ESR indirectly measures many proteins associated with inflammation. 1
Causes of Inflammation There are many conditions that cause inflammation. Genetics play a role, as does the environment. Environmental factors include diet, exposure to toxins, germs, pollutants, and inhalants. Some people have a genetic predisposition to increased inflammation, which can cause them to develop an illness such as rheumatoid arthritis. 4,5
Acute inflammation is a complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the body to remove the injurious stimuli as well as to initiate the healing process for the tissue. Chronic inflammation is a pathologic condition characterized by concurrent active inflammation, tissue degeneration, and attempts at repair. Chronic inflammation is not characterized by the classic signs of acute inflammation (i.e., swelling, redness, pain, heat, loss of function). Instead, chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (i.e., monocytes, macrophages, lymphocytes, plasma cells) and tissue destruction, which include angiogenesis and fibrosis.
Cigarette smoking, hypertension, atherogenic lipoproteins, and hyperglycemia are well-established promoting factors in atherogenesis. These risk factors give rise to a variety of noxious stimuli that cause the release of certain chemicals and the activation of cells involved in the inflammatory process. These events are thought to contribute not only to the formation of plaque but may also contribute to its disruption, resulting in the formation of a blood clot. Thus, virtually every step in atherogenesis is believed to involve substances involved in the inflammatory response and cells that are characteristic of inflammation. 6
In addition, there is research that indicates that an infection--possibly one caused by a bacterium or a virus--might contribute to or even cause atherosclerosis. 7 The infectious bacterium Chlamydia pneumoniae has been shown to have a role in atherosclerotic plaque. The herpes simplex virus has also been proposed as an initial inflammatory infectious agent in atherosclerosis. Viral infections tend to give a lower CRP level than bacterial infection. Bacterial infection with Helicobacter pylori is now known to be the major cause of inflammatory stomach lesions. The treatment for this condition routinely includes antibiotic therapy.
In diseases such as allergies, anemia, arthritis, fibromyalgia, fibrosis, heart attack, aortic valve stenosis, kidney failure, lupus, pancreatitis, and psoriasis, the levels of inflammatory cytokines are elevated, which induces damage to the tissues. In surgical complications, the inflammatory cytokines prevent healing.
CRP and New Cardiovascular Events Scientific studies have found that the higher the hs-CRP levels, the higher the risk of having a heart attack. In fact, the risk for heart attack in people with high hs-CRP levels has been determined to be twice that of those whose hs- CRP levels are lower. These prospective studies included men, women, and the elderly. Studies have also found an association between sudden cardiac death, peripheral arterial disease, and high hs-CRP levels. However, not all of the established cardiovascular risk factors were controlled for when the association was examined. The true independent association between hs-CRP and new cardiovascular events has yet to be established. 8
CRP and Recurrent Events A growing number of studies have examined whether high hs-CRP levels can predict recurrent cardiovascular disease, stroke, and death in different settings. High levels of hs-CRP consistently predict recurrent coronary events in patients with unstable angina and acute myocardial infarction (heart attack). Higher hs-CRP levels also are associated with lower survival rates in these patients. Many studies have suggested that after adjusting for other prognostic factors, hs-CRP is useful as a risk predictor. 8
Studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it has been opened by balloon angioplasty. High levels of hs-CRP in the blood also seem to predict prognosis and recurrent events in patients with stroke or peripheral arterial disease. CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarctions. 8
When to Measure CRP If a person's cardiovascular risk factors (i.e., smoking, hypertension, high blood cholesterol, diabetes, being overweight or obese, physical inactivity) are low, the possibility of developing cardiovascular disease is less than 10% in 10 years, and no test is immediately warranted. If the risk factors are in the intermediate range, the possibility is 10% to 20% in 10 years, and such a test can help predict a cardiovascular or stroke event as well as help direct further evaluation and therapy. However, the benefits of therapy based on this strategy remain uncertain. A person with a high-risk score (>20% in 10 years) or established heart disease or stroke should be treated intensively regardless of hs-CRP levels. 9
Diagnostic Criteria As previously mentioned, CRP is used mainly as a marker of inflammation. Measuring and charting CRP values can prove useful in determining cardiovascular and noncardiovascular disease progress or the effectiveness of treatments. Blood samples are analyzed in a medical laboratory or at the point of testing. Patients who are scheduled for a CRP test will be asked not to eat or drink anything for 12 hours before the test.
The ranges for evaluating hs-CRP levels are given in Table 1. If, after repeated testing, patients have persistently unexplained, markedly elevated hs-CRP levels (>10.0 mg/L), they should be evaluated to exclude noncardiovascular causes. Patients with autoimmune diseases or cancer, as well as other infectious diseases, may also have elevated CRP levels. 10
Mode of Action The CRP gene is located on the first chromosome and is a 224-residue protein with a monomer molar mass of 25106 dalton. The protein is an annular pentameric disk in shape. Proteins with this type of configuration are known as pentraxins. CRP binds to phosphorylcholine on microbes. It is thought to assist in complement binding to foreign and damaged cells, and it enhances phagocytosis by macrophages, which express a receptor for CRP. It is also believed to play an important role in innate immunity, as an early defense system against infections. 11
Arterial damage is thought to result from inflammation due to chemical insults. CRP can be used as a marker for the extent of this damage, but by itself it is not a specific prognostic indicator. Clinicians only look at the CRP values with prolonged elevation, so a single measurement would be meaningless.
In different disease states, one or two amino acids get "lopped off" CRP. It retains its activity, but these losses open it up to glycosylation, and it may have sugars such as glucose, galactose, and mannose attached to it. The patterns of glycosylation vary in different diseases, but are similar among patients who have the same disease. Previous work has shown that CRP increased the rate at which a particular parasite could invade blood cells. 12 The study showed that the various CRPs had very different potencies in this regard. The authors speculate that subtyping CRP may give us more insight into heart attack mechanisms. Although the study did not demonstrate whether this glycosylation of CRP was a "good" or a "bad" thing, it offered circumstantial evidence that the differing glycosylation is part of CRP's mode of action. 12
The Role of CRP in Cancer The role of inflammation in cancer is well known. Some organs of the body show greater risk of cancer when they are chronically inflamed. Blood samples of persons with colon cancer have an average CRP concentration of 2.69 mg/L. Persons without colon cancer average 1.97 mg/L. The difference was statistically significant (P <.001). 13 These findings concur with previous studies that indicated that anti-inflammatory drugs could lower colon cancer risk. 14
Pharmacist Recommendation It is important for patients to make lifestyle changes to reduce their risk for cardiovascular disease, especially if the CRP level is intermediate or high (Table 2). 15 For those with an elevated CRP level, taking aspirin may provide protection from cardiovascular disease. Statins, the most commonly prescribed drugs for lowering cholesterol, may also reduce CRP levels. Clinicians should prescribe the correct medications and dosage to treat the disease condition. http://www.uspharmacist.com/content/c/10944/?t=men's_health,cardiovascular_disease
Elevated C-reactive Protein (CRP)
What is elevated C-reactive protein? C-reactive protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. An elevated CRP level is identified with blood tests and is considered a non-specific "marker" for disease. Data from a large number of studies suggest that over time chronic, imperceptible, low-level internal inflammation can lead to many serious, age-related diseases including heart disease, some forms of cancer and neurodegenerative conditions such asAlzheimer's and Parkinson's disease. However, CRP levels don't appear to help predict the risk of heart disease in patients already being treated for risks such as high blood pressure or high LDL ("bad") cholesterol. A 2010 analysis of British data on 4,853 patients found that CRP levels didn't yield any more information about the risk of heart disease than LDL ("bad") cholesterol levels or high blood pressure in patients who already were being treated with a cholesterol-lowering statin drug or with medication to lower blood pressure. For those reasons, the researchers concluded that measuring CRP in patients with other known risk factors for heart disease may not be necessary. These results, presented at a 2010 American Heart Association meeting and later published in the European Heart Journal, conflict with findings from an earlier study with more than 17,000 patients which showed that treating elevated CRP with statin drugs reduced cardiovascular events by 37 percent in healthy individuals whose only risk factor for heart disease was elevated CRP. This earlier study called JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) found that patients taking the drug rosuvastain were half as likely to need angioplasty or bypass surgery, half as likely to suffer a heart attack or stroke, and 20 percent less likely to die than study participants who received the placebo. That study was published in 2008 in The New England Journal of Medicine. What are the symptoms of elevated C-reactive protein? Elevated CRP levels have no outward, noticeable symptoms. What are the causes of elevated C-reactive protein? The inflammation signaled by CRP is influenced by genetics, a sedentary lifestyle, too much stress, and exposure to environmental toxins such as secondhand tobacco smoke. Diet has a huge impact, particularly one that contains a lot of refined, processed and manufactured foods. How is elevated C-reactive protein diagnosed? CRP levels can be measured via a blood test. In evaluating cardiac risk, physicians look at a very narrow range of CRP levels, from zero to 3.0 and above. This requires a special test called high sensitivity CRP (hs-CRP), which may be able to reveal inflammation at the micro-vascular level. If this test shows that CRP is less than 1.0 mg per liter of blood, the risk of heart disease is considered low; if it is between 1.0 and 3.0, the risk is average; if it is above 3.0, the risk is deemed high. The American Heart Association (AHA) recommends CRP testing when doctors aren't sure how to treat patients with an intermediate risk of heart disease, such as a 10-20 percent risk of having a heart attack in the next 10 years However, AHA guidelines do not recommend CRP testing for individuals at either high risk of low risk. (Other physicians, including Dr. Weil, think that all adults should have an hs-CRP test whenever their cholesterol is tested.) There are two tests for CRP. One can show a non-specific elevation of CRP that occurs with general inflammatory changes in the body; the other test is hs-CRP - highly sensitive CRP - which is a measure of inflammation in blood vessels. This is the test needed to help establish heart disease risk. People who have arthritic conditions tend to have high CRP levels because inflammation underlies these disorders. Arthritis may push test results far beyond the range used to assess heart disease risk. When inflammation levels are being assessed in patients with rheumatoid arthritis, inflammatory bowel disease or other autoimmune conditions, the hs-CRP test is not used. Instead, inflammation is evaluated with a test that measures levels in excess of 10 mg/L. With most active infections and inflammatory processes, CRP levels are above 100 mg/L. Under these circumstances, the CRP test is used to follow the trend. Declining CRP levels are a sign that inflammation is decreasing. When checking CRP for arthritic and autoimmune disorders, a level of 10 mg/L or lower is considered "normal." Because an hs-CRP test isn't useful to assess cardiovascular risk among people with inflammatory diseases, these patients have to rely on such well-recognized risk factors as high blood pressure or high cholesterol, whether or not they smoke, their weight and their risk of diabetes. In addition to such standard measures for reducing the risk of cardiovascular disease as exercise, keeping weight under control, practicing stress reduction techniques and getting adequate sleep, Dr. Weil recommends that people with these disorders make an effort to reduce inflammation and their risk of heart disease by following an anti-inflammatory diet. What is the conventional treatment of elevated C-reactive protein? Conventional physicians may prescribe the same (statin) drugs used to lower LDL cholesterol to also lower levels of C-reactive protein. In addition, they will typically recommend exercise and weight loss where appropriate, since both can help lower CRP. In general, conventional physicians recommend the same lifestyle changes shown to reduce heart disease - diet, exercise, not smoking, drinking less alcohol, following a heart-healthy diet - to lower levels of CRP. What therapies does Dr. Weil recommend for elevated C-reactive protein? Dr. Weil recommends an anti-inflammatory diet that includes two to three servings of fish such as salmon or sardines per week. If you don't eat fish, he suggests taking fish oil supplements. He also recommends taking anti-inflammatory herbs including ginger andturmeric and following your doctor's recommendations for heart health - quit smoking, watch your diet (particularly avoid foods that predominantly consist of flour and/or sugar), and get regular exercise. A recent study at Johns Hopkins showed that as fitness levels decline, CRP levels go up. The researchers weren't sure if poor fitness leads to an increase in CRP or vice versa, but exercise is an important part of maintaining heart health in any case. http://www.drweil.com/drw/u/ART03424/Elevated-Creactive- Protein-CRP.html
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