C-reactive protein
Encyclopedia
C-reactive protein is a protein
found in the blood, the levels of which rise in response to inflammation
(i.e. C-reactive protein is an acute-phase protein). Its physiological role is to bind to phosphocholine
expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system
via the C1Q complex
.
CRP is synthesized by the liver
in response to factors released by fat cells (adipocytes). It is a member of the pentraxin family of proteins. It is not related to C-peptide
or protein C
. C-reactive protein was the first pattern recognition receptor
(PRR) to be identified.
Discovered by Tillett and Francis in 1930 , it was initially thought that CRP might be a pathogenic secretion as it was elevated in people with a variety of illnesses including cancer, however, discovery of hepatic synthesis demonstrated that it is a native protein.
(1q21-q23). CRP is a 224-residue protein with a monomer molar mass of 25106 Da. The protein is an annular pentameric disc in shape and a member of the small pentraxins
family.
The physiological role of CRP is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system. CRP binds to phosphocholine on microbes and damaged cells and enhances phagocytosis by macrophages. Thus, CRP participates in the clearance of necrotic and apoptotic cells.
CRP is a member of the class of acute-phase reactants, as its levels rise dramatically during inflammatory
processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophage
s as well as adipocyte
s. CRP binds to phosphocholine
on microbes. It is thought to assist in complement
binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin mediated phagocytosis
), which express a receptor for CRP. It is also believed to play another important role in innate immunity, as an early defense system against infections.
CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and therefore its level is mainly determined by the rate of production (and hence the severity of the precipitating cause).
Serum amyloid A
is a related acute-phase marker that responds rapidly in similar circumstances.
, polymyositis
, and dermatomyositis
often elicit little or no CRP response. CRP levels also tend not to be elevated in SLE unless serositis or synovitis is present. Elevations of CRP in the absence of clinically significant inflammation can occur in renal failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease.
and cardiovascular disease
. A study of over 700 nurses showed that those in the highest quartile
of trans fat
consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate ischemic necrosis
in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial
and cerebral
infarcts; so far, this has been demonstrated in animal models only.
It has been hypothesized that a high CRP levels might reflect a large benefit from statins. This is based on the JUPITER trial
that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. A subsequent trial however failed to find that CRP was useful for determining statin benefit.
To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.
Blood samples of persons with colon cancer have an average CRP concentration of 2.69 milligrams per liter. Persons without colon cancer average 1.97 milligrams per liter. The difference was statistically significant. These findings concur with previous studies that indicate that anti-inflammatory drugs
could lower colon cancer risk.
, there are few known factors that interfere with CRP production.
Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. Blood
, usually collected in a serum-separating tube
, is analysed in a medical laboratory
or at the point of care. Various analytical methods are available for CRP determination, such as ELISA
, immunoturbidimetry, rapid immunodiffusion
, and visual agglutination
.
A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser nephelometry
. The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L.
Normal concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with aging. Higher levels are found in late pregnant
women, mild inflammation
and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burn
s (>200 mg/L).
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR. The half-life of CRP is constant. Therefore, CRP level is mainly determined by the rate of production (and hence the severity of the precipitating cause). In the first 24 h, ESR may be normal and CRP elevated. CRP returns to normal more quickly than ESR in response to therapy.
invasion and inflammation
within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific
prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
found in the blood, the levels of which rise in response to inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
(i.e. C-reactive protein is an acute-phase protein). Its physiological role is to bind to phosphocholine
Phosphocholine
Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
via the C1Q complex
C1Q complex
The C1q complex is potentially multivalent for attachment to the complement fixation sites of immunoglobulin.The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM....
.
CRP is synthesized by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
in response to factors released by fat cells (adipocytes). It is a member of the pentraxin family of proteins. It is not related to C-peptide
C-peptide
C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...
or protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
. C-reactive protein was the first pattern recognition receptor
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...
(PRR) to be identified.
History and nomenclature
CRP was so named because it was first discovered as a substance in the serum of patients with acute inflammation that reacted with the C- (capsular) polysaccharide of pneumococcus.Discovered by Tillett and Francis in 1930 , it was initially thought that CRP might be a pathogenic secretion as it was elevated in people with a variety of illnesses including cancer, however, discovery of hepatic synthesis demonstrated that it is a native protein.
Genetics and biochemistry
The CRP gene is located on the first chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(1q21-q23). CRP is a 224-residue protein with a monomer molar mass of 25106 Da. The protein is an annular pentameric disc in shape and a member of the small pentraxins
Pentraxins
Pentraxins, also known as pentaxins, are an evolutionary conserved family of proteins characterised by containing a pentraxin protein domain. Proteins of the pentraxin family are involved in acute immunological responses...
family.
Function
The acute phase response develops in a wide range of acute and chronic inflammatory conditions like bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury or necrosis. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver. During the acute phase response, levels of CRP rapidly increase within 2 hours of acute insult, reaching a peak at 48 hours. With resolution of the acute phase response, CRP declines with a relatively short half-life of 18 hours. Measuring CRP level is a screen for infectious and inflammatory diseases. Rapid, marked increases in CRP occur with inflammation, infection, trauma and tissue necrosis, malignancies, and autoimmune disorders. Because there are a large number of disparate conditions that can increase CRP production, an elevated CRP level does not diagnose a specific disease. An elevated CRP level can provide support for the presence of an inflammatory disease, such as rheumatoid arthritis, polymyalgia rheumatica or giant-cell arteritis.The physiological role of CRP is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system. CRP binds to phosphocholine on microbes and damaged cells and enhances phagocytosis by macrophages. Thus, CRP participates in the clearance of necrotic and apoptotic cells.
CRP is a member of the class of acute-phase reactants, as its levels rise dramatically during inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s as well as adipocyte
Adipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
s. CRP binds to phosphocholine
Phosphocholine
Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
on microbes. It is thought to assist in complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin mediated phagocytosis
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...
), which express a receptor for CRP. It is also believed to play another important role in innate immunity, as an early defense system against infections.
CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and therefore its level is mainly determined by the rate of production (and hence the severity of the precipitating cause).
Serum amyloid A
Serum amyloid A
Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli . These proteins are produced predominantly by the liver...
is a related acute-phase marker that responds rapidly in similar circumstances.
Clinical significance
SclerodermaScleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
, polymyositis
Polymyositis
Polymyositis is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis.-Signs and symptoms:...
, and dermatomyositis
Dermatomyositis
Dermatomyositis is a connective-tissue disease related to polymyositis and Bramaticosis that is characterized by inflammation of the muscles and the skin.- Causes :...
often elicit little or no CRP response. CRP levels also tend not to be elevated in SLE unless serositis or synovitis is present. Elevations of CRP in the absence of clinically significant inflammation can occur in renal failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease.
Role in cardiovascular disease
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes, hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. A study of over 700 nurses showed that those in the highest quartile
Quartile
In descriptive statistics, the quartiles of a set of values are the three points that divide the data set into four equal groups, each representing a fourth of the population being sampled...
of trans fat
Trans fat
Trans fat is the common name for unsaturated fat with trans-isomer fatty acid. Because the term refers to the configuration of a double carbon-carbon bond, trans fats are sometimes monounsaturated or polyunsaturated, but never saturated....
consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate ischemic necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and cerebral
Cerebral infarction
A cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic. Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid...
infarcts; so far, this has been demonstrated in animal models only.
It has been hypothesized that a high CRP levels might reflect a large benefit from statins. This is based on the JUPITER trial
JUPITER trial
The JUPITER trial is a study aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.- Study rationale :JUPITER was a randomized double-blind placebo-controlled study...
that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. A subsequent trial however failed to find that CRP was useful for determining statin benefit.
To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.
Role in cancer
The role of inflammation in cancer is not 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 milligrams per liter. Persons without colon cancer average 1.97 milligrams per liter. The difference was statistically significant. These findings concur with previous studies that indicate that anti-inflammatory drugs
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
could lower colon cancer risk.
Diagnostic use
CRP is used mainly as a marker of inflammation. Apart from liver failureLiver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
, there are few known factors that interfere with CRP production.
Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. Blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, usually collected in a serum-separating tube
Serum-separating tube
Serum-separating tubes, also known as serum separator tubes or SSTs, are used in medical clinical chemistry tests requiring blood serum.SSTs are sometimes called "marble-top tubes" or "yellow topped tubes", referring to the stoppers which are either gold or red-gray...
, is analysed in a medical laboratory
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...
or at the point of care. Various analytical methods are available for CRP determination, such as ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
, immunoturbidimetry, rapid immunodiffusion
Immunodiffusion
Immunodiffusion is a diagnostic test which involves diffusion through a substance such as agar.Two commonly known forms are Ouchterlony double immunodiffusion and radial immunodiffusion....
, and visual agglutination
Agglutination (biology)
Agglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue."This occurs in biology in three main examples:...
.
A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser nephelometry
Nephelometry
Nephelometry is a technique used in immunology to determine levels of IgM, IgG, and IgA.It is performed by measuring the turbidity in a water sample by passing light through the sample being measured...
. The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L.
Normal concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with aging. Higher levels are found in late pregnant
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
women, mild inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burn
Burn
A burn is an injury to flesh caused by heat, electricity, chemicals, light, radiation, or friction.Burn may also refer to:*Combustion*Burn , type of watercourses so named in Scotland and north-eastern England...
s (>200 mg/L).
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR. The half-life of CRP is constant. Therefore, CRP level is mainly determined by the rate of production (and hence the severity of the precipitating cause). In the first 24 h, ESR may be normal and CRP elevated. CRP returns to normal more quickly than ESR in response to therapy.
Cardiology diagnostic test
Arterial damage results from white blood cellMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
invasion and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific
Specific
Specific may refer to:* Specificity* Specific, a cure or therapy for a specific illnessLaw:* Specific deterrence, focussed on an individual* Specific finding, intermediate verdict used by a jury in determining the final verdict...
prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear.
External links
- Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein (American Heart AssociationAmerican Heart AssociationThe American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
)